Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:23])[N:10]=2)=[CH:5][CH:4]=1.[O:24]=[C:25]1[N:29]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:28]2[CH:36]=[CH:37][CH:38]=[CH:39][C:27]=2[NH:26]1>CO.C1COCC1>[Cl:23][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:33]3[CH2:32][CH2:31][CH:30]([N:29]4[C:28]5[CH:36]=[CH:37][CH:38]=[CH:39][C:27]=5[NH:26][C:25]4=[O:24])[CH2:35][CH2:34]3)=[CH:4][CH:5]=2)[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CBr)cc2)nc1Cl
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 6-[4-(bromomethyl)phenyl]-2-chloro-5-phenylnicotinonitrile (2-5; 0.078 g, 0.203 mmol) in MeOH (1 mL) and THF (1 mL) was added 4-(2-keto-1-benzimidazolinyl)-piperidine (0.066 g, 0.305 mmol; commercially available) and DIEPA (0.131 g, 1.02 mmol). The mixture was stirred at rt overnight and concentrated. The residue was treated with aqueous Na2CO3 solution (5 mL, 2 M) and extracted with with CH2Cl2 (3×10 mL). The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (3-5% MeOH in CH2Cl2) to give 2-chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl]-5-phenylnicotinonitrile (2-6). 1H-NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.31-7.37 (m, 4H), 7.25-7.29 (m, 4H), 7.17-7.19 (m, 2H), 7.05-7.09 (m, 3H), 4.31-4.36 (m, 1H), 3.54 (s, 2H), 2.97-2.99 (m, 2H), 2.41-2.47 (m, 2H), 2.12-2.17 (m, 2H), 1.78-1.80 (m, 2H). LRMS m/z (M+H) Calcd: 520.0, found: 520.0.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(Cc2cccc(Br)c2)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Under argon, 14.8 ml (105.48 mmol) of diisopropylamine were initially charged in 66 ml of dry THF, and the mixture was cooled to −40° C. 42.2 ml (105.48 mmol) of n-butyllithium solution (2.5 M in hexane) were slowly added dropwise, and the mixture was stirred for 30 min. The reaction solution was then cooled to −78° C., and a solution of 10.0 g (70.32 mmol) of tert-butyl cyclopropanecarboxylate in 17 ml of THF were added. After 4 h of stirring at −78° C., a solution of 19.34 g (77.36 mmol) of 3-bromobenzyl bromide in 17 ml of THF was added. Slowly, the reaction mixture was warmed to RT overnight, ammonium chloride solution was then added carefully and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography on 750 g of silica gel (mobile phase cyclohexane/dichloromethane 50:1, then 5:1). This gave 13.3 g (60.7% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:33]=[CH:32][S:31][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]3)[N:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[ClH:34]>O1CCOCC1>[ClH:34].[NH2:23][CH:20]1[CH2:21][CH2:22][N:18]([C:16]2[N:17]=[C:12]([NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[N:7]=3)[C:13]3[N:33]=[CH:32][S:31][C:14]=3[N:15]=2)[CH2:19]1
Reactant: COc1ccc(Nc2nc(N3CCC(NC(=O)OC(C)(C)C)C3)nc3scnc23)nc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)nc1OC

Procedure:
A solution of tert-butyl 1-(7-(5,6-dimethoxypyridin-2-ylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamate (260 mg, 0.549 mmol) in 20 mL of saturated HCl in dioxane was stirred at room temperature for 24 hours. The solvent was evaporated to give 5-(3-aminopyrrolidin-1-yl)-N-(5,6-dimethoxypyridin-2-yl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (283 mg, crude) as a yellow solid. It was used directly in the next step without further purification. LC-MS: 187.6 [M/2+H]+, 374.0 [M+H]+, tR=1.18 min.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17](B4OC(C)(C)C(C)(C)O4)=[CH:16][CH:15]=3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[N:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>>[ClH:29].[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]3[CH:15]=[CH:16][C:17]([C:30]4[N:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)=[CH:18][CH:19]=3)=[O:13])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCCN(C4CCC4)CC3)cc2)OC1(C)C
Product: Cl
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)nn2)cc1)N1CCCN(C2CCC2)CC1

Procedure:
The title compound (E22) was prepared in a similar manner to Example 11 from 1-cyclobutyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl)hexahydro-1H-1,4-diazepine (D7) and 3-chloro-6-(trifluoromethyl)pyridazine (Goodman, Stanforth and Tarbit, Tetrahedron, 1999, 55, 15067). The crude product after work-up was by purified by flash chromatography [silica gel, gradient 0-100% EtOAc-MeOH) and the free base was converted into the title hydrochloride salt (E22). 1H NMR δ (methanol-d4): 1.8-1.95 (2H, m), 2.15-2.48 (6H, m), 3.07-3.25 (2H, m), 3.48-3.95 (6H, m), 4.3-4.5 (1H, m), 7.72 (2H, d, J=8 Hz), 8.21 (1H, d, J=8 Hz), 8.32 (2H, d, J=8 Hz), 8.45 (1H, d, J=8 Hz).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.CN(C=O)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22](F)[CH:23]=1)[C:19]#[N:20]>CCOCC.O>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([S:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=2)[CH:23]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: Cn1ccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Cn1ccnc1Sc1cc(F)cc(C#N)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 9.2 %

Procedure:
A mixture of NaH (60%, 3.16 g, 79 mmol) in oil was rinsed with dry pentane by syringe (3×10 mL) and excess solvent removed under a steam of N2. Solid 2-mercapto-1-methylimidazole (9.03 g, 79 mmol) was added followed by 200 mL of DMF under ice-bath cooling which resulted in a vigorous evolution of gas. After 15 min, solid 3,5-difluorobenzonitrile (10.00 g, 71.9 mmol) was added and the resulting mixture stirred for 5 days at 60° C. After cooling to rt the mixture was diluted with 500 mL ether and 500 mL water. The resulting white solid was collected by filtration and triturated in 50 mL of boiling ethanol which after cooling to rt was collected by filtration and dried under high vacuum to provide 1.54 g (9%) of 3-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile: 1H NMR (500 MHz, DMSO-d6): δ 3.54 (s, 3H), 7.40 (d, 1H, J=2 Hz), 7.52 (d, 1H, J=2 Hz), 7.96 (dt, 1H, J=8, 2 Hz), 8.13 (m, 1H), 8.15 (dt, 1H, J=8, 2 Hz); LCMS (m/z): 234.1 [C11H8FN3S+H]+. The ether layer was separated from the filtrate and washed with water, brine, dried (MgSO4) and evaporated. The residue was recrystallized from 30 mL of boiling ethanol to provided after filtration and drying a further 1.57 g (9%) which by HPLC was 75% enriched in 3-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile. The filtrate was evaporated to provide 5 g of crude product enriched in the title compound. This was adsorbed to 15 g of SiO2 from CH2Cl2 and subjected to MPLC on a 120 g column of SiO2 eluting with % EtOAc in hexanes (time): 35% (10 min), 35-50% (5 min ramp), 50% (20 min) which provided 1.2 g (7%) of 90% HPLC pure title compound as well as 1.96 g (12%) of 98% HPLC pure title compound: 1H NMR (500 MHz, DMSO-d6): δ 3.66 (s, 3H), 7.20 (d, 1H, J=1 Hz), 7.22 (ddd, 1H, J=8, 3, 2 Hz), 7.34 (t, 1H, J=2 Hz), 7.55 (d, 1H, J=1 Hz), 7.72 (ddd, 1H, J=8, 3, 2 Hz); LCMS (m/z): 234.1 [C11H8FN3S+H]+.
Reaction SMILES: [F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22](C(=O)C(F)(F)F)[CH2:23]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:32][CH3:33])[N:7]=1.N>CO>[F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][NH:22][CH2:23]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:32][CH3:33])[N:7]=1
Reactant: COc1cc(NS(=O)(=O)c2ccc3c(c2)CN(C(=O)C(F)(F)F)CC3)nc(SCc2cccc(F)c2F)n1
Agent: N
Solvent: CO
Product: COc1cc(NS(=O)(=O)c2ccc3c(c2)CNCC3)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl) 2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (0.805 g) was added to a solution of 7N NH3 in MeOH (20 ml), sealed and stirred at room temperature for 2 h. The reaction was reduced in vacuo and the resulting residue purified by prep HPLC to give the title compound as a white solid. Yield: 70 mg
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH2:32])[CH:20]=[CH:21][C:22]=1[S:23]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].O>CN(C)C(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:32][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:20]=[CH:21][C:22]=1[S:23]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: COc1cc(N)ccc1S(=O)(=O)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1S(=O)(=O)c1ccncc1
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.79 g, 11.3 mmol) in N,N-dimethylacetamide (20 mL) was added thionyl chloride (1.34 g, 11.3 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 3-Methoxy-4-(4-pyridylsulfonyl)benzeneamine (2.00 g, 7.6 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and-the aqueous solution filtered through Celite. The Celite was washed with methylene chloride (100 mL), the methylene chloride solution dried (MgSO4) and concentrated in vacuo to an off-white solid. Trituration with ethyl ether yielded the title propanamide as a white solid (1.65 g, 54%); mp 238°-240° C. 1H-NMR (250 MHz, d6-DMSO): 1.58 (s, 3H, CH3) 3.70 (s, 3H, OCH3) 7.60 (s, 1H, OH)7.71 (d, 1H, J=4.6 Hz, aromatic) 7.75-7.79 (m, 3H, aromatic) 7.96 (d, 1H, J=8.8 Hz, aromatic) 8.85 (dd, 2H, J=4.6, 1.1 Hz, aromatic) 10.39 (s, 1H, NH). MS (CI, CH4): 405 (M+1). Analysis for C16H15F3N2O5S: Calculated: C, 47.53; H, 3.74; N, 6.93; Found: C, 47.45; H, 3.79; N, 6.79;
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([NH:15][C:16]([NH:10][S:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])(=[O:9])=[O:8])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN=C=O
Reactant: Cc1ccsc1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1sccc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 150 ml of acetone and 3-methyl-2-thiophenesulfonamide was added 11 g of n-butyl isocyanate and 14 g of anhydrous potassium carbonate. After stirring at ambient temperature for 24 hours, the mixture was concentrated to 2/3 of its volume and poured into ice-water. The pH was adjusted to 3 by the addition of hydrochloric acid and the solid thus obtained was filtered, air dried and triturated with 1-chlorobutane to yield 10.6 g of N-(butylaminocarbonyl)-3-methyl-2-thiophenesulfonamide melting at 144°-146°. It showed absorption peaks by NMR (60 MC) at 2.6 δ (singlet, CH3), 1-1.8 δ (mult., C3H7), 3.42 δ (trip., N--CH2 --of butyl) and at 7.1 δ and 7.7 δ (2 doublets for CH's of thiophene) consistent for the desired structure.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])/[CH:7]=[C:8](\[CH3:18])/[CH2:9]P(OCC)(OCC)=O)[CH3:4].[Br:20]/[C:21](=[C:24](/[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1)\[CH3:25])/[CH:22]=O>C1COCC1>[CH2:3]([O:5][C:6](=[O:19])/[CH:7]=[C:8](\[CH3:18])/[CH:9]=[CH:22]/[C:21](/[Br:20])=[C:24](\[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1)/[CH3:25])[CH3:4]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: C/C(=C(\Br)C=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C=C/C(Br)=C(/C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
290 mg of NaH (50% in mineral oil) was suspended in 8 ml of abs. THF and treated at 0° C. with 1.69 g of 4-(diethoxyphosphinyl)-3-methyl-crotonic acid ethyl ester. When the development of H2 had ceased (1/2 hour at 0° C.), 1.04 g of (E)-2-bromo-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enal, dissolved in 8 ml of abs. THF, was added and stirring continued for 3/4 hour at 0° C. and for 1 hour at room temperature. The reaction mixture was then quenched with crashed ice and extracted with EtOEt. Twice washing with brine, drying over Na2SO4 and evaporation of the solvent afforded the crude product which was purified by flash chromatography (silica gel, hexane/AcOEt=98:2) to give 527 mg of (2E,4E,6E)-6-bromo-3-methyl-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-octa-2,4,6-trienoic acid ethyl ester as yellow crystals of m.p. 97°-98.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C(N(CC)CC)C.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](Cl)=[O:38].O>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([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])=[C:2]([NH:1][C:37]([C:28]2[CH:29]=[CH:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)=[O:38])[CH:7]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Nc1cc(Cl)ccc1N1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cc(Cl)ccc1N1C(=O)c2ccccc2C1=O)c1ccc2ccccc2c1
Yield: 44.7 %

Procedure:
A reaction solution of N-(2-amino-4-chlorophenyl) phthalimide (0.5 g), triethylamine (0.28 g) and 2-naphthoyl chloride (0.35 g) in anhydrous tetrahydrofuran (50 ml) was heated at reflux temperature for 6 hr under nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by column chromatography on silica gel using ethyl acetate-hexane (1:5) to give the title compound (0.35 g) as a yellow solid.
Reaction SMILES: CN[C:3]([N:5]([S:14]([CH3:17])(=[O:16])=[O:15])[N:6]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][CH2:8][Cl:9])=[O:4].[C:18](#N)[CH3:19].CNC(Cl)=[O:24]>C(N(CC)CC)C>[CH3:13][S:10]([N:6]([CH2:7][CH2:8][Cl:9])[N:5]([S:14]([CH3:17])(=[O:16])=[O:15])[C:3]([O:24][CH2:18][CH3:19])=[O:4])(=[O:12])=[O:11]
Reactant: CNC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O
Reactant: CNC(=O)Cl
Reactant: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O
Temperature: 90 °C

Procedure:
In the present invention two novel methods relate to syntheses of VNP40101M with higher yields. Method B directly uses the intermediate BMH, the starting material for preparation of VNP4090CE. As showed in FIG. 3, a one-pot reaction of BMH with methylcarbamic chloride (MCC) affords VNP40101M in a 60+% yield. In this method, the carbonyl coupling reaction of the substituted hydrazine and the chloro-replacement reaction of the alkyl mesylate take place concurrently. Triethylamine (TEA) is preferably used as a base for the reaction, and acetonitrile is usually used as solvent. The molar ratio of the reactant, BMH to MCC to TEA, is preferable in 1:2:2. The two concurrent reactions are usually heated at approximately 90° C. Other important aspects of the present invention include improvement over the prior art synthesis. In the prior art (FIG. 1), product from the mesylation reaction was not isolated and directly used for the chloro-replacement reaction to generate VNP4090CE in an approximately 20% yield. In the instant invention the mesylated product BMH is isolated as a pale solid in a 55+% yield by easy operations of precipitation and filtration. Thus the total yield of the process to VNP40101M can be increased to 30+%. By the performing this mesylation and two concurrent reactions, the instant invention, in addition to reducing the number of steps required for the synthesis and improving overall yield, also makes handling easier and therefore makes commercial large-scale production easier. Alternatively, the two concurrent reactions in method B were changed to two separation reactions by using an alkyl or aryl chloroformate ClC(O)OR to form a stable carbamade intermediate, followed by a conversion of the carbamade into the corresponding urea (VNP40101M). For example, the reaction of ethyl chloroformate ClC(O)OEt with BMH resulted in a stable intermediate 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(ethyloxycarbonyl)-hydrazine (CEE), which were reacted with methylamine in the presence of a Lewis acid (preferable AlCl3) to form VNP40101M (FIG. 4). R in ClC(O)OR could be alkyl (e.g. methyl, ethyl, t-butyl, and etc) and aryl (e.g. phenyl, 4-nitrophenyl, and etc). The Lewis acid could be AlCl3, SnCl4, TiCl4, FeCl3, and etc.
Reaction SMILES: [C:1]([Cu])#[N:2].[CH3:4][O:5][C:6]([C@H:8]1[N:12]2[C:13](=[O:35])[C:14](Br)=[C:15]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[S:10][CH2:9]1)=[O:7]>CN1C(=O)CCC1>[CH3:4][O:5][C:6]([C@H:8]1[N:12]2[C:13](=[O:35])[C:14]([C:1]#[N:2])=[C:15]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[S:10][CH2:9]1)=[O:7]
Reactant: N#C[Cu]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(Br)c(=O)n21
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Temperature: 220 °C
Yield: 81 %

Procedure:
CuCN (120 mg, 1.3 mmol) was added to a stirred solution of 5a (150 mg, 0.30 mmol) in NMP (1.0 mL) at rt. The reaction mixture was heated at 220° C. for 20 min using microwave irradiation and the solvent was then removed by lyophilisation from deionised water. The residue was thoroughly extracted with CH2Cl2, dried and concentrated. Purification by silica gel chromatography (heptane:EtOAc, 1:1) gave 6a as a white foam (110 mg, 82%):[α]D−83 (c 1.0, CHCl3); IR λ 3012, 2956, 2217, 1751, 1654, 1486, 1442, 1369 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=7.8, 1H), 7.70 (d, J=8.1, 1H), 7.62 (d, J=8.2, 1H), 7.47-7.29 (m, 3H), 7.19-6.92 (m, 5H), 6.87 (d, J=7.3, 1H), 5.79 (dd, J=8.9, 2.3, 1H), 4.41-4.27 (m, 2H), 3.89 (s, 3H), 3.75 (dd, J=11.9, 8.9, 1H), 3.52 (dd, J=11.9, 2.3, 1H); 13C NMR (100 MHz, CDCl3) δ 167.6, 160.7, 158.7, 155.2, 134.4, 133.6, 132.4, 131.4, 129.7, 129.2, 128.8 (broad and splitted), 128.6, 127.6, 126.1, 125.7, 125.3, 125.2, 122.7, 117.1, 115.2, 101.3, 64.4, 53.7, 35.3, 31.8; HRMS (EI+) calcd for C27H20N2O3S 452.1195, obsd 452.1192.
Reaction SMILES: [S:1](=[O:4])(=O)=[O:2].C[N:6](C)C=O.[CH2:10]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH:11]([CH3:13])[CH3:12].S(Cl)(Cl)=O>ClCCl>[CH2:10]([C:14]1[S:15][C:16]([S:1]([NH2:6])(=[O:4])=[O:2])=[CH:17][C:18]=1[CH3:19])[CH:11]([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: Cc1ccsc1CC(C)C
Reactant: O=S(=O)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(S(N)(=O)=O)sc1CC(C)C
Temperature: 80 °C

Procedure:
To a mixture of 0.368 g of the complex of sulfur trioxide with dimethylformamide in 1.5 ml dichloromethane was added 0.309 g 2-isobutyl-3-methyl-thiophene and the mixture was heated to 55° C. for 30 min. and to 80° C. for an other 30 min. The mixture was cooled to room temperature and 0.286 g thionylchloride was added. The mixture was heated to 55° C. for ca 30 min cooled to room temperature and poored onto ice and extracted with ethyl acetate, the phases were separated and the organic phase was washed with water and brine and evaporated. The residue was taken up in 10 ml acetone and mixed with 1 ml 25% aqueous ammonia for ca 30 min. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with ethyl acetate:heptane=1:3 to yield 0.16 g of the title compound as oil. MS (ISN) M−H+=232.0
Reaction SMILES: II.[Mg].[CH3:4][N:5]1[CH2:10][CH2:9][CH:8](Cl)[CH2:7][CH2:6]1.CN(OC)[C:14](=[O:27])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=1>BrC(Br)C.O1CCCC1>[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([C:14](=[O:27])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)[CH2:7][CH2:6]1
Reactant: CN1CCC(Cl)CC1
Reactant: CON(C)C(=O)COc1ccc(NC(C)=O)cc1
Agent: CC(Br)Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OCC(=O)C2CCN(C)CC2)cc1
Temperature: 0 °C
Reaction time: 0.01 h
Yield: 47 %

Procedure:
A crystal of iodine was added to 0.45 gm (18.7 mMol) magnesium turnings covered with 6 mL tetrahydrofuran. To this mixture were added 5-6 drops of dibromoethane and the mixture was heated with a heat gun to initiate the reaction. Once the iodine color disappeared, 2 mL (15 mMol) 1-methyl-4-chloropiperidine were added and heating continued for an additional 30 seconds. After the exothermic reaction no longer maintained reflux temperature, the reaction mixture was heated at reflux for 30 minutes and was then cooled to 0° C. To the cold mixture was added the previously prepared N-methyl-N-methoxy 2-(4-acetamidophenoxy)acetamide and the resulting mixture stirred for 30 minutes at 0° C. and then an additional hour after warming to room temperature. The reaction was quenched by the addition of water and the resulting mixture extracted well with ethyl acetate. The combined organic extracts were washed saturated aqueous ammonium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, eluting with dichloromethane containing 5% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 0.90 gm (47%) of the desired ketone.