Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.OO.S(=O)(=O)(O)[OH:13].CC1C=C(C)C=C(O)C=1O>CC(C)CC(=O)C>[CH3:8][C:6]1[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[C:7]=1[OH:13]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C)cc(O)c1
Agent: Cc1cc(C)c(O)c(O)c1
Agent: OO
Solvent: CC(=O)CC(C)C
Product: Cc1cc(O)cc(C)c1O

Procedure:
In a vessel used in Example 52 were placed 100 g. (819 m. moles) of 3,5-dimethylphenol, 3.61 g. (36.1 m. moles) of 4-methyl-2-pentanone, 2.88 g. (50.8 m. moles) of 60 percent hydrogen peroxide and 0.01 g. of sulfuric acid, and the mixture was reacted at 110° C. for 20 minutes in the same manner as in Example 52. The reaction mixture was analyzed with gas chromatography. As products, 3.19 g. (23.1 m. moles) of 3,5-dimethylcatechol and 2.24 g. (16.2 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 77.4 percent.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH2:7]([S:11][CH:12]=[C:13]1[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][CH3:20])[C:14]1=[O:21])[CH2:8][CH2:9][CH3:10].[CH2:22](Br)C=C.CCOCC>CCCCCC>[CH2:19]([C:15]1([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][C:13](=[CH:12][S:11][CH2:7][CH2:8][CH2:9][CH3:10])[C:14]1=[O:21])[CH:20]=[CH2:22]
Reactant: CC(C)(C)[O-]
Reactant: C=CCBr
Reactant: CCCCSC=C1CCCC(CC)C1=O
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Product: C=CCC1(CC)CCCC(=CSCCCC)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a well stirred solution of potassium tert-butoxide (17.95 g, 0.16 mole) in dry redistilled tert-butanol (160 ml) under nitrogen, 2-[(butylthio)methylene]6-ethylcylcohexanone (9.05 g, 0.04 mole), described in Example 3, is added slowly. The mixture is stirred at room temperature for 5 minutes and then chilled in an ice bath. Allyl bromide (21.8 g, 0.18 mole) is added rapidly to the chilled mixture. The mixture is then stirred at room temperature for 48 hr. Most of the solvent is then removed under reduced pressure and water (about 150 ml) is added. The aqueous solution is extracted with ether (3 ×). The combined ether extracts are washed with brine, dried (MgSO4) and concentrated to yield an oil. The oil is subjected to chromotography on silica gel (320 g) using 4% ether in hexane as eluant. Concentration of the eluate gives 2-allyl-6-[(butylthio)methylene]-2-ethylcyclohexanone, nmr(CDCl3) δ 0.85 (t, J=7, 3H), 2.85 (t, J=7, 2H), 4.80 - 6.0 (m, 3H), 7.5 (t, J=2, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:11][N:12]([CH3:33])[C:13]1[CH:32]=[CH:31][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[S:27](Cl)(=[O:29])=[O:28])=[CH:15][CH:14]=1.C1COCC1>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:27]([C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[CH2:17][C:16]1[CH:15]=[CH:14][C:13]([N:12]([CH3:11])[CH3:33])=[CH:32][CH:31]=1)(=[O:28])=[O:29]
Reactant: Cc1noc(N)c1Cl
Reactant: CN(C)c1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc(N(C)C)cc3)sc3ccccc23)c1Cl

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzyl)-benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-chloro-3-methyl-5-aminoisoxazole (0.52 mmoles, 69 mg), NaH (1.3 mmoles, 31 mg), 2-(4-dimethylaminobenzyl)-benzo[b]thiophene-3-sulfonylchloride (0.58 mmoles, 0.21 g) and THF (4 ml). Flash chromatography (5% methanol/chloroform) provided 0.16 g (66%) of a yellow gummy solid, m.p. 105-1 10° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]([NH2:20])=[O:19])[C:7]2=O)#[N:2]>C(O)(=O)C>[C:1]([C:3]1[C:4]2[CH2:5][C:6]3[N:13]4[CH:17]=[CH:16][N:15]=[C:14]4[C:18](=[O:19])[NH:20][C:7]=3[C:8]=2[CH:9]=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1cccc2c1CC(n1ccnc1C(N)=O)C2=O
Solvent: CC(=O)O
Product: N#Cc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Yield: 42.9 %

Procedure:
9-Cyano-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one can be obtained in the following way: 1 g of 1-[(4-cyano-1-oxoindan-2-yl)]imidazole-2-carboxamide is dissolved in 10 ml of acetic acid and the solution is brought to reflux for 22 hours. After cooling the reaction mixture, the suspension is filtered and washed with 5 ml of acetic acid, distilled water and ethyl ether. The solid is dried under reduced pressure (15 mm Hg; 2 kPa) at 30° C. and 0.4 g of 9-cyano-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one is thus obtained, which product melts at a temperature greater than 260° C. (Analysis C14H8N4O1.0.2H2O; % Calculated C: 67.74, H: 3.25, N: 22.57, O: 6.45; % Found C: 68.1, H: 3.3, N: 22.6, O: 6.7).
Reaction SMILES: [Si]([O-])([O-])([O-])[O-].[Al+3].[Si]([O-])([O-])([O-])[O-].[Si]([O-])([O-])([O-])[O-].[Al+3].[Al+3].[Al+3].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28]O>>[NH:20]1[C:21]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:27][CH2:28]1
Reactant: Nc1ccccc1CCO
Agent: [Al+3]
Agent: [O-][Si]([O-])([O-])[O-]
Product: c1ccc2c(c1)CCN2
Temperature: 240 °C
Reaction time: 126 h
Yield: 4245 %

Procedure:
In a stainless steel reactor equipped with distillation column, 0.8 g of a commercially available amorphous aluminium silicate (KETJEN® LA-100-3P) consisting of 13.3% by weight of Al2O3 and 86.3% by weight of SiO2, and having a BET inner surface area of 403 m2 /g and a pore volume of 0.52 cm3 /g, are suspended in 80 g (72 ml) of 2-(2'-aminophenyl)ethanol using a magnetic stirrer. The suspension is heated to 240° C. under normal pressure and the resultant indoline/water mixture is distilled off through the packed column at a rate of 25 g of indoline per hour. During this distillation, the volume in the reactor is kept constant with a level probe by the continuous addition of fresh 2-(2'-aminophenyl)ethanol. To maintain this distillation rate, the reaction temperature is gradually raised during the entire duration of the experiment of 126 hours from initially 240° C. to 270° C. After 126 hours, the addition of 2-(2'-aminophenyl)ethanol is discontinued and the indoline remaining in the reactor is distilled off through the column, affording 2.95 kg (97-98% of theory) of indoline in 99% purity.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1.C1(C)C=CC(S(O[CH2:22][CH2:23][O:24][CH2:25][CH3:26])(=O)=O)=CC=1>CO>[CH2:23]([O:24][CH2:25][CH2:26][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)[CH3:22]
Reactant: Cc1ccc(O)cn1
Reactant: CCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOCCOc1ccc(C)nc1
Reaction time: 0.08 h

Procedure:
A solution of 994 g (18.4 mmol) of sodium methylate in 20 ml of abs. methanol is added dropwise to a solution of 2 g (18.4 mmol) of 5-hydroxy-2-methylpyridine in 20 ml of abs. methanol. The mixture is stirred for 5 minutes and then a solution of 5.83 g (23. 9 mmol) of (2-ethoxy)ethyl p-toluenesulphonate in 15 ml of abs. methanol is added. The mixture is heated under reflux for 72 hours. It is evaporated to dryness, the residue is taken up in ethyl acetate and washed with saturated NaCl solution. Drying over sodium sulphate and evaporation result in 2.1 g (70% of theory) of a pale yellow oil. 1NMR (CDCl3, δ[ppm]): 1.2 (t, 3H); 2.5 (s, 3H); 3.6 (q, 2H); 3.8 (m, 2H); 4.15 (m, 2H); 7.05 (d, 1H); 7.15 (dd, 1H); 8.2 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:6](=[O:7])[N:5]([C:14]2[CH:26]=[CH:25][C:17]3[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[NH:20][C:16]=3[CH:15]=2)[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH:35]=[CH2:36].O>CN(C)C=O>[CH3:1][N:2]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:6](=[O:7])[N:5]([C:14]2[CH:26]=[CH:25][C:17]3[N:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[N:20]([CH2:36][CH:35]=[CH2:34])[C:16]=3[CH:15]=2)[C:3]1=[O:4]
Reactant: C=CCBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3nc(C(F)(F)F)[nH]c3c2)c1=O
Agent: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3[nH]c(C(F)(F)F)nc3c2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(C(F)(F)F)nc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 1.3 grams (0.003 mole) of a tautomeric mixture of 1-methyl-3-(2-trifluoromethylbenzimidazol-5-yl)-6-trifluoromethyluracil and 1-methyl-3-(2-trifluoromethylbenzimidazol-6-yl)-6-trifluoromethyluracil (prepared in Example 4) in 15 mL of N,N-dimethylformamide was stirred, and 0.9 gram (0.007 mole) of potassium carbonate was added. The reaction mixture was then stirred at ambient temperature for one hour, and 0.5 gram (0.004 mole) of 3-bromopropene was added in one portion. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for an additional two hours. The reaction mixture was then poured into water, and the resultant solid precipitate was collected by filtration. The solid was washed with water and then with diethyl ether. Thin layer chromatographic analysis of the solid indicated it to be a 1:1 mixture of the proposed products. The solid was subjected to high pressure liquid chromatography, with 5% 1-methylethanol in hexane as the eluant. The appropriate product-containing fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of 1-methyl-3-[1-(2-propen-1-yl)-2-trifluoromethylbenzimidazol-6-yl]-6-trifluoromethyluracil, mp 171°-173° C. (compound 9). Other appropriate product-containing fractions were combined and concentrated under reduced pressure, yielding 0.4 gram of 1-methyl-3-[1-(2-propen-1-yl)-2-trifluoromethylbenzimidazol-5-yl]-6-trifluoromethyluracil, mp 185°-187° C. The NMR spectra were consistent with the proposed structures.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:31]#[N:32].[Na+].[I-].[Na+].O>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][C:31]#[N:32])[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: [C-]#N
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (80 mg, 0.173 mmol), sodium cyanide (17 mg, 0.35 mmol, 2.0 eq.), and sodium iodide (2.6 mg, 0.017 mmol, 0.1 eq.) in anhydrous DMF (1.7 mL) was stirred at 100° C. for 16 h. The reaction mixture was cooled to rt and poured into water. The aqueous layer was extracted with 3×25 mL of EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (47.5 mg, 67%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8.54 (s, 1H), 7.91 (s, 1H), 7.80 (d, 1H), 7.59 (s, 1H), 7.36 to 7.30 (m, 5H), 7.15 (dd, 1H), 6.65 (s, 1H), 5.65 (s, 2H), 3.00 (t, 2H), 2.59 (t, 2H), 2.04 to 1.96 (m, 2H); ES-MS m/z 408.3 [M+H]+, RT (min) 2.95.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9])[CH3:2].Cl[CH:24]([CH3:26])[CH3:25].IC(C)C.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[CH2:5][CH2:6][C:7]([CH:24]([CH3:26])[CH3:25])([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9])[CH3:2]
Reactant: CC(C)Cl
Reactant: CCOC(CCC(C#N)c1ccc(OC)c(OC)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: CCOC(CCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C)OCC
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
The resulting acetal derivative of formula 5 is then alkylated with about 1 eq of an alkylhalide using a strong metallic base and a catalytic amount of an iodide source, e.g., 2-iodopropane or NaI, in a polar aprotic solvent at about 10°-40° C. for 2-18 hours, followed by treatment with sufficient ice water to decompose excess base, to yield a dialkylated derivative of formula 6. For example, 2-(3,3-diethoxypropyl)-2-(3,4-dimethoxyphenyl)acetonitrile (5) in DMF is treated with a slight molar excess of 2-chloropropane (and 0.1-5 mol% 2-iodopropane) at 20° C., stirred for 10 minutes, then treated with 1 eq NaH in mineral oil and slowly heated to 40° C. After adding 200 mL ice water and purifying the product, 2-(3,3-diethoxypropyl)-2-(prop-2-yl)-2-(3,4-dimethoxyphenyl)acetonitrile (6) is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:14]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:14]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Agent: C=CCOc1ccc(C(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
15.0 g of PPE, 2.65 g (15.2 mmol) of the compound (12) and 4.50 g (13.4 mmol) of 4-octyloxy-4'-hydroxybiphenyl were dissolved in 120 ml of chloroform under an argon gas atmosphere and the whole was stirred at room temperature overnight. After addition of water to the reaction mixture, the whole was extracted with methylene chloride. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 5.30 g of 4- (4'-octyloxybiphenyl p-allyloxybenzoate (25) as a white solid (yield: 86.2%).
Reaction SMILES: [C-:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].N1C=CC=CC=1.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CCOCC>[C:21]([O:8][CH2:7][CH2:6][C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:25])[C:22]([CH3:24])=[CH2:23].[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: OCC[c-]1cccc1
Reactant: C=C(C)C(=O)Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(C)C(=O)OCC[c-]1cccc1
Reaction time: 4 h

Procedure:
2-ferrocenylethyl alcohol obtained from Example 1 (0.8 g) is dissolved in 300 ml anhydrous ether and 0.4 g of pyridine are added. The solution of 0.5 ml methacryloyl chloride in 30 ml ether is added dropwise and the reaction is continued for four hours. The precipitate is removed by filtration and the ether solutions are combined, washed with 5% sodium bicarbonate, 5% hydrochloric acid, sodium bicarbonate again and dried. The ether is evaporated, leaving a brown viscous oil that is further purified by chromatography over silica (ether as eluent).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[F:11].C(O)C.O.O.[Sn](Cl)Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of 2-bromo-1-fluoro-4-nitrobenzene (A. Groweiss, Org. Process Res. Dev., 2000, 4, 30-33) in tetrahydrofuran (75 ml) and ethanol (75 ml) was added tin(II) chloride dihydrate and the mixture left to stir at ambient temperature for 4 h. The solvent was evaporated and the residue was treated with ice-cold 2 N sodium hydroxide solution (200 ml). The resulting slurry was stirred for 30 min then extracted with dichloromethane (3×200 ml). The combined organic phase was washed with water (200 ml) and brine (200 ml), dried (MgSO4), filtered and evaporated to give 3-bromo-4-fluorophenylamine (7.92 g, 92%) as a yellow oil: 1H NMR (360 MHz, CDCl3) δ 3.53 (2H, s), 6.53-6.57 (1H, m), 6.83-6.85 (1H, m), 6.90 (1H, dd, J 9, 9 Hz).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[O:13]1[CH2:16][CH:15]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH:15]3[CH2:16][O:13][CH2:14]3)[CH2:18][CH2:19]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: C1CN(C2COC2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCN(C2COC2)CC1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzonitrile (7 g, 1.2 eq, 41.2 mmol), 1-(oxetan-3-yl)piperazine (5.0 g, 1.0 eq, 35.2 mmol) was dissolved in annhydrous DMF (100 mL). K2CO3 (12.2 g, 2.5 eq, 87.9 mmol) was added to the above solution and the reaction mixture was stirred at room temperature for over night. The reaction mixture was diluted with of EtOAc (100 mL) and partitioned with H2O (100 mL). Layers were separated and the aqueous layer was washed once with of EtOAc (100 mL). Combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to leave a crude oil. Purification of the crude mixture by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 1:9 to 4:6) as eluent gave 5-nitro-2-(4-(oxetan-3-yl)piperazin-1-yl)benzonitrile in 97% yield.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([CH2:12][C:13](OCC1C=CC=CC=1)=[O:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C>CCOCC>[CH2:1]([O:8][C:9]([C@@H:10]1[NH:11][C:13](=[O:14])[CH2:12]1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1C[C@H](C(=O)OCc2ccccc2)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
In 485 ml of dry ether was dissolved 45 g (143.8 m mol) of D-aspartic acid dibenzyl ester (42) and after cooling the solution to 0° C. under an argon atmosphere, 20 ml (143.8 m mol) of triethylamine was added dropwise to the solution. Then, 15.6 g (143.9 m mol) of trimethylsilyl chloride was further added dropwise to the mixture at the same temperature as above and the resultant mixture was stirred for one hour. Precipitates thus formed were filtered off under an argon atmosphere and the filtrate was cooled to 0° C. to -5° C. and then 134.8×1.01 m mol of an ether solution of t-butyl magnesium chloride was added dropwise to the mixture with stirring. After further stirring the mixture for 2 hours at 0° C. and then for 3 hours at room temperature, the mixture was cooled to 0° C., 100 ml of 2N HCl (saturated with NH4Cl) was added to the mixture and after stirring the mixture for 30 minutes, 100 ml of a saturated aqueous ammonium chloride solution was added to the mixture. The ether layer thus formed was separated and the aqueous layer was extracted twice each time with 200 ml of ethyl acetate. The ether layer was combined with the ethyl acetate extract, and after washing the mixture with 300 ml of a saturated aqueous ammonium chloride solution and drying with anhydrous magnesium sulfate, ether and ethyl acetate were distilled off under reduced pressure. To the residue was added 10 ml of ethyl acetate to form crystals, which were collected by filtration to provide 13.7 g of (R)-4-benzyloxycarbonyl-2-azetidinone (43). In addition, the mother liquor was concentrated and purified by silica gel column chromatography (eluant:ethyl acetate-n-hexane (2:1)) to provide 5.1 g of the desired product. M. p. 136°-138° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7](=[O:18])[C:8]([CH2:16][OH:17])=[CH:9][CH:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:28](N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[OH:17][CH2:16][C:8]1[C:7](=[O:18])[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:27]([CH3:28])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][C:11]([CH:13]([CH3:15])[CH3:14])=[CH:10][CH:9]=1
Reactant: CCN(CC)CC
Reactant: NCCc1ccccc1
Reactant: CC(C)c1ccc(CO)c(=O)c(OCCCBr)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1ccc(CO)c(=O)c(OCCCN(C)CCc2ccccc2)c1
Yield: 73.6 %

Procedure:
2-(3-bromopropoxy-7-hydroxymethyl 4-isopropyl-2,4,6-cycloheptatrien-1-one (280 mg, 0.89 mmol), N-phenethylamine (0.15 ml, 1.03 mmol), triethylamine (0.15 ml, 1.08 mmol) were dissolved in chloroform (5 ml), and the solution was heated and refluxed for 5 hours. The solution was diluted with dichloromethane, washed with water and dried over sodium sulfate. After solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent: chloroform/methanol (10:1)] to give 242 mg of 7-hydroxymethyl-4-isopropyl-2-[3-(N-methyl-N-phenethylamino)propoxy]-2,4,6-cycloheptatrien-1-one as a yellowish brown oil (yield: 74%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][N:39]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[N:1]1([CH2:7][C:8]2[C:16]([C:17]([F:19])([F:18])[F:20])=[CH:15][C:11]([C:12]([NH:44][C:41]3[CH:42]=[CH:43][N:38]=[N:39][CH:40]=3)=[O:13])=[C:10]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:9]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccnnc1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnnc1)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 50; 120 mg, 0.30 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.11 ml, 0.61 mmol), 4-pyridazinamine (43.3 mg, 0.46 mmol), 1-hydroxy-7-azabenzotriazole (53.7 mg, 0.40 mmol) and EDC (116 mg, 0.61 mmol). The reaction was stirred for 3 hours and the solvent was removed in vacuo to give yellow oil. Purification by MDAP gave the title compound as a white solid. 72 mg.