Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[N:8]1([CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2/[CH:19]=[CH:18]/[C:17]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Brc1ccccc1COCCN1CCCC1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccccc1COCCN1CCCC1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
A mixture of 1-{2-[(2-bromobenzyl)oxy]ethyl}pyrrolidine (11.3 g, 39.7 mmol), ethyl acrylate (8.6 ml, 79.4 mmol), potassium carbonate (13.7 g, 99.3 mmol), tetra-n-butylammonium bromide (12.8 g, 39.7 mmol), tri-o-tolylphosphine (483 mg, 1.59 mmol) and palladium acetate (178 mg, 0.79 mmol) in toluene (40 ml) was stirred at room temperature. The resulting mixture was degassed under reduced pressure and replaced with nitrogen. The mixture was stirred at 100° C. under nitrogen atmosphere for 15 h. After cooling to room temperature, the catalyst was filtered through a pad of celite, and filter cake was washed with toluene then ethyl acetate. The filtrate was evaporated in vacuo and the residue was dissolved with ethyl acetate-hexane (1:1)(200 ml)-2N HCl aq. (50 ml). The aqueous layer was separated and the organic layer was extracted with 2N HCl aq. (40 ml). The combined aqueous layers were basified to pH 9-10 with 2N NaOH aq. at 0° C. and extracted with ethyl acetate-hexane (1:1)(×3). The combined solution was washed with water, brine and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to give crude product (dark orange oil), which was purified by column chromatography on NH2 silica gel (500 g) (hexane/ethyl acetate 5/1-3/1 as eluent) to afford the titled compound (8.27 g, 69.0%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(Cl)cc2)cc1
Yield: 68.2 %

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole from Example 1 (6.2 g, 15.4 mmol) and p-toluenesulfonic acid monohydrate (0.9 g, 4.7 mmol) in toluene (300 mL) was heated to reflux for 84 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentrating in vacuo, the crude mixture was purified by chromatography on silica gel using hexane/ethyl acetate (1/1) to give pure 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole (4.21 g, 71%) as a white solid: mp (DSC) 183° C. Anal. Calc'd. for C17H12N2SO2F3Cl: C, 50.94, H, 3.02, N, 6.99. Found: C, 50.64, H, 3.03, N, 6.85.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[O:9][CH3:10].[NH2:13][CH2:14][C@@H:15]1[C@@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:19][CH2:18][N:17]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:16]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:28]([N:17]1[CH2:18][CH2:19][C@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C@@H:15]([CH2:14][NH:13][C:8](=[O:11])[O:9][CH3:10])[CH2:16]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccccc1[C@H]1CCN(Cc2ccccc2)C[C@@H]1CN
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)NC[C@H]1CN(Cc2ccccc2)CC[C@@H]1c1ccccc1C
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
111 μL of triethylamine and 37 μL of methyl chlorocarbonate were added to chloroform (2 mL) solution of 93 mg of (3S*,4S*)-3-aminomethyl-1-benzyl-4-o-tolyl-piperidine obtained in Production Example 37, and stirred at room temperature for 50 minutes. Aqueous 1 M sodium hydroxide solution was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through preparative thin-layer chromatography (chloroform/methanol=20/1) to obtain 78 mg of the entitled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]=1.[Li]CCCC.[CH3:20][CH:21]([CH3:25])[C:22](Cl)=[O:23]>C1COCC1.CCCCCC>[CH3:14][O:13][CH2:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[C:22](=[O:23])[CH:21]([CH3:25])[CH3:20]
Reactant: CC(C)C(=O)Cl
Reactant: COCOc1cccc(OCOC)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1cccc(OCOC)c1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
1,3-bis{[(methyloxy)methyl]oxy}benzene (Intermediate 35, 2.2 g) was dissolved under nitrogen in THF (8.0 mL) and a solution of BuLi (8.32 mL of a 1.6 M solution in hexane, 13.3 mmol) was added. After stirring at room temperature for 1 hour, cooling down to −78° C., 2-methylpropanoyl chloride (4.65 ml, 44.4 mmol) was added and the reaction mixture was stirred at that temperature for 1 hour. After quenching with water, the reaction mixture was extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated. The residue obtained was then charged on a silica gel column (Biotage SP1 system) and eluted with Cyclohexane/EtOAc (from all 10/0 to 9/1, then 9/1, then from 9/1 to 8/2, then 8/2) to afford the title compound (825 mg).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C[O:6][C:7](=O)[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[N:10][C:9]=1[C:15]#[N:16].CC(C[AlH]CC(C)C)C>C1COCC1>[NH2:16][CH2:15][C:9]1[C:8]([CH2:7][OH:6])=[C:13]([CH3:14])[CH:12]=[CH:11][N:10]=1
Reactant: COC(=O)c1c(C)ccnc1C#N
Agent: CC(C)C[AlH]CC(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccnc(CN)c1CO
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
A solution of AlCl3 (0.15 g, 1.1 mmol) in anhydrous THF (1.1 mL) was added dropwise to a stirred solution of 2-cyano-4-methyl-nicotinic acid methyl ester (0.10 g, 0.57 mmol) at −35° C. DIBAL (1.5 M in toluene, 3.0 mL, 4.5 mmol) was then added at −95° C. The reaction mixture was allowed to warm to 4° C. over 5 h and was then quenched by the addition of water (0.20 mL) at −20° C. ACN (17 mL) and concentrated aqueous NH3 (1.4 mL) was added to the mixture. After vigorous stirring for 30 min, the suspension was centrifuged and the precipitate suspended in a solution of ACN (5 mL) and concentrated aqueous NH3 (0.5 mL). After vigorous stirring for 30 min the suspension was centrifuged. The combined supernatants were concentrated in vacuo to give the title compound. MS (m/z): 153.0 [M+H+].
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.OC1C=CC(C(OC)=O)=CC=1.[CH3:31][O:32][C:33]1[CH:34]=C(CCO)C=C[CH:38]=1>>[CH3:31][O:32][C:33]1[CH:38]=[C:1]([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH:3]=[CH:2][CH:34]=1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Reactant: COc1cccc(CCO)c1
Agent: COC(=O)c1ccc(O)cc1
Product: COc1cccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)c1
Yield: 92 %

Procedure:
The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (4.26 g, 28.0 mmol) and 2-(3-methoxyphenyl)ethanol (4.32 mL, 31.0 mmol) to give 8.54 g of the title compound (colorless crystal, yield: 92%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]([OH:35])[CH2:33][OH:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:36]([O:40][C:41]([NH:43][CH2:44][C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([O:34][CH2:33][CH:32]([C:29]1[CH:30]=[N:31][C:26]([C:24]2[NH:25][C:21]([CH:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[CH:12][CH:11]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:22][CH:23]=2)=[CH:27][CH:28]=1)[OH:35])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)cc1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)OCC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of 1-[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]ethane-1,2-diol (245 mg) in N,N-dimethylformamide (5 mL) were added N-(tert-butoxycarbonyl)glycine (86.0 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (80.0 mg) and N-methylmorpholine (162 μL) under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (110 mg, yield 34%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 654 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[CH:12]=2)[N:5]=1)([CH3:3])[CH3:2].Br[C:28]1[S:32][CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC1CCCO1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:16]=[C:15]([C:28]3[S:32][CH:31]=[N:30][CH:29]=3)[CH:14]=[C:13]([CH3:26])[CH:12]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Brc1cncs1
Reactant: Cc1cc(Nc2nccc(C(C)C)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC1CCCO1
Product: Cc1cc(Nc2nccc(C(C)C)n2)cc(-c2cncs2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
To a solution of 4-isopropyl-N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (500 mg, 1.42 mmol) in 2-methyl tetrahydrofuran (7.1 mL) were added 5-bromothiazole (318 mg, 1.84 mmol), PdCl2(dppf)-CH2Cl2 (58 mg, 0.07 mmol), and aqueous sodium carbonate (2 M, 1.42 mL). The reaction was sealed and purged with N2 for 5 minutes. The reaction was stirred at 80° C. for 16 h and cooled to room temperature. Water was added and extracted with EtOAc (3×). The combined organic layers were dried over magnesium sulfate, concentrated in vacuo, and purified by flash chromatography to give 4-isopropyl-N-(3-methyl-5-(thiazol-5-yl)phenyl)pyrimidin-2-amine (366 mg, 1.18 mmol, 83% yield) as an off-white solid. MS ESI: [M+H]+ m/z 311.1. 1H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.05 (s, 1H), 8.38 (d, J=4.7, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.51 (s, 1H), 7.11 (s, 1H), 6.77 (d, J=5.1, 1H), 2.87 (m, 1H), 2.30 (s, 3H), 1.25 (d, J=6.8, 6H).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15]>>[N+:8]([C:7]1[C:2]([O:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: OCC(CO)CO
Product: O=[N+]([O-])c1cccnc1OCC(CO)CO

Procedure:
Prepared analogously to example XII.1 using 2-fluoro-3-nitropyridine (142 mg) and 2-(hydroxymethyl)-1,3-propanediol (148 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[CH:25](OC)(OC)OC>O>[C:15]1([CH2:14][O:13][C:11]([N:8]2[CH2:7][CH2:6][CH:5]([N:4]3[C:3]4[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=4[N:1]=[CH:25]3)[CH2:10][CH2:9]2)=[O:12])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(OC)OC
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(n2cnc3ccccc32)CC1

Procedure:
A solution of 2-amino-1-N-[1-(phenylmethyloxycarbonyl)-piperidin-4-yl]aniline (Method C) (500 mg, 1.4 mmol), trimethyl orthoformate (1 ml, 9.7 mmol) and para-toluenesuphonic acid monohydrate (30 mg, 0.16 mmol) were stirred at 100° C. After 2 h the mixture was cooled and water (10 ml) was added. The solution was partitioned with EtOAc (3×20 ml) then the organics were combined, washed with water (10 ml), dried (MgSO4) and concentrated to give the title compound as an oil that did not need further purification (410 mg, 1.2 mmol); NMR: 2.0 (m, 4H), 3.0 (m, 2H), 4.2 (d, 2H), 4.6 (m, 1H), 5.1 (s, 2H), 7.2 (m, 2H), 7.4 (m, 5H), 7.65 (d, 2H) and 8.3 (s, 1H); MS: 336.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:30])=[C:19]([NH:23]C(=O)OCC=C)[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:30])=[C:19]([CH:20]=[CH:21][CH:22]=2)[NH2:23])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
In a round bottom flask 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (800 mg, 1.79 mmol) was dissolved in DCM (30 mL) and water (0.5 ml). Tri-n-butyltin hydride (0.480 mL, 1.79 mmol) was added followed by tetrakis(triphenylphosphine)palladium (0) (103 mg, 0.090 mmol). This mixture was stirred 3 h at rt. By TLC all starting material is consumed. The reaction was concentrated to dryness. The crude was then dissolved into a small amount of DCM and injected onto a 25 g silica gel column. The column was eluted with EtOAc and hexanes. The title compound was obtained (0.594 g, 1.47 mmol, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (d, J=5.3 Hz, 1H), 6.96-7.08 (m, 2H), 6.91 (t, J=8.2 Hz, 1H), 6.64 (t, J=6.7 Hz, 1H), 5.33 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]2=[O:21])#[N:2].[ClH:22]>CO.[Pd]>[ClH:22].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C:6]2=[O:21]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(C#N)cc2C1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(CN)cc2C1=O
Reaction time: 4 h
Yield: 163 %

Procedure:
A mixture of tert-butyl 2-(5-cyano-1,3-dioxoisoindolin-2-yl)acetate (0.440 g, 1.537 mmol), aqueous 1M HCl (0.768 ml, 0.768 mmol) and 10% w/w Pd/C (a catalytic amount) in MeOH (30 ml) was hydrogenated in a Parr apparatus at 40 psi for 4 hours. 37% HCl aqueous solution (0.0316 ml, 0.384 mmol) was added, and the mixture hydrogenated at 45 psi for additional 4 hours. The mixture was filtered, and the solution evaporated under vacuum. The crude was dissolved in MeOH (25 ml) and added to a suspension of new 10% w/w Pd/C (a catalytic amount) in MeOH (5 ml); 37% HCl (0.0316 ml, 0.384 mmol) was added at 0° C., and the mixture was hydrogenated at 45 psi 3 hours. The catalyst was filtered off, and the solution concentrated under vacuum. The crude was triturated with diethyl ether to afford tert-butyl 2-(5-(aminomethyl)-1,3-dioxoisoindolin-2-yl)acetate hydrochloride (0.409 g, 1.252 mmol, 81% yield, MS/ESI+ 291.1 [MH]+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:22]([O:25][CH2:26][C:27](Cl)=[O:28])(=[O:24])[CH3:23].O>C(Cl)Cl>[C:22]([O:25][CH2:26][C:27]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]=1[C:4]#[N:5])=[O:28])(=[O:24])[CH3:23]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#Cc1c(N)cccc1N1CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1cccc(N2CCCCC2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-piperidinobenzonitrile (8.8 g) in methylene chloride (100 ml) is added pyridine (3.3 ml), and thereto is added dropwise acetoxyacetyl chloride (4.3 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (3.2 g) having the following physical properties.
Reaction SMILES: [Cl-].[CH3:2][C:3]([CH3:17])=[CH:4][CH2:5][N+:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH:7]=1.C1(CCN2CCCC(C(C)=O)=C2)C=CC=CC=1>>[CH3:2][CH:3]([CH3:17])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C:8]([C:12]([CH2:13][CH2:14][CH3:15])=[O:16])=[CH:7]1
Reactant: CCCC(=O)c1ccc[n+](CC=C(C)C)c1
Agent: CC(=O)C1=CN(CCc2ccccc2)CCC1
Agent: [Cl-]
Product: CCCC(=O)C1=CN(CCC(C)C)CCC1

Procedure:
1-(3-Methyl-2-butenyl)-3-butyryl pyridinium chloride was hydrogenated according to the procedure described in Part (b) of Example 6 to give propyl 1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (14). The product was distilled as a pale yellow oil (b.pt. 126-129°C./0.02 mm Hg).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10]([CH3:27])=[C:11]([NH:15][C:16]([C:18]3[S:22][C:21]4[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=4[CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:5][C:4]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[CH:31][N:30]=1.Cl.ClCCl.O>O1CCOCC1>[CH3:27][C:10]1[C:9]([C:6]2[CH:5]=[C:4]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)=[CH:31][N:30]=3)[C:3](=[O:2])[NH:8][CH:7]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH:15][C:16]([C:18]1[S:22][C:21]2[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=2[CH:19]=1)=[O:17]
Reactant: COc1ncc(-c2cccc(NC(=O)c3cc4c(s3)CCCC4)c2C)cc1Nc1ccc(N2CCN(C)CC2)cn1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1c[nH]c(=O)c(Nc2ccc(N3CCN(C)CC3)cn2)c1
Temperature: 100 °C
Yield: 73.5 %

Procedure:
In a 25 mL, round-bottomed, single-necked flask equipped with a magnetic stirring bar and a condenser was placed N-(3-(6-methoxy-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)pyridine-3-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-carboxamide (18) (0.070 g, 0.13 mmol) and 3 N HCl (1 mL) in dioxane (3 mL). The reaction mixture was heated at 100° C. for 2 h. To this was added dichloromethane (10 mL) and H2O (10 mL), and the layers were separated. The aqueous phase was extracted with dichloromethane (3×5 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-33% MeOH in dichloromethane, to afford 0.053 g (80%) of N-(2-methyl-3-(5-(5-(4-methylpiperazin-1-yl)pyridine-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (19); Exact mass m/z 554.25; M=H m/z 555.20.
Reaction SMILES: C([C:4]1([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=O)C.[OH:20]O>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([CH2:12][CH2:11][C:4]1([C:5]([OH:10])=[O:20])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(=O)C1(CCC(=O)OC(C)(C)C)CCCCC1=O
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
To a solution of 2-acetyl-2-[2-(tert-butoxycarbonyl)ethyl]-cyclohexanone (see Preparations 1 and 2) (2.0 g, 7.45 mmol) and concentrated sulphuric acid (98% w/w, one drop) in toluene (6.0 ml) was added, dropwise, a 30% aqueous solution of hydrogen peroxide (1.05 ml, 9.31 mmol) at room temperature. The mixture was stirred for 68 hours at room temperature, treated with a further quantity of a 30% aqueous solution of hydrogen peroxide (0.4 ml, 3.72 mmol) and stirred for a further 16 hours at room temperature. The mixture was partitioned between toluene (25 ml) and 5% aqueous sodium sulphite solution and the layers separated. The toluene layer was washed with dilute aqueous ammonia solution (25 ml of 0.880 ammonia in 200 ml of distilled water, 4×25 ml). The combined aqueous extracts were washed with toluene (25 ml), acidified to pH 2-3 with 5.0N aqueous hydrochloric acid solution and extracted with toluene (3×25 ml). The combined toluene extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give an oil, (1.11 g, 61%). The crude product was crystallized from pentane (7.5 ml/g) to give the title compound as a colorless solid. Rf. 0.28 (silica, hexane/ethyl acetate 2:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=CC=2)[N:4]=1.[OH-].[Na+].[CH3:24]O>>[CH3:1][O:2][C:3]1[N:4]=[C:5]([S:13][C:14]2[CH:15]=[CH:20][C:19]([CH3:24])=[CH:18][CH:21]=2)[CH:6]=[CH:7][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CO
Reactant: COC(=O)c1ccc(SCc2ccc(C)cc2)nc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1nc(Sc2ccc(C)cc2)ccc1C(=O)O
Temperature: 25 °C

Procedure:
To a suspension of 9.25 g (31.96 mmol) of methyl 2-methoxy-6-(4-methyl benzylthio)pyridine-3-carboxylate in 80 mL of methanol was added 38.36 mL (38.36 mmol) of 1N-sodium hydroxide aqueous solution, and the mixture was refluxed for 1 hour. After the reaction mixture was cooled to the room temperature, the solvent was removed under reduced pressure and the residue was diluted with water. Then 2N-HCl was added to the solution and the resultant precipitate was collected to obtain 8.92 g (quantitative) of the title compound.