Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[K+].C([Li])(C)(C)C.[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>C1COCC1.CCCCC.C(OCC)(=O)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:22]3([OH:25])[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc3[nH]ccc3c2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 33.2 %

Procedure:
To a solution of 5-bromo-1H-indole (5.0 g, 25.5 mmol) in THF at −10° C. under argon, was added a solution of potassium hydride (1.13 g, 28.1 mmol) in THF (7 mL). The reaction mixture was then cooled to −78° C., and t-butyllithium (52.5 mL of a 1.7 M solution in pentane, 89.3 mmol) was added slowly, via syringe. The mixture was stirred for 15 minutes, and 1-methyl-4-piperidone (6.75 mL, 54.8 mmol) was quickly added. After the mixture was stirred at −78 ° C. for one hour, the solution was warmed to −20° C. and poured into a mixture of a buffer solution (20 mL, pH 7.0) and ethyl acetate (30 mL). The organic layer was washed with brine (30 mL) and dried (Na2SO4). The product was purified by column chromatography over silica gel using 5% 2M ammonia in methanol in dichloromethane as the eluent to provide the title compound (1.95 g, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:15].C([O-])(O)=[O:17].[Na+].[CH3:21][O:22][C:23]([C:25]1[C:33]2[N:32]=[C:31]([C:34](Cl)(Cl)Cl)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:24]>C1COCC1.O.C(Cl)Cl>[CH3:21][O:22][C:23]([C:25]1[C:33]2[N:32]=[C:31]([C:34](=[O:17])[NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)=[O:9])=[CH:4][C:3]=3[F:15])[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:24]
Reactant: COC(=O)c1cccc2[nH]c(C(Cl)(Cl)Cl)nc12
Reactant: O=C([O-])O
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1F
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc2[nH]c(C(=O)Nc3ccc(C(=O)N4CCCC4)cc3F)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
59.0 mg (0.28 mmol) (4-Amino-3-fluoro-phenyl)-pyrrolidin-1-yl-methanone was dissolved in 6 mL THF and 3 mL water. 238.0 mg (2.83 mmol) NaHCO3 were added. Finally 75.6 mg (0.26 mmol) 2-Trichloromethyl-1H-benzoimidazole-4-carboxylic acid methyl ester were added and the resulting mixture was stirred vigorously for 3 h at RT. The mixture was diluted with 25 mL CH2Cl2 and washed with a saturated NaHCO3-solution and with brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. After purification by preparative RP-HPLC (CH3CN/H2O gradient and 0.05% formic acid) pure 2-[2-Fluoro-4-(pyrrolidine-1-carbonyl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester was obtained in form of a colorless amorphous solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH:14]([N:27]1[CH2:30][CH:29](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH:14]([N:27]1[CH2:30][CH:29]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:28]1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h

Procedure:
To 17.90 g (111.80 mmol) of diethyl malonate dissolved in 250 ml of tetrahydrofuran was added 4.07 g (101.75 mmol) of 60% sodium hydride at room temperature, followed by 2 hours of stirring. Thereafter, thereto was added 20 g (50.82 mmol) of 1-benzhydryl-3-(p-toluenesulfonyloxy)azetidine which has been dissolved in 90 ml of tetrahydrofuran, followed by 1 week of heating under reflux. The reaction solution was mixed with 10% citric acid aqueous solution and then tetrahydrofuran was evaporated. The resulting residue was mixed with saturated sodium bicarbonate aqueous solution, extracted with chloroform (200 ml×3) and dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (230-400 mesh silica gel 450 ml, ethyl acetate:hexane 1:3) to yield quantitative amount of the title compound.
Reaction SMILES: C([O:3]/C=C\[Sn](CCCC)(CCCC)CCCC)C.C([Li])CCC.[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[C:30]1([C:36]2[CH:37]=[C:38]([CH:43]=[CH:44]C=2)C=CC=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[C:26]1([C:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:37]/[CH:38]=[CH:43]/[CH:44]=[O:3])[CH:25]=[CH:24][CH:29]=[CH:28][CH:27]=1
Reactant: O=CC=Cc1cccc(-c2ccccc2)c1
Reactant: CCCCCC
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C/C=C/C=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
To a -78° C. solution of (Z)-1-ethoxy-2-tri-n-butylstannylethylene (17.85 g, 49.3 mmol) in anhydrous THF (250 ml) was added a solution of n-butyllithium in hexane (23.8 ml, 2.5M, 59.5 mmol) dropwise via syringe. The resulting solution was stirred at -78° C. for 1 hour, then a solution of 3-phenylcinnamaldehyde (7.0 g, 33.6 mmol) in anhydrous THF (100 ml) was added via syringe. The resulting bright purple solution was stirred at -78° C. for 4 hours, then allowed to warm to room temperature. The mixture was quenched with saturated aqueous sodium bicarbonate (200 ml), allowed to stir 10 minutes and diluted with water (300 ml). The phases were separated and the aqueous phase was extracted with ether. The combined organic phases were dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 7.75 g of crude product. Purification by flash chromatography (1:3 ethyl acetate:hexane) gave 4.46 g (56.7% yield) of title product having properties identical to those of the preceding Preparation.
Reaction SMILES: C[N:2]([CH3:22])[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([F:20])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].NC(C(N)=O)[C:25]([NH2:27])=[O:26]>CC(O)=O>[NH2:27][C:25]([C:22]1[NH:2][CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([F:20])[CH:12]=1)=[O:26]
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc([N+](=O)[O-])c(F)c1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
A 50 mL round bottomed flask was charged with of ethyl 3-(dimethylamino)-2-(3-fluoro-4-nitrobenzoyl)acrylate (51.74 g, 166.75 mmol) and 2-aminomalonamide (23.4 mg, 200 mmol) and AcOH (1 L). The reaction mixture was heated to 80° C. over night. The starting material appeared consumed by TLC. The AcOH was removed under reduced pressure and TFA (300 mL) was added. The mixture was heated over night at 60° C. The reaction was cooled to room temperature and the TEA was removed under reduced pressure. The orange oil was treated with saturated aqueous NaHCO3 (1 L), then solid NaHCO3 was added until the solution was neutral. The solids were filtered and placed in a 1 L erlenmeyer flask. The solids were washed with H2O (3×1 L) and the water was decanted off through the filter. On the last washing the solids were poured onto the filter and allowed to air dry. The solids were once again removed from the filter and washed with Et2O (4×500 mL). The Et2O was decanted off through the filter and on the final washing the solids were transferred to the filter. An addition portion of Et2O (200 mL) was used to wash the flask and the filter cake. The desired product was dried in a vacuum oven at 40° C. to provide a light tan solid (36.8 g, 114.5 mmol, 69% yield). 1H-NMR (DMSO-d6) δ 12.28 (br s, 1H), 8.07 (app t, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.46 (dd, J=12.6, 1.6 Hz, 1H), 7.28 (dd, J=8.4, 1.6 Hz, 1H), 7.25 (br s, 1H), 6.72 (br s, 1H), 4.01 (q, J=7.2 Hz, 2H), 1.07 (t, J=7.2 Hz, 3H); LCMS* RT=4.45 min; MS {M−H]+=320.1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([NH2:13])=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].C([O-])([O-])OC.C([O-])(=O)C.[NH4+:24].[CH3:25]O>>[N+:1]([C:4]1[CH:12]=[C:8]2[C:7](=[CH:6][C:5]=1[OH:14])[N:13]=[CH:25][NH:24][C:9]2=[O:11])([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: Nc1cc(O)c([N+](=O)[O-])cc1C(=O)O
Reactant: CO
Agent: CC(=O)[O-]
Agent: COC([O-])[O-]
Product: O=c1[nH]cnc2cc(O)c([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
In a 10-mL volume stainless steel pressure-resistant vessel were placed 0.50 g (7.5 mmol) of 5-nitro-4-hydroxyanthranilic acid, 0.80 g (7.5 mmol) of methyl orthoformate, 0.58 g (7.5 mmol) of ammonium acetate, and 5.0 mL of methanol. The reaction was carried out at 120° C. for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and methanol was distilled off under reduced pressure. Then, 5 mL of water was added to the reaction mixture. The precipitated crystalline product was collected by filtration and dried under reduced pressure to give 0.29 g (isolated yield: 55%) of 6-nitro-7-hydroxyquinazolin-4-one as a yellow crystalline product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: Cc1ccccc1-c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(CN2CCNCC2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.5 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[6-methyl-5-(2-methylphenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate (1.00 g, 2.62 mmol, 1.00 equiv), dichloromethane (20 mL). Trifluoroacetic acid (2.5 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 0.800 g (crude) of 1-[[6-methyl-5-(2-methylphenyl)pyridin-2-yl]methyl]piperazine as a yellow solid. LCMS (ESI, m/z): 282 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:17]3[S:18][C:19]([C:23]([O-:25])=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1.O1CCCC1.CO.[OH-].[Na+].Cl>O>[N:1]1([C:6]2[CH:7]=[C:8]([C:17]3[S:18][C:19]([C:23]([OH:25])=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1nc(-c2ccc(OCC(C)C)c(-n3ccnc3)c2)sc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(OCC(C)C)c(-n3ccnc3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A reaction mixture solution prepared by dissolving the crude product of 2-[3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate obtained above in 1 mL of a mixed solution of tetrahydrofuran/methanol=1/1 followed by the addition of 0.2 mL of 2 M sodium hydroxide aqueous solution was stirred at room temperature for 4 hours. After the addition of 0.2 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using 4 mL of ethyl acetate. The organic phase was concentrated, followed by purifying by a conventional method to obtain 2.50 mg of 2-[3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[S:16]([C:19]1[CH:20]=[C:21]([C:25]2[C:34]([CH3:36])([CH3:35])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:37]([O:39][CH3:40])=[O:38])[CH:31]=3)[N:26]=2)[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17]>ClCCl>[CH3:35][C:34]1([CH3:36])[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:37]([O:39][CH3:40])=[O:38])[CH:31]=2)[N:26]=[C:25]1[C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([S:16]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:18])=[O:17])[CH:20]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N3CCCC3)c1)=N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a stirred solution of pyrrolidine (38 mg, 0.54 mmol) and N,N-diisopropylethylamine (116 mg, 0.90 mmol) in dichloromethane (4 mL) was added methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (175 mg, 0.45 mmol) portionwise. The resultant yellow solution was stirred for 3 h at room temperature. The mixture was purified on preparative Thin layer chromatography to afford 163 mg of methyl 3,3-dimethyl-2-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[N:6][C:5]=1Cl.[C:13]([Cu])#[N:14]>CN1C(=O)CCC1.O.Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[N:6][C:5]=1[C:13]#[N:14]
Reactant: N#C[Cu]
Reactant: COC(=O)c1c(C)ccnc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1c(C)ccnc1C#N
Temperature: 180 °C
Reaction time: 16 h

Procedure:
A suspension of 2-chloro-4-methyl-nicotinic acid methyl ester (2.64 g, 14.3 mmol) and CuCN (6.4 g, 71 mmol) in NMP (5.3 mL) was heated to 180° C. for 30 min. The reaction mixture was then cooled to room temperature and diluted with water (80 mL). After vigorous stirring for 16 h, the suspension was centrifuged and the precipitate suspended in a solution of FeCl3.6H2O (5.8 g, 21 mmol) in aqueous HCl (4 M, 80 mL). After vigorous stirring for 1 h, the suspension was extracted with DCM (3×70 mL). The organic layer was dried over Na2SO4/Na2CO3, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with EA/DCM 1:10) to give the title compound. MS (m/z): 177.0 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[O:24][C:23]([C:25]5([NH:33]C(=O)OC(C)(C)C)[CH2:30][O:29]C(C)(C)[O:27][CH2:26]5)=[CH:22][C:21]=4[CH:41]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OCCCC)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:33][C:25]([C:23]1[O:24][C:20]2[CH:19]=[CH:18][C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH3:11])=[C:2]([Br:1])[CH:3]=4)[O:16][N:15]=3)=[CH:41][C:21]=2[CH:22]=1)([CH2:26][OH:27])[CH2:30][OH:29]
Reactant: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Br
Agent: CCCCOC(=O)NC1(c2cc3cc(-c4noc(-c5ccc(OCCC)c(Cl)c5)n4)ccc3o2)COC(C)(C)OC1
Product: CCCOc1ccc(-c2nc(-c3ccc4oc(C(N)(CO)CO)cc4c3)no2)cc1Br
Yield: 10 %

Procedure:
When the product of Step C is substituted for tart-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 10% yield, as light yellow solid. 1H NMR (CD3OD) 8.32 (b, 2H); 8.1 (d, 1H, J=8.46 Hz); 8.00 (d, 1H, J=8.52 Hz); 7.59 (d, 1H, J=8.61 Hz); 7.18 (d, 1H, J=8.58 Hz); 6.91 (s, 1H); 4.1 (t, 2H, J=6.06 Hz); 3.91 (d, 2H, J=10.98 Hz); 3.03 (d, 2H, J=10.95 Hz); 3.32 (b, 2H); 1.9-1.8 (m, 2H); 1.1 (t, 3H, J=7.35 Hz).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[N:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[N:17]=1
Reactant: Clc1cccc(I)n1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1cccc(Cl)n1
Yield: 87 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloro-6-iodopyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 129 mg, 87%) which was obtained as a light yellow oil. MS: m/e=295.1/297.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([OH:15])[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].O[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([O:15][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[CH2:12][CH2:13][CH3:14])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCC[C@@H](O)c1ccc(CC(C)C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC[C@H](Oc1ccc(C(=O)OC)cc1)c1ccc(CC(C)C)cc1
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
To a solution of 1-(R)-(4-isobutylphenyl)butanol (1.13 g), methyl 4-hydroxybenzoate (917 mg) and triphenylphosphine (1.58 g) in toluene (40 ml) and tetrahydrofuran (10 ml) was added diethyl azodicarboxylate (0.95 ml) at -20° C. The mixture was stirred at -15°--20° C. for 1.5 hours and then added water (0.5 ml). The mixture was evaporated, dissolved in a mixture of n-hexane and ethyl acetate (4:1), filtered off and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and dichloromethane (1:1) to give methyl 4-[1-(S)-(4-isobutylphenyl)butoxy]benzoate as an oil (1.48 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(CO)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a cold (ice-water) solution of the title A compound, 3-benzyloxy-4-nitro-benzaldehyde (6.13 g, 23.8 mmol) in methanol (60 mL) is added in portions with stirring sodium borohydride (906 mg, 24 mmol) and the mixture is allowed to warm up to RT overnight. The mixture is evaporated to dryness at aspirator pressure and the residue is triturated with 2N aqueous HCl and extracted 3 times with EtOAc. The organic extracts are washed with brine, dried over anhydrous MgSO4, filtered and evaporated to give 3-benzyloxy-4-nitro-benzyl alcohol which solidifies on standing at RT under vacuum.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].[CH2:13](Cl)Cl.CO.[Si](C=[N+]=[N-])(C)(C)C>C(O)(=O)C>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3]
Reactant: ClCCl
Reactant: C#CCC1CCC(C(=O)O)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: C#CCC1CCC(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 88 (240 mg, 1.45 mmol) in 7:3 CH2Cl2:MeOH (10 mL) was added TMS Diazomethane (2.0 M in hexanes) (0.9 mL, 1.8 mmol) in 0.2 ml aliquots until the color remained yellow. The reaction was allowed to stir for an additional 0.25 hours at room temperature. After stirring, glacial acetic acid was added dropwise until the solution became colorless. The reaction was concentrated in vacuo to an oil which was purified by flash chromatography on silica gel using ether:petroleum ether (1:9) to yield 89 (210 mg, 80%) as a clear oil. 1H NMR (CDCl3) δ 3.60 (s, 3H), 2.25-2.13 (m, 1H), 2.08-1.94 (m, 3H), 1.95-1.90 (m, 2H), 1.49-1.31 (m, 3H), 1.10-0.93 (m, 2H); 13C NMR (CDCl3) δ 176.7, 83.3, 69.8, 51.9, 43.4, 36.7, 31.9, 29.2, 26.3; APCI m/z (rel intensity) 181 (MH+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=1.Cl.[CH2:25](O)[CH3:26]>>[C:11]([C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:16]3[CH:17]=[C:18]([C:19]([OH:21])=[O:20])[CH:22]=[CH:23][C:15]3=[N:1]2)=[CH:7][CH:8]=1)([O:13][CH2:25][CH3:26])=[O:12]
Reactant: CCO
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Product: CCOC(=O)c1ccc2c(=O)n3cc(C(=O)O)ccc3nc2c1

Procedure:
A mixture of 2.00g (11.1 mmol) of 2-aminoterephthalic acid, 1.73g (11.1 mmol) of 6-chloronicotinic acid, 2.5ml of conc. HCl and 25ml of ethanol was heated at reflux for 67 hours. The mixture was cooled and filtered to give 0.90g of solid, mp. 275°-324°. The crude material was recrystallized from 1-propanol and gave 0.40g of the mono-esterified product, mp. 283°-293° dec.
Reaction SMILES: [Br-].C([O:6][C:7]([CH2:9][N+:10]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[C@@H:12]([O:18][C:19](=[O:34])[C:20]([OH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:11]2)=[O:8])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([O-:39])=[O:38].[C:7]([CH2:9][N+:10]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[C@@H:12]([O:18][C:19](=[O:34])[C:20]([OH:33])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:11]2)([OH:8])=[O:6]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: O=C(O)C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-1-tert-Butoxycarbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide (Example 60) (0.14 g, 0.264 mmol) in chloroform (5 ml) is added trifluoroacetic acid (1 ml). The reaction mixture is left to stir at room temperature overnight. The solvent is removed in vacuo and purification of the residue by chromatography on C18 silica, eluting with water:acetonitrile affords the titled compound as a white solid.
Reaction SMILES: O1CCCC1.[C:6]1([Mg]Cl)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.[Cl-].[NH4+]>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1.CN1CCCC1=O>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: Cl[Mg]c1ccccc1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(-c2ccccc2)cc1

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 1.090 g (8 mmol) of zinc chloride and 4 ml of N-methylpyrrolidinone were weighed in the flask. The flask was purged with argon, followed by stirring. 3.4 ml (7.5 mmol) of 2.2M tetrahydrofuran solution of phenylmagnesium chloride was added dropwise at 25° C. over a period of 30 minutes, followed by stirring at 25° C. for 30 minutes. The reaction liquid previously obtained was added, followed by stirring at 25° C. for 30 minutes. Further, 0.688 g (5 mmol) of 4-chlorobenzonitrile was added, followed by stirring at 120° C. for 9 hours. After the completion of the reaction, 10 ml of toluene and 10 ml of saturated aqueous ammonium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.670 g of 4-cyanobiphenyl (yield: 75 mol % based on 4-chlorobenzonitrile). The identification of the product was made by mass spectroscopy.