Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]([OH:7])([CH2:5]Cl)[CH2:3][OH:4].[H-].[Na+].[CH3:10][O:11][C:12]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([O:22][CH3:23])=[C:16]([CH3:24])[C:13]=1[CH2:14][Li].COC1C(C)=C(C)C(OC)=C(C)C=1C>O1CCCC1.O>[CH3:1][C@:2]([OH:7])([CH2:5][CH2:21][C:18]1[C:19]([CH3:20])=[C:12]([O:11][CH3:10])[C:13]([CH3:14])=[C:16]([CH3:24])[C:17]=1[O:22][CH3:23])[CH2:3][OH:4]
Reactant: [Li]Cc1c(C)c(OC)c(C)c(C)c1OC
Reactant: C[C@@](O)(CO)CCl
Agent: COc1c(C)c(C)c(OC)c(C)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A solution of 9.78 g (80 mmol) of (2R)-2-methyl-3-chloropropane-1,2-diol in 100 ml of tetrahydrofuran was reacted with 4.3 g (180 mmol) of sodium hydride at room temperature by the portionwise addition while stirring for 1 hour. To the suspension obtained there was added dropwise, while stirring at room temperature, a solution of 88 mmol of 2,5-dimethoxy-3,4,6-trimethylbenzyl lithium (obtained by reacting 17.2 g (88 mmol) of 2,5-dimethoxy-1,3,4,6-tetramethylbenzene in 20 ml of n-pentane with 88 mmol of tert.butyl lithium at room temperature) and the mixture was subsequently stirred at room temperature for an additional 16 hours. The mixture was then treated with 50 ml of water while stirring, the volatile constituents were removed by distillation in a vacuum (~15 mbar) and the separated material was removed by filtration and washed with water. The filter residue was recrystallized from ether/hexane and there were obtained 23 g of (2S)-2-methyl-4-(2,5 -dimethoxy-3,4,6-trimethylphenyl)-1,2-butanediol in the form of white crystals with a melting point of 83°-85° C. and [α]D20 =+2.86° (c=1.5% in CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:10]([CH:9]=1)[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:17])#[N:8]
Reactant: N#CCc1ccc(O)cc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: N#CCc1ccc(O)c(C(=O)CCC(=O)O)c1

Procedure:
4-Hydroxybenzyl cyanide was reacted with succinic anhydride and aluminum chloride in a similar manner to that described in Example 11(i) to give 3-(5-cyanomethyl-2-hydroxybenzoyl)propionic acid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10][CH2:11][C@@:12]2([C:25]3[CH:30]=[CH:29][C:28]([O:31]COC)=[C:27]([F:35])[CH:26]=3)[CH2:14][C@H:13]2[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)=[O:16])=[CH:5][N:4]=1.[OH-].[Na+]>C1COCC1>[CH3:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10][CH2:11][C@@:12]2([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([F:35])[CH:26]=3)[CH2:14][C@H:13]2[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)=[O:16])=[CH:5][N:4]=1
Reactant: COCOc1ccc([C@]2(COc3cnc(C)nc3C)C[C@H]2C(=O)Nc2ccc(F)cn2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ncc(OC[C@@]2(c3ccc(O)c(F)c3)C[C@H]2C(=O)Nc2ccc(F)cn2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
5 N hydrochloric acid (15 ml) was added to a THF (15 ml) solution of the compound 321-9 (1.01 g), and the obtained mixture was stirred at room temperature for 2 hours. A 5 N sodium hydroxide aqueous solution was added to the reaction solution under cooling on ice for neutralization, and the mixture was then extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration, so as to obtain the title compound 321 (721 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>>[CH3:28][O:27][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:19]=1[CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:6]2[C:5]3[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=3)[N:8]([CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:7]=2)=[O:12])[CH2:14][CH2:15]1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN(C)C(=O)CCl
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)N(C)C)c3ccccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [CH2:1]([O:6][CH2:7][C:8]#[CH:9])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:10]([O:12]CC)C.C([Li])CCC.C=O>CCCCCC.O>[CH2:1]([O:6][CH2:7][C:8]#[C:9][CH2:10][OH:12])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C#CCOCCCCC
Reactant: CCOCC
Agent: C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CCCCCOCC#CCO
Temperature: -78 °C

Procedure:
To a 500 mL 3 neck flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 10 grams (g) of 3-(pentyloxy)prop-1-yne (0.72 mmol), and 140 mL of dry ethyl ether. The reaction mixture was cooled to −78° C. with stirring followed by the dropwise addition of 37.5 mls (60 mmole) of 1.6M n-Butyl lithium solution in hexane. The temperature was adjusted to 0° C. and 5.4 g (180 mmole) of solid paraformaldehyde was added. The mixture was then stirred at ambient temperature overnight. Ether and water was added to the mixture and the ether layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum on a rotary evaporator. Isolated 9.44 g of a colorless liquid which was consistent with the desired structure upon analysis by 300 MHz 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Br)=[CH:4][CH:3]=1.C([O:14][CH:15](OCC)[C:16]([NH2:18])=[S:17])C>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:18]=[C:16]([CH:15]=[O:14])[S:17][CH:7]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCOC(OCC)C(N)=S
Solvent: CCO
Product: O=Cc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g (23.04 mmol) of 4-fluorophenacyl bromide and 3.76 g (23.04 mmol) of 2,2-diethoxythioacetamide in 100 ml of ethanol were stirred at room temperature for 2 h. After concentration, the residue was treated with ethyl acetate and filtered. The filtrate was concentrated and the obtained residue, which consisted of the diethyl acetal of 4-(4-fluoro-phenyl)-thiazole-2-carbaldehyde, was treated with 100 ml of acetone/water and 1 ml of 2 N hydrochloric acid. After stirring at room temperature for 2 h, the reaction mixture was evaporated. Yield: 4.22 g.
Reaction SMILES: [Cl:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([Cl:23])=[C:17](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F-].[Na+].O>CN1CCCC1=O>[Cl:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([Cl:23])=[C:17]2[C:3]=1[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[CH:14]1[CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(Cl)c(F)c(F)c1Cl
Agent: [F-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)c(Cl)c2c1=O

Procedure:
19.1 g (0.05 mol) of ethyl 2-(2,5-dichloro-3,4,6-trifluorobenzoyl)-3-cyclopropylamino-acrylate are heated at 160°-170° C. together with 4.2 g (0.1 mol) of sodium fluoride in 100 ml of N-methyl-2-pyrrolidone for 5 hours. After cooling, the mixture is poured onto 200 ml of water. The solid which has precipitated is filtered off with suction, washed with water and dried at 80° C. in a drying cabinet.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].C(Cl)(Cl)Cl>C(O)C.N1C=CC=CC=1>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([Br:2])=[CH:4][CH:5]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2ccc(Br)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
p-Bromophenylhydrazine hydrochloride (10 mmol, 2.5 g) was added to 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) in ethanol (10 mL) and pyridine (10 mL). The mixture was stirred overnight at room temperature. Thin layer chromatographic (TLC) analysis using chloroform indicated the reaction was complete. The solvents were removed under vacuum. The residue was dissolved in 150 mL ether, then washed with 50 mL water to remove the pyridine. The ether, was dried over sodium sulfate (NaSO4), the solids filtered, then the solvents were removed under vacuum. The resulting oil was purified on a silica column. The named product crystallized upon standing in the column effluent, m.p. 71° C.-73° C. Analysis by 1H-NMR and 13C-NMR verified synthesis the named product.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])(=[S:56])C.C(N(C(C)C)CC)(C)C.N#N>O1CCOCC1>[SH:56][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: O=C1CCc2c(Br)cccc21
Reactant: CC([O-])=S
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2c(S)cccc21
Temperature: 120 °C
Yield: 54 %

Procedure:
4-Bromo-indanone (500 mg, 2.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (137 mg, 0.24 mmol), thioacetate (541 mg, 4.74 mmol) and diisopropylethylamine (1.64 mL, 5.69 mmol) are dissolved in 1,4-dioxane (2 mL). The mixture is degassed with N2 and tris(dibenzylideneacetone)palladium(0) (217 mg, 0.24 mmol) is added and heated under microwave irradiation at 120° C. for 2 hours. The solution is concentrated under vacuum. The crude product obtained is purified by flash chromatography (10-80% ethyl acetate in cyclohexane) to give the title compound (Yield: 210 mg). LC (METHOD 5): tR=0.89 min; Mass spectrum (ES−): m/z=163 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:7](=[O:14])[N:8]([CH2:9][C:10](OC)=[O:11])[C:4]=2[C:3]=1[N+:22]([O-])=O>CC(O)=O.O.[Fe]>[Cl:1][C:2]1[C:3]2[NH:22][C:10](=[O:11])[CH2:9][N:8]3[C:7](=[O:14])[N:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:5]([C:4]=23)=[CH:20][CH:21]=1
Reactant: COC(=O)Cn1c(=O)n(CC(=O)OC)c2c([N+](=O)[O-])c(Cl)ccc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cn1c(=O)n2c3c(c(Cl)ccc31)NC(=O)C2
Temperature: 70 °C

Procedure:
To a solution of dimethyl 2,2′-(5-chloro-4-nitro-2-oxo-1H-benzimidazole-1,3-diyl)diacetate (100 mg, 0.28 mmol) from Step D in AcOH (1.0 mL) and water (0.1 mL) was added fine granular iron (78 mg, 1.4 mmol) and the slurry was heated at 70° C. for 1 h. The reaction was cooled, filtered, concentrated and dissolved in DMF (4 mL). The DMF solution was added dropwise to H2O (30 mL) with stirring and the precipitate was isolated by filtration to give the title compound. MS: m/z=296 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH:29]=5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.C(O)(=O)C>[Pd].C(O)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(C3=CCN(C)CC3)cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(C3CCN(C)CC3)cc2c1=O
Yield: 49.1 %

Procedure:
N-Cyclopropyl-4-methyl-3-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (0.284 g) and 10% Palladium on carbon (0.028 g) were stirred in ethanol (6 ml) and acetic acid (0.5 ml) under an atmosphere of hydrogen for 24 hours. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate+1% aqueous ammonia solution to give the title compound (0.140 g) as a white foam solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 1.78 (m, 4H), 2.00 (m, 2H), 2.13 (s, 3H), 2.20 (s, 3H), 2.67 (m, 1H), 2.88 (m, 3H), 7.52 (d, 1H), 7.71 (d, 1H), 7.82 (m, 2H), 7.90 (d, 1H), 8.02 (s, 1H), 8.24 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 417.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CC#N>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: COc1ccc(C(=O)c2cc(Br)sc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc(Cc2cc(Br)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.4 %

Procedure:
To a solution of methanone 2 (2.68 g, 8.08 mmol) in CH2Cl2/CH3CN (20 mL/20 mL) were added triethylsilane (3.9 mL, 24.2 mmol) and boron trifluoride diethyl etherate (3.1 mL, 24.2 mmol) at 0° C. The mixture was warmed up to room temperature slowly and stirred at room temperature for 15 hours. To the mixture was added aq. saturated K2CO3 solution (50 mL) slowly and extracted with EtOAc (50 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the desired product 3 (2.09 g, 82%).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([C@@:6]1([CH2:26][CH3:27])[C@@H:15]2[N:10]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][CH:21]=4)[NH:16][C:14]=32)[CH2:9][CH2:8][CH2:7]1)[CH3:5].[OH-].[K+].C(O)C>>[CH2:26]([C@:6]1([CH:4]([CH3:5])[C:3]([OH:28])=[O:2])[C@@H:15]2[N:10]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][CH:21]=4)[NH:16][C:14]=32)[CH2:9][CH2:8][CH2:7]1)[CH3:27]
Reactant: CC[C@@]1(C(C)C(=O)OC)CCCN2CCc3c([nH]c4cc([N+](=O)[O-])ccc34)[C@@H]21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@]1(C(C)C(=O)O)CCCN2CCc3c([nH]c4cc([N+](=O)[O-])ccc34)[C@@H]21
Yield: 81 %

Procedure:
A solution containing 0.385 g (0.001 mole) of (-)-(1S,12bS)-1d-ethyl-10-nitro-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-1-yl-propionic acid methyl ester (prepared as described in Example 53) dissolved in the mixture of 0.169 g. (0.003 moles) of potassium hydroxide in 8 moles of 96% ethanol is refluxed for 20 minutes, then evaporated. The residue is dissolved in a little amount of water and acidified to pH 6 by adding acetic acid. The precipitate is filtered, washed with water and dried to give 0.300 g. (81% yield) of the title compound which can be used without purification for the preparation of the acid amide.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:13]1([S:19]([C:22]#[N:23])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(OCCCC)(OCCCC)OCCCC>>[C:13]1([S:19]([C:22]2[CH:1]=[C:2]([CH3:12])[CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:23]=2)(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: CC(C)=CC(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Product: Cc1cc(-c2ccccc2)nc(S(=O)(=O)c2ccccc2)c1
Temperature: 112 °C
Yield: 27.2 %

Procedure:
First, 0.96 g (6.00 mmol) of 3-methyl-1-phenyl-2-buten-1-one and 0.84 g (5.00 mmol) of benzenesulfonyl cyanide were introduced to a 3-necked flask (25 ml volume) equipped with a thermometer, a magnetic stirrer, a Dean-Stark water type distilling receiver and a condenser tube. Toluene (5 ml) as the solvent and butanol (0.5 ml) were added, and 0.12 g (0.50 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 8 hours while agitating at an internal temperature of 112° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was recrystallized with 5 ml of ethyl acetate to give 0.42 g of 2-benzenesulfonyl-4-methyl-6-phenylpyridine with the following properties as colorless crystals (purity of 99%, yield of 28% based on benzenesulfonyl cyanide).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[CH:16][CH:15]=1>>[C:2]1([N:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CNc1ccc(OC)cc1
Reactant: Clc1nccc2ccccc12
Product: COc1ccc(N(C)c2nccc3ccccc23)cc1
Temperature: 140 °C
Yield: 54.8 %

Procedure:
A mixture of 1-chloroisoquinoline (50 mg, 0.31 mmol) and (4-methoxy-phenyl)-methyl amine (300 mg, 2.2 mmol) was heated in a sealed tube at 140° C. overnight. The crude product was purified by chromatography (5-6% ethyl acetate/hexanes) on silica gel to give the title compound (46 mg, 0.17 mmol, 57%). 1H NMR (CDCl3): 8.22 (d, 1H, 5.7), 7.68 (d, 1H, J=8.1), 7.62 (d, 1H, J=8.7), 7.47 (ddd, 1H, J=0.9, 6.9, 8.1), 7.24 (d, 1H, J=6.0), 7.19 (ddd, 1H, J=1.5, 6.9, 8.7), 6.94 (m, 2H), 6.79 (m, 2H), 3.76 (s, 3H), 3.52 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[N:34]1([CH2:39][CH2:40]Cl)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:40][CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: ClCCN1CCCC1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCCN4CCCC4)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 2-(pyrrolidin-1-yl)ethyl chloride essentially as previously described. mp 143° C., NMR, IR, MS 555.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:4][N:3]=1.C[O-].[Na+].[CH3:16][O:17][CH2:18]Cl>CN(C)C=O>[CH3:16][O:17][CH2:18][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: Oc1cc(-c2ccccc2)on1
Reactant: COCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
3-Hydroxy-5-phenylisoxazole (8.05 g) was dissolved in dimethylformamide (80 ml), and sodium methoxide (28% methanol solution, 3.24 g) was added dropwise thereto, followed by stirring of the resulting mixture at room temperature for one hour. While the reaction mixture was cooled to 5° C., chloromethyl methyl ether (4.83 g) was added thereto, followed by stirring of the resulting mixture at the same temperature for one hour. The reaction mixture was poured into ice-cold water (200 ml) and extracted with ether (200 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (6.30 g, 61%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24].CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCC(=O)Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added butanoyl chloride (0.42 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (20 ml) and filtered to give 0.55 g (80%) of product as an off-white solid: mp 171–173° C.; 1H NMR (DMSO-d6) d 11.14 (s, 1H), 9.68 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 5.15 (dd, J=5.2 and 12.6 Hz, 1H), 2.96–2.84 (m, 1H), 2.65–2.42 (m, 4H), 2.11–2.06 (m, 1H), 1.73–1.58 (m, 2H), 0.95 (t, J=7.4 Hz, 3H); 13C NMR (DMSO-d6) d 172.70, 171.84, 169.72, 167.70, 166.63, 136.54, 136.07, 131.41, 126.17, 118.23, 116.89, 48.90, 30.91, 21.96, 18.25, 13.46; Anal. Calcd. For C17H17N3O5: C, 59.47; H, 4.99; N, 12.24. Found: C, 59.45; H, 4.82; N, 12.15.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[NH2:9][CH:10]=[C:11]([CH3:14])[CH:12]=O.C(N(CC)CC)C.C([O-])(=O)C.[NH4+]>CCOCC>[CH3:14][C:11]1[CH:10]=[N:9][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:12]=1
Reactant: CC(C=O)=CN
Reactant: O=C1CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cnc2c(c1)C(=O)CCC2
Reaction time: 12 h

Procedure:
A mixture of cyclohexane-1,3-dione (11.2 g. 0.1 m), 3-amino-2-methylacrolein (8.5 g. 0.1m) triethylamine (5 ml.) and ammonium acetate (100 mg) were heated with stirring at 120° in an oil bath for 12 hours. The cooled reaction mixture was diluted with ether (50 ml.) and the solution washed with 2N HCl (3 × 15 ml.) The combined washings were adjusted to pH 9.0 with sodium carbonate and extracted with ether (3 × 50 ml.) The combined extracts were dried, evaporated in vacuo and the residual oil distilled at 0.2 mm Hg to give the 3-methyl-7,8-dihydro-5(6H)-quinolone as a colorless crystalline solid b.p. 80° (7.5 g. 48%). A mixture of 3-methyl-7,8-dihydro-5(6H)-quinolone (20 g.), hydrazine hydrate (14 ml), diethylene glycol (150 ml.) and sodium hydroxide (14 g) was heated at reflux with stirring for 1 hour. The condenser was replaced by a Dean and Stark Water Separator and the heating continued for a further 3 hours. The cooled reaction mixture was diluted with water (200 ml.) and extracted with ether (3 × 150 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo and the residual oil distilled at 15 mm Hg to give the title compound as a colourless oil b.p.116° (17 g, 93%) G.L.C. (3% SE30, T=150°) RF =3.5 min.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH2:17]>C1COCC1>[C:1]([O:5][C:6](=[O:8])[NH:17][CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A solution of di-tert-butyldicarbonate (29.314 g, 134.27 mmol) in THF (250 ml) was cooled to 0° C. and methyl amine (71 ml, 2M in THF) was added through a funnel. After stirring at 0° C. for 2 hours, the reaction mixture was allowed to warm up to room temperature and the solvent was removed using a rotary evaporator. The resulting residue was purified by flash chromatography to give methylcarbamic acid tert-butyl ester as a pale oil (11.518g, 65%). 1H NMR (CDCl3, 300 MHz) δ: 2.73(d, 3H, J=4.93 Hz), 1.45(s, 9H).