Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[O:4][CH:5]=[C:6]([CH2:8][CH2:9][CH:10]=O)[CH:7]=1.C1(P(=[CH:33][CH:34]=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[O:4][CH:5]=[C:6]([CH2:8][CH2:9][CH:10]=[CH:33][CH:34]=[O:35])[CH:7]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)c1cc(CCC=O)co1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(CCC=CC=O)co1

Procedure:
3-(2-Trimethylsilyl-4-furyl)propan-1-al is treated with (triphenylphosphoranylidene) acetaldehyde in tetrahydrofuran to give 5-(2-trimethylsilyl-4-furyl)-pent-2-en-1-al which is hydrogenated in the presence of a palladium catalyst to give 5-(2-trimethylsilyl-4-furyl)-pentan-1-al. Treating this intermediate with C9H19COCH2PO)OCH3)2 and sodium hydride in tetrahydrofuran gives 3-(7-oxo-5-hexadecenyl)-5-trimethylsilylfuran and oxidizing gives 4-(7-oxo-5 -hexadecenyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]([OH:31])([CH3:30])[CH3:29])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:18]2[S:19][C:15](=[CH:14][C:10]3[CH:9]=[C:8]4[C:13](=[CH:12][CH:11]=3)[N:5]([CH2:4][C:3]3[CH:24]=[CH:25][C:26]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:27][C:2]=3[Cl:1])[N:6]=[CH:7]4)[C:16](=[O:23])[N:17]=2)[CH2:41][C@@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3Cl)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4Cl)c3)S2)C[C@@H]1CO

Procedure:
4-(5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-2-ethylsulfanyl-thiazol-4-one and 2-(R)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][NH:10][C:11]([C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[O:8])=[CH:5][CH:4]=1)#[N:2].[SH2:27]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][NH:10][C:11]([C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[O:8])=[CH:5][CH:4]=1)(=[S:27])[NH2:2]
Reactant: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C#N)cc2)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C(N)=S)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the product of step (b) (10 g) in a mixture of pyridine (500 ml) and triethylamine (80 ml) was covered with a blanket of H2S gas and stirred at ambient temperature overnight. The dark green reaction mixture was evaporated to dryness and the residue was triturated with dry ether. The resultant solid was collected and washed thoroughly with ether to give methyl 4-[3-(4-thiocarbamoylbenzoyl)carbazoyl]phenoxyacetate (10.5 g) as a yellow solid; NMR Spectrum (DMSO-d6) 3.72 (3H, s), 4.90 (2H, s), 7.06 (2H, d), 7.90 (2H, d), 7.95 (4H, m), 9.62 (1H, br s), 10.01 (1H, br s), 10.40 (1H, br s), 10.55 (1H, br s); Mass Spectrum m/Z 388 (M+H)+.
Reaction SMILES: C[Si](O[Si](C)(C)C)(C)C.[C:10]([O-:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:19](Cl)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Li+].N1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[C:10]([O:18][C:10]1[CH:11]=[CH:12][C:21]2[C@H:22]3[CH2:31][CH2:32][C:33]4[C@H:15]([C@@H:23]3[CH2:24][CH2:25][C:20]=2[CH:19]=1)[CH2:14][CH2:13][C:34]=4[CH3:35])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C([O-])c1ccccc1
Reactant: c1ccncc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: CO
Product: CC1=C2CC[C@@H]3c4ccc(OC(=O)c5ccccc5)cc4CC[C@H]3[C@@H]2CC1
Reaction time: 0.17 h

Procedure:
After an unsuccessful attempt to convert the trimethylsilyl ether directly to the benzoate 7a (R = C6H5CO2) by heating with benzoyl chloride and lithium chloride in pyridine, the trimethylsilyl group was completely hydrolyzed by brief (about 1 minute) reflux in methanol. After removal of the methanol at reduced pressure, the benzoate-phenol mixture was treated with 2 ml of benzoyl chloride in 25 ml of pyridine for 10 minutes, followed by 2 ml of 85% lactic acid for 10 minutes to destroy excess reagent. The mixture was poured into water, extracted with ether, and the ether layer was thoroughly washed with dilute H2SO4 and saturated NaHCO3, followed by the usual work up to afford 4.02 g (theoretical yield 3.84 g) of brown crystalline solide, mp 100°-120°. An analytical sample was obtained by recrystallization from methanol, colorless plates, mp 114°-116°.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[F:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1>>[F:44][C:45]1[CH:46]=[CH:47][C:48]([OH:51])=[C:49]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])[CH:50]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(F)ccc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-fluorophenol, the title compound was obtained (53%): 1H NMR (300 MHz, CDCl3) δ 9.42-9.14 (br, 1H), 7.53-6.86 (m, 6H), 6.56-6.48 (m, 1H), 4.58-4.28 (br, 1H), 3.79-3.58 (m, 2H), 1.77-1.61 (m, 2H), 1.41-1.24 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 312 (M−17), 352 (M+23).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)=[O:13].IC.[C:28]([O-])([O-])=O.[Na+].[Na+].COC1C=C(C(C2C=CC(OC)=C(OC)C=2OC)=O)C=C(OC)C=1>>[CH3:28][O:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1)=[O:13]
Reactant: COc1cc(C(=O)c2ccc(OC)c(OC)c2O)cc(OC)c1OC
Reactant: O=C([O-])[O-]
Agent: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2OC)c1
Agent: [Na+]
Solvent: CI
Product: COc1cc(C(=O)c2ccc(OC)c(OC)c2OC)cc(OC)c1OC
Yield: 84 %

Procedure:
(2-hydroxy-3,4-dimethoxyphenyl)-(3,4,5-trimethoxyphenyl)methanone (4.44 g, 12.75 mmol), iodomethane (1.59 ml, 25.51 mmol), and Na2CO3 (2.7 g, 25.51 mmol) were treated in the same manner as described above for the synthesis of (3,5-Dimethoxy-phenyl)-(2,3,4-trimethoxy-phenyl)-methanone. The crude material was purified via flash column chromatography (20% EtOAc in hexane) to give (2,3,4-trimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone as an off-white solid (3.88 g, 84%); mp, 122-124° C.: 1HNMR (CDCl3) δ7.11 (d, J=8 Hz, 1H, Ar), 7.08 (s, 2H, Ar), 6.73 (d, J=8 Hz, 1H, Ar), 3.94 (s, 6H, 2OCH3), 3.91 (s, 3H, OCH3), 3.86 (s, 6H, 2OCH3), 3.81 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 194.4, 156.1, 152.9, 152.7, 142.6, 142.3, 133.5, 126.5, 124.9, 107.6, 106.8, 62.1, 61.1, 56.4, 56.3; Anal. Calcd. For C19H22O7: C, 62.98; H, 6.12. Found: C, 63.14; H, 6.13. The product was carried over to the next step.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[N+:18]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].[Cl-].CCOC(C)=O>CO.[Zn]>[F:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9]/[CH:8]=[CH:7]/[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([CH:13]=1)[NH2:18]
Reactant: O=[N+]([O-])c1cc(F)ccc1OC/C=C/c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(F)ccc1OC/C=C/c1ccccc1
Temperature: 25 °C

Procedure:
4-Fluoro-2-nitrophenyl (2E)-3-phenylprop-2-enyl ether (5-1, 20.2 g, 73.9 mmol) was dissolved in MeOH (300 mL) and treated with NH4Cl (20.5 g, 370 mmol) and Zn powder (24.2 g, 370 mmol) in small portions to prevent temperature from exceeding 50° C. during the addition. The suspension was vigorously stirred at 25° C. and then at 60° C. until completion as monitored by TLC and LC/MS. Upon completion, EtOAc was added (900 mL) and the reaction was filtered through celite and concentrated. The product was recrystallized from EtOAc/hexanes after a filtration to remove insoluble NH4Cl, and pure 5-fluoro-2-{[(2E)-3-phenylprop-2-enyl]oxy}aniline (5-2) was isolated as a brown solid. 1H NMR (300 MHz, CDCl3) δ 7.38 (m, 5H), 6.74 (dd, J=8.8, 4.9 Hz, 1H), 6.72 (d, J=17.4 Hz, 1H), 6.47 (dd, J=9.7, 3.1 Hz, 1H), 6.42 (m, 2H), 4.67 (dd, J=5.9, 1.3 Hz, 2H), 3.22 (br s, 2H); MS (M+H+, C15H14FNO) 244.2 found 244.3 required.
Reaction SMILES: C([N:4]1[CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:6]=2[CH2:5]1)(=O)C.Cl>[OH-].[Na+].CO.O.C(OCC)C>[CH2:17]([N:7]1[C:6]2[CH2:5][NH:4][CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCn1c2c(c3ccccc31)CCN(C(C)=O)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CCCCCn1c2c(c3ccccc31)CCNC2

Procedure:
A portion of the crude 2-acetyl-9-(n pentyl)1,2,3,4-tetrahydro-β-carboline (1.7 g) as heated at reflux for 4.5 hours in 2 N NaOH (50 mL) in methanol:water (2:3, v/v). The methanol was removed by evaporation under vacuum, and the crude 9-(n-pentyl)1,2,3,4-tetra-hydro-β-carboline free base was extracted into chloroform. This extract was dried over anhydrous MgSO4, filtered, and the filtrate evaporated under vacuum. The hydrochloride salt was prepared by passing dry HCl through a solution of the crude free base in diethyl ether. The resulting precipitate was filtered and recrystallized from acetonitrile to yield pure 9-(n-pentyl)1,2,3,4-tetrahydro-β-carboline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].[I:14]I>O1CCOCC1.O>[I:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: O=Cc1ccc2[nH]ncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
20 g (137 mmol) 1H-indazole-5-carbaldehyde [preparation described in US 2005/0227968-A1 (Intermediate 1)], dissolved in 1,4-dioxane (640 ml), were treated with a solution of sodium hydroxide (82 g, 2053 mmol) in water (640 ml). Then, 43.2 g (170 mmol) iodine were added, and the mixture was stirred at room temperature for 1 h. Subsequently, a second batch of 43.2 g (170 mmol) iodine was added, and the mixture was again stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure yielding a solid precipitate. After filtration, the precipitate was washed with water and dried under high vacuum over phosphorous oxide in a desiccator for 12 h affording the title compound (26.6 g, 72% of th.) as a pale yellow solid.
Reaction SMILES: [ClH:1].Cl[CH2:3][C:4](=N)OCC.[CH2:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[CH:14][C:13]=1[NH2:22])[CH3:10]>CCO>[Cl:1][CH2:10][C:9]1[N:11]([CH2:3][CH3:4])[C:12]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[N:15]=[CH:14][C:13]=2[N:22]=1
Reactant: CCNc1cc(C(F)(F)F)ncc1N
Reactant: CCOC(=N)CCl
Reactant: Cl
Solvent: CCO
Product: CCn1c(CCl)nc2cnc(C(F)(F)F)cc21
Temperature: 25 °C

Procedure:
The HCl salt of ethyl 2-chloro-acetimidate (3.90 g, 24.58 mmol) is added to a solution of N4-ethyl-6-trifluoromethyl-pyridine-3,4-diamine (1.44 g, 7.02 mmol) in EtOH (20 mL) and refluxed for 3 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with CH2Cl2, washed with NaHCO3 solution, dried over Na2SO4, and concentrated to obtain 2-chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine. 1H NMR (300 MHz, CDCl3): δ 9.14(s, 1H), 7.66 (s,1H), 7.26 (s, 1H), 4.87 (s, 2H), 4.40 (t, J=7.5 Hz, 2H), 1.58 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl.CCOCC>[ClH:1].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][Cl:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cl
Product: ClCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 500 ml of CHCl3 was dissolved 47.3 g (0.33 mole) of 6-chloro-3-pyridylmethanol followed by dropwise addition of 99.3 ml of thionyl chloride with stirring at room temperature. After completion of the dropwise addition, the mixture was further stirred for 1.5 hours and, then, allowed to stand overnight. The CHCl3 was distilled off under reduced pressure, whereby crystals and oil were obtained as a residue. The residue was diluted with ether, collected by filtration and dried to give 45.2 g of 6-chloro-3-pyridylmethyl chloride hydrochloride as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH3:19])[CH3:2].CN(C)CCCN=C=NCC.[CH3:32][C:33]1[N:34]=[C:35]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[S:36][C:37]=1[C:38](O)=[O:39]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:38]([C:37]3[S:36][C:35]([C:41]4[CH:42]=[CH:43][C:44]([C:47]([F:50])([F:48])[F:49])=[CH:45][CH:46]=4)=[N:34][C:33]=3[CH3:32])=[O:39])[CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH3:19])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Reactant: CCOC(=O)CNc1cc(C2CCCNC2)ccc1C
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(=O)CNc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.1 %

Procedure:
(2-Methyl-5-piperidin-3-yl-phenylamino)-acetic acid ethyl ester (Example 13-1; 63 mg, 0.23 mmol) was dissolved in 2 mL CH2Cl2 and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (87 mg, 0.46 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (65 mg, 0.23 mmol) were added. The reaction was stirred at ambient temperature under nitrogen for 24 h. The reaction was flash chromatographed with 30% ethyl acetate/hexanes to yield 19 mg (15%) of the desired (2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenylamino)-acetic acid ethyl ester as a clear oil.
Reaction SMILES: O[CH:2]([N:10]1[C@H:13]([S:14][CH2:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[O:17])[C@H:12]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]1=[O:34])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].N1C(C)=CC=CC=1C.S(Cl)([Cl:45])=O.C(OCC)(=O)C>C1COCC1>[Cl:45][CH:2]([N:10]1[C@H:13]([S:14][CH2:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[O:17])[C@H:12]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]1=[O:34])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)C(O)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SCC(=O)C1CCCCO1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(Cl)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SCC(=O)C1CCCCO1

Procedure:
t-Butyl 2-hydroxy-2-[(3R,4R)-3-phenylacetamido-4-[(RS)-tetrahydropyran-2-ylcarbonylmethylthio]azetidin-2-on-1-yl]acetate (1.9g) in dry THF (10ml) was treated with 2,6-lutidine (0.62g, 0.67ml) followed by thionyl chloride (0.69g, 0.42ml) in THF (5ml) dropwise at <-20° C. under argon. The reaction mixture was allowed to warm slowly to ca 0° C. at which point no starting material was observed by t.l.c. (ethyl acetate). The reaction mixture was filtered and solvent removed in vacuo, the residue dissolved in toluene and evaporated to afford crude t-butyl (RS)-2-chloro-2-((3R,4R)-3-phenylacetamido-4-[(RS)-tetrahydropyran-2-ylcarbonylmethylthio]azetidin-2-on-1-yl]acetate as a brown gum. This was dissolved in dry dioxan (10ml) and treated with tri-n-butylphosphine (1.79g, 2.2ml). The reaction mixture was stirred until loss of starting material was observed by t.l.c. (ethyl acetate) ca 0.5h. After removal of solvent in vacuo the title compound was obtained by flash chromatography (eluting with 50,60,80% ethyl acetate in hexane, ethyl acetate) as a pale brown foam (1.95g, 75%); vmax (CH2Cl2) 3417(w), 1762, 1681, 1625cm-1. [Mass spectrum +ve ion (thioglycerol) MH+ (677)].
Reaction SMILES: O[N:2]([OH:10])[C:3]([CH3:9])([C:5]([CH3:8])([NH2:7])[CH3:6])[CH3:4].I([O-])(=O)(=O)=[O:12].[Na+].C(Cl)(Cl)Cl.CO>O>[CH3:4][C:3]1([CH3:9])[C:5]([CH3:8])([CH3:6])[N+:7]([O-:12])=[N+:2]1[O-:10]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(N)C(C)(C)N(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)[N+]([O-])=[N+]([O-])C1(C)C

Procedure:
The product could also be obtained by oxidation of the dihydroxylamino precursor with sodium periodate. Thus, N,N-dihydroxy 2,3-dimethyl-2,3-diaminobutane (1.5 g) in water (50 ml) was stirred for 30 min. with aqueous sodium periodate (4.5 g in ca. 100 ml water). The product precipitated out and was washed with water, dried (MgSO4), and evaporated to give the product (800 mg. 65°) T.L.C. (silica, CHCl3 /MeOH;4/1) one spot, Rf 0.8
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][O:29]C(=O)C)[C@H:21]([O:22]C(=O)C)[C@@H:16]3[O:17]C(=O)C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][OH:29])[C@H:21]([OH:22])[C@@H:16]3[OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Cl)cccc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CC(C)Nc1nc2c(Cl)cccc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 68.4 %

Procedure:
4-Chloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (2.24 g, 4.79 mmol), sodium carbonate (0.67 g, 6.32 mmol), water (7 mL), methanol (14 mL) and ethanol (20 mL) were used according to general procedure III. The product was purified by silica gel chromatography using 10:1 dichloromethane/methanol to afford 1.12 g (68%) of a white solid: m.p. 225-227° C. Anal. calcd for C15H20ClN3O4: C, 52.77; H, 5.91; N, 12.32. Found: C, 52.79; H, 5.96; N, 12.25.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].[CH:45]1(Br)[CH2:47][CH2:46]1>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:3]1([O:8][C:9]2[C:17]3[N:16]=[C:15]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=4)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:47][CH2:45][CH2:46]1
Reactant: BrC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OC4CCCC4)cccc32)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole trifluoroacetate (300 mg, 0.6 mmol, 1 eq) in anhydrous N,N-dimethylformamide (3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The resulting mixture was stirred for thirty minutes at room temperature. Cyclopropyl bromide (0.66 mmol, 1 eq) was added to the reaction and the resulting mixture was stirred for two hours at room temperature. The reaction was quenched with the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash column chromatography to yield the title product as a crystalline product in 50% yield.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9](=[N:11][OH:12])[NH2:10])=[N:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19](Cl)=O>>[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]1[O:12][N:11]=[C:9]([C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=2)[N:10]=1
Reactant: NC(=NO)c1ncc([N+](=O)[O-])s1
Reactant: O=C(Cl)c1sccc1Cl
Product: O=[N+]([O-])c1cnc(-c2noc(-c3sccc3Cl)n2)s1

Procedure:
The title compound was prepared from 5-nitro-thiazole-2-amidoxime (17.2 mg, 0.0914 mmol) and 3-chloro-thiophene-2-carbonyl chloride (16.4 mg, 0.0905 mmol) similar to Example 16, and yielded 6.7 mg (23%) of yellow solid. 1H NMR (CDCl3): 8.74 (s, 1H), 7.70 (d, J=5.22 Hz, 1H), 7.18 (d, J=5.22 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[CH:14]1([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([OH:13])=[C:6]3[C:11]=2[NH:10][C:9](=[O:12])[CH2:8][CH2:7]3)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(O)c2c1NC(=O)CC2
Solvent: c1ccncc1
Product: O=C1CCc2c(O)ccc(NC(=O)C3CCCCC3)c2N1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
10.7 g of 8-amino-5-hydroxy-3,4-dihydrocarbostyril was dissolved in 100 ml of pyridine, and 10.0 g of cyclohexylcarbonyl chloride was added to the solution while vigorously stirring at room temperature followed by stirring at 50° C. for 30 minutes. The precipitated crystals were recovered by filtration, washed with ethanol, dried and dissolved in 200 ml of a 10% aqueous sodium hydroxide solution. Activated carbon was added to the solution, and the mixture was stirred and filtered. The filtrate was rendered acidic with hydrochloric acid under ice cooling, and the precipitated crystals were recovered by filtration, washed with water and dried. Recrystallization from methanol yielded 6.6 g of 8-cyclohexylcarbonylamino-5-hydroxy-3,4-dihydrocarbostyril as colorless amorphous crystals having a melting point of 304.2°-304.8° C.