Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:30])([CH3:29])[CH2:9]/[CH:10]=[CH:11]/[C@H:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[C@@H:13]2[CH2:18][CH2:19][S:20][C:21]2[S:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[CH3:38][CH3:39].[Cl-].[Na+]>CN(C)C=O>[CH:1]1([CH2:7][C:8]([OH:30])([CH3:29])[CH2:9]/[CH:10]=[CH:11]/[C@H:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[C@@H:13]2[CH2:18][CH2:19][S:20][C:21]2[S:22][CH:23]=[C:24]([C:26]([O:28][CH2:38][CH3:39])=[O:27])[N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)(C/C=C/[C@H]1CC[C@H](O)[C@@H]1CCSc1nc(C(=O)O)cs1)CC1CCCCC1
Reactant: CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(SCC[C@H]2[C@@H](O)CC[C@@H]2/C=C/CC(C)(O)CC2CCCCC2)n1
Temperature: 25 °C

Procedure:
To a solution of the compound 50 in N,N-dimethylformamide (10 mL) were added potassium carbonate (1.20 g) and ethane iodide (0.350 mL) at 0° C. and the solution was stirred at room temperature for 3 Hours. To the reaction solution was added an aqueous saturated sodium chloride solution and the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (1.03 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[N:6](S(C(C)C)(=O)=O)[C:5]2[CH:13]=[CH:14][C:15]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][C:4]=2[N:3]=1.O.[OH-].[Na+]>CC(C)=O>[CH:21]1[CH:20]=[CH:19][C:18]([C:17]([C:15]2[CH:14]=[CH:13][C:5]3[N:6]=[C:2]([NH2:1])[NH:3][C:4]=3[CH:16]=2)=[O:24])=[CH:23][CH:22]=1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2cc(C(=O)c3ccccc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 25 °C

Procedure:
A slurry of 50 g of 2-amino-1-isopropylsulfonyl-5-benzoylbenzimidazole was heated in 300 ml of acetone and 500 ml of water with 350 ml of 1N sodium hydroxide on a steam bath for two hours. The heating was continued to remove the acetone. Afterwards the solution was cooled to room temperature with stirring. When the cleavage was complete, the precipitate title compound was filtered and washed with water. m/e=237, 160, 105, 77.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[CH2:37][CH2:36][N:35]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH:8]=2)[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Product: Cc1ccc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC(C)C)n2)cc1
Yield: 97.7 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and 1-benzylpiperazine were reacted to yield the title compound as a pale yellow oil (yield: 97.7%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH3:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH3:19])[CH:11]=2)[CH2:29][CH2:28]1
Reactant: CCCc1cc(CCC=O)n(Cc2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(Cc2ccccc2)n1

Procedure:
86 mg (84.5%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-benzyl-3-propyl-1H-pyrazol-5-yl)propanal (62 mg, 0.242 mmol), 1-(2-fluorophenyl)piperazine (76 mL, 0.484 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH3:10])[CH3:9].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([OH:21])[CH:15]=1.O>CN(C)C=O.C(OC(=O)C)C>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([O:20][CH:8]([CH3:10])[CH3:9])[CH:19]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(O)cc(OC(C)C)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 30042.8 %

Procedure:
After adding 41.0 g (0.30 mmol) of potassium carbonate and 23.8 g (0.19 mmol) of 2-bromopropane to a solution of 25.0 g (0.15 mol) of 3,5-dihydroxybenzoic acid methyl ester in N,N-dimethylformamide (250 ml), the reaction mixture was stirred at 80° C. for 4 hours. Water was added to the reaction mixture, extraction was performed with acetic acid ethyl ester, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=5:1) to obtain 12.0 g of 5-hydroxy-3-isopropoxybenzoic acid methyl ester (yield: 38%) as a colorless oil.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1.[Fe]>[CH2:3]([O:10][C:11]1[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(OCc2ccccc2)nc1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
Ammonium chloride (325 mg, 6.0 mmol) in water (10 mL) was added to a solution of 2-benzyloxy-5-nitro-pyridine (350 mg, 1.5 mmol) in THF (15 mL) and the resulting mixture stirred at 75° C. for 30 minutes. Iron powder (340 mg, 6 mmol) was then added portion wise and the mixture stirred for 5 hours at 75° C. The reaction mixture was filtered over celite. The filtrate was basified with sodium bicarbonate solution and the product extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and concentrated to afford 320 mg (100%) of 6-benzyloxy-pyridin-3-ylamine.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=CC(OCC)=O)C=CC=CC=1.O1C=CC=C1C=O.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1/[CH:38]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41]>C1COCC1.C(O)C.[Pd]>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)/C=C/c1ccco1
Agent: [Pd]
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: O=Cc1ccco1
Product: CCOC(=O)CCc1ccco1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 2-triphenylphosphoranylideneacetate (34.84 g, 100 mmol, 1 eq) and furan-2-carbaldehyde (9609 mg, 100 mmol, 1 eq) in anhydrous THF (200 ml) was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure and the residue triturated with ether to produce a brown solution and a precipitate. The solid was filtered, washed and removed. The filtrate was then evaporated. The product was purified by column chromatography on silica eluting with 0-20% ethyl acetate in hexanes. The desired fractions were evaporated to yield a cis/trans mixture of ethyl (E)-3-(2-furyl)prop-2-enoate as a pale yellow oil (NMR suggested mainly trans product) (15.5 g, 93%). b) A cis/trans mixture of ethyl (E)-3-(2-furyl)prop-2-enoate (15.5 g, 93.27 mmol, 1 eq) was stirred in ethanol (120 ml) containing 10% palladium on charcoal (775 mg, 5% by w). The reaction mixture was stirred under hydrogen for 4 h. A further quantity of 10% Pd/C (775 mg, 5% by w) was added. The reaction was stirred under hydrogen for an additional 95 mins. The reaction was filtered and evaporated under reduced pressure. The crude product was purified by silica column chromatography eluting with 20% ethyl acetate in hexanes. The desired fractions were evaporated under reduced pressure and ethyl 3-(2-furyl)propanoate was obtained as a clear oil (3.69 g, 24% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=2)=[N:6][CH:7]=1.[F-].[Cs+].[O:46]1CCO[CH2:48][CH2:47]1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC>CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:20]2[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([C:4]3[CH:3]=[C:2]([C:47](=[O:46])[CH3:48])[CH:7]=[N:6][C:5]=3[NH:8][C:9]3[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=3)[N:19]=2)=[CH:28][CH:29]=1
Reactant: C1COCCO1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: [Pd+2]
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: CC(=O)[O-]
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 110 °C

Procedure:
A stirred mixture of 4-(5-chloro-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 313, Step 2; 0.6020 g, 1.000 mmol), X-Phos-Pd(OAc)2 re-milled mix (1:1, 0.070 g, 0.100 mmol), and cesium fluoride (0.129 mL, 3.50 mmol) in 1,4-dioxane (5.00 mL, 58.5 mmol) was treated with tributyl(1-ethoxyvinyl)stannane (0.507 mL, 1.500 mmol) under nitrogen. The mixture was sealed and heated at 110° C. for 16 h. The reaction mixture was then cooled to room temperature and passed through a short plug of Celite® (diatomaceous earth). The filter cake was washed with EtOAc (3×20 mL) and the combined filtrates were concentrated in vacuo. The residue was loaded onto a short column of silica gel, tin byproducts were eluted with DCM, and the desired product was then eluted with 5% MeOH/DCM to give a mixture of desired product and a small amount of dechlorinated product. Chromatographic purification of this mixture (silica gel, 0% to 30% EtOAc/hexanes) gave 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (0.482 g, 0.791 mmol, 79% yield) as a light yellow solid. m/z (ESI, positive ion) 610 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][NH:24][C:20]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:28][CH2:27]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: NCC1CC1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NCC2CC2)s1
Yield: 58 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (56 mg, 58%) which was obtained as a light yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=385.2 [M+H]+.
Reaction SMILES: [Cl:1]C1C(C#N)=NC(Cl)=C(Cl)C=1Cl.F[C:14]1[C:15]([C:23]#[N:24])=[N:16][C:17]([F:22])=[C:18]([F:21])[C:19]=1[F:20]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:14]1[C:15]([C:23]#[N:24])=[N:16][C:17]([F:22])=[C:18]([F:21])[C:19]=1[F:20]
Reactant: N#Cc1nc(F)c(F)c(F)c1F
Reactant: N#Cc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: ClCCl
Product: N#Cc1nc(F)c(F)c(F)c1Cl
Temperature: 160 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4,5,6-tetrachloropicolinonitrile (16.1 g, 66 millimoles (mmol)) and 3,4,5,6-tetrafluoropicolinonitrile (5.9 g, 33 mmol) were heated to 160° C. under nitrogen to form a solution. To this stirred solution was added tetrabutyl phosphonium chloride (Bu4PCl; 0.36 g, 1.2 mmol), and the solution was held at 160° C. for 1 h. An aliquot was dissolved in methylene chloride (CH2Cl2) and passed through a short pad of silica gel before GC analysis. The profile of halogenated picolinonitriles was: 11.2% Cl4-PN; 11.3% 4,6-F2—PN; 2.3% 5,6-F2—PN; 19% 3,6-F2—PN; 52.6% 6-F-PN and 3.6% 4-F-PN. About 80% of the mixture is useful in the halogen exchange reaction to produce 3-chloro-4,5,6-trifluoropicolinonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][N:6]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]/[CH:27]=[C:28]1/[C:29]2[CH:42]=[C:41]([C:43]([OH:46])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:30]=2[O:31][CH2:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]/1=2>C(#N)C.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([CH2:25][CH2:26][CH:27]=[C:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[N:38][C:33]=3[CH2:32][O:31][C:30]3[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]2=3)[CH2:8][CH2:7][N:6]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:4]
Reactant: COC(=O)C1CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(4-chloro-phenyl)-piperazine-2-carboxylic acid methyl ester (0.14 g, 0.53 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.083 g, 0.6 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 5 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography on silica using gradient elution from ethyl acetate (100%) to ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 1.05 (6H, s), 2.20-2.70 (8H, 2×m), 3.00 (1H, m), 3.10-3.40 (3H, 2×m), 3.55 (3H, s), 4.50 (1H, br, s), 5.30 (2H, br, s), 6.20 (1H, t), 6.70-6.90 (3H, 2×d), 7.10-7.35 (4H, m), 7.50 (2H, d), 8.50 (1H, dd). ESI-MS m/z: 548 (M+1), UV retention time: 1.62 min.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:9]2[C:14](=[O:15])[CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.C(OCC)C.[Pd]>[C:18]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH:9]2[C:14](=[O:15])[CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C2CCN(CC2)C1C=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: O=C1C2CCN(CC2)C1CC(c1ccccc1)c1ccccc1
Reaction time: 4 h

Procedure:
25.7 Parts of a mixture of the isomers (cis and trans) of 2-(2,2-diphenylethylidenyl)-1-azabicyclo[2.2.2]octan-3-one, and 2-(2,2-diphenylethenyl)-1-azabicyclo[2.2.2]octan-3-one is dissolved in 1000 parts by volume of ethanol. Then 5 parts of 5% palladium-on-carbon is added and the mixture is hydrogenated using a Parr low-pressure hydrogenator, at room temperature and a pressure of 60-30 psi for 4 hours. After the hydrogenation is completed the catalyst is removed by filtration. The solution is then stripped in vacuum to give a solid. The solid is dissolved in 500 parts by volume of hot ethyl ether. The solution is filtered and then concentrated on a steam bath to a volume of about 150 parts by volume. The concentrated solution is cooled in an ice-bath to afford a precipitate which is filtered off from the solvent, washed with cold ethyl ether and dried in vacuo to provide a white solid. This solid is recrystallized from ethyl ether to afford 2-(2,2-diphenylethyl)-1-azabicyclo[ 2.2.2]octan-3-one melting at 103°-107° C. This compound is represented by the following structural formula ##STR3##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCOCC.C1CCCCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12]
Reactant: COc1cccc2c1CCC2=O
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: CCOCC
Product: COc1cccc2c1CCC2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
To a solution of 9.38 g (0.057 mol) of 4-methoxy-1-indanone in 250 mL of ether cooled to 0° C. was added dropwise over 5 rain 33.72 mL (0.0607 mol) of 1.8 M phenyllithium in cyclohexane/ether and the mixture was stirred at room temperature for 1 h. An additional (10 mL) phenyllithium solution was added and stirred at room temperature for 1 h. To the reaction mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×100 mL), and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 14.3 g of crude 4-methoxy-1-phenyl-indan-1-ol which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:12][CH2:13][CH2:14][OH:15])[C:8]1=[O:24].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:12][CH2:13][CH2:14][O:15][S:33]([CH3:32])(=[O:35])=[O:34])[C:8]1=[O:24]
Reactant: COc1cc(CN2CCC(CCCO)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-hydroxypropyl)-2-oxopyrrolidine (2.6 mmol), and dichloromethane (15 mL). Cool to −5° C. using a salt-ice bath. Add dropwise, methanesulfonyl chloride (0.19 g, 1.62 mmol) at such a rate as to maintain the reaction temperature below 0° C. After 1 hour, the reaction mixture is extracted with 1 M hydrochloric acid solution and then a 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound: Rf=0.71 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:20](=[O:21])[CH:19]=[C:18]3[C:13]([N:14]=[C:15](Br)[CH:16]=[CH:17]3)=[CH:12]2)[CH:5]=1.[C:24]1([CH2:30][C:31]#[CH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:20](=[O:21])[CH:19]=[C:18]3[C:13]([N:14]=[C:15]([C:32]#[C:31][CH2:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=[CH:17]3)=[CH:12]2)[CH:5]=1
Reactant: COC(=O)c1cccc(Cn2cc3nc(Br)ccc3cc2=O)c1
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2cc3nc(C#CCc4ccccc4)ccc3cc2=O)c1

Procedure:
The coupling of 3-(7-bromo-3-oxo-2H-8-azaisoquinolin-2-ylmethyl)benzoic acid methyl ester (1.20 g, 3.22 mmol) with 3-phenyl-1-propyne (1.00 mL, 8.06 mmol) using triethylamine (0.92 mL, 6.60 mmol), CuI (0.044 g, 0.23 mmol), and Pd(Ph3P)4 (0.15 g, 0.13 mmol) in dimethylformamide is carried out as described in Example 1, Step (2). A portion of the resulting red oil is purified on the preparatory HPLC using 80:20 acetonitrile/water (0.1% TFA), evaporated to dryness, dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over MgSO4 and evaporated to dryness. Drying will afford the desired product.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH3:29])=[O:14])[CH:2]=[CH2:3].[H-].[Na+].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:21][CH:22]=2)[N:17]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:16]=1[CH3:29])=[O:14])[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCOc1cc(OC)ccc1C(=O)c1c(C)[nH]c2cc(OC(F)(F)F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(OC)ccc1C(=O)c1c(C)n(S(=O)(=O)c2ccc(C)cc2)c2cc(OC(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6 (8.0 g, 20 mmol) in DMF (200 mL) was added NaH (1.5 eq). Mixture stirred for 15 min before addition of TsCl (1.5 eq, 5.6 g). After 1 hour, the reaction mixture was poured into ice water and extracted with CH2Cl2. The organic layer was washed with NH4Cl (2×), NaHCO3 and brine, then dried with Na2SO4 and concentrated. Purification via flash chromatography eluding with 20% EtOAc/hexanes afforded the product as a viscous yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:15][C:16](=[O:26])[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N+:13]=[N-:14])=[CH:8][CH:7]=1.C([O:30][CH:31](OCC)[C:32]#[CH:33])C>O1CCOCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:15][C:16](=[O:26])[C:17]1[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=1[CH3:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:33]=[C:32]([CH:31]=[O:30])[N:14]=[N:13]2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccc(N=[N+]=[N-])cc1)NC(=O)c1c(C)cc(C)cc1C
Reactant: C#CC(OCC)OCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(Cc1ccc(-n2cc(C=O)nn2)cc1)NC(=O)c1c(C)cc(C)cc1C
Reaction time: 0.17 h

Procedure:
250 mg (0.68 mmol) of (13) and 684 μl (4.77 mmol) of 3,3-diethoxy-propyne were dissolved in 3 ml of dioxane. 500 μl of saturated Cu(AcO)2 solution in H2O were added and the solution was stirred for 10 min. After pouring in ethyl acetate the organic layer was washed with saturated NaHCO3, water, brine and dried over Na2SO4. The crude product was dissolved in 500 μl THF with 10% of HCl and stirred for 1 h. The solution was poured in 20 ml of saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over Na2SO4. The solvent was removed at the evaporator. The product was used in the next step without further purification.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Br)cc1)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 68B and 2-(4-bromophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.56 (d, J=8.1, 1H), 8.38 (dd, J=8.0, 0.9, 1H), 8.14-8.08 (m, 1H), 8.01 (ddd, J=7.3, 4.4, 1.2, 3H), 7.80 (ddd, J=7.0, 4.0, 1.2, 1H), 7.68 (dd, J=10.6, 5.0, 2H), 7.58-7.51 (m, 2H), 7.25 (d, J=8.4, 2H), 3.66 (s, 2H); MS (ESI+) M/Z 498 (M+H)+, 515 (M+NH4)+, 556 (M+CH3CN+NH4)+.