Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=O)[CH2:4][OH:5].[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=C.Cl>CCOCC.C(OCC)(=O)C.CCCCCC>[CH3:14][O:13][C:9]([CH:10]1[C:4](=[O:5])[CH2:3][O:7][CH2:8]1)=[O:12]
Reactant: COC(=O)CO
Reactant: C=CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)C1COCC1=O
Yield: 53.6 %

Procedure:
To a suspension of NaH (6.66 g, 166.5 mmol) in ether (500 mL) add methyl glycolate (15.0 g, 166.5 mmol) drop wise. Stir the reaction until evolution of H2 gas ceases. Concentrate and dissolve the solid in DMSO (300 mL). Cool the reaction to 0° C. and add methyl acrylate (16.6 mL, 183.17 mmol) drop wise. Warm the reaction to room temperature and stir overnight. Acidify the reaction with 10% HCl and extract with ether (3×). Combine organic extracts and wash with brine. Dry the organic solution (Na2SO4), filter, and concentrate in vacuo. Purify by flash chromatography (250 g SiO2, 40 mL/min, 0-50% ethyl acetate/hexane for 20 minutes and then 50% ethyl acetate/hexane for 13 minutes) to yield 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester 4a (12.9 g, 89.2 mmol, 54%) as a colorless oil. 1H NMR (δ, 400 MHz, CDCl3): 4.50 (dd, 1H, J=8.4, 9.6 Hz), 4.46 (dd, 1H, J=8.4, 9.6 Hz), 4.05 (d, 1H, J=16.8 Hz), 3.79, (s, 3H), 3.97 (d, 1H, J=16.8, Hz), 3.54 (t, 1H, J=8.4Hz). MS calcd. 144; found (EI) 144.
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[CH:15]=1)=[CH:5][NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[CH3:20])[C:13]([C:4]1[C:3](=[O:23])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][N:9]=2)[NH:6][CH:5]=1)=[O:22]
Reactant: COC(=O)C(=CNc1cccnc1)C(=O)c1ccc(C)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Temperature: 250 °C
Yield: 66.7 %

Procedure:
1.12 g (3.61 mmol) of 2-(3,4-Dimethyl-benzoyl)-3-(pyridin-3-ylamino)-acrylic acid methyl ester was dissolved in 30 mL of diphenyl ether and the solution was heated at 250° C. After 2.5 h the solution was cooled to rt and 50 mL of hexane was added. The mixture was filtered and the solid washed with hexane to yield 0.67 g of 3-(3,4-Dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[N:4][C:5]([C:8](=[S:10])[NH2:9])=[N:6][CH:7]=1.Cl[CH:21]([C:25](=O)[CH3:26])[C:22](=[O:24])[CH3:23].CCN(CC)CC>CCO>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:18][CH2:19]3)[NH:14][N:13]=2)=[N:4][C:5]([C:8]2[S:10][C:21]([C:22](=[O:24])[CH3:23])=[C:25]([CH3:26])[N:9]=2)=[N:6][CH:7]=1
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)c1sc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)nc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
A mixture of crude 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carbothioamide (1.2 g, 4.1 mmol), 3-chloropentane-2,4-dione (548 mg, 4.1 mmol, 1.0 eq) and Et3N (1.0 mL) in EtOH (30 mL) was stirred at 80° C. for 2 h, then, concentrated. The residue was recrystallized with EtOH to produce 1-(2-(5-Chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-4-methylthiazol-5-yl)ethanone (Compound 297) (300 mg, 20%). LC-MS (m/z)=375.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.67-0.80 (m, 2H), 0.92-1.05 (m, 2H), 1.91-1.97 (m, 1H), 2.60 (s, 3H), 2.73 (s, 3H), 6.60 (s, 1H), 8.54 (s, 1H), 9.69 (s, 1H), 12.37 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:8]([CH2:13]O)=[C:9]([S:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1>CC(C)=O.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[C:3]2[N:4]([C:8]([CH3:13])=[C:9]([S:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc2c(Br)cccn2c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CSc1nc2c(Br)cccn2c1C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
The resulting [8-bromo-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]methanol (640 mg) was dissolved in acetone (50 mL), then activated manganese (IV) oxide (4 g) was added thereto, and the mixture was stirred overnight. Manganese (IV) oxide was filtered off through Celite, and the filtrate was evaporated. The resulting residue was purified by column chromatography using silica gel (ethyl acetate:n-hexane=1:10), to give 8-bromo-3-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridine (120 mg) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:19]#[N:20].[C:21]([C:27]([O:29][CH3:30])=[O:28])#[C:22][C:23]([O:25][CH3:26])=[O:24]>>[NH2:20][C:19]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([C:27]([O:29][CH3:30])=[O:28])[N:1]=[C:2]2[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=[C:4]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:3]=12
Reactant: COC(=O)C#CC(=O)OC
Reactant: N#Cc1c(-c2ccccc2)nn(-c2ccccc2)c1N
Product: COC(=O)c1nc2c(c(-c3ccccc3)nn2-c2ccccc2)c(N)c1C(=O)OC

Procedure:
Using 2.60 g (10 mmol) of 5-amino-1,3-diphenylpyrazole-4-carbonitrile [see J. Org. Chem., 29, 1915 (1964)] and 1.42 g (10 mmol) of dimethyl acetylenedicarboxylate, the entitled product having a melting point of 277° to 279° C. was obtained in the same manner as in Example 2-(2).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[CH2:24][CH2:25]OC.P(Br)(Br)[Br:29]>C(Cl)(Cl)Cl>[Br:29][CH2:25][CH2:24][C:3]1[CH:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:2]=1[CH3:1]
Reactant: COCCc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1C
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: Cc1c(CCBr)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a solution of 1-(4-fluoro)phenyl-3-(2-hydroxyethyl)-2-methyl-5-[4-methylsulphonyl)phenyl]-1H-pyrrole (example 23) (1.30 mmol) in CHCl3, PBr3 (5 mL) was added. The resulting mixture was stirred at r.t. for 2 h. The solution was cooled, the reaction quenched with ice, and the mixture basified with a saturated Na2CO3 solution and then extracted with CH2Cl2. The organic phase was washed to neutrality with brine, dried and evaporated under reduced pressure. The residue, purified by flash-chromatography (EtOAc/hexane 4:6 v/v), gave the expected compound as yellow oil (yield 36%) 1H-NMR (CDCl3) δ ppm: 2.03 (s, 3H), 2.96-3.06 (m, 5H), 3.52 (t, 2H, J=7.5), 6.41 (s, 1H), 7.05-7.15 (m, 6H), 7.61-7.66 (m, 2H).
Reaction SMILES: C(=O)=O.C([O:6][C:7]([C:9]1[C:10]([CH3:25])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=O)C.CC(C[AlH]CC(C)C)C.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:25][C:10]1[C:9]([CH2:7][OH:6])=[CH:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[N:11]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CO
Temperature: -70 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a dry ice chilled solution of 1.66 g (5.35 mmol) 4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester in 20 ml THF was dropped at −70° C. 12.35 ml (16.05 mmol) 1.2M DIBALH solution in toluene. The reaction mixture was stirred 1 h at −70° C. and after attaining RT the reaction was stirred for another 2 h at this temperature. A solution of 50 ml of 1N HCl was added dropwise, then the reaction mixture partitioned between ether and water. The ether solution was concentrated under reduced pressure to provide 1.42 g of pure [4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:22][C:23]([O:25]C)=[O:24])([CH:6]([CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])[CH3:2].Cl>C(O)(=O)C>[CH2:1]([O:3][P:4]([CH2:22][C:23]([OH:25])=[O:24])([CH:6]([CH2:13][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])[CH3:2]
Reactant: CCCCCCC(CC(=O)c1ccccc1)P(=O)(CC(=O)OC)OCC
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCCC(CC(=O)c1ccccc1)P(=O)(CC(=O)O)OCC
Temperature: 25 °C
Reaction time: 46 h

Procedure:
A solution of the product from part (b) (3.10 g., 8.115 mmole) in glacial acetic acid (10 ml.) is treated with concentrated hydrochloric acid (5 ml.) and stirred at room temperature for 46 hours. The mixture is poured onto an ice-water mixture and extracted with ethyl acetate. The ethyl acetate extract is washed with water, saturated sodium chloride solution, dried over Na2SO4 and evaporated. The residue is purified by flash chromatography on silica gel (85 g.) eluting with acetic acid/methanol/dichloromethane (0.5:3.0:100) to give 470 mg. of recovered starting material and 2.0 g. of [ethoxy[1-(2-oxo-2-phenylethyl)heptyl]phosphinyl]acetic acid as a colorless glass, Rf (acetic acid/methanol/dichloromethane 0.5:5:100) 0.32.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)C=1>>[CH:11]1([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:24](=[O:33])[N:25]([CH3:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:7][CH:6]=2)=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: O=C(Nc1ccc(O)cc1)C1CCCCC1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(NC(=O)C2CCCCC2)cc1)c1ccccc1
Yield: 80.3 %

Procedure:
The title compound (283 mg, 80% yield, white crystals) was prepared from cyclohexanecarboxylic acid (4-hydroxyphenyl) amide (219 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=353 (M+1); Rt=4.23 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])[C:5]([OH:7])=[O:6].[N:13](OC(C)(C)C)=O.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1.C(Cl)(Cl)Cl>[C:5]([C:4]1[CH:3]=[C:2]2[C:10]([C:11]([CH3:12])=[N:13][NH:1]2)=[CH:9][CH:8]=1)([OH:7])=[O:6]
Reactant: CCc1ccc(C(=O)O)cc1N
Reactant: CC(C)(C)ON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2cc(C(=O)O)ccc12
Temperature: -12 °C
Reaction time: 0.33 h
Yield: 17.3 %

Procedure:
To chloroform (75 ml), which had been passed through an alumina column, was added boron trifluoride diethyl ether complex (3.75 g, 26.4 mmol) and the mixture was cooled at −12° C. A solution of 3-amino-4-ethylbenzoic acid (2.5 g, 15.1 mmol) in tetrahydrofuran (25 ml) was dropwise added thereto for 20 min. After the completion of the addition, t-butyl nitrite (1.87 g, 18.1 mmol) was added and the mixture was heated to 5° C. The mixture was stirred at 5° C. for 1.5 hr. Then potassium acetate (7.4 g, 75.4 mmol) and 18-crown-6-ether (400 mg, 1.51 mmol) were added and the mixture was stirred at room temperature for 40 hr. The brown reaction mixture was concentrated under reduced pressure. Ethyl acetate/acetone (7/3, 100 ml) and 1N hydrochloric acid (25 ml) was added to the residue and the mixture was stirred at room temperature for 1 hr. Saturated brine (25 ml) was added thereto. The insoluble matter was filtered off and the filtrate was partitioned. The water layers were extracted with ethyl acetate/acetone (7/3, 40 ml) and the combined organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained brown oil (4.3 g) was dissolved in ethyl acetate, and then hydrogen chloride-diethyl ether (61 of hydrogen chloride in 40 ml of ether) and diethyl ether (100 ml) were added. The precipitated solid was collected by filtration. The obtained solid was extracted with ethyl acetate/acetone (7/3, 100 ml) and saturated brine (25 ml), and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained solid was washed with diethyl ether to give the objective compound (0.46 g, 17%) as brown crystals.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].[Na].[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].[H-].[Na+]>>[CH:14]([C:13]([O:20][CH3:21])=[O:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:3][CH:2]([C:1]([O:10][CH3:11])=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: COC(=O)CC(CC(C(=O)OC)C(=O)OC)C(=O)OC

Procedure:
Conventionally, a method for producing cyclopentanone-2,3,5-tricarboxylic acid triester, which is comprised of allowing dimethyl itaconate to react with sodium salt of dimethyl malonate that is prepared from sodium hydride and dimethyl malonate, isolating a product (tetramethyl 1,1,3,4-butanetetracarboxylate) from resulting reaction mixture by purification with distillation after neutralizing with an acid, and then cyclizing the product in the presence of not less than one equivalent of sodium methoxide, and isolating a target compound from resultant reaction mixture after neutralizing with an acid, has been known (see U.S. Pat. No. 4,272,437, columns 361-362).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[CH:22][CH:21]=3)[C:15]2=[O:37])=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>O1CCCC1.O>[O:37]=[C:15]1[C:16]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])=[O:28])=[CH:22][CH:21]=2)=[CH:17][CH:18]=[CH:19][N:14]1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc(NC(=O)Nc4ccccc4C)cc3)c2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(-c2cccn(Cc3ccc(CCC(=O)O)cc3)c2=O)cc1

Procedure:
3-(4-{2-Oxo-3-[4-(3-o-tolyl-ureido)phenyl)2H-pyridin-1-ylmethyl}phenyl)propionic acid ethyl ester (P9, 55 mg, 0.11 mmol) and lithium hydroxide (50 mg, 2.5 mmol) were stirred at 60° C. for 30 minutes in tetrahydrofuran (5 mL) and water (5 mL). The reaction mixture was acidified to pH 1 with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate) and evaporated to dryness to afford the title compound as a solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH2:11])[CH2:9][O:8][CH2:7]2)[CH2:3][CH2:2]1.Br[C:13]1[C:14](=[O:25])[N:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:17][N:18]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH:11][C:13]3[C:14](=[O:25])[N:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:17][N:18]=3)[CH2:9][O:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: N[C@@H]1COC[C@H]1OCC1CC1
Reactant: CCOC(=O)Cn1ccnc(Br)c1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1ccnc(N[C@@H]2COC[C@H]2OCC2CC2)c1=O
Temperature: 25 °C

Procedure:
A stirred solution of trans-3-cyclopropylmethoxy-4-aminotetrahydrofuran from step 4 above (1.1 g, 7.0 mmol), 3-bromo-1-ethoxycarbonylmethylpyrazinone (1.8 g, 7.0 mmol), and DIEA (1.4 mL, 8.0 mmol) in toluene (20 mL) was heated to reflux for 24 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed with aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient elution of 50-67% tOAc:hexanes to give the title compound as an amorphous solid (1.4 g; TLC Rf=0.4, 3:2 EtOAc:hexanes; HPLC RT=5.05 min, method A).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[N+](C1C=CC=CC=1COC(CCCCCCCCN)=O)([O-])=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][O:7][C:19]([NH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:20])([O-:3])=[O:2]
Reactant: O=C=NC1CCCCC1
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: NCCCCCCCCC(=O)OCc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)OCc1ccccc1[N+](=O)[O-]

Procedure:
[[(2-nitrobenzyl)oxy]carbonyl]cyclohexylamine was prepared using 2-nitrobenzylalcohol, cyclohexylisocyanate, and toluene solvent in the same preparation method of [[(2-nitrobenzyl)oxy]carbonyl]octylamine as in Example 1.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([O:23]C)[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[OH2:23].[ClH:1].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(Nc2ccnc3c(OC)cccc23)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1ccc(Nc2ccnc3c(O)cccc23)cc1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
In a flame dried single-neck round bottom flask equipped with a Dean-Stark trap and a condenser, a solution of 1.0 g (2.9 mmol) of N-(4-butylphenyl)-8-methoxyquinolin-4-amine hydrochloride and 20 mL of toluene was treated with 1.9 g (14.5 mmol) of anhydrous aluminum chloride. This was heated under reflux for five hours, and then allowed to cool to room temperature. The reaction solution was treated dropwise with water until a sticky solid formed. Work-up of the mixture eventually afforded mg of crude product. This was recrystallized from water-formic acid to furnish 340 mg (34%) of the title compound: m.p. 269° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]#[CH:17].[NH2:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:24])=[CH:21][C:20]=1[O:35][CH3:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>CO>[CH3:36][O:35][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:19]=1[NH:18][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]#[CH:17])=[CH:11][N:12]=1)[C:23]([NH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)=[O:24]
Reactant: C#CCN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: C#CCN1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc21
Temperature: 150 °C

Procedure:
9-chloro-2-methyl-6-prop-2-ynyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-3-one (Intermediate 154; 53 mg, 0.21 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 66 mg, 0.25 mmol) p-toluenesulphonic acid monohydrate acid (80 mg, 0.42 mmol) and isopropanol (4 mL) were combined in a 10 mL microwave reactor tube and heated in by microwave irradiation at 150° C. for 80 minutes. The sample was transferred to an SCX (10 g) cartridge pre-wet with methanol, washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as an off white gum (4 mg, 3%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[NH:16])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Br:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35](Cl)=[O:36]>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[N:16][C:35]([C:30]1[C:31]2[C:26](=[C:25]([Br:24])[CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:28][CH:29]=1)=[O:36])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1cccc2c(Br)cccc12
Reactant: COC(=N)Cc1cccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(Cc1cccc2ccccc12)=NC(=O)c1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
According to the procedure of Soto et al, Synthesis, 483, (1983), to a stirred suspension of methyl-2-(1-naphthalenyl)acetimidate hydrochloride (prepared in Step 1) (11.7 g, 0.050 mol), in dry toluene (150 mL) was added triethylamine (11.5 g, 0.114 mol). 5-Bromo-1-naphthoyl chloride (13.4 g, 0.050 mol) was added in one portion and the resulting mixture was stirred at room temperature for 16 hours. The precipitated salt was removed by filtration and washed with toluene. The filtrate was concentrated in vacuo to give an orange oil (21.5 g, 100%) which was used without purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[C:21](=[O:32])[CH2:22][CH2:23][O:24][Si](C(C)(C)C)(C)C)=O)(C)(C)C.CO.[ClH:35]>>[ClH:35].[OH:13][C@H:11]1[CH2:12][NH:8][C@H:9]([C:21](=[O:32])[CH2:22][CH2:23][OH:24])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)CCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: O=C(CCO)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2S,4R)-N-tert-Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(3-tert-butyldimethylsiloxy-1-oxopropyl)pyrrolidine (4.87 g, 10.0 mmol) was dissolved in a 3.3N hydrogen chloride--methanol solution (16.5 ml). The solution was stirred at room temperature for 24 h, and then concentrated in vacuo to obtain the title compound (2.29 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:19]3[CH2:20][CH:17]([CH2:18]3)[C:8]3[NH:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([CH3:41])[N:33]=1>CN(C)C=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:19]3[CH2:18][CH:17]([CH2:20]3)[C:8]3[N:9]([CH2:31][C:32]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]([CH3:41])[N:33]=4)[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:21]=1
Reactant: CCOC(=O)c1nc2c([nH]1)C1CC(C1)c1ccc(I)cc1-2
Reactant: Cn1nc(CCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c(n1Cc1nn(C)c3ccccc13)C1CC(C1)c1ccc(I)cc1-2
Temperature: 50 °C
Yield: 97.4 %

Procedure:
To a mixture of ethyl 9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (150 mg, 0.38 mmol), potassium carbonate (79 mg, 0.57 mmol) and sodium iodide (114 mg, 0.76 mmol) was introduced a solution of 3-(chloromethyl)-1-methyl-1H-indazole (137 mg, 0.76 mmol) in N,N-dimethylformamide (5 mL). After warming to 50° C. for 2 hr the reaction mixture was evaporated in vacuo. The residue was suspended in ethyl acetate (40 mL), washed with saturated aqueous sodium bicarbonate (15 mL). After washing the basic aqueous extract with ethyl acetate (3×10 ml), all the organic extracts were combined, washed with water (15 mL) and brine (15 mL), and dried over sodium sulfate. Following filtration of the ethyl acetate extract, the filtrate was evaporated onto silica gel in vacuo. The dry-loaded material was purified by silica gel flash column chromatography (eluent: heptanes/ethyl acetate gradient) to furnish the title compound (198 mg, 0.37 mmol, 97%) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ1.48 (t, J=7.2 Hz, 3H), 1.55-1.57 (m, 2H), 2.79 (dq, J=8.2, 2.8 Hz, 2H), 3.53 (td, J=7.9, 3.8 Hz, 1H), 3.73 (td, J=7.6, 4.1 Hz, 1H), 3.99 (s, 3H), 4.50 (q, J=7.2 Hz, 2H), 6.13 (s, 2H), 6.77 (d, J=7.8 Hz, 1H), 7.05 (ddd, J=7.9, 6.3, 1.3 Hz, 1H), 7.32-7.34 (m, 3H), 7.41 (dd, J=7.9, 1.9 Hz, 1H), 8.89 (s, 1H); M+H=539.