Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][N:12]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:11]2=[O:25])[CH:5]=1.[I-].[Li+]>N1C=CC=CC=1>[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([N:12]2[CH2:13][C:14](=[O:15])[N:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:26])=[O:2])[C:11]2=[O:25])=[CH:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: COC(=O)c1cccc(N2C(=O)CN(c3ccc(C(C)C)cc3)C2=O)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)c1ccc(N2CC(=O)N(c3cccc(C(=O)O)c3)C2=O)cc1

Procedure:
A solution of methyl-3-[3-(4-isopropylphenyl)-2,5-dioxo-imidazolidin-1-yl]-benzoate (0.69 g, 1.96 mmol) and lithium iodide (2.62 g) in pyridine (10 mL) was heated to reflux for 40 h. The solution was cooled and evaporated, and the residue was partitioned between ethyl acetate and 1 N aqueous HCl. The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and evaporated. The residual material was separated by column chromatography (silica gel, 50:50 ethyl acetate-hexane then ethyl acetate) to afford the product, 3-[3-(4-isopropylphenyl)-2,5-dioxo-imidazolidin-1-yl]-benzoic acid, as a powder (0.33 g, 0.98 mmol, 50%). m.p. 224-226° C. TLC Rf (20:80 CH3OH—CH2Cl2) 0.3. 1H NMR (CDCl3, 300 MHz): δ 8.24 (1H, t, J=2 Hz), 8.14 (1H, dt, J=8, 2 Hz), 7.73 (1H, dt, J=8, 2, 1 Hz), 7.61 (1H, t, J=7 Hz), 7.51 (2H, d, J=8 Hz), 7.28 (2H, d, J=8 Hz), 4.50 (2H, s), 2.92 (1H, m, J=7 Hz), 1.25 (6H, d, J=7 Hz). Mass spectrum (ES+): m/z 340 (21), 339 (100). Elemental analysis: calculated for C19H18N2O4.0.149H2O C 66.91, H 5.41, N 8.21; observed C 66.82, H 5.17, N 8.19.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[I:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:30][NH2:31]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:30][N:31]=[C:18]([NH:17][C:14]4[CH:15]=[CH:16][C:11]([I:10])=[CH:12][CH:13]=4)[C:7]=3[CH2:8][C:2]1=2
Reactant: O=C1CCc2sccc21
Reactant: NN
Reactant: S=C=Nc1ccc(I)cc1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Ic1ccc(Nc2n[nH]c3c2Cc2sccc2-3)cc1
Reaction time: 8 h
Yield: 32 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Iodo-4-isothiocyanato-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(4-iodo-phenyl)-amine as brown solid in 32% yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:26]([C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:10]2[C:11]([C:21](=[O:24])[NH:22][CH3:23])=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1>N1C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:13][C:9]3[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:26]([C:27]4[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=4)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:10]=3[C:11]=2[C:21](=[O:24])[NH:22][CH3:23])=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
Methanesulfonyl chloride (303 μL, 3.88 mmol) was added to a stirring solution of ethyl 3-(6-amino-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (1.40 g, 3.24 mmol) in pyridine (32 mL) at 25° C. It was allowed to stir overnight at rt. The reaction was concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (1.01 g, 61%). LC-MS retention time: 1.53 min; m/z (MH+): 511. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]([CH:29]([CH3:31])[CH3:30])=[O:28])[CH2:22][CH2:21]1)=[S:17])(=O)C1C=CC=CC=1>O.CO>[CH:29]([C:27]([NH:26][CH:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:18][C:16]([NH2:15])=[S:17])[CH2:21][CH2:22]1)=[O:28])([CH3:31])[CH3:30]
Reactant: CC(C)C(=O)NC1CCC(CNC(=S)NC(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)C(=O)NC1CCC(CNC(N)=S)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
K2CO3 (2 equivalents) in water was added to a solution of N-benzoyl-N′-[4-(isopropylformylamino)cyclohexyl]methyl-thiourea in MeOH and stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOH. The solution was filtered to remove a white precipitate and the filtrate concentrated. The crude product was chromatographed to yield the desired product: 100% yield; 100% yield; 258 (ESMS, MH+); 1H NMR (CD3OD) δ 8.15 & 8.13 (two s, 1H), 4.15 & 3.73 (two m, 1H) 3.34 & 2.97 (two m, 1H), 3.29 (m, 2H), 1.26 (d, 3H, J=6.7 Hz), 1.23(d, 3H, J=6.7 Hz), 1.91-1.03 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][C:25]3[NH:26][CH:27]=[CH:28][N:29]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:30]I.[H-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][C:25]3[N:29]([CH3:30])[CH:28]=[CH:27][N:26]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)N2C(CCc3ncc[nH]3)CCC2c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2C(CCc3nccn3C)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, light yellow oil, MS: m/e=428.5 (M+H+), was prepared by methylation of (2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole in accordance with the general method of example 8 (methyl iodide, sodium hydride).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([OH:14])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50]O)[CH2:45][CH2:44]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.O1CCCC1>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([O:14][CH2:50][CH2:49][N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Reactant: CN1CCN(CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 0 °C
Yield: 23.9 %

Procedure:
To a homogeneous mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]-triazin-6-ol (100 mg, 0.33 mmol) and triphenylphosphine (129 mg, 0.49 mmol) in 4 mL of 1:1 anhydrous dichlormethane/anhydrous tetrahydrofuran, cooled to 0° C. under a nitrogen atmosphere, was added dropwise a mixture of 2-(4-methylpiperazin-1-yl)ethanol (71 mg, 0.49 mmol) and diisopropylazodicarboxylate (0.10 μL, 0.49 mmol) in 2 mL of 1:1 anhydrous dichlormethane/anhydrous tetrahydrofuran. The mixture was stirred and allowed to warm to room temperature. The reaction was stirred for twelve hours before being concentrated in vacuo. The residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 50% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove methanol. The mixture was extracted with chloroform (3×10 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (34 mg, 24%) as a yellow solid. 1H NMR (CDCl3) δ 8.20–8.10 (m, 2H), 7.82 (s, 1H), 7.58–7.52 (m, 1H), 7.49 (s, 1H), 4.16 (t, 2H, J=5.7 Hz), 2.87 (t, 2H, J=5.7 Hz), 2.80–2.40 (m, 8H), 2.45 (s, 3H), 2.31 (s, 3H); MS(ESI+) m/z 431.3 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[Cl:23])=[CH:20][CH:19]=[CH:18][CH:17]=2>ClCCl>[Cl:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:12][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc2ccccc2c1Cl
Reaction time: 8 h

Procedure:
Acetyl chloride (3.41 mL, 1.25 eq) and triethylamine (6.79 mL, 1.4 eq) were added sequentially to a solution of 3-amino-4-chloroquinoline (6.22 g, 1.0 eq) in dichloromethane (100 mL). The reaction mixture was stirred overnight and then washed sequentially with aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated under reduced pressure to provide 6.68 g of N-(4-chloroquinolin-3-yl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1.[O:18]1CCOCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[C:11]3=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2cc(-c3cccc(Cl)c3)ccc2N1
Reactant: C1COCCO1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C1=O
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one (10.0 g, 41 mmol) in dioxane (200 cm3) and SeO2 (22.8 g, 205 mmol) was brought to reflux for 2 h then cooled to RT and concentrated onto Florisil. The Florisil was washed (acetone:CHCl3 1:9) and the combined organic extracts were evaporated. The residue was purified by column chromatography (SiO2, acetone:CHCl3 1:8) to afford the subtitled compound (8 g, 31 mmol, 76%) as a tan solid: m.p. 256-258° C., 1H NMR (THF-d8) δ 6.96 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.4 (dd, J=7.7, 7.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.68 (dd, J=1.84, 1.84 Hz, 1H), 7.83-7.86 (m, 2H), 10.05 (br s, 1H); 13C NMR (DMSO-d6) δ 113.30 (d), 119.08 (s), 123.44, 125.57, 126.65, 127.92, 131.41 (d), 133.88, 134.47 (s), 137.25 (d), 141.51, 150.99, 160.15, 184.83 (s); MS (EI) m/z 256 (M−H)+; Anal. (C14H8ClNO2.0.1H2O) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.C([O-])(=O)C.[NH4+:18].C([BH3-])#[N:20].[Na+]>CO>[NH4+:20].[OH-:2].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH2:18])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCC(N)C2
Product: [OH-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 6-methoxy-2-tetralone (10.0 g; 56.7 mmol) dissolved in MeOH (400 mL) is added ammonium acetate (65 g; 0.84 mol) and the reaction was stirred for 30 min. at RT. To the reaction is then added sodium cyanoborohydride (17.8 g; 0.28 mol) and the reaction was refluxed for 1-2 h. The reaction is cooled, the solvent removed under reduced pressure, the residue diluted with EtOAc and 1N NaOH added to quench the reaction. The aqueous phase is separated and the organic phase washed with H2O, brine, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to afford a crude residue which was purified by flash chromatography (SiO2) eluting with CH2Cl2/MeOH:NH4OH (10%) to provide 5.0 g (50%) of 6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine as a dark oil. To a solution of titled compound in ether (100 mL) cooled to 0° C. is bubbled HCl (g) until the solution is saturated.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:22]=[CH:21][CH:20]=[CH:19][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:11].Cl[CH2:24][CH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(Cl)Cl.CC(=O)OCC>CN(C=O)C>[F:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([CH2:25][CH2:24][S:7][C:8]2[N:22]=[CH:21][CH:20]=[CH:19][C:9]=2[C:10]([NH:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:11])(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: O=C(NCc1cccs1)c1cccnc1S
Reactant: O=S(=O)(CCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1cccs1)c1cccnc1SCCS(=O)(=O)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
303 mg (2.2 mmol) of K2CO3 were added to a solution of 500 mg (2.0 mmol) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide in DMF (5 ml), and stirring was carried out for 30 min at RT. 445 mg (2.0 mmol) of 1-(2-chloroethylsulfonyl)-4-fluorobenzene were then added and stirring was continued for a further 2 days at RT. The mixture was then concentrated in vacuo, the residue was taken up in EA, and 1M aqueous NaHCO3 solution was added. The phases were separated and the aqueous phase was extracted with EA. The combined organic phases were dried over MgSO4, filtered through silica gel and concentrated in vacuo. CC (DCM/EA 4:1) of the residue yielded 365 mg (0.84 mmol, 48%) of 2-[2-(4-fluorophenyl)sulfonylethylthio]-N-(2-thienylmethyl)-nicotinamide. MS: m/z 437.0 [M+H]+
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[C:34]2[N:33]=[CH:32][N:31]([CH3:35])[C:30]=2[CH:29]=[CH:28][CH:27]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[C:34]3[N:33]=[CH:32][N:31]([CH3:35])[C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH:6]=1
Reactant: Cn1cnc2c(Nc3cc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nnc3C(N)=O)cccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc2c(Nc3cc(N[C@@H]4CCCC[C@@H]4N)nnc3C(N)=O)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (132 mg, 275 μmol) in CH2Cl2 (5 mL) was treated with TFA (4.08 g, 2.76 mL, 35.8 mmol) and the reaction mixture stirred to room temperature for 18 h. The solvent was evaporated and the residue purified by chromatography (spherical silica 20-45 μM, 80 g, Versaflash Supelco, 0 to 10% of a 9:1 MeOH:NH4OH solution in CH2Cl2, 30 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxamide (70 mg, 67%) as an off-white solid. 1H NMR (DMSO-d6) δ: 11.06 (s, 1H), 8.23 (br. s., 1H), 8.16 (s, 1H), 7.50 (br. s., 1H), 7.15-7.37 (m, 3H), 6.75 (s, 1H), 6.70 (d, J=7.6 Hz, 1H), 4.09 (br. s., 1H), 3.84 (s, 3H), 3.08 (br. s., 1H), 1.54 (br. s., 6H), 1.26 (d, J=17.0 Hz, 2H); LC-MS 381.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[O:13]1[CH2:15][C@H:14]1[CH2:16]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:16][C@@H:14]2[CH2:15][O:13]2)=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: CC(=O)Nc1cc(Cl)ccc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Cl)ccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A mixture of N-(5-chloro-2-hydroxyphenyl)acetamide (500 mg, 2.69 mmol), (2S)-oxiran-2-ylmethyl3-nitrobenzenesulfonate (697 mg, 2.69 mmol) and Cs2CO3 (1.04 g, 3.22 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in petroleum ether) to give the subtitled compound (600 mg).
Reaction SMILES: ClCCl.Cl.[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH2:20][S:19][C:18](=[O:21])[NH:17][N:16]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH2:42]([N:44](CC)CC)[CH3:43]>>[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH2:20][S:19][C:18](=[O:21])[N:17]([CH2:43][CH2:42][NH:44][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])[N:16]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCN(CC)CC
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc2cc(C3=NNC(=O)SC3)ccc21
Agent: Cl
Solvent: ClCCl
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2cc(C3=NN(CCNS(=O)(=O)c4ccccc4)C(=O)SC3)ccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 2 ml of dichloromethane in 177 μl (1.28 mM) of triethylamine are added 150 mg (0.32 mM) of 342-aminoethyl)-5-{1-methyl-2-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-5-yl}-3,6-dihydro-2H-1,3,4-thiadiazin-2-one hydrochloride and 67.7 μl (0.38 mM) of benzenesulfonyl chloride. The mixture is stirred at room temperature for 20 hours. The solid is filtered off and washed with water to give, after drying, 138 mg of N-{2-[5-{1-methyl-2-[3-(trifluoromethyl)phenyl]-1H-benzimidazol-5-yl}-2-oxo-2H-1,3,4-thiadiazin-3(6H)-yl]ethyl}benzenesulfonamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])([O-:19])=[O:18]
Reactant: N#Cc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Temperature: 100 °C
Yield: 95.5 %

Procedure:
In 50 ml of N,N-dimethylformamide were dissolved 5.0 g of 3-cyanophenol and 5.93 g of 2-fluoronitrobenzene followed by addition of 8.71 g of potassium carbonate, and the mixture was stirred with heating at 100° C. for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water 3 times, dried and concentrated. The residue was crystallized from diisopropyl ether to give 9.63 g of the title compound as light yellow crystals.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:22]([NH:24][N:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26](=[O:39])[C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1C(OC(C)(C)C)=O)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[ClH:48]>O1CCOCC1.C(OCC)C>[ClH:48].[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:22]([NH:24][N:25]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:26](=[O:39])[C@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@H]1CCCN1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.656 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-(N-tert.-butoxycarbonyl-D-prolyl)-4-methylvalerohydrazide in 8 ml of dioxan was treated with 4 ml of 4M hydrogen chloride in dioxan. The mixture was stirred for 2 hours at room temperature and diluted with diethyl ether. The solid was filtered off, washed with diethyl ether and dried to give 0.367 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-2′-(D-prolyl)-4-methylvalerohydrazide hydrochloride in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[C:22]([Br:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1COCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][C:21]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[C:22]([Br:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: NCc1ccncc1
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cnc(NCc2ccncc2)c(Br)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a vessel containing a stir bar was added {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), 4-aminomethylpyridine (0.015 g, 0.133 mmol), THF [3 mL]. The reaction vessel was sealed and heated to 70° C. for 18 hours, cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in a solution of chloroform/trifluoroacetic acid (1/1) [2 mL] and was allowed to stir at room temperature for 2 hours. The reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound. ESI-MS (m/z): Calcd. for C17H16BrN5O2S3: 499.44 (M+H); found 498.0, 500.0.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:28](=[O:29])[CH2:27][Cl:26])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)CCl)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Chloroacetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-trifluoromethyl- 1,3,4-thiadiazol-2-yl)-3-methyl-6-chloroacetyloxy- 2(1H)-pyrimidinone as the residue.