Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=2[CH:14]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1nc2cc(OC(=O)c3ccccc3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (7.0 g., 0.03 mole), triethylamine (4.2 ml., 0.03 mole) and 4-dimethylaminopyridine (200 mg., catalyst) in dimethylformamide (25 ml.) is added benzoyl chloride (1.4 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 11/2 hours and then poured into ice water (150 ml.) containing excess hydrochloric acid to give 2-sulfamoyl-5-benzothiazolyl benzoate.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5](=[O:21])[CH2:4][O:3]1.[ClH:22]>O1CCOCC1.C(O)(C)C>[ClH:22].[NH:11]1[CH2:12][CH2:13][CH:8]([CH2:7][N:6]2[C:5](=[O:21])[CH2:4][O:3][C:2]2=[O:1])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2C(=O)COC2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C1COC(=O)N1CC1CCNCC1
Reaction time: 17 h

Procedure:
A suspension of 12.51 g (41.95 mmol) of 1,1-dimethylethyl 4-[(2,4-dioxo-1,3-oxazolidin-3-yl)methyl]piperidine-1-carboxylate, obtained in step 2.2., in 65 ml of dioxane is admixed with 38.10 ml (209.75 mmol) of a solution of hydrochloric acid (5N) in isopropanol. Stirring is continued at approximately 60° C. for 17 hours. The suspension is allowed to return to ambient temperature. The solid formed is collected by filtration and then washed repeatedly with ether and dried under vacuum at approximately 70° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[CH2:33]([O:32][C:30]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1)=[O:31])[CH3:34]
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice bath cooled solution containing 1.0 g 3.4mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole prepared as in Example 16 and 0.5 ml (3.6mmole) of triethylamine in 10 ml of methylene chloride is added 0.33 ml (3.5 mmole) of ethyl chloroformate. The reaction is allowed to warm to room temperature and stirred for several hours. Workup and chromatography in a manner analogous to that outlined in Example 18 affords the desired titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])([CH3:17])[C:7](=[O:16])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][C:3]=1[NH:19][CH:20]([CH3:22])[CH3:21].Br[C:24]#[N:25]>O.C1COCC1>[NH2:25][C:24]1[N:19]([CH:20]([CH3:21])[CH3:22])[C:3]2=[CH:4][C:5]3[C:6]([CH3:18])([CH3:17])[C:7](=[O:16])[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]=3[CH:10]=[C:2]2[N:1]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(C)C)c(N)cc21
Reactant: N#CBr
Solvent: O
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(N)n3C(C)C
Yield: 97.5 %

Procedure:
Analogously to general procedure (III) 6-amino-5-isopropylamino-3,3-dimethyl-1-pentyl-1,3-dihydro-indol-2-one (180 mg) is cyclized using BrCN (3 M; 0.2 ml; 600 μmol) at RT in water (2.5 ml) and THF (1 ml). After aqueous work-up the desired compound (190 mg) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15]>C(OCC)(=O)C.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:12][N:13]([CH3:18])[S:14]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)(=[O:16])=[O:15]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Yield: 32.3 %

Procedure:
To 5-aminoindolin-2-one (100 mg, 0.68 mmol) in ethyl acetate/DMF 1:1 (2 mL) was added dimethylsulfamoyl chloride (290 mg, 2.04 mmol) and DMAP (1 mg). After 72 h the product was precipitated with ether, filtered and dried to give 56 mg, 32% of a white solid. 1H NMR (400 MHz, CD3OD) δ 7.21 (s, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.53 (s, 2H), 2.77 (s, 6H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)=[O:14]>CCOCC.CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:14]
Reactant: COc1ccc2[nH]nc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc2[nH]nc(C(=O)NCC3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
2 M HCl in Et2O (1.8 L) was added to a solution of compound 7a (92.8 g, 0.24 moles) in MeOH (500 mL). The mixture was stirred for 3 hours at room temperature then the resulting solid was filtered and dried to give 5-methoxy-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamide hydrochloride 7b (61.1 g, 89% yield).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[C:20](#N)C.C(=O)([O-])[O-].[K+].[K+]>>[CH3:20][N:14]1[CH2:19][CH2:18][N:17]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[CH2:16][CH2:15]1
Reactant: CC#N
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCN(CCOc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C

Procedure:
Into a 30 mL vial, 1-(2-Bromo-ethoxy)-4-nitro-benzene (5.00 g, 0.0203 mol), piperazine, 1-methyl-(4.51 mL, 0.0406 mol), Acetonitrile (15.0 mL, 0.287 mol) and Potassium carbonate (5.62 g, 0.0406 mol) were added. The reaction was heated at 80° C. for 4 hours. The reaction was partitioned with water and extracted with Et2O (3×100 mL). The Combined organic was washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum to afford 1-Methyl-4-[2-(4-nitro-phenoxy)-ethyl]-piperazine as an off white solid (3.89 g, 73%). NMR 1H (DSMO-d6-8.20 (dd, 2H, JJ=2.04, 5.12 Hz), 7.16 (dd, 2H, JJ=2.04, 5.08 Hz), 4.22 (t, 2H, J=5.76 Hz), 2.71 (t, 2H, J=5.72 Hz), 2.18-2.6 (bm, 8H), 2.13 (s, 3H)
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:18][CH2:13][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: O=Cc1ccc(OCC2CO2)cc1
Product: CCCCNCC(O)COc1ccc(C=O)cc1

Procedure:
To 4-(2,3-epoxypropoxy)benzaldehyde (8.9 gms., 0.05 m) is added n-butylamine (30 ml.) and the resulting solution is refluxed 17 hours. The excess n-butylamine is removed under reduced pressure (20 mm). The oil is dissolved in 6N hydrochloric acid (30 ml.) and the solution is heated on a steam bath for 40 minutes. The hot acidic solution is poured into a hot saturated aqueous sodium carbonate solution with nitrogen bubbling through it. The basis solution is extracted with chloroform. The chloroform is dried over sodium sulfate and concentrated to yield 4-(3-n-butylamino-2-hydroxypropoxy)benzaldehyde, as an oil.
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH3:10]OC(OC)N(C)C.O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1>>[CH2:8]([C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:10][N:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:28]=1)[CH3:9]
Reactant: COc1ccc(NN)cc1
Reactant: CCC(=O)CC(=O)OC
Reactant: COC(OC)N(C)C
Solvent: O
Product: CCc1nn(-c2ccc(OC)cc2)cc1C(=O)OC
Yield: 84 %

Procedure:
Using methyl 3-oxopentanoate (3.3 g), dimethylformamide dimethylacetal (3.6 mL) and p-methoxyphenylhydrazine monohydrate (4.7 g) and in the same manner as in Example 15(1), the title object compound (6.0 g, 84%) was obtained as an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH:14](S(C)(=O)=O)[CH2:15]S(C)(=O)=O)[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1C=CC=CC=1.O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH:14]2[C:10]([C:11]#[N:12])([CH2:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CC(CN(CCC#N)Cc1ccccc1)S(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: N#CC12CC1CN(Cc1ccccc1)C2
Reaction time: 2 h
Yield: 49 %

Procedure:
N-Benzyl-N-(2-cyanoethyl)-2,3-dimethanesulfonylpropylamine (32.25 g, 85.2 mmol) was dissolved in benzene (800 ml), cooled to -10°, and treated with sodium hexamethyldisilazide (170 ml of a 1M solution in tetrahydrofuran, 170 mmol). After 2 hours, the reaction mixture was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with methylene chloride. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatographic purification (eluant: 4:1 hexane:ethyl acetate) gave the title product as a yellow oil (8.23 g, 41.5 mmol, 49% yield. 1H NMR (CDCl3): 7.26 (m, 5H), 3.59 (s, 2H), 3.11 (d, J=9 Hz, 1H), 2.94 (d, J=9 Hz, 1H), 2.54 (d, J=9 Hz, 1H), 2.47 (dd, J=10, 4 Hz, 1H), 2.03 (m, 1H), 1.57 (m, 1H), 1.10 (dd, J=8, 5 Hz, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[N:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:37][C:27]1[CH:28]=[C:29]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:30]=[C:31]([F:32])[C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][C:9]3[N:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[N:13]=3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OCCn1nnc(Cc2cccc(Br)n2)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(Cc4nnn(CCO)n4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-{5-[(6-bromopyridin-2-yl)methyl]-2H-tetrazol-2-yl}ethanol (114 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the general procedure in Example 1.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][C@@H:4]([O:8]/[CH:9]=[C:10]2\[C@H:11]3CC=C[C@H:12]3[NH:13][C:14]\2=[O:15])[CH:3]=1.C[N+]1([O-])CC[O:23]CC1.[CH3:27][C:28]([CH3:30])=[O:29].O>CC(O)(C)C.O=[Os](=O)(=O)=O>[OH:29][CH:28]1[CH:30]([OH:23])[C@H:12]2[NH:13][C:14](=[O:15])/[C:10](=[CH:9]/[O:8][C@H:4]3[CH:3]=[C:2]([CH3:1])[C:6](=[O:7])[O:5]3)/[C@H:11]2[CH2:27]1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC1=C[C@H](O/C=C2/C(=O)N[C@@H]3C=CC[C@H]23)OC1=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CC1=C[C@H](O/C=C2/C(=O)N[C@@H]3C(O)C(O)C[C@H]23)OC1=O
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of (3E,3aR,6aR)-3-[[(2R)-4-methyl-5-oxo-2H-furan-2-yl]oxymethylene]-1,3a,4,6a-tetrahydrocyclopenta[b]pyrrol-2-one Ia-1′ (137 mg, 0.55 mmol) in tBuOH (3 mL) was added NMO (77.9 mg, 0.67 mmol) and acetone (0.5 mL) followed by OsO4 (2.5-wt % in tBuOH, 560 mg, 0.055 mmol) and water (15 mg, 0.84 mmol). After 1 h at room temperature, H2Cl2 was added then the crude mixture was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification using flash chromatography (CH2Cl2/MeOH, gradient) afforded the desired compound as a yellow foam (59 mg, 38%); 1H NMR (400 MHz, MeOH-d4) 7.25 (1H, d), 7.14 (1H, m), 6.34 (1H, m), 4.02 (1H, m), 3.84 (1H, dd), 3.76 (1H, dd), 3.55 (1H, m), 2.15 (1H, dt), 1.96 (3H, dd), 1.86 (1H, ddd): LCMS (Method D): 0.24 min; ES+282 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14](O)[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.P(Cl)(Cl)([Cl:19])=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)C>[Cl:19][C:14]1[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=[C:2]([CH3:1])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2ccc3cccnc3c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(Cl)c2ccc3cccnc3c2n1
Temperature: 25 °C

Procedure:
To a 500 mL round-bottomed flask equipped with a reflux condenser containing 2-methyl-[1,10]phenathrolin-4-ol, (10.20 g, 48.5 mmol), was slowly added phosphorus oxychloride (200 mL) and the mixture was refluxed for 3 hours. The reaction flask was allowed to cool down to room temperature and the solvent was removed in a rotary evaporator. The solid obtained was treated with methylene chloride (200 mL) and saturated NaHCO3 (200 mL) and transferred to a separatory funnel. The aqueous layer was further extracted with methylene chloride (200 mL) and the combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue obtained was treated with ethyl ether (100 mL), filtered and dried yielding a light brown solid (9.00 g). A second crop of 0.60 g of material was obtained from the mother liquors as a light yellow solid, with an overall yield of 9.60 g (87% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.C1COCC1.N1C=CC=CC=1.C(Cl)Cl>[CH:12]1([C:18]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:2]([F:1])[CH:3]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
3-Fluoro-4-Nitroaniline (1 mmol, 0.15 g) was dissolved in a 3:1 mixture of CH2Cl2/THF (4 mL) and pyridine (0.2 mL) was added to the mixture, which was cooled in an ice-water bath under nitrogen. Cyclohexanecarbonylchloride (1.1 mmol, 0.162 g) was dissolved in CH2Cl2 (1 mL) and added dropwise to the above solution at 4° C. and stirred at room temperature for 3 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with 1N HCl, 10% NaHCO3, brine and water, dried over Na2SO4 and the solvent evaporated to afford cyclohexyl-N-(3-fluoro-4-nitrophenyl)carboxamide (0.215 g) of product (Yield: 81%).
Reaction SMILES: [CH3:1][C:2]1([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[OH:28]OS([O-])=O.[K+].C(=O)(O)[O-].[Na+].O>CO>[CH3:1][C:2]1([CH2:9][S:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[O:28])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8]
Reactant: O=S([O-])OO
Reactant: CC1(CSc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)NC(=O)NC1=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(CS(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)NC(=O)NC1=O
Yield: 43.3 %

Procedure:
5-methyl-5-[({4′-[(trifluoromethyl)oxy]-1,1′-biphenyl-4-yl}thio)methyl]imidazolidine-2,4-dione (48 mg, 0.112 mmol) was stirred at room temperature with oxone (50 mg), sodium bicarbonate (50 mg), water (5 ml) and Methanol (10 ml) for 18 hours. The solid was filtered off and crystallised from ethanol to give 20 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)NCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (1 eq.) in DCM was added TEA (3 eq.). The reaction was cooled to 0° C. Acetyl chloride (1 eq.) was filtered through a pad of alumina then added dropwise in solution in DCM to the reaction at 0° C. The reaction was stirred at 20° C. for 4 h. The crude was diluted with DCM, washed twice with water, then twice with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford (2-acetylamino-ethyl)-carbamic acid tert-butyl ester. The compound was used as such without further purification.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:13][C:14]1[CH:19]=C[CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CC#[N:28]>>[N:28]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:13][S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:19]=1
Reactant: CC#N
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccccc1SCc1cccnc1
Temperature: 25 °C

Procedure:
A mixture of compound 2 (70.0 g, 0.4167 mol), 1-(bromomethyl)benzene (82.8 g, 0.5 mol), K2CO3 (350 g, 2.49 mol) and CH3CN (500 mL) was refluxed overnight. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure. After addition of water, the mixture was extracted with CH2Cl2 (3×500 mL). The organic layers were combined, washed with aq. Na2CO3 (2×200 mL), water (2×300 mL), brine (300 mL) and dried over Na2SO4. After evaporation, crude compound 3 was obtained (64.0 g, 59.4%). This was used without further purification.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47](CN)[CH:46]=1.[NH2:53][C:54](C)(C)CO>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:53]([C:47]4[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=4)[CH3:54])=[CH:35][CH:36]=3)=[C:28]([CH:42]([CH3:43])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(C)(N)CO
Reactant: NCc1cccnc1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCCN(C)c2cccnc2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 57 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 3-picolylamine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol, respectively.
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([N:13]1[C:17]2[CH:18]=[C:19]([C:22]([O:24]CC)=[O:23])[CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:27][CH2:28][CH3:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O>[CH2:6]([N:13]1[C:17]2[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:27][CH2:28][CH3:29])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCc1nc2ccc(C(=O)OCC)cc2n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1
Yield: 96 %

Procedure:
10% sodium hydroxide aqueous solution (3.61 g), ethanol (5 ml), and water (3 ml) are added to 1-benzyl-6-ethoxycarbonyl-2-n-propylbenzimidazole (0.97 g) (example 51), and the solution is refluxed by heating for one hour. The acidity of the reaction solution is adjusted to pH 6 with 10% hydrochloric acid. The solution is concentrated under reduced pressure, ethanol is added to the obtained residue, and the inorganic salt is separated through filtration. The filtrate is concentrated under reduced pressure, and 1-benzyl-6-carboxy-2-n-propylbenzimidazole (0.85 g) (example 80) is obtained. 1H-NMR (DMSO-d6, δ): 0.94 (3H, t, J=7.4 Hz), 1.73-1.81 (2H, m), 2.85 (2H, t, J=7.3 Hz), 5.59 (2H, s), 7.07 (2H, dd, J=1.1 and 8.3 Hz), 7.27 (1H, t, J=7.3 Hz), 7.33 (2H, t, J=7.4 Hz), 7.65 (1H, d, J=8.4 Hz), 7.79 (1H, dd, J=1.5 and 8.4 Hz), 8.04 (1H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:20])=O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: ClCCOCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 2-benzyloxyethanol (11.7 g) and pyridine (6.08 g) in dichloromethane (50 ml) was added thionyl chloride (6.7 ml) under ice-cooling, and the resulting mixture was stirred at refluxing temperature for 2.5 hr. Ice-water was added to the reaction mixture, and the organic layer was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform) to give 10.3 g of 2-benzyloxyethyl chloride.
Reaction SMILES: [Cl:1]C[C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[Cl-:1].[CH3:8][C:7]1[S:6][C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[N:4][C:3]=1[P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1sc(N2CCOCC2)nc1CCl
Solvent: CC#N
Product: Cc1sc(N2CCOCC2)nc1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Yield: 93.4 %

Procedure:
A mixture of 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)morpholine (1.00 g), triphenylphosphine (1.13 g) and acetonitrile (50 mL) was heated under reflux for 15 hrs. After concentration of the reaction mixture, the precipitated crystals were washed with acetonitrile and diethyl ether to give (5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)triphenylphosphonium chloride as pale-yellow crystals (1.93 g, yield 91%). Recrystallization from acetonitrile-diethyl ether gave colorless prism crystals. melting point: 242-243° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][O:15][CH2:16][CH2:17][Br:18]>>[BrH:18].[CH3:14][O:15][CH2:16][CH2:17][N:4]1[C:3]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:2]([CH3:1])[S:6][C:5]1=[NH:7]
Reactant: COCCBr
Reactant: Cc1sc(N)nc1-c1ccccc1
Product: Br
Product: COCCn1c(-c2ccccc2)c(C)sc1=N

Procedure:
A mixture of 5-methyl-4-phenyl-thiazol-2-ylamine (300 mg, 1.58 mmol) and 2-bromoethyl methyl ether (300 μL, 3.20 mmol) was processed using the method described in Example 12A to provide the title compound.