Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:27][CH2:26][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([OH:25])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:28][C@H:29]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:30]([F:33])([F:32])[F:31])[N:3]=1.Cl.Cl[CH2:49][CH2:50][N:51]([CH3:53])[CH3:52].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])=[O:24])[CH2:12]3)[CH2:26][CH2:27]2)[CH:5]=[C:4]([O:28][C@H:29]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:30]([F:32])([F:31])[F:33])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)n1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCCN(C)C)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 65 °C

Procedure:
To a solution of (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (1.6 g, 2.45 mmol) in DMF (24 mL) were added (2-chloro-ethyl)-dimethyl-amine hydrochloride (535 mg, 3.7 mmol) and K2CO3 (1.0 g, 7.4 mmol), and the reaction mixture was heated at 65° C. for 16 h. Then the reaction was cooled to RT, partitioned between EtOAc and water, and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification via prep-HPLC column chromatography (CH2Cl2/MeOH/NH4OH) provided (S)-2-tert-butyl 3-(2-(dimethylamino)ethyl) 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](/[CH:14]=[N:15]/[NH:16][C:17]3[N:22]=[CH:21][C:20]([C@@H:23]([N:28]4[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]4)[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][C:5]=1[F:41])[CH3:2].C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:22]4[CH:21]=[C:20]([C@@H:23]([N:28]5[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:29]5)[C:24]([F:27])([F:25])[F:26])[CH:19]=[CH:18][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][C:5]=1[F:41])[CH3:2]
Reactant: CCOc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F
Agent: O=Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To tert-butyl (S)-1-((R)-1-(6-((E)-2-((7-ethoxy-6-fluoro quinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (368 mg, 0.638 mmol) in DCM was added iodosobenzene acetate (267 mg, 0.830 mmol) and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl (S)-1-((R)-1-(3-(7-ethoxy-6-fluoroquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (265 mg, 72.3% yield) as a beige solid
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([CH:2]=[C:3]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]2=3)=[CH:22][CH:21]=1
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(C=C2c3ccccc3CCc3ccccc32)cc1

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and 4-(trifluoromethyl)phenyl boronic acid (0.33 g, 1.75 mmol using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product: MS (m/e): 350 (M+). HPLC (ISO80-10M)) t=17.32 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10]([O:13]C(=O)C)(=O)[CH3:11].[Br:17]Br.OO>C(O)(=O)C.O>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:6]([Br:17])=[C:4]([NH:5][C:10]([CH3:11])=[O:13])[CH:3]=1
Reactant: BrBr
Reactant: Cc1ccc(N)cc1C
Reactant: CC(=O)OC(C)=O
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C)c(C)cc1Br
Temperature: 120 °C
Reaction time: 2 h
Yield: 182.9 %

Procedure:
To a stirred solution of 50.0 g (0.41 mol) of 3,4-dimethylaniline in 250 mL of glacial acetic acid was added 46.0 g (0.45 mol) of acetic anhydride was added dropwise with ice-bath cooling. The reaction was heated for 15 minutes at 120° C., then cooled to 10° C. Bromine (32.8 g, 0.21 mol) was added dropwise over 25 minutes. The addition funnel was washed with a small amount of acetic acid, and 27.2 g (0.24 mol) of 30% hydrogen peroxide was added over 30 minutes. The reaction was stirred for 2 hours at 10°-15° C. and then poured into 1200 mL of cold water. The precipitated product was collected by filtration, washed with water, and dried under vacuum to give 93.0 g (94% yield) of crude 2-bromo-4,5-dimethylacetanilide which was used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([NH:17][C:18](=[O:20])[OH:19])([CH3:16])([CH3:15])[CH3:14].[CH:21]1([S:24]([NH2:27])(=[O:26])=[O:25])[CH2:23][CH2:22]1.C(I)C(C)C>C1COCC1>[CH2:14]([C:21]1([S:24]([NH2:27])(=[O:26])=[O:25])[CH2:23][CH2:22]1)[CH:13]([CH3:16])[CH3:15].[C:13]([NH:17][C:18](=[O:19])[O-:20])([CH3:16])([CH3:15])[CH3:14]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)NC(=O)O
Agent: CC(C)CI
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[O-]
Product: CC(C)CC1(S(N)(=O)=O)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
Step 31a) To a solution of N,N-diisopropylamine (1.1 ml, 9.54 mmol) dissolved in THF (10 mL) cooled to −78° C., was added n-BuLi (1.6 M in hexane, 5.9 mL, 9.54 mmol). The mixture was stirred for 1 h, and a THF (10 mL) solution of cyclopropylsulfonylamine tert-butyl carbamate (1.0 g, 4.52 mmol) was added dropwise, the generated solution was stirred for 1 h. To this solution was added neat iso-butyl iodide (0.57 mL, 5.0 mmol). The reaction mixture was allowed slowly to warm up overnite. The reaction mixture was poured into cold pH 4.0 buffer and the pH was adjusted to <4 and extracted with EtOAc (3×). The combined extracts were dried (MgSO4), concentrated. The residue was chromatographed over SiO2 eluting with EtOAC/Hexanes (0% to 50%) to afford the product in 69% yield (0.87 g) as a white solid: 1H NMR (CDCl3) □ ppm 0.92 (m, 2H), 0.95 (d, J=6.71 Hz, 6H), 1.49 (s, 9H), 1.69 (m, 2H), 1.71 (s, 2H), 1.95 (m, 1H), 6.80 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][C@@H:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>ClCCl>[CH:12]([C@@H:13]1[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][C@@H:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11]
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A cold (−76° C.), stirred solution of oxalyl chloride (0.8 mole) in dichloromethane (1.4 L) was treated with dimethyl sulfoxide (116 mL, 1.64 mole) over 40 minutes while keeping the internal temperature below −60° C. After stirring the solution for 45 minutes, a solution containing (−)-(4R*,5R*)-5-hydroxymethyl-1-methyl-4-phenylpyrrolidin-2-one (150 g, 0.73 mole) in dichloromethane (1L) was added over a 30 minute period (T<−60° C.) and stirring continued for 45 minutes. Hunig's base (diisopropylethylamine, 509 mL, 2.92 mole) was then added dropwise (T<−60° C.), the mixture was stirred for 45 minutes and then quenched with 1N hydrochloric acid solution (cold, 1.5L) while warming to 0° C. The layers were separated and the organic layer was washed twice with hydrochloric acid (700 mL of 2N, then 500 mL of 1N), dried over magnesium sulfate, filtered and concentrated in vacuo to give (−)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one as tan, crystalline solids, 137 g (93%). NMR (CDCl3) 67 2.81 (m, 2, CH2), 2.91 (s,3H, CH3) 4.02 (q, J=9 Hz, 1H, CH), 4.38 (dd, J=9.1, 1.9 Hz), 7.21-7.39 (m, 5H, Ar), 9.17 (d, J=1.9 Hz, 1H, CHO).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C@@H:5]([CH3:9])[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:18]=1[NH:17][C:6](=[O:8])[C@H:5]([CH3:9])[CH2:4][C:3]([O:2][CH3:1])=[O:10]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: COC(=O)C[C@@H](C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@@H](C)C(=O)Nc1cc(Cl)ccc1C(=O)OC
Temperature: 22 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
(R)-(+)-2-Methylsuccinic acid 4-methyl ester (1 g, 6.8 mmol) was dissolved in CH2Cl2 (40 mL). Oxalyl chloride [2M in CH2Cl2 (3.7 mL, 7.4 mmol)] was then added followed by a few drops of DMF (0.1 mL). The mixture was stirred at 22° C. for 3 h, after which it was concentrated under reduced pressure. The resulting residue was then suspended in CH2Cl2 (10 mL) and added slowly to a stirring solution of methyl 2-amino-4-chlorobenzoate (i-i) (1.26 g, 6.8 mmol) in triethylamine (3.76 mL, 27.2 mmol) in CH2Cl2 (40 mL). The reaction mixture was allowed to stir at 22° C. for 1 h. The mixture was then partitioned between CH2Cl2 (50 mL) and H2O (50 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The resulting orange residue was purified by column chromatography, eluting with 20% ethyl acetate in hexane to give ii-i as a clear oil (1.8 g, 85% yield): MS m/z═314 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]1[N:11]([CH3:30])[C:12](=[O:29])[C:13]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=1.N1C=CC=CC=1.[C:37]1([C:43](Cl)=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[C:43]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]1[N:11]([CH3:30])[C:12](=[O:29])[C:13]([O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=1)(=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1nc(C2Cc3ccccc3N2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1nc(C2Cc3ccccc3N2C(=O)c2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
THF was added to the crude product of Step 1, followed by pyridine (2 eq.) and PhCOCl (1 eq.). After being stirred at room temperature overnight, the reaction mixture was evaporated to give the crude title product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC#N.Cl[CH2:27][C:28]([N:30]1[CH2:33][CH:32]([O:34][CH3:35])[CH2:31]1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([CH2:27][C:28]([N:30]3[CH2:33][CH:32]([O:34][CH3:35])[CH2:31]3)=[O:29])[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC1CN(C(=O)CCl)C1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COC1CN(C(=O)CN2CCN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)CC2)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine and MeCN was added to 2-chloro-1-(3-methoxyazetidin-1-yl)ethanone (130 mg) and potassium carbonate (219 mg), followed by stirring at 80° C. for 3 hours. CHCl3 was added to the reaction mixture, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain 2-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}-1-(3-met hoxyazetidin-1-yl)ethanone (354 mg).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][C:3](=[O:13])[CH2:2]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[H-].[Na+]>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][CH2:2][C:3]1=[O:13]
Reactant: O=C1CNc2ccccc2C(=O)N1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CNc2ccccc2C(=O)N1CCCCBr
Yield: 64 %

Procedure:
A solution of 84.2 mg of 2,3,4,5-tetrahydro-1,4-benzodiazepine-3,5-dione dissolved in 10 ml of dimethylformamide was ice-cooled, and then 0.0874 ml (1.5 equivalents) of 1,4-dibromobutane and 23.0 mg (1.2 equivalents) of 60% sodium hydride were added, followed reaction treatment and purification were conducted in the desired compound (yield 64%)
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:56])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][C:30]3([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:58][OH:59].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CO>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:56])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][C:30]3([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=[N:58][OH:59])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=O)CC(C)(COc1ccc(CC3(CC(=O)OC(C)(C)C)SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=NO)CC(C)(COc1ccc(CC3(CC(=O)OC(C)(C)C)SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Reaction time: 120 h

Procedure:
A mixture of 350 mg of di-t-butyl α,α'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl -4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate (prepared as described in Example 50), 122 mg of hydroxylamine hydrochloride, 122 mg of pyridine and 4 ml of methanol was allowed to stand at 25°-+° C. for 5 days. Ethyl acetate and an aqueous solution of potassium carbonate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluted with a 20:1 by volume mixture of benzene and ethyl acetate) to obtain the title compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[C:5]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>>[CH2:1]([S:3]([C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([F:15])([F:16])[F:17])[N:7]=[C:6]([C:18]([F:21])([F:19])[F:20])[C:5]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:35])[CH3:2]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1SCC
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1S(=O)CC
Yield: 90.2 %

Procedure:
To a 0° C. solution of 4.8 g (0.012 mol) of product of Example 33 in 30 ml of CH2C2 was added 4.08 g (0.024 mol) of MCPBA. The reaction was monitored by TLC. The reaction mixture was filtered, washed with NaHCO3, dried (MgSO4) and concentrated in vacuo to give 4.56 g of solid which was purified by HPLC using 8% ehthyl acetate/cyclohexane to elute the first fraction (1.52 g) followed by 15% ethyl acetate cyclohexane to elute 1.46 g of the desired product. Recrystallization of the 1.46 g solid in hot hexane afforded 0.88 g (17.4%) of product as a white solid; mp 87°-88.5° C.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O=[C:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH:12]1[C:23](OCC)=[O:24].Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:13][C:12]=3[C:23](=[O:24])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: CCOC(=O)C1CC(c2ccccc2)CCC1=O
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: O=c1oc2cc(O)cc(O)c2c2c1CC(c1ccccc1)CC2

Procedure:
A solution of phloroglucinol (1.56 g) and ethyl 2-oxo-5-phenylcyclo-hexane-carboxylate (2.52 g) in ethanol (25 ml) was treated with dry HCl as described in example 1a. The precipitate was filtered and washed with water and ETOH. Yield 1.0 g (32%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[C:14]1([CH:20]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[C:21]([O:23][C@@H:24]2[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C.C(OCC)(=O)C>[Cl-:1].[C:8]1([C:6]2[O:5][N:4]=[C:3]([CH2:2][N+:26]34[CH2:27][CH2:28][CH:29]([CH2:30][CH2:31]3)[C@@H:24]([O:23][C:21](=[O:22])[CH:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])[CH2:25]4)[N:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: ClCc1noc(-c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccccc1NC(C(=O)O[C@H]1C[N+]2(Cc3noc(-c4ccccc4)n3)CCC1CC2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.3 %

Procedure:
3-(Chloromethyl)-5-phenyl-1,2,4-oxadiazole (I45) (79 mg, 0.40 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-phenyl-2-(o-tolylamino)acetate (I23) (129 mg, 0.37 mmol) in acetonitrile (1.2 ml) and ethyl acetate (2.4 ml). The yellow solution was stirred at room temperature for 48 hours. The solution was evaporated, and the residue was purified by flash chromatography (DCM/MeOH=9/1) to obtain (3R)-1-((5-phenyl-1,2,4-oxadiazol-3-yl)methyl)-3-(2-phenyl-2-(o-tolylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane chloride (39 mg, 19% yield, mixture of diastereomers).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH3:17]N.[Cl-].[Na+]>CO>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)NCCCCCC(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCCCNC(C)=O
Temperature: 25 °C

Procedure:
Methyl 6-acetamidohexanoate was prepared as a low-melting solid by sequential treatment of 6-acetamido hexanoic acid with thionyl chloride and methanol. Five grams of this compound, (27 mmol) was dissolved in an excess of 40% aqueous methylamine solution, and the resulting mixture was stirred for sixteen hours at room temperature. The reaction mixture was saturated with sodium chloride and extracted several times with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was removed in vauo to yield a crude residue. Recrystallization from THF yielded 4.5 grams (90%) of pure product, melting point 99°-100° C.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:10]=[C:11]([C:14]([OH:16])=O)[S:12][CH:13]=1)(=[O:7])[CH3:6].C(OC1C=C(C(Cl)=O)SC=1)(=O)C.[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([NH2:41])=[O:40])[C:34](=[O:42])[CH2:33]2>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([NH2:41])=[O:40])[C:34](=[O:42])[CH:33]2[C:14](=[O:16])[C:11]1[S:12][CH:13]=[C:9]([O:8][C:5](=[O:7])[CH3:6])[CH:10]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CC(=O)Oc1csc(C(=O)O)c1
Agent: CC(=O)Oc1csc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)Oc1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Yield: 81.5 %

Procedure:
The title compound was prepared according to the procedure of Example 32. The reaction of 15 ml of thionyl chloride with 3.58 g (19.23 mmoles) of 4-acetoxy-2-thiophenecarboxylic acid (prepared according to Bohlmann, F., et al., Chem. Ber. 106:497 (1973)) gave a yellow oil. A 3.32 g (16.22 mmoles) sample of 4-acetoxy-2-thiophenecarbonyl chloride was coupled to 2.85 g (13.52 mmoles) of 5-chloro-2-oxindole-1-carboxamide in the presence of 4.16 g (34.07 mmoles) 4-(N,N-dimethylamino)pyridine to give 5.40 g of crude yellow product. Purification by recrystallization gave 4.18 g (11.02 mmoles, 82%) of pure title compound as a yellow solid, m.p. 222-224° C. (acetic acid).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-])=O)=[C:6]([CH2:8][CH:9]([C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:10]#N)[CH:7]=1>C1COCC1.CO.[C].[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:19][CH2:10][CH:9]([C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH2:8]2
Reactant: Cc1ccc([N+](=O)[O-])c(CC(C#N)c2ccc(C)nc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c(c1)CC(c1ccc(C)nc1)CN2
Temperature: 40 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
A mixture of 3-(5-methyl-2-nitrophenyl)-2-(6-methylpyridin-3-yl)propanenitrile (0.3 g, 0.00106 mol), 10% palladium carbon (0.180 g) in THF (1 mL) and MeOH (6 mL) was stirred under atmospheric hydrogen pressure at 40° C. for 24 h. After completion of reaction (monitored by TLC), catalyst was removed by filtration through Celite, and the filtrate concentrated under reduced pressure. The product was purified by column chromatography (25% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to give the desired compound as a yellow colored solid (0.075 g, 30% yield).