Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH:10]=O.[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[C:25]([C:27](=[CH:10][C:9]1[CH:12]=[C:5]([O:4][C:3]2[C:2]([Cl:1])=[CH:19][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:17][C:16]=2[Cl:24])[CH:6]=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14])[C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 52.6 %

Procedure:
19 g of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-benzaldehyde, 5.7 g of ethyl cyanoacetate, 0.6 g of acetic acid, 0.3 g of piperidine and 120 ml of toluene were mixed and heated to the boil for 6 hours under a water separator. 200 ml of toluene was then added and the organic phase was washed with water. The solvent was distilled from the organic phase and the residue was caused to crystallise by digestion with methanol. 12.5 g (53% of theory) of ethyl 2-cyano-3-(5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-phenyl)-propenoate, of melting point 99° C., were obtained in the form of pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]([O:11][CH3:12])([O:9][CH3:10])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:1][O:2][CH:3]1[C:8]([O:11][CH3:12])([O:9][CH3:10])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1CNCCC1(OC)OC
Reaction time: 3 h

Procedure:
The title compound was prepared by taking tert-butyl 3,4,4-trimethoxypiperidine-1-carboxylate (424 mg, 0.00154 mol) in Methylene chloride (10 mL, 0.2 mol) and adding Trifluoroacetic Acid (1 mL, 0.02 mol). The reaction was stirred for 3 h. The solvent was removed in vacuo and the crude taken to the next step (270 mg, 99%). MS calculated for C8H17NO3: (M+H) 176; found 176.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1.CCN(CC)CC.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: NCc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Some starting materials may be obtained from Adesis Inc., New Castle, Del.) To a mixture of (2-chloro-5-(4-morpholinoquinolin-6-yl)pyridin-3-yl)methanamine (50 mg, 141 μmol) and Et3N (300 μl, 2152 μmol) in DCM (5 mL) was added pivaloyl chloride (100 μL, 813 μmol). The solution was stirred at rt for 1 h. The mixture was partitioned between DCM (10 mL) and aqueous NaHCO3 (20 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified on silica with 1-5% (2N NH3-MeOH) in DCM to give the product as a yellow solid after concentration (20 mg, 32%). LCMS (ESI, pos. ion): calc'd for C24H27ClN4O2:438.2; found: 439.2 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.21-1.28 (m, 12 H) 3.19-3.35 (m, 4 H) 3.95-4.08 (m, 4 H) 4.58 (d, J=6.06 Hz, 2 H) 6.37 (br. s., 1 H) 6.93 (d, J=4.89 Hz, 1 H) 7.83 (dd, J=8.90, 1.66 Hz, 1 H) 8.00 (d, J=2.15 Hz, 1 H) 8.10-8.25 (m, 5 H) 8.61 (d, J=2.15 Hz, 2 H) 8.79 (d, J=4.89 Hz, 2 H)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])=[CH:5][C:4]=2[N:3]=1.[C:35](Cl)(=[O:37])[CH3:36].CS(OS(C)(=O)=O)(=O)=O>>[C:35]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17])[C:13]([CH2:23][O:24][CH2:25][CH3:26])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(C)=O
Agent: CS(=O)(=O)OS(C)(=O)=O
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(C)=O)ccc3c2n1CC(C)(C)NC(C)=O
Yield: 36.7 %

Procedure:
A modification of the method described in Part K of Example 45 was followed using N-{2-[4-amino-7-(6-aminohexyloxy)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide (1.2 g, 2.5 mmol) as the starting material and acetyl chloride (200 μL, 3 mmol) in lieu of methanesulfonic anhydride. Following chromatographic purification, the solid was recrystallized from acetonitrile, and the crystals were dissolved in dichloromethane:methanol, concentrated under reduced pressure, and further dried under high vacuum at 60° C. to provide 0.47 g of N-(2-{7-[6-(acetylamino)hexyloxy]-4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)acetamide as a white powder, mp 190-192° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH2:35][CH2:34]4)=[N:21][N:22]3[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[C:23]3[C:19](=[CH:18][CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:24]=3)[C:20]([CH:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([OH:42])=[O:41])[CH2:35][CH2:34]3)=[N:21]2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(F)cc3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CN1CCC(c2nn(Cc3ccc(F)cc3)c3cc(/C=C/C4CCNCC4)ccc23)CC1

Procedure:
4-{2-[3-(1-tert-Butoxycarbonylmethyl-piperidin-4-yl)-1-(4-fluoro-benzyl)-1H-indazol-6-yl]-(E)-vinyl}piperidine-1-carboxylic acid tert-butyl ester (181 mg, 0.29 mmol) was stirred in trifluoroacetic acid (10 ml), containing water (1 ml) at +25° for 2.5 h. The solution was evaporated in vacuo and the residue purified by preparative h.p.l.c. using standard conditions (gradient profile 10-30% (ii) in 1 min, 30% (ii) isochratic for 30 min, 30-10% (ii) in 1 min), but with a flow rate of 20 ml/min. The collected eluant (Rf 21.2 min) was evaporated in vacuo and triturated with ether to give the title compound as a cream solid (80 mg). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25 min) Rf 12.5 min
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:8]([C:15](O)=O)[C:9](CC(O)=O)=O.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>Cl>[CH2:18]([N:25]1[CH:3]2[CH2:2][CH2:1][CH2:15][CH:8]1[CH2:9][C:5](=[O:6])[CH2:4]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: O=CCCCC=O
Reactant: O=C(O)CC(=O)CC(=O)O
Agent: Cl
Product: O=C1CC2CCCC(C1)N2Cc1ccccc1
Yield: 33 %

Procedure:
To a 1 L round-bottomed flask equipped with a condenser and nitrogen inlet were added 80 g (0.2 mol) of a 25% aqueous solution of glutaraldehyde, 29.2 g (0.2 mol) 1,3-acetonedicarboxylic acid, and 11.4 g (0.2 mol) benzylamine. After the initial reaction had subsided, the pH was adjusted to 5 and maintained for 14 hours. The reaction was then taken up in 6N HCl, washed with ethyl acetate, and basified with 6N sodium hydroxide solution. The aqueous layer was extracted with methylene chloride, and the organic layer filtered through diatomaceous earth (Celite [trademark]) and evaporated. The residue was chromatographed on silica gel with ethyl acetate/methylene chloride as eluent to afford 15.034 g (33%) of a pale orange solid, mp 70-73C.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.Cl[C:15]([O:17][CH3:18])=[O:16].O>CCOC(C)=O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)Cl
Reactant: Fc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An oven-dried round bottom flask successively purged and evacuated with N2 was charged with anhydrous THF (84 ml) and placed in a −78° C. dry ice/acetone bath. To this was added n-butyllithium (2.5 M in hexanes) (18 ml, 46 mmol) and the mixture was stirred for 10 min before adding 1-chloro-3-fluorobenzene (5.48 g, 42.0 mmol) neat. The solution was stirred for 2 hrs before adding neat methyl chloroformate (4.0 ml, 50 mmol). The resultant solution was stirred at −78° C. for 3 hrs and then allowed to warm to RT. Water was added followed by EtOAc. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a clear liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:3]=12.[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[N:10]=[C:9]2[CH2:11][CH2:12][CH3:13])=[CH:30][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCc1nc2nccc(C)c2[nH]1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A suspension of 7-methyl-2-propylimidazo[4,5-b]pyridine (1.00 g, 5.71 mmol) and NaH (189 mg, 1.1 eq) in DMF (25 mL) was stirred for 1 hour and then cooled to 0° C. 4-Benzyloxybenzyl chloride (1.46 g; 1.1 eq) was then added and the ice bath removed. The reaction mixture was stirred for 2.5 hours and was then concentrated in vacuo. The residue was chromatographed on a silica gel flash chromatography column (30×100 mm) eluted with 30% ethyl acetate/hexane to yield 1.07 g (50%) of product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23]1[N:28]=[C:27](NCCNC2C=CC([N+]([O-])=O)=CN=2)[CH:26]=[CH:25][C:24]=1[C:42]1[NH:43][CH:44]=[CH:45][N:46]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23]1[N:28]=[C:27]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][N:6]=2)[CH:26]=[CH:25][C:24]=1[C:42]1[NH:46][CH:45]=[CH:44][N:43]=1
Reactant: NCCNc1ccc(C(F)(F)F)cn1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: FC(F)(F)c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
[6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)](2-{[5-(trifluoromethyl) (2-pyridyl)]amino}ethyl)amine was prepared from (2-aminoethyl)[5-(trifluoromethyl) (2-pyridyl)]amine using the general method for [6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:21]=[C:20]2[C:11]([O:12][CH2:13][CH2:14][N:15]3[C:19]2=[N:18][C:17]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[C:24]([CH3:30])[N:23]=2)=[CH:16]3)=[CH:10][N:9]=1)[CH3:7])(=O)=O.[C:31]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1>[C:31]([N:35]1[CH2:40][CH2:39][N:38]([C@H:6]([C:8]2[N:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:14][N:15]4[CH:16]=[C:17]([C:22]5[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[C:24]([CH3:30])[N:23]=5)[N:18]=[C:19]4[C:20]=3[CH:21]=2)[CH3:7])[CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N1CCNCC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C(C)OS(C)(=O)=O)ncc2OCC3)n(C(C)C)n1
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2cc([C@H](C)N4CCN(C(C)(C)C)CC4)ncc2OCC3)n(C(C)C)n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 1-{4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,12-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate (240 mg) and 1-tert-butylpiperazine (281 mg, 1.97 mmol) in dioxane (5.00 mL) was stirred at 100° C. for 16 hrs under N2 atmosphere. After removal of the solvents, the residue was purified with reverse phase Combi-flash eluting with a 20-28% gradient of CH3CN in 0.3% NH4HCO3 to afford the desired product. The isolated solid was further separated by chiral SFC (AD-H column, EtOH (0.1% DEA) isocratic) to give the two enantiomers 303 and 305.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:12])[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2].[CH2:13]([Li])[CH2:14]CC.CN(C)CCN(C)C.ICC.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:3]1([CH2:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2]
Reactant: CCC1=c2ccccc2=NC1=O
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1(CC)C(=O)Nc2ccccc21
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A solution of 3-ethyl-indol-2-one (16 g, 0.1 mol) in dry THF (200 ml) under N2 was cooled to −25° C. and treated drop wise with n-butyllithium (2.5M in hexanes, 80 ml, 0.2 mol). To the resulting solution was added N,N,N′,N′-tetramethylethylenediamine (30 ml, 0.2 mol). After 30 min. iodoethane (8 ml, 0.1 mol) was added and the reaction mixture was allowed to warm to RT and stirred over night. The reaction mixture was poured into an aqueous NH4Cl solution, extracted with EtOAc (2×) and the combined organic layers were washed with dil. HCl, water, brine, dried (MgSO4) and concentrated. The residual oil was triturated with hexane to afford 3,3-diethylindol-2-one (9 g, 45%), m.p. 156-159° C.; 1H NMR (DMSO-d6) δ10.44 (s, 1H), 7.70-7.69 (t, 1H), 7.62-7.59 (m, 1H), 7.58 (d, 1H J=1.7 Hz), 7.53-7.50 (m, 1H), 7.45-7.41 (t, 1H), 7.36-7.35 (m, 1H), 7.34-7.33 (m, 1H), 6.91-6.89 (d, 1H J=8.2 Hz), 1.87-1.80 (m,2H), 1.77-1.70 (m, 2H), 0.54-0.50 (t, 6H); MS (+ESI) m/z 190 (M+H).
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:38])([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1.COC(C)(C)C>C1(C)C=CC=CC=1>[F:31][C:30]([F:32])([F:33])[C:29]([C:26]1[CH:25]=[CH:24][C:23]([N:13]2[CH2:12][CH2:11][CH:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH2:15][CH2:14]2)=[CH:28][CH:27]=1)([OH:38])[C:34]([F:35])([F:37])[F:36]
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: O=S(=O)(c1ccccc1)C1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 100 °C
Yield: 89.1 %

Procedure:
A 15-mL reaction vial was charged with 4-(phenylsulfonyl)piperidine (1.05 g, 4.66 mmol, BetaPharma, Brandford, Conn.), sodium t-butoxide (0.98 g, 10.24 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.50 g, 4.66 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos Palladacycle) (0.170 g, 0.233 mmol, Strem Chemicals, Inc, Newburyport, Mass.), and toluene (10 mL). The vial was closed and purged with nitrogen for several minutes. The reaction mixture was heated at 100° C. for 2.5 h and allowed to cool to room temperature. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL). The organic extract was washed with water (5 mL) and dried over Na2SO4. The solution was filtered and concentrated and then absorbed onto a plug of silica gel and purified by column chromatography (40 g of silica gel, 10 to 30% EtOAc in hexanes) to provide 1,1,1,3,3,3-hexafluoro-2-(4-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)-2-propanol (1.94 g) as white solid
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:13](=[O:15])(=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C@@:24]12([CH2:34][S:35]([OH:38])(=[O:37])=[O:36])[C:31]([CH3:33])([CH3:32])[CH:28]([CH2:29][CH2:30]1)[CH2:27][C:25]2=[O:26]>C(O)C>[Br:1][C:2]1[S:6][C:5]([C@:7]2([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:13](=[O:15])(=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C@@:24]12([CH2:34][S:35]([O-:38])(=[O:36])=[O:37])[C:31]([CH3:33])([CH3:32])[CH:28]([CH2:29][CH2:30]1)[CH2:27][C:25]2=[O:26]
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(Br)s2)CCNCCS1(=O)=O
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@]1(c2ccc(Br)s2)CCNCCS1(=O)=O
Product: CC1(C)C2CC[C@]1(CS(=O)(=O)[O-])C(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a solution of tert-butyl 2-[7-(5-bromo-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate (3.03 g) in ethanol (90 ml) was added (1R)-10-camphorsulfonic acid (912 mg) at 80° C. The clear solution was allowed to cool to room temperature with stirring for 2 hours to form crystalline solids. After being cooled on an ice bath for 30 minutes, the solids were collected and washed with ethanol to give tert-butyl 2-[(S)-7-(5-bromo-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate•(1R)-10-camphorsulfonate (1.79 g, 91.6% ee) as a white solid.
Reaction SMILES: [CH2:1]1[CH:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[CH:4][CH2:3][O:2]1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[O:19]1[C:5]23[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1][O:2][CH2:3][CH:4]13
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=C2CCCCC2COC1
Solvent: ClCCl
Product: C1CCC23OC2COCC3C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3,5,6,7,8,8a-hexahydro-1H-isochromene (0.410 g, 2.97 mmol) in CH2Cl2 (10 mL) at 0° C. was added MCPBA (˜77%, 1.24 g, 445 mmol). The mixture was stirred at rt for 3 hr. It was quenched with sated aq. sodium sulfite. The mixture was diluted with CH2Cl2 and sat'd. aq. NaHCO3 then extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound.
Reaction SMILES: C(S[C:4]1[C:5]([C:14]2[N:27]([CH3:28])[C:17]3=[N:18][CH:19]=[C:20]([S:22][C:23]([F:26])([F:25])[F:24])[CH:21]=[C:16]3[N:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)C.Cl[C:30]1C=CC=C(C(OO)=O)[CH:31]=1.C(=O)([O-])O.[Na+].[S:45]([O-:49])([O-])(=[O:47])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:30]([S:45]([C:4]1[C:5]([C:14]2[N:27]([CH3:28])[C:17]3=[N:18][CH:19]=[C:20]([S:22][C:23]([F:26])([F:24])[F:25])[CH:21]=[C:16]3[N:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:11])([F:13])[F:12])[CH:9]=1)(=[O:49])=[O:47])[CH3:31]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1cc(C(F)(F)F)cnc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(C(F)(F)F)cnc1-c1nc2cc(SC(F)(F)F)cnc2n1C

Procedure:
To a mixture of 2-(3-ethylsulfanyl-5-trifluoromethyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (299 mg) and chloroform (30 ml) was added m-chloroperbenzoic acid (purity: not less than 65%) (0.34 g) while ice-cooling, and the mixture was stirred while ice-cooling for 5 hours. To the reaction mixture were poured saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 2-(3-ethylsulfonyl-5-trifluoromethyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (0.24 g), which is hereinafter referred to as “the present compound 44”.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])(=[O:4])=[O:3].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH2:28])[N:21]=1>ClCCl>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:16]([NH:15][S:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:3])=[O:4])(=[O:13])=[O:14])=[O:17])[N:21]=1
Reactant: CS(=O)(=O)c1ccccc1CS(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cc2ccccc2S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.0 g of the product from Example 10 in 30 ml dry dichloromethane was added 1.2 g of 4,6-dimethoxy-2-aminopyrimidine and the yellow homogeneous solution was stirred at room temperature overnight. The desired product, which had precipitated, was collected by filtration, washed with 1-chlorobutane, and dried in vacuo. The yield of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-(methylsulfonyl)phenylmethanesulfonamide, m.p. 180°-182° C., was 2.4 g of white solid.
Reaction SMILES: C1(C)C(S([O-])(=O)=[O:8])=CC=CC=1.C1(C)C(S([O-])(=O)=O)=CC=CC=1.[CH2:23]([Sn+2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2]>CN(C)C=O.O>[CH2:23]([Sn:27](=[O:8])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn+2]CCCC
Reactant: Cc1ccccc1S(=O)(=O)[O-]
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC[Sn](=O)CCCC

Procedure:
Employing the same formulation as in Example 1, dibutyltin bis-toluenesulfonate (DBTTS) was evaluated, using a solution of this catalyst in dimethylformamide. A portion of this catalyst solution was diluted with 10% water and aged at room temperature for three weeks. From the results reported in Table 2, it is seen that no apparent change in activity occurred in the aged sample. Addition of water to a stannous octoate solution, on the other hand, produces an immediate precipitate of dibutyltin oxide which is relatively inactive as a co-catalyst for urethane production.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[CH3:17][C:18]1[S:22][C:21](/[CH:23]=[CH:24]/[C:25](Cl)=O)=[CH:20][CH:19]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53]>C(OCC)(=O)C>[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53].[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:25](/[CH:24]=[CH:23]/[C:21]3[S:22][C:18]([CH3:17])=[CH:19][CH:20]=3)=[N:16][C:5]=2[CH:4]=1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Reactant: Cc1ccc(/C=C/C(=O)Cl)s1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1ccc(C)s1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-(5-methyl-2-thienyl)acryloyl chloride (Sekiya, T.; Hiranuma, H.; Hata, S.; Mizogami, S.; Hanazuka, M.; Yamada, S. J. Med Chem., 1983, 26, 411) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from MeOH/n-hexane yielded the titled compound. MW: 437.48; mp: 190.0-191.0° C.; 1H-NMR (DMSO) δ: 8.67-8.63 (1H, m), 8.06 (1H, td, J=7.9, 1.9 Hz), 7.79 (1H, d, J=15.6 Hz), 7.59 (1H, d, J=7.9 Hz), 7.54-7.48 (1H, m), 7.22 (1H, d, J=8.7 Hz), 7.12-7.08 (2H, m), 6.77 (1H, dd, J=8.7, 2.5 Hz), 6.71-6.68 (1H, m), 6.66 (1H, d, J=15.6 Hz), 3.72 (3H, s), 2.33 (3H, s).