Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[C:23]3[C:22]4[C:17](=[CH:18][C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=4)[NH:16][C:15]=3[N:14]=[C:13]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35](=[N:40]OS(C4C=CC(C)=CC=4)(=O)=O)[C:36]([F:39])([F:38])[F:37])[CH:30]=3)[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:52]>C(Cl)Cl>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[C:23]3[C:22]4[C:17](=[CH:18][C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=4)[NH:16][C:15]=3[N:14]=[C:13]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4([C:36]([F:39])([F:38])[F:37])[NH:52][NH:40]4)[CH:30]=3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NOS(=O)(=O)c4ccc(C)cc4)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Reactant: N
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C4(C(F)(F)F)NN4)c3)nc(NCCCN3CCCCC3)c12
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 77.9 %

Procedure:
To a solution of methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.188 g, 0.260 mmol) in DCM (5.00 mL) cooled to −78° C., ammonia (1.689 mL, 78 mmol) was added and the tube was sealed and warmed to 20° C. The reaction mixture turned blue over time and after 3.5 hours it was cooled again to −78° C. and then slowly warmed to 20° C. with septa+nitrogen outlet to evaporate most of the ammonia. After 3.5 hours, the reaction mixture was filtered over Buchner to remove most of the ammonium p-toluenesulfonate), the solids were washed with DCM (3×1.5 mL) and the filtrate was concentrated to dryness to give a yellow foam which was purified by flash chromatography to afford methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(3-(trifluoromethyl)diaziridin-3-yl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (115 mg, 78% yield) as a white foam: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.43 (m, 2H) 1.50 (quin, J=5.3 Hz, 4H) 1.80 (dt, J=14.1, 7.0 Hz, 2H) 2.32 (m, J=6.7, 6.7 Hz, 6H) 3.58-3.67 (m, 2H) 3.88 (s, 3H) 3.93 (br. d, J=7.4 Hz, 1H) 4.05 (br. d, J=8.6 Hz, 1H) 4.07 (s, 2H) 7.32-7.43 (m, 3H) 7.47 (m, J=6.3 Hz, 1H) 7.59 (s, 1H) 7.81 (dd, J=8.4, 1.2 Hz, 1H) 7.99 (d, J=1.2 Hz, 1H) 8.35 (d, J=8.4 Hz, 1H) 12.07 (s, 1H); MS m/z 568.2 (M+H)+; HPLC >94%, RT=1.72 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:11]=2[CH:10]=[CH:9]1
Reactant: NCCCO
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Product: Cc1ccccc1-n1ccc2c(NCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-chloro-6-trifluoromethoxypyrrolo[3,2-c]quinoline(377 mg, 1.0 mmol) was dissolved in 3-amino-1-propanol(10 ml) in the pressure tube, then reacted at the same condition of Step 3 in the Example 6 to obtain 303 mg of desired compound as solid in 73% of yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([O:15]CC2C=CC=CC=2)[CH:6]=1>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:14])[F:13])[CH:8]=[C:7]([OH:15])[CH:6]=1
Reactant: COC(=O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1cc(O)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
(3-Benzyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester (4.8 mmol) in EtOH was treated with 10% palladium on carbon (10% by weight), and stirred under a balloon of H2 at 60° C. overnight. The mixture was filtered to remove the palladium, and then concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].ClCCl>CO>[CH2:12]([O:11][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([OH:8])=[O:7])[CH3:13]
Reactant: CCOC(=O)CC(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCOC(CC(=O)O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 25 g of ethyl 3,3-diethoxypropionate (131 mmol) in 79 mL of methanol there are added 13.1 mL of aqueous 35% sodium hydroxide solution (452 mmol). The reaction mixture is stirred at ambient temperature for 3 hours. The reaction mixture is then concentrated to remove the methanol. After dissolving the undissolved material by adding water, aqueous 5N HCl solution is added to obtain a pH of 5. Dichloromethane is added and then the organic phase is washed with brine. After drying over MgSO4 and concentrating to dryness, the title product is obtained in the form of an oil which is used in the next Step without being otherwise purified.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])[CH:14]=1.C1N2CCN(CC2)C1>ClCCl>[OH:20][CH:19]([C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)[C:2](=[CH2:3])[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=Cc1cccnc1
Reactant: C=CC(=O)Oc1ccc(Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: C=C(C(=O)Oc1ccc(Cl)cc1)C(O)c1cccnc1
Reaction time: 1 h
Yield: 18 %

Procedure:
A mixture of 37 mg (0.20 mmol) of 4-chlorophenyl acrylate, 22 mg (0.22 mmol) of pyridine-3-carboxaldehyde, and 22 mg (0.20 mmol) of DABCO was thoroughly shaken on a Vortex mixer. After 1 hr at room temperature, the mixture was diluted with dichloromethane. The DCM solution was washed with dilute aqueous acetic acid, and the DCM removed by rotoevaporation. The residue was purified by preparative HPLC to give 10 mg (0.035 mmol, 18% yield) of the desired Baylis-Hillman adduct, 4-chlorophenyl β-hydroxy-α-methylene-3-pyridinepropanoate. 1H NMR (CDCl3): δ 5.70 (1H), 6.14 (1H), 6.64 (1H), 7.76 (d of t, 1H), 8.55 (d of d, 1H), and 8.64 ppm (d, 1H). MS m/z: 290.0 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1cnccn1
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cnccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2-pyrazinecarboxylic acid (7.5 g), N,N'-carbonyldiimidazole (9.7 g) and 2-amino-7-chloro-1,8-naphthyridine (10.8 g). The insoluble product is separated by filtration, washed with tetrahydrofuran (3×50 cc) and then with water (300 cc) and dried in the air. The product is suspended in acetonitrile (100 cc), stirred for 1 hour at 25° C. and separated by filtration, and then dried at 50° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-2-pyrazinecarboxamide (11.75 g), m.p. 308° C., is thereby obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:21])[CH2:13][CH:14](C(O)=O)[C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1>C1(C)C=CC=CC=1>[CH3:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:21])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(C(=O)CC(C(=O)O)C(=O)O)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
The 2-(2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-oxoethyl)malonic acid (4.8 g) was suspended in toluene (20 ml), and the mixture was heated to reflux for 7 hours. The mixture was allowed to cool to room temperature overnight. The desired product crystallized out, and the suspension was stored at 5° C. for 4 hours. The solid was collected by filtration and dried under vacuum to give 2.2 grams of 4-[3-(2,6-dimethylbenzyloxy)-phenyl]-4-oxobutanoic acid. The mother liquor was evaporated and the residue was triturated with saturated sodium bicarbonate solution (2×50 ml). The aqueous solution was filtered, and the filtrate was acidified with hydrochloric acid to pH 1. The resulting suspension was extracted with ethyl acetate (100 ml), and the organic layer was washed with brine. The ethyl acetate extract was dried over sodium sulfate, filtered, and evaporated under vacuum to give an additional 0.4 grams of the desired product. Total of 2.6 g (69% yield). NMR (CDCl3, δ) 7.59-7.65 (m, 2H), 7.40 (t, 1H), 7.15-7.23 (m 2H), 7.06-7.10 (2s, 2H), 5.09 (s, 2H), 3.32 (t, 2H), 2.82 (t, 2H), 2.39 (s, 6H). HPLC: DPA-9.02 minutes.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:6]2[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.[OH-:22].[Li+]>CO>[OH:22][C:6]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:2]2[CH:3]=[C:4]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn2c(O)cc(-c3ccccc3)nc12
Agent: [Li+]
Solvent: CO
Product: O=C(O)c1cnn2c(O)nc(-c3ccccc3)cc12
Temperature: 80 °C
Yield: 79 %

Procedure:
Ethyl 7-hydroxy-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylate (3.1 g, 11 mmol) was taken into 27 mL methanol and 2 M aqueous lithium hydroxide (27 mL) and heated in an 80° C. oil bath for 4 h. The solution was allowed to cool to room temperature and concentrated in vacuo to remove methanol. The subsequent basic aqueous mixture was washed with ethyl acetate (10% methanol) and then acidified to pH 3 using concentrated hydrochloric acid. A solid formed and was collected via vacuum filtration to yield 2.2 g (79%) of crystalline 7-hydroxy-5-phenylpyrazolo[1,5-c]pyrimidine-3-carboxylic acid. 1H NMR (400 MHz, d6-DMSO): 8.21 (s, 1H), 7.76 (m, 2H), 7.57 (m, 3H), 6.24 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([C:7](OC)=O)[C:3]([O:5]C)=[O:4].[Na].[C:12]1([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2CBr)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[OH-].[K+]>O>[C:12]1([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH2:7][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1-c1cccc2ccccc12
Reactant: COC(=O)C(C)C(=O)OC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(Cc1ccccc1-c1cccc2ccccc12)C(=O)O
Temperature: 130 °C

Procedure:
75 g (0.43 mmol) of dimethyl methylmalonate dissolved in 50 cm3 of H2O-free EtOH are added dropwise at room temperature to 10 g (0.43 mmol) of sodium in 100 cm3 of H2O-free EtOH. Subsequently, 140 g (0.43 mmol) of 7 in 200 cm3 of H2O-free EtOH were added dropwise and the mixture was heated under reflux for 3 hours. 85 g (1.3 mol) of KOH dissolved in 100 cm3 of H2O were added at room temperature and the mixture was heated under reflux for a further 4 hours. The solvents were removed under reduced pressure, the residue was admixed with H2O until completely dissolved and acidified with concentrated aqueous HCl to a pH of 1. The precipitate formed was filtered off with suction, dried and heated at 130° C. for 1 hour. This gave 96 g (77%) of 8 as a viscous oil.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9](=[O:11])[CH3:10])[N:7]=[C:6]([NH:12][C:13]3[C:18](I)=[CH:17][N:16]=[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:14]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28].N(C)(C1CCCCC1)C1CCCCC1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([N:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]([NH:12][C:13]2[C:18](/[CH:28]=[CH:27]/[C:26]([O:30][CH3:31])=[O:29])=[CH:17][N:16]=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)=[N:7]1)(=[O:11])[CH3:10]
Reactant: CC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2I)cc1C1CC1
Reactant: C=CC(=O)OC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)n(C(C)=O)n1
Temperature: 120 °C
Yield: 7.4 %

Procedure:
A mixture of 1-(5-cyclopropyl-3-(5-iodo-2-phenylpyrimidin-4-ylamino)-1H-pyrazol-1-yl)ethanone (3 g, 6.72 mmol, 1.0 equiv.), methyl acrylate (2.28 g, 26.8 mmol, 4.0 equiv.), Pd2(dba)3 (600 mg, 0.6 mmol, 0.1 equiv.), Cy2NMe (1.35 g, 7.2 mmol, 1.1 equiv.) and P(t-Bu)3 (540 mg, 2.4 mmol, 0.4 equiv.) in dioxane (100 mL) was heated to 120° C. for 3 h under nitrogen atmosphere. Then, the reaction mixture was cooled to room temperature and filtered. The residue was crystallized with methane/diisopropyl ether to afford (E)-methyl 3-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-2-phenylpyrimidin-5-yl)acrylate (200 mg, 7.3%). LC-MS (m/z): 404.1 [M+H]+. 1H NMR: (400 MHz, DMSO-d6) δ 0.83-0.84 (m, 2H), 1.03-1.04 (m, 2H), 2.04 (m, 1H), 2.64 (s, 3H), 3.77 (s, 3H), 6.83 (d, J=16.0 Hz, 1H), 6.84 (s, 1H), 7.57-7.58 (m, 3H), 7.71 (d, J=16.0 Hz, 1H), 8.34 (m, 2H), 8.97 (s, 1H), 10.74 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([OH:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:29][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccccc1I

Procedure:
One ml of o-iodobenzoyl chloride was reacted with 2.7 g of 1-octadecanol in accordance with the procedure of Example 8. There was obtained 2.36 g of octadecyl o-iodobenzoate, mp 35°, Rf 0.66.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9](Cl)=[N:10][C:11]=2[NH2:15].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH:24][CH2:20][CH2:21][CH2:22][CH3:23])=[N:10][C:11]=2[NH2:15]
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1cccc(Br)c1
Reactant: CCCCN
Solvent: CCCCO
Product: CCCCNc1nc(N)c2ncn(Cc3cccc(Br)c3)c2n1
Temperature: 170 °C

Procedure:
9-(3-bromobenzyl)-2-chloro-9H-purin-6-amine (2.3 g) (100 mg, 0.295 mmol), n-butylamine (0.5 mL) and n-butanol (1 mL) were combined and heated in the microwave at 170° C. for 15 minutes. The solvent was evaporated under vacuum and the residue was partitioned between water and ethylacetate. The organic layer was washed with brine, dried with Na2SO4 and evaporated under vacuum. The crude product was triturated with diethylether and filtered giving 9-(3-bromobenzyl)-N2-butyl-9H-purine-2,6-diamine (Compound 54) (60.9 mg) as off-white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[Cl:18])=[CH:6][CH:7]=1.[C:19]([NH:22][NH2:23])(=O)[CH3:20]>C(O)CCC>[CH3:20][C:19]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=3[Cl:18])[CH:6]=[CH:7][C:2]2=[N:23][N:22]=1
Reactant: CC(=O)NN
Reactant: FC(F)(F)c1ccc(Cl)c(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cc(C(F)(F)F)ccc3Cl)nn12

Procedure:
As in Example 36, a mixture of 2.2 g. of 3-chloro-6-[2-chloro-5-(trifluoromethyl)phenyl]pyridazine and 1.11 g. of acetylhydrazine in 50 ml. of n-butanol is refluxed for 48 hours to give the product of the example.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(=O)(O)[O-].[Na+].Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[I-].[K+]>C(O)C>[CH2:25]([O:24][C:22]([CH2:21][CH2:27][N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[CH:2]1[CH3:1])=[O:23])[CH3:26]
Reactant: CCOC(=O)C(C)Br
Reactant: CC1NCCc2ccc([N+](=O)[O-])cc21
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1C
Yield: 65.8 %

Procedure:
0.90 g of 1-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 20 ml of ethanol, and 1.97 g of sodium bicarbonate, 2.55 g of ethyl bromopropionate, and a catalytic amount of potassium iodide were added to the solution. The solution was heated overnight under ref lux with stirring, and extracted with ethyl acetate. After washing with water and saturated aqueous solution of sodium chloride, the solution was dried with anhydrous sodium sulfate. The desiccant was separated by filtration, and the filtrate was purified by silica gel column chromatography to obtain 0.90 g of 2-[2-(ethoxycarbonyl)ethyl]-1-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline, which was an oily product (yield: 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=S)[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1>O1CCCC1.[Ni]>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(=S)n3c(nc2c1)CCCCC3
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N=C1CCCCCN1C2

Procedure:
To a mechanically stirred solution of 5 g of 3-methyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazoline-12(6H)-thione in 150 mL of boiling tetrahydrofuran was added in small portions wet Raney nickel (W-2, Davison Chemical, Chattanooga, Tenn.). The progress of the reaction was followed by TLC. When the reaction was complete, the mixture was filtered, solids on the filter were washed thoroughly with tetrahydrofuran and the filtrate was concentrated down. The rest of the workup was identical to that described in method A.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9](OCC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH2:9][OH:10]
Reactant: CCOC(=O)c1cccc(-c2ccco2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cccc(-c2ccco2)c1
Yield: 83 %

Procedure:
Ethyl 3-(2-furyl)benzoate J. Chem. Soc., (B), 1971, 2305] was dissolved in 5 ml of anhydrous ethyl ether, and with stirring under ice cooling, 23 mg of lithium aluminum hydride was added. The mixture was stirred for 40 minutes. After the reaction, the reaction mixture was extracted by adding water and ethyl ether. The extract was worked up in a customary manner to give 170 mg (yield 83%) of 3-(2-furyl)benzyl alcohol.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]1
Reactant: O=[N+]([O-])c1cc[nH]c1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A mixture of 3-nitropyrrole (500 mg, 4.46 mmol), cesium carbonate (3.63 g, 11.2 mmol, 2.5 equiv), 1-chloro-2-dimethylaminoethane (835 mg, 5.8 mmol, 1.3 equiv) and DMF (5 mL) was stirred for 16 h at rt. The reaction mixture was quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with DCM/MeOH (9:1, v/v). The organic phase was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM DCM/MeOH, 97:3) to afford 656 mg of the title compound as a yellow oil. Title compound: ESI-MS: 184.1 [M+H]+; TLC: Rf=0.38 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]([CH3:9])([C:5]([CH3:8])([CH3:7])[CH3:6])[CH:3]=[O:4]
Reactant: CC(C)(C)C(C)(C)CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(C)(C)C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
A 1000 mL round-bottom-flask was equipped with a stir bar, flushed with Ar and charged with 500 mL dry CH2Cl2 and 2,2,3,3-tetramethyl-butanol (12.9 g, 99.2 mmol, 1.0 equiv). Pyridinium chlorochromate (PCC) (20.7 g, 96 mmol) was added portionwise over 5 min. The reaction mixture turned dark rapidly and was stirred at room temperature for 3 h. The reaction solvent was then decanted, washed 1 N HCl (1×250 mL), and concentrated on a rotary evaporator. The resulting pasty residue was stirred with hexanes (300 mL) for 10 min then filtered. The filtrate was dried with Na2SO4, filtered, and concentrated to provide 8.3 g (65% yield) of the desired 2,2,3,3-tetramethyl-butanal which was used without further purification.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:30][CH:29]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)OC(=O)N1CCC(CO)CC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(CSc2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
Methanesulfonyl chloride (0.28 mL, 3.6 mmol) was added dropwise to a solution of 1-methylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (prepared as in Example 9, Step 1, 600 mg, 3 mmol), triethylamine (0.627 mL, 4.5 mmol), and CH2—Cl2 (10 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, then at ambient temperature for 2 h. The mixture was washed with water, and the organics were concentrated. The resulting crude material was mixed with 4-bromobenzenethiol (567 mg, 3 mmol) and K2CO3 (829 mg, 6 mmol) in DMF (10 mL), and the mixture was stirred at ambient temperature overnight. The mixture was charged with water, and extracted with EtOAc. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 10% EtOAc/hexanes to give 292 mg (26%) of 1-methylethyl 4-{[(4-bromophenyl)thio]methyl}-1-piperidinecarboxylate as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.37 (d, 2H, J=8.5 Hz), 7.15 (d, 2H, J=8.5 Hz), 4.95-4.82 (m, 1H), 4.15-4.09 (m, 2H), 2.80 (d, 2H, J=6.9 Hz), 2.72-2.60 (m, 2H), 1.85-1.77 (m, 2H), 1.70-1.60 (m, 1H), 1.24-1.08 (m, 8H); LRMS (ESI), m/z 372/374 (M+H).
Reaction SMILES: CC(OO)=[O:3].[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([CH2:11][C:12]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=1>C(O)(=O)C.ClC(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]23[O:3][C:13]2([C:19]([O:21][CH3:22])=[O:20])[C:14]([CH3:18])([CH3:17])[CH2:15][CH2:16]3)=[CH:23][CH:24]=1
Reactant: CC(=O)OO
Reactant: COC(=O)C1=C(Cc2ccc(Cl)cc2)CCC1(C)C
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C12OC1(Cc1ccc(Cl)cc1)CCC2(C)C

Procedure:
23.5 g (3 equivalents) "PROXITANE 4002" (Trade Mark: 36-40% (w/w) peracetic acid in acetic acid) were added to 9.8 g (35.1 mmols) 1-(4-chlorobenzyl)-3,3-dimethyl-2-methoxycarbonylcyclopent-1-ene prepared as described in Example 1 (f) in 90 ml trichloromethane. The resulting mixture was refluxed for 3 hours and then extracted twice with 50 ml aliquots of trichloromethane, backwashed once with 50 ml dilute aqueous sodium bicarbonate solution and twice with 50 ml aliquots of saturated aqueous sodium metabisulphite solution, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate and flashed to give 12 g of a pale yellow oil which crystallised on cooling. Trituration in 30/40 petroleum gave 5.8 g 1-(4-chlorobenzyl)-1,2-epoxy-3,3-dimethyl-2-methoxy-carbonylcyclopentane as a white crystalline solid, m.pt. 86°-87° C. Yield: 56%.