Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[F:54][C:55]1[CH:62]=[CH:61][C:58]([CH2:59][NH2:60])=[CH:57][CH:56]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([NH:60][CH2:59][C:58]3[CH:61]=[CH:62][C:55]([F:54])=[CH:56][CH:57]=3)=[O:21])=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.32 g, 1.00 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.20 g, 1.30 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.80 mmol) in N,N-dimethylformamide (20 mL) was added 1-hydroxybenzotriazole (0.16 g, 1.20 mmol). The resulting mixture was stirred at ambient temperature for 15 minutes and 4-fluorobenzylamine (0.17 mL, 1.45 mmol) was added. The reaction mixture was kept stirring for 27 hours at ambient temperature, then was diluted with ethyl acetate (300 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography to afford the title compound as a white powder in 58% yield (0.25 g): mp 147-148° C.: 1H NMR (300 MHz. DMSO-6) δ 7.35-7.20 (m, 7H), 7.02-6.96 (m, 2H), 6.00 (s, 1H), 4.55-4.44 (m, 4H), 4.04 (t, J=7.5 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.8, 162.4, 160.5, 157.3, 155.3, 153.2, 135.5, 133.8, 129.4, 128.9, 128.2, 117.0, 115.7, 47.9, 43.2, 42.0, 41.6, 17.1; MS (ES+) m/z 425.2 (M+1).
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[C:24]([C:27]1[S:31][C:30]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([O:44]C)=[O:43])=[CH:40][CH:39]=3)[C:33]2=[O:48])=[N:29][C:28]=1[CH3:49])(=[O:26])[CH3:25]>>[C:24]([C:27]1[S:31][C:30]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=3)[C:33]2=[O:48])=[N:29][C:28]=1[CH3:49])(=[O:26])[CH3:25]
Reactant: COC(=O)c1ccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)cc1
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: CC(=O)c1sc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)nc1C
Yield: 85 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with methyl 4-((3-(5-acetyl-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate, the title compound was obtained in 85% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.89 (br s, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.39 (d, J=7.5 Hz, 2H), 4.49 (s, 2H), 4.05-3.90 (m, 2H), 3.52-3.40 (m, 2H), 2.51 (s, 3H), 2.42 (s, 3H); MS (ES+) m/z 360.1 (M+1).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].CC1(C)[O:27][C:26](=O)[CH:25]=[C:24]([CH3:29])O1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:29])[NH:17][C:13]=2[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)[nH]c2n(C)c1=O
Temperature: 160 °C
Reaction time: 0.33 h

Procedure:
Alternatively, (R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione was prepared as follows: To a mixture of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (2.1 g, 7.41 mmol) in xylenes (70 ml) heated to 160° C. was added over 30 minutes a solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (2.0 ml, 15.3 mmol) in xylenes (30 ml). After stirring at 160° C. for 20 minutes, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate-toluene to afford(R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.37 g, 53% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.20 (d, 3H), 1.25-1.71 (m, 6H), 2.00 (s, 3H), 2.46 (s, 3H), 3.62 (s, 3H), 4.00 (t, 2H), 4.86 (sextet, 1H), 6.49 (s, 1H), 12.15 (s, 1H).13C NMR (75 MHz, CDCl3) δ 19.64, 20.96, 22.46, 25.02, 27.19, 29.15, 35.19, 40.67, 70.29, 94.48, 105.71, 150.09, 150.73, 164.92, 165.18, 167.82, 170.15.
Reaction SMILES: [CH2:1]([C:4]1O[C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>C(Cl)(Cl)Cl.C(O)CO.O>[CH2:15]([N:22]1[C:8](=[O:10])[C:7]2[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]1[CH2:1][CH2:2][CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CCCc1nc2ccccc2c(=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: OCCO
Solvent: O
Product: CCCc1nc2ccccc2c(=O)n1Cc1ccccc1

Procedure:
A solution of 2-propyl-4H-3,1-benzoxazin-4-one (1—1, 2.84 g, 15.0 mmol, 1 equiv.) and benzylamine(1.77 g, 16.5 mmol, 1.10 equiv.) in chloroform (10 mL) was heated at reflux for 4 hours. The reaction mixture was concentrated and the residue was heated in a mixture of NaOH (60 mg, 1.5 mmol, 0.1 equiv.) in ethylene glycol (10 mL) at 135° C. for 5 hours. The reaction mixture was cooled and diluted with water. The pH of the resulting mixture was adjusted to 7 by the addition of 6 N HCl. The insoluble solid was collected by filtration and recrystallized from acetone/water to give 3-benzyl-2-propylquinazolin-4(3H)-one (1–2) as cream-colored crystals. 1H NMR (500 MHz,CDCl3)δ8.31 (d, J=8 Hz, 1H), 7.74 (t, J=7 Hz, 1H),7.66 (d,J=8 Hz, 1H), 7.46 (t, J=8 Hz, 1H), 7.32 (m, 2H), 7.26 (m, 1H), 7.18 (d, J=7 Hz, 2H), 2.72 (t, J=7 Hz, 2H), 1.80 (m, 2H), 0.99 (t, J=7 Hz, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20](C(OCC)=O)[CH2:19][CH2:18]1.[OH-].[K+]>O.CC(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)N1CCC(Nc2nc3cccnc3n2Cc2ccco2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: c1coc(Cn2c(NC3CCNCC3)nc3cccnc32)c1
Yield: 85 %

Procedure:
A mixture of 50 parts of ethyl 4-[[3-(2-furanylmethyl)-3H-imidazo-[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate, 50 parts of potassium hydroxide, 400 parts of 2-propanol and 20 drops of water was stirred and refluxed for about 5 hours. The reaction mixture was evaporated and water was added to the residue. The product was extracted twice with 4-methyl-2-pentanone. The combined extracts were dried, filtered and evaporated. The solid residue was stirred in 1,1'-oxybisethane. The product was filtered off and dried, yielding 34 parts (85%) of 3-(2-furanylmethyl)-N-(4-piperidinyl)-3H-imidazo-[4,5-b]pyridin-2-amine; mp. 159.0° C. (81).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]1([CH3:30])[CH3:29].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]3([CH3:30])[CH3:29])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C(C)(C)C1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C(C)(C)C1
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 600 mg, 2.186 mmol), (R)-tert-butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate (549 mg, 2.404 mmol) and DIPEA (0.764 mL, 4.37 mmol) in DMA (3.0 mL) was heated at 90° C. for 3 h. The mixture was cooled and added to crushed ice, stirred for 30 min, then extracted with EtOAc (100 mL×3). The combined organic extracts were washed with brine, filtered and concentrated to afford brown oil, which was added to water and stirred for 2 h to afford a solid which was collected by vacuum filtration and dried to afford the title compound as a tan solid (546 mg, 1.17 mmol, 54%). HPLC (Method B) retention time=3.91 min. LCMS (m+1)=466/468(1:1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13]>>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCCCCl
Reactant: C1CCNC1
Product: N#CCCCCCN1CCCC1

Procedure:
Using pyrrolidine and 6-chloro-hexanenitrile as substrates. MS (ion spray) m/z 167 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[NH:10][N:11]=[CH:12][N:13]=2)[CH:3]=1.Cl[CH2:15][C:16](Cl)=[O:17].[OH-].[Na+].Cl>O1CCOCC1.N1C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:16](=[O:17])[CH2:15][N:10]3[C:9](=[N:13][CH:12]=[N:11]3)[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Br)cc1-c1ncn[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C1Cn2ncnc2-c2cc(Br)ccc2N1
Temperature: 11 °C
Reaction time: 1.25 h
Yield: 45.7 %

Procedure:
A solution of 4-bromo-2-(2H-[1,2,4]triazol-3-yl)-phenylamine (25.0 g, 105 mmol) in dioxane (870 mL) and pyridine (10.0 mL) was cooled to 12° C. A solution of chloroacetyl chloride (9.56 mL, 121 mmol) in diethylether (34.7 mL) was added dropwise over a period of 8 min. The mixture was stirred at 10-12° C. for 75 min and treated within 5 min with aq NaOH 2N (126 mL, 251 mmol). The mixture was stirred for 17.5 h at ambient temperature. The pH thereby dropped to about pH=9 and it was adjusted to pH=8 with 3N HCl (6 mL). After evaporation the residue was stirred at 15° C. for 30 min in water (650 mL) and ethyl acetate (22 mL). The crystals were filtered off, washed with cold water and dried in vacuo. Trituration in ethyl acetate (100 mL) afforded the title compound (13.4 g, 46%) as a light yellow solid. MS: m/e=279.0/281.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13](CC#N)=[CH:12][CH:11]=2)=[C:4]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:3]=1.[OH-:25].[Na+].[CH2:27]([OH:29])[CH3:28]>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:28][C:27]([OH:25])=[O:29])=[CH:12][CH:11]=2)=[C:4]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1
Temperature: 25 °C

Procedure:
The suspension of the wet product from step (iv) (5.90 g) in 10% aq.NaOH (34.2 g) and ethanol (24.9 g) was heated at 85° C. for 5 hours. The mixture was cooled to 25° C., and the pH of the solution was adjusted to pH 6.5 with 18% aq. acetic acid (31.1 g). The resulting precipitate was collected by filtration, washed with water (18.6 g) and acetonitrile (15.5 g) respectively, and dried to give the subtitle compound as a white solid, 4.43 g.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[C:20]([N:24]([CH3:33])[C:25](N1C=C[N+](C)=C1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:25](=[O:26])[N:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:33])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)C(C)(C)C
Agent: [I-]
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(C)(C)C

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(tert-Butyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to preparative HPLC (34%, white crystals). HPLC-MS m/z=369.1 (M+1), Rt: 5.17 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:9])[S:5][C:6]=1[CH:7]=[O:8].[OH:15]OS([O-])=O.[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:9])[S:5][C:6]=1[C:7]([OH:15])=[O:8]
Reactant: O=S([O-])OO
Reactant: CCOC(=O)c1c(C)sc(C=O)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)sc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 4-chloro-5-formyl-2-methylthiophene-3-carboxylate (F-4) (9.72 g, 41.77 mmol, 1.0 eq) in DMF (150 mL), Oxone (77.1 g, 125.3 mmol, 3.0 eq) is added in portions and the resulting mixture is stirred at RT overnight. The mixture is poured into H2O (800 mL) and stirred for 30 min. The precipitate is collected by filtration, rinsed with H2O (100 mL) and then slurried in H2O (80 mL) for 30 min. The solid is collected by filtration, rinsed with H2O (3×60 mL) and petroether (3×60 mL), and dried in vacuo to afford the product, 3-chloro-4-(ethoxycarbonyl)-5-methylthiophene-2-carboxylic acid (F-5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=[O:15].[H-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:15][C:14](=[O:16])[CH2:13][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:8]([CH2:26][C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[C:7]=2[CH3:12])=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)OCc1ccc(Cl)cc1)c(C)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-methoxy-2-methyl-3-indoleacetic acid (4 g, 18.3 mmol) in anhydrous DMF (20 mL) at 0°-5° C. was added NaH (1.6 g, 60% dispersion in oil, 40 mmol) and stirred at room temperature for 40 min., then cooled again to 0°-5° C., and treated with 4-chlorophenylmethyl chloride (5.9 g, 36.6 mmol) and let stand at room temperature overnight. Water (50 ml) was added and the mixture was extracted with ethylacetate (100 mL), washed with brine and dried (MgSO4), evaporated in vacuo, and purified by chromatography (silica gel, 10% ethylacetate in pentane) to yield 1-(4-chlorophenylmethyl)-5-methoxy-2-methyl-3-indoleacetic acid 4-chlorophenylmethyl ester.
Reaction SMILES: CS(OCCOC12[CH2:19][C:13]3([CH3:20])[CH2:14][C:15]([CH3:18])([CH2:17][C:11]([CH2:21][N:22]4[C:26]([CH3:27])=[C:25]([I:28])[CH:24]=[N:23]4)([CH2:12]3)[CH2:10]1)[CH2:16]2)(=O)=O.[CH3:29][OH:30]>CN>[CH3:18][C:15]12[CH2:16][C:29]3([O:30][CH2:11][CH2:21][NH:22][CH3:26])[CH2:19][C:13]([CH3:20])([CH2:12][C:11]([CH2:21][N:22]4[C:26]([CH3:27])=[C:25]([I:28])[CH:24]=[N:23]4)([CH2:10]3)[CH2:17]1)[CH2:14]2
Reactant: Cc1c(I)cnn1CC12CC3(C)CC(C)(C1)CC(OCCOS(C)(=O)=O)(C3)C2
Reactant: CO
Agent: CN
Product: CNCCOC12CC3(C)CC(C)(CC(Cn4ncc(I)c4C)(C3)C1)C2

Procedure:
A solution of 2-({3-[(4-iodo-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec-1-yl}oxy)ethyl methanesulfonate (2.5 g) in 2 M methylamine in methanol (15 mL) was heated to 100° C. for 20 minutes in a Biotage Initiator microwave reactor. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic layer was dried with sodium sulfate, filtered and concentrated to give the title compound which was used in the next reaction without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([NH:22][CH:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:19]=[C:18]([N:30]([CH3:37])[CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:17]=2)=[CH:11][C:10]=1Cl)C1C=CC=CC=1.C([O-])=O.[NH4+].C(Cl)Cl>O.CO.[Pd]>[CH:23]1([NH:22][C:20]2[N:19]=[C:18]([N:30]([CH3:37])[CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:17]=[C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[N:21]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CN(c1nc(Nc2ccc(OCc3ccccc3)c(Cl)c2)nc(NC2CCCCCC2)n1)C1CCNCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CN(c1nc(Nc2ccc(O)cc2)nc(NC2CCCCCC2)n1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
In a dry round bottomed flask was added 10% Pd/C (301.5 mg) and was wetted with 3-5 drops of water. Nitrogen was blown over the Pd/C for about 5 minutes, then methanol (10 mL) was added cautiously and nitrogen was blown on the mixture for another 5 minutes. Triazine E3 (251.8 mg, 0.50 mmol) dissolved in methanol (5 mL) was added followed by ammonium formate (381.5 mg, 6.0 mmol), and the reaction was stirred and heated reflux for about 1.5 hours. Methylene chloride was added and allowed to cool to room temperature. The mixture was filtered by vacuum through Celite with a methylene chloride rinsing and the filtrate was concentrated in vacuo. The material was purified by silica gel flash chromatography eluting with 90:9:1 by volume methylene chloride:methanol:ammonium hydroxide, and the collected fractions were dried over anhydrous magnesium sulfate, filtered and then concentrated in vacuo to give a light yellow solid (E4) (98 mg, 44%); mp 130° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 [KH2PO4(0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 3.2 min, 99.6% purity; MS (TOF ES+) m/z 412 (M+H, 100), 235.6 (87.2), 206.6 (16.1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)=[CH:29][CH:28]=1.NC1C=NC(C)=CC=1>>[CH3:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][C:34]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:35])=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: Cc1ccc(NC(=O)Oc2ccccc2)cn1
Agent: Cc1ccc(N)cn1
Agent: Cl
Product: Cc1ccc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1

Procedure:
Following the procedure in Example 1, Step 6, 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (150 mg, 0.40 mmol, from Example 1, Step 5) and phenyl 6-methylpyridin-3-ylcarbamate (92 mg, 0.40 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-amino-6-methylpyridine, 3B Medical Systems, Inc.) were used to provide the title compound (184 mg). MS (APCI 10V) AP+ 469.3, AP− 467.2, 448.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.41-2.44 (m, 2H) 2.46 (s, 3H) 2.58 (td, J=5.80, 0.83 Hz, 2H) 3.51-3.57 (m, 2H) 3.60-3.67 (m, 2H) 6.45 (s, 1H) 6.97-7.05 (m, 2H) 7.09-7.17 (m, 2H) 7.20 (d, J=8.50 Hz, 1H) 7.40 (td, J=7.70, 0.78 Hz, 1H) 7.77 (dd, J=8.37, 2.52 Hz, 1H) 8.08 (ddd, J=8.71, 2.56, 0.50 Hz, 1H) 8.42 (d, J=0.54 Hz, 1H) 8.43 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:17](OC)=[O:18].Cl>O1CCCC1.COCCOC>[F:13][C:14]1[CH:15]=[C:16]([C:17](=[O:18])[CH2:3][S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH:21]=[CH:22][C:23]=1[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CS(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CS(=O)(=O)c2ccccc2)cc1F

Procedure:
A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 60° C. for one hour under an atmosphere of argon. To this solution is then added a solution of 5.0 g. of methyl 3-fluoro-4-(hexadecylamino)benzoate and 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid to pH 3 and then extracted with chloroform. The organic layer is separated, washed three times with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness. The crude solid is chromatographed on silica gel, eluting with methylene chloride to yield 3'-fluoro-4'-(hexadecylamino)-2-(phenylsulfonyl)acetophenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 34.7 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (65 mg, 0.19 mmol) obtained in Example 31 and piperidine (0.022 ml, 0.21 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (27 mg, 0.066 mmol, yield 35%).
Reaction SMILES: Cl.[C:2]1([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C(C[P+](C)(C)C)#N.O[CH2:23][C:24]1[CH:33]=[N:32][C:31]2[N:30]3[CH2:34][CH2:35][CH2:36][C@H:29]3[C:28](=[O:37])[NH:27][C:26]=2[CH:25]=1.CCN(C(C)C)C(C)C>C(#N)CC>[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:23][C:24]3[CH:33]=[N:32][C:31]4[N:30]5[CH2:34][CH2:35][CH2:36][C@H:29]5[C:28](=[O:37])[NH:27][C:26]=4[CH:25]=3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C1Nc2cc(CN3CCN(c4ccccc4)CC3)cnc2N2CCC[C@@H]12
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
1-Phenylpiperazine hydrochloride (11.9 mg, 0.060 mmol), (cyanomethyl)trimethylphosphonium iodide (0.025 g, 0.102 mmoles), and (S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (0.014 g, 0.063 mmoles) were diluted with propionitrile (0.5 ml) and treated with DIPEA (0.017 ml, 0.100 mmol). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was washed with water (1 mL) and concentrated. The residue was dissolved in DMSO (1 mL) and purified using HPLC (acetonitrile-water, NH4HCO3 buffered). The fractions were concentrated in vacuo, dissolved in dioxane-water (1:1:, 2 mL) and lyophilized to yield the title compound as a white solid (5.1 mg, 23%). [M+H] calc'd for C21H25N5O 364; found, 364.