Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[O:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:23][C:12]1[CH:13]=[C:14]2[C:15](=[CH:20][C:11]=1[CH2:10][C:9]1[CH:24]=[CH:25][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:7][CH:8]=1)[C:16](=[O:17])[N:32]([CH:29]1[CH2:30][CH2:31][O:26][CH2:27][CH2:28]1)[CH2:21]2
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1C=O
Reactant: NC1CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)N(C1CCOCC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.10 g), tetrahydro-2H-pyran-4-amine (0.03 g) and anhydrous magnesium sulfate (0.07 g) in THF (2.00 mL) was stirred at room temperature for 1 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (2.00 mL) and THF (2.00 mL), sodium triacetoxyborohydride (0.13 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]2=[O:24])(=O)=O)=CC=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)(C)(C)C>[N:26]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:18](=[O:24])[CH2:19][O:20][CH2:21][C:22]2=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN2C(=O)COCC2=O)cc1
Reactant: C1CCNCC1
Solvent: CC(C)(C)O
Product: O=C1COCC(=O)N1CCCCCCN1CCCCC1

Procedure:
To a solution of 19.6 grams (53.2 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate in 54 milliliters of tertiary butyl alcohol was added 5.3 milliliters of tertiary (53 millimoles) of piperidine in 54 milliliters of tertiary butyl alcohol. The reaction mixture was heated at reflux temperature for about 22 hours to obtain 4-(6-piperidinohexyl)-3,5-dioxomorpholine.p-toluenesulfonate product which crystallized from tertiary butyl alcohol-ether mixture in a yield of 13.45 grams (56 percent) as an off-white solid, m.p. 125°-128° C. A portion of this product after purification by (a) chromatographing on Silicar CC4 Special (Silica gel, product of Mallinkrodt) employing 10:1 dichloromethanemethanol as eluant, (b) recovering from the effluent and (c) recrystallizing from tertiary butyl alcohol-ether, was a white solid, m.p. 121°-122.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br>CCO.O.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([Br:18])=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: c1ccc(COc2cccn3ccnc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Brc1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-benzyloxy-imidazo[1,2-a]pyridine (25.46 g) in EtOH (250 mL) was added Br2 (7.03 mL) in water (7 mL) dropwise at RT. The resulting dark orange suspension was stirred at RT for 1 h. The reaction mixture was diluted with NaOH (90 mL, 1 N) and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The product crashed in the column and tubing during attempted purification. Recovered product provided 8-benzyloxy-3-bromo-imidazo[1,2-a]pyridine (21 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:13]2[NH:14][C:15](=[O:22])[C:16]([CH:19]([CH3:21])[CH3:20])([CH3:18])[N:17]=2)[N:4]=1.S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl>[Cl:25][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:13]2[NH:14][C:15](=[O:22])[C:16]([CH:19]([CH3:21])[CH3:20])([CH3:18])[N:17]=2)[N:4]=1
Reactant: COC(=O)c1ccc(CO)nc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CCl)nc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
To a solution of 8.7 g of methyl 6-hydroxymethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate in 90 mL chloroform, stirred at room temperature, is added dropwise 4.2 mL of thionyl chloride. When the addition is complete, the solution is heated at reflux for 1 hour. The reaction is concentrated in vacuo, and the residue is dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is dried and concentrated in vacuo to an oil. Trituration of this oil affords the desired product as a solid. Recrystallization from methylene chloride-hexane gives analytically pure material, mp 127°-129° C.
Reaction SMILES: [H-].[Na+].COC1C=CC(C(C2C=CC(OC)=CC=2)[O:12][CH:13](C2C=CC=CC=2)[CH:14]2[O:18][CH:17]([N:19]3[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:20]3=[O:26])[CH:16]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:15]2[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=CC=1.[CH3:57][O:58][C:59]1[CH:66]=[CH:65][C:62]([CH2:63]Cl)=[CH:61][CH:60]=1.C1(S(O)(=O)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[Si:28]([O:27][C@@H:16]1[C@H:15]([O:35][Si:36]([C:39]([CH3:41])([CH3:42])[CH3:40])([CH3:37])[CH3:38])[C@@H:14]([CH2:13][OH:12])[O:18][C@H:17]1[N:19]1[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH2:63][C:62]2[CH:65]=[CH:66][C:59]([O:58][CH3:57])=[CH:60][CH:61]=2)[C:20]1=[O:26])([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:30])[CH3:29]
Reactant: COc1ccc(C(OC(c2ccccc2)C2OC(n3ccc(=O)[nH]c3=O)C(O[Si](C)(C)C(C)(C)C)C2O[Si](C)(C)C(C)(C)C)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=S(=O)(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 58.8 %

Procedure:
Following the procedure (Myers, A. G.; Gin, D. Y.; Rogers, D. H., J. Amer. Chem. Soc., 1994, 116, 4697-4718), a suspension of sodium hydride (1.55 g, 38.75 mmole, 60% oil dispersion) in anhydrous dimethylformamide (40 ml) was cooled at 0° C. under argon, and to this mixture was added a solution of 1-[5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-3,4-bis-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-2-yl]-1H-pyrimidine-2,4-dione (20 g, 25.8 mmole, obtained from Reference Example 1) in anhydrous dimethylformamide (35 ml) over a period of 15 min. Neat p-methoxybenzyl chloride (7 ml, 51 mmole) was added to this solution. The resulting mixture was stirred at 0° C. for 15 h under argon, and diluted with ethyl acetate (700 ml). The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The oily residue was dissolved in chloroform (200 ml) and cooled at 0° C. under nitrogen. Benzenesulfonic acid (6 g, 37.93 mmole) was added portionwise, and the resulting red solution was stirred at 0° C. under nitrogen for 2 h. The mixture was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The residue was chromatographed (flash column, silica gel, methylene chloride:diethyl ether:methanol=95:3:2) to give 1-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-(4-methoxybenzyl)-2,4(1H,3H)-pyrimidinedione as white solid (9 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:10]2)=[C:5]([OH:22])[CH:4]=1.C([O-])(=O)C.[Tl+].[I:28]I.[Tl]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10]2)=[C:5]([OH:22])[C:4]=1[I:28]
Reactant: II
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(OC)cc3o2)cc1
Agent: CC(=O)[O-]
Agent: [Tl+]
Agent: [Tl]
Solvent: ClCCl
Product: COc1ccc(-c2cc(=O)c3c(O)c(I)c(OC)cc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of 6 (2.98 g, 10.0 mmol) in 300 mL CH2Cl2 was added thallium(I) acetate (3.16 g, 10.2 mmol). With magnetic stirring, a solution of iodine (2.54 g, 10.0 mmol) in 200 mL CH2Cl2 was added dropwise over 1 h. During the addition, a fine suspension of thallium salts precipitated. The solution was stirred at room temperature overnight, then filtered through a bed of celite to remove the precipitated salts. The filtrate was extracted sequentially with 500 mL each of 5% NaHCO3, 10% Na2S2O4, and saturated brine, then dried over magnesium sulfate and filtered. Evaporation in vacuo provided an orange solid. Recrystallization from 300 mL CHCl3/EtOH (1:2) afforded fine yellow needles (3.10 g, 73.1%); mp 227-228° C. (lit.13 mp 205-207° C.); 1H NMR (CDCl3) δ 3.90 (s, 3 H), 4.00 (s, 3 H), 6.54 (s, 1 H), 6.64 (s, 1 H), 7.02 (d, 2 H, J=9.0 Hz), 7.85 (d, 2 H, J=9.0 Hz), 13.84 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 181.7, 164.4, 163.5, 162.9, 161.3, 158.3, 128.2, 123.3, 114.6, 104.4, 104.3, 90.5, 90.4, 56.8, 55.5; EI-MS m/z 424 (M+, 100). Anal. calcd for C17H13IO5: C, 48.14; H, 3.09. Found: C, 48.30; H, 3.11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(O)[CH:9]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH3:10])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH3:10])=[CH:18][CH:19]=1
Reactant: CC(n1cncn1)C(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)n1cncn1

Procedure:
1,1-bis(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)propan-1-ol (2.0 g) from Example 3xi was dissolved in dry toluene (40 ml), and a catalytic amount of p-toluene sulphonic acid added. The mixture was refluxed in a round bottom flask fitted with a soxhlet extractor filled with molecular sieves (4A) and condenser. Reflux was continued until there was no starting material remaining on tlc. The mixture was poured into water and extracted, washed with water (3X) then dried over anhydrous magnesium sulphate and evaporated on a rotary evaporator. The product was purified by chromatography on silica gel eluted with CH2Cl2 /ethylacetate (3:2). 1,1-bis(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)prop-1-ene was obtained as a white solid (1.0 g) by recrystallisation from hexane.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH2:19][CH3:20])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCCBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(Br)cc1C=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In DMF (160 ml) was dissolved 5-bromosalicylaldehyde (20 g). To the mixture was added at room temperature potassium carbonate (17.9 g) and then was added 1-bromopropane (10.8 ml), and the mixture was stirred at 90° C. for 3 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1) to give 5-bromo-2-propoxybenzaldehyde (21.9 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17]=1[SH:25].[OH-].[Na+]>O>[CH3:15][O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:25][C:17]2[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]=2)[C:8]=1[CH3:9]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COCCCOc1ccnc(CCl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Temperature: 65 °C

Procedure:
To this 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridin solution was added 2-benzimidazole thiol (8.71 g (58.0 mmol)) at room temperature. A 25% aqueous sodium hydroxide solution (40.6 g) was added gradually as the temperature (internal temperature) was gradually raised to 65° C. The reaction mixture was stirred for about an hour and a half at 65° C. (internal temperature). Water (60.0 ml) was added to the reaction mixture at 65° C., after which 25% aqueous sodium hydroxide solution (0.2 g) was added and stirred. This reaction mixture was allowed to stand, and the water layer was separated. The organic layer was washed with water (20.0 ml) twice, and toluene (79.6 ml) and methanol (21.5 ml) were added to the organic layer to obtain a 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole solution.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:67][C:68]1[S:69][C:70]2[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=1>>[S:69]1[C:70]2[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=[C:68]1[S:67][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[O:36])[CH2:32][CH2:33]1
Reactant: Sc1nc2ccccc2s1
Reactant: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCOCC2)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCSc3nc4ccccc4s3)CC2)c(N2CCOCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzothiazole, to thereby yield the title compound as a colorless foamed substance.
Reaction SMILES: [NH2:1][C:2]1[C:3](O)=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.C([O:16][C:17](=N)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])C>CO>[CH2:18]([C:17]1[O:16][C:7]2[CH:6]=[CH:5][C:4]([CH2:8][C:9]([OH:11])=[O:10])=[CH:3][C:2]=2[N:1]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Nc1cccc(CC(=O)O)c1O
Reactant: CCCCCC(=N)OCC
Agent: Cl
Solvent: CO
Product: CCCCCc1nc2cc(CC(=O)O)ccc2o1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (3-aminohydroxy-phenyl)-acetic acid (4.65 g, 27.8 mmol) in methanol (79 ml) was treated with hexanimidic acid ethyl ester hydrochloride (5.00 g, 27.8 mmol) and stirred for 14 hours at RT. The solvent was evaporated in vacuum and the residue purified by silica gel chromatography (eluent: DCM/methanol 10/1). Crystallization from Cyclohexane/n-pentane provided the title compound as colorless crystals. mp: 58.2/57.1° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:11][CH3:12])=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][CH:16]([C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]1.[Cl:24][C:25]1[C:38]([N:39]=[C:40]=S)=[C:37]([Cl:42])[CH:36]=[CH:35][C:26]=1[CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].CC(C)N=C=NC(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([F:22])([F:20])[F:21])[CH2:15][CH2:14]2)=[CH:6][C:7]2[N:11]([CH3:12])[C:40]([NH:39][C:38]3[C:37]([Cl:42])=[CH:36][CH:35]=[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]=3[Cl:24])=[N:10][C:8]=2[CH:9]=1)=[O:23]
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)OC)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2cc1N1CCC(C(F)(F)F)CC1

Procedure:
The sub-title compound is prepared in analogy to 6c from methyl-2-[4-trifluoromethyl-piperidinyl]-4-methylamino-5-amino-benzoate (1.60 g, 4.82 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (1.53 g, 4.82 mmol), DIC (0.82 mL, 5.3 mmol) and DMF (20 mL). Yield: 2.54 g. HPLC Rt=1.42 min (method A). MS m/z: 614 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=O)[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:26][OH:27]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=[N:26][OH:27])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)C(CC1CCC(=NO)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of the 2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (prepared as in Example 43, 144.6 mg, 0.38 mmol) and hydroxylamine hydrochloride (39.7 mg, 0.57 mmol) in methanol (1.1 mL) and pyridine (1.1 mL) was heated under reflux for 3 h. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. The resulting residue was diluted with ethyl acetate (75 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (75 mL) and a saturated aqueous sodium chloride solution (75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 70% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-hydroxyimino-cyclopentyl)-N-thiazol-2-yl-propionamide (138.9 mg, 92%) as a white foam: mp 98-101° C. (foam to gel); (ES)+-HRMS m/e calcd for C17H17Cl2N3O2S (M+H)+ 398.0492. found 398.0496.
Reaction SMILES: [H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1([C:30](OCC)=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26].C1COCC1>CCOCC>[OH:31][CH2:30][C:20]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCCO1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(CO)CCCCO1
Temperature: 25 °C

Procedure:
A 1M solution of lithium tri-tert-butoxyaluminum hydride (8.79 mL, 8.79 mmol) was added dropwise to a cold (0° C.) stirred solution of diethyl tetrahydro-2H-pyran-2,2-dicarboxylate (0.810 g, 3.52 mmol) in an. THF (9 mL). After the addition is complete the mixture was allowed to warm to rt and heated to reflux for 4-5 h. The reaction mixture was cooled, diluted with ether and quenched with 20% NaHSO4 solution with vigorous stirring. The organic layer was separated, washed with brine and dried over MgSO4. The crude isolate was purified by silica gel FCC (5% MeOH in DCM) to afford ethyl 2-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.29 (q, J=7.0 Hz, 2H), 3.95-3.87 (m, 2H), 3.71 (dd, J=11.2, 8.2 Hz, 1H), 3.62 (dd, J=11.2, 5.1 Hz, 1H), 2.24-2.16 (m, J=8.0, 5.3 Hz, 1H), 2.14-2.06 (m, 1H), 1.84-1.72 (m, 1H), 1.64-1.50 (m, 4H), 1.37-1.29 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH2:7][CH2:8][S:9]([CH2:11][C:12]([OH:14])=O)=[O:10])=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:40]1([CH2:46][C:47]2[CH:48]=[C:49]([CH:56]=[CH:57][CH:58]=2)[O:50][CH2:51]/[CH:52]=[CH:53]\[CH2:54][NH2:55])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C)C=O.ClCCl>[N:40]1([CH2:46][C:47]2[CH:48]=[C:49]([CH:56]=[CH:57][CH:58]=2)[O:50][CH2:51]/[CH:52]=[CH:53]\[CH2:54][NH:55][C:12](=[O:14])[CH2:11][S:9]([CH2:8][CH2:7][NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:10])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CCOC(=O)NCCS(=O)CC(=O)O
Reactant: NC/C=C\COc1cccc(CN2CCCCC2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)NCCS(=O)CC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
There was dissolved 1.64 g (0.0074 mol) of 2-[2-(ethoxycarbonylamino)ethylsulfinyl]acetic acid in 80 ml of 50% dimethylformamide-dichloromethane and added 1.13 g (0.0074 mol) of HOBt and 1.52 g (0.0074 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 1.91 g (0.0074 mol) of 4-[3-(piperidinomethyl)-phenoxy]-cis-2-butenylamine and the mixture was stirred for 18 hours at room temperature. The obtained precipitate was filtrated off, and the filtrate was washed with 5% aqueous solution of sodium hydroxide and with water successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1). Then the obtained crystals were recrystallized from ethyl acetate-n-hexane (1:1) to give 1.3 g of the titled compound.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[N:32]=[C:33]([C@@H:36]6[CH2:44][CH:43]7[CH:38]([CH2:39][CH2:40][CH2:41][CH2:42]7)[N:37]6C(OC(C)(C)C)=O)[NH:34][CH:35]=5)=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[N:18]=2)[CH:12]2[CH2:52][CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.O>CO>[CH:9]12[CH2:52][CH:12]([CH2:11][CH2:10]1)[C@@H:13]([C:14]1[NH:15][CH:16]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[CH:27][C:28]([C:31]5[N:32]=[C:33]([C@@H:36]6[CH2:44][CH:43]7[CH:38]([CH2:39][CH2:40][CH2:41][CH2:42]7)[NH:37]6)[NH:34][CH:35]=5)=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)[N:18]=1)[NH:8]2
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6CCCCC6N5C(=O)OC(C)(C)C)n4)cc3)cc2)c[nH]1
Solvent: CO
Solvent: O
Product: c1cc(-c2c[nH]c([C@@H]3CC4CCCCC4N3)n2)ccc1-c1ccc(-c2c[nH]c([C@H]3NC4CCC3C4)n2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Compound 8 were taken in 9 ml methanol; 1 ml Conc. HCL and 0.2 ml water was added. Resulting reaction was stirred for 5 h at 50° C. (oil bath temp) completed, after completion of the reaction monitor by HPLC. The resulting slurry was cooled to RT and held with agitation for about 1H. Filtration of the slurry afforded a solid; washed with 15 ml acetone dried directly used in the next reaction.