Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[O:11][C:5]([CH3:12])([CH:6]([N+:8]([O-:10])=[O:9])[CH2:7]1)[CH:4]=[CH:3]2.[H][H]>C.[Pd].C(O)C>[CH3:12][C:5]12[O:11][C:2]([CH3:1])([CH2:3][CH2:4]1)[CH2:7][CH:6]2[N+:8]([O-:10])=[O:9]
Reactant: CC12C=CC(C)(O1)C([N+](=O)[O-])C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC12CCC(C)(O1)C([N+](=O)[O-])C2
Yield: 86.2 %

Procedure:
5.5 g of 1,4-dimethyl-5-nitro-7-oxabicyclo[2.2.1]hept-2-ene was placed in a 1/2 liter Parr bomb with 50 ml of ethanol and 10% palladium on powdered charcoal catalyst. The bomb was charged with hydrogen gas under 50 lb pressure. After using 3 lb of hydrogen gas, the reaction mixture was removed from the bomb, filtered to remove the catalyst, and stripped. The residue taken up in ether, was washed with water, dried (MgSO4), filtered and stripped to yield 4.8 g of the desired product as a brownish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[I-].[K+].[OH:13][CH2:14][C:15]1[CH:27]=[C:26]2[N:17]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:13][CH2:14][C:15]1[CH:27]=[C:26]2[N:17]([C:18](=[O:28])[N:19]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[N:16]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(Cn2c(=O)n3nc(CO)cc3c3ccccc32)cc1

Procedure:
210 g of p-methoxybenzyl bromide and 40 g of potassium iodide are added to 114 g of 2-(hydroxymethyl)pyrazolo[1,5-c]-quinazolin-5(6H)-one and 276 g of potassium carbonate in 2 1. of methanol. After refluxing for 5 hours, the reaction is cooled, poured into 6 1. of water and the title compound is filtered off and dried.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:28]([O:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[O:33][CH2:34][CH2:35][NH2:36])[CH3:29]>O1CCCC1>[CH2:28]([O:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[O:33][CH2:34][CH2:35][NH:36][C:10](=[O:12])[CH2:9][CH2:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)[CH3:29]
Reactant: CCOc1ccccc1OCCN
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OCCNC(=O)CCC(=O)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 10.4 g of 3-(4-fluorobenzoyl)propionic acid and 6.0 g of triethylamine in 120 ml of tetrahydrofuran was added dropwise 6.0 g of ethyl chloroformate at a temperature below 0° C. After stirring was continued for half an hour, to the mixture was added a solution of 9.6 g of 2-(2-ethoxyphenoxy)ethylamine in 10 ml of tetrahydrofuran. Further stirring was continued at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was concentrated to a residue under reduced pressure. The residue was recrystallized from benzene-hexane to give N-[2-(2-ethoxyphenoxy)ethyl]-3-(4-fluorobenzoyl)-propionamide melting at 98° - 100° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[OH:19])=[O:8].[CH3:20]CCCCCC>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:7](=[O:8])[C:9]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=2)[O:19][CH:20]=1
Reactant: CCCCCCC
Reactant: COc1cc(O)c(C(=O)CCCCCBr)cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2occ(CCCCBr)c(=O)c2cc1OC
Reaction time: 5 h
Yield: 53 %

Procedure:
2nd method: A solution of 500 mg (1.5 mmol) of the compound of the above Step, 6-bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)-hexan-1-one, in 30 ml of dry toluene is refluxed, with stirring, with 0.6 ml (4.5 mmol) of DMF dimethylacetal. Reflux is continued for 5 h. After concentration, and purification by flash chromatography with a gradient of pure heptane to heptane-ACOEt 80-20, 270 mg (yield=53%) of 3-(4-bromobutyl)-6,7-dimethoxychromen-4-one are obtained, after evaporation, in the form of white crystals identical to those obtained by the 1st method. TLC SiO2 hept-AcOEt 70-30 Rf=0.3. 1H NMR (DMSO): 8.19 (s, 1H), 7.36 (s, 1H), 7.16 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.65 (t, 2H, J=6.3 Hz), 2.38 (t, 2H, J=7.3 Hz), 1.72 (m, 2H), 1.64 (m, 2H), 1.55 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].[B].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2>>[CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C@H:4]1[OH:9]
Reactant: COC1(OC)CCOCC1=O
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: [B]
Product: COC1(OC)CCOC[C@H]1O

Procedure:
reacting 4,4-dimethoxydihydro-2H-pyran-3(4H)-one with a boron reducing agent and S-(−)-2-methyl-CBS-oxazaborolidine, over a period of at least six hours to provide the (R)-4,4-dimethoxytetrahydro-2H-pyran-3-ol in at least 60% enantiomeric excess.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[Li]CCCC.[CH3:17][O:18]C=O>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH:17]=[O:18]
Reactant: FC(F)(F)c1cccc(Cl)c1
Reactant: COC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-3-trifluoromethylbenzene (1.0 g, 5.54 mmol) in THF (15 mL) cooled to −78° C., under N2 protection was added dropwise n-BuLi (3.81 mL of a 1.6 M solution in hexane, 6.1 mmol). After an hour, formic acid methyl ester (664.8 mg, 11.08 mmol) was added slowly to the solution. After the addition, the solution was warmed to ambient temperature slowly and stirred for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (15:1) as eluent to give 2-chloro-6-trifluoromethylbenzaldehyde as a colorless oil.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:5][O:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][O:12][CH3:13])[CH2:1][C:2]#[CH:3]
Reactant: C#CCBr
Reactant: COCCNCCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN(CCOC)CCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Propargyl bromide (17.8 g, 150 mmol) was added dropwise to a mixture of bis(2-methoxy-ethyl)amine (20 g, 150 mmol) and cesium carbonate (49 g, 150 mmol) in 350 mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered off, and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were then evaporated to give 20 g of bis-(2-methoxy-ethyl)-prop-2-ynyl-amine: mass spectrum (m/e): M+H 172.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:10][CH2:11]2)(=[O:21])=[O:22])=[CH:24][CH:25]=1)[C:31]#[C:32][CH3:33]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(F)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester (9.5 g, 20 mmol) dissolved in THF:methanol 3:1 (100 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 5.7 g (63%); white solid; mp 106-106° C.; MS: 447 (M+H)+
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][S:8]([CH3:11])(=[O:10])=[O:9].[NH2:12][C:13]([CH3:30])([CH3:29])[CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](OC)=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.C(O)(C(F)(F)F)=O>CS(C)=O>[NH2:12][C:13]([CH3:30])([CH3:29])[CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](=[O:26])[CH2:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1
Reactant: COC(=O)c1ccc2c(ccn2CCC(C)(C)N)c1
Reactant: CS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)(N)CCn1ccc2cc(C(=O)CS(C)(=O)=O)ccc21
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Potassium tert. butoxide (741 mg, 6.62 mmol) is added in two batches to a solution of dimethylsulphone (661 mg, 7.03 mmol) in 5 ml DMSO. After 10 minutes stirring at RT a solution of methyl 1-(3-amino-3-methyl-butyl)-indole-5-carboxylate (Component IV) (520 mg, 2.00 mmol) in 2 ml DMSO is added dropwise over 10 minutes. The reaction mixture is stirred for 16 hours at 70° C., acidified with TFA while cooling with ice and chromatographed on Microsorb C18-reverse-phase [acetonitrile (0.1% TFA)/water (0.13% TFA)=10:90→100:0]. Then the residue is chromatographed again on silica gel (DCM/methanol/ammonia=90:9:1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.CN(C)[CH:18]=[O:19].Cl>CCCCCC.C(OCC)C>[S:10]1[CH:11]=[C:7]([CH:18]=[O:19])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]1=2
Reactant: Brc1csc2ccccc12
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1csc2ccccc12
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17 ml of a 1.6M solution of n-butyl lithium in hexane and 100 ml of dry diethyl ether at -70° C. was added a solution of 5.3 g of 3-bromobenzo[b]thiophene in 65 ml of diethyl ether. After stirring for about 30 minutes, 2.2 ml of dry dimethylformamide in 2.5 ml of dry diethyl ether were added. The mixture was stirred for about 3.5 hours at -70° C., and then allowed to warm to -5° C. Approximately 100 ml of 1N hydrochloric acid were added and the reaction mixture was stirred at 0° C. for 15 minutes. The layers were separated and the aqueous layer was extracted with one liter of ether. The organic extracts were combined, dried over magnesium sulfate, and evaporated in vacuo. The resulting oil was held at 0° C. overnight at which time an orange solid had formed. Approximately 4.6 g of this solid was recovered and identified by proton NMR to be the desired subtitle carboxaldehyde intermediate. The carboxaldehyde intermediate was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([SH:52])[CH3:51].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:50]([S:52][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1)[CH3:51]
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)cc(SCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Temperature: 70 °C
Yield: 48 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.6 g), ethylmercaptan (0.08 ml) and potassium carbonate (0.25 g) in acetonitrile (10 ml) was heated at 70° C. for 2 hours with stirring. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (2 ml) was added to the solution, followed by stirring at room temperature for 21 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless powders (0.2 g, 48%).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[NH2:25][C:26]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3([OH:39])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)[CH2:28][CH2:27]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:25][C:26]2([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4([OH:39])[CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[CH2:27][CH2:28]2)=[CH:11][CH:10]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: NC1(Cc2ccc(C3(O)CC3)cc2)CC1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4ccc(C5(O)CC5)cc4)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 203 mg (1 mmol) 1-[4-(1-amino-cyclopropylmethyl)-phenyl]-cyclopropanol. Yield: 29 mg (6%, trifluoroacetate); mass spectroscopy: [M+H]+=411.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[C:51]([C:53]1([NH2:59])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)#[CH:52]>C(Cl)Cl>[C:51]([C:53]1([NH:59][C:18](=[O:19])[CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)#[CH:52]
Reactant: C#CC1(N)CCCCC1
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC1(NC(=O)C(CCN2CCN(c3ccccc3OC)CC2)c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylbutanoic acid (1.772 g, 5 mmole), triethylamine (1.518 g, 15 mmole), and N,N-bis(2-oxo-3-oxazolidinyl)phosphoramidic chloride (1.527 g, 6 mmole) was stirred in methylene chloride (80 mL) under exclusion of moisture at ambient temperature for 30 minutes, after which 1-ethynylcyclohexylamine (0.668 g, 6 mmole) was added at once at 0° C. The reaction mixture was stirred at room temperature overnight, washed with water (2×100 mL), dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. Chromatography on silica gel with methanol/chloroform as eluant, followed by trituration from diethyl ether/hexane gave 0.72 g of the title compound as the 0.12 methylene chloride solvate, m.p. 127°-9° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:16]([N-:19]C(C)C)(C)[CH3:17].[Li+].BrCC#N.Cl>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:17][C:16]#[N:19])[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: N#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC#N)CCC2(CC1)OCCO2
Temperature: -5 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (1.0 g) in THF (8 mL) was added dropwise over a period of 10 minutes to a solution of lithiumdiisopropylamide (2M in THF/heptane/ethyl benzene, 4.67 mL) in THF (12 mL) kept at −5° C. (ice/methanol bath). Stirring was continued for 1 hour at 0° C. The reaction mixture was re-cooled to −5° C. and a solution of bromoacetonitrile (0.65 mL, [CAS Reg. No. 590-17-0]) in THF (4 mL) was added dropwise over a period of 10 minutes. Stirring was then continued for 16 hours at RT. The reaction mixture was poured into ice/water and was acidified with 1M aqueous HCl solution (50 mL). The aqueous layer was extracted two times with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a brown liquid (528 mg, 45%). MS (ESI): 254.2 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[C:10](I)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:33]([Si:35]([C:40]#[C:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:34]>CN(C=O)C>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:40]([Si:35]([CH2:38][CH3:39])([CH2:33][CH3:34])[CH2:36][CH3:37])[O:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](C#Cc1ccccc1)(CC)CC
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1oc2c(c1-c1ccccc1)c(=O)ccn2Cc1ccccc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A 250-ml round bottom flask was charged with 1-benzyl-4-benzyloxy-3-iodo-2-pyridone (6.00 g, 14.40 mmol), dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (1.18 g, 1.44 mmol), DMF (60 mL), Hunig's base (3 mL, 17.30 mmol), triethylsilyl phenylacetylene (9.34 g, 43.10 mmol). The system was evacuated and purged with N2 three times, and the reaction was stirred at 110° C. for 12 hrs. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was purified by silica gel column chromatography, eluting with 50/50/1, EtOAc/Hexane/MeOH, to give 7-benzyl-3-phenyl-2-(triethylsily)furo[2,3-b]pyridine-4(7H)-one as a solid. MS (MH+) 416.0; Calculated 415 for C26H29NO2Si.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:29]12CC[CH:32]([CH2:33][CH2:34]1)[CH:31](O)[CH2:30]2.[H-].[Na+]>[Cl-].[Na+].O>[C:8]1([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH:27]2[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[O:25])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)N1CCc2ccccc2C1c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OC1CN2CCC1CC2)N1CCc2ccccc2C1c1ccccc1
Temperature: 140 °C
Reaction time: 48 h
Yield: 12.2 %

Procedure:
To a 30 ml toluene solution containing 0.70 g of ethyl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate and 0.41 g of 3-quinuclidinol, 0.03 g of sodium hydride (60%) was added. The resulting mixture was stirred at 140° C. for 2 days while removing the ethanol formed. The reaction mixture was cooled to room temperature, brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:1→chloroform:methanol:28% aqueous ammonia=10:1:0.1), thereby 0.11 g of 3-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate was obtained as yellow oil. The resulting oil was dissolved in 10 ml of ethanol, followed by the addition of 27 mg of oxalic acid. Then, the solvent was removed under reduced pressure. The resulting solid was recrystallized from isopropanol and isopropyl ether, thereby 0.08 g of 3-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate monooxalate was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=2)=[N:12]1)=[O:5])[CH3:2].[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]1[CH:30]=[CH:29][CH:28]=[C:9]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25](=[O:26])[NH:43][CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])=[CH:22][CH:23]=3)=[N:12]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CC(=O)O)cc3)ccc2=O)c1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CC(=O)NCCCCNC(=O)OC(C)(C)C)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
120 mg (0.295 mmol) of 4-[1-(3-ethoxycarbonylaminobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl]phenylacetic acid are suspended in 2 ml of DMF, and 68 μl (0.354 mmol) of N-tert-butyloxycarbonyl-1,4-diaminobutane, 66 μl (0.59 mmol) of 4-methylmorpholine, 41 mg (0.3 mmol) of 1-hydroxybenzotriazole and 114 (0.59 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 24 h and purified by means of preparative HPLC.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]C>>[CH2:30]([C:21]1[C:20]2[C:19]([F:22])=[CH:18][C:17]([F:23])=[CH:16][C:15]=2[N:14]=[C:13]2[C:24]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:27])[C:8]1[CH2:7][O:6][C:5](=[O:28])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:29])[C:26]=1[CH:25]=3)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Product: CCCCCCCCCCc1c2c(nc3cc(F)cc(F)c13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 100 is treated with undecanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[N:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C.O>[N+:15]([C:13]1[CH:12]=[CH:11][C:10]2[O:18][C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[N:8][C:9]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: Cc1ccsc1C=Nc1cc([N+](=O)[O-])ccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccsc1-c1nc2cc([N+](=O)[O-])ccc2o1
Yield: 41.5 %

Procedure:
2-[[(3-Methyl-2-thienyl)methylene]amino]-4-nitrophenol (13.1 g, 0.05 mole) is heated to reflux in 500 ml of glacial acetic acid and lead tetraacetate (22.2 g, 0.05 mole) is added to the hot mixture. After heating for 10 minutes, the mixture is diluted with 1 liter of water and the precipitated product collected. The crude material is dissolved in chloroform (350 ml) and treated with activiated charcoal. The chloroform is evaporated yielding 5.4 g of product, melting point 174°-176°C.