Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([O:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: O=C(NCCCO)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCCNC(=O)OCc1ccccc1
Yield: 111 %

Procedure:
In 200 ml of methylene chloride was dissolved 21 g of the 3-(benzyloxycarbonylamino)propanol, and 11 g of triethylamine was added thereto, after which 8.6 g of acetyl chloride was added thereto dropwise at -10° C. to -5° C. The resulting mixture was subjected to reaction at the same temperature for 1 hour. Subsequently, at room temperature, the reaction mixture was washed successively with 50 ml of diluted hydrochloric acid, 50 ml of a saturated aqueous sodium hydrogencarbonate solution and 50 ml of water, and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 28 g of oily 1-acetoxy-3-(benzyloxycarbonylamino)propane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:14]2[B:15]([OH:18])[O:16][CH2:17][C:13]=2[CH:12]=1)[C:5]#[N:6].[CH:21]1(I)[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C)C=O.[H-].[Na+]>O>[CH:21]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][C:11]2[CH:20]=[CH:19][C:14]3[B:15]([OH:18])[O:16][CH2:17][C:13]=3[CH:12]=2)[C:5]#[N:6])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(O)c1
Reactant: IC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
A solution of 3-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.500 g, 1.87 mmol), cyclopentyl iodide (0.65 mL, 5.61 mmol), and N,N-dimethylformamide (30 mL) under a nitrogen balloon was cooled to 0° C. on an ice water bath. Sodium hydride (0.224 g, 5.61 mmol) was added and then the reaction was stirred for 5 minutes on the ice water bath. The reaction was then stirred at room temperature for 2 hours. More cyclopentyl iodide (0.22 mL, 1.87 mmol) was added and the reaction was cooled to 0° C. on an ice water bath. Sodium hydride was added (0.075 g, 1.87 mmol) and the reaction was stirred at 0° C. for 5 minutes. The reaction was then stirred at room temperature for another 2 hours. Water was added to quench excess sodium hydride and the reaction was then neutralized using 1 M HCl. Water was added and the solution was extracted using ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 3-(cyclopentyloxy)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.396 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (m, 2H), 1.38 (m, 2H), 1.50 (m, 2H), 1.73 (m, 2H), 4.86 (m, 2H), 6.84 (s, 1H), 6.87 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 9.06 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1)[CH3:2].P([O-])(O)(O)=[O:11].[Na+].Cl([O-])=O.[Na+].[OH-].[Na+]>C(#N)C.O.OO>[CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:11])=[O:9])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=O)s1
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: CCc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 210.5 %

Procedure:
1,3-Dimethyl-2-(2-thienyl)imidazolidine (5.46 g) (synthesized in accordance with the method described in Tetrahedron, 41, 3803 (1985)) and N,N,N',N'-tetramethylethylenediamine (4.7 ml) were dissolved in tetrahydrofuran (150 ml). The mixture was cooled to -78° C., and n-butyllithium (1.6M in hexane, 19.5 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours, and iodoethane (2.4 ml) was added. The mixture was slowly heated to room temperature and then stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and 10% sulfuric acid (200 ml) was added to the residue. The mixture was stirred for 24 hours and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-ethyl-2-thiophenecarbaldehyde (1.68 g) as oil. 5-ethyl-2-thiophenecarbaldehyde (1.68 g) was dissolved in acetonitrile (20 ml), and sodium dihydrogen phosphate (0.54 g) in water (10 ml) and 30% hydrogen peroxide (2.0 ml) were added. Sodium chlorite (3.0 g) in water (20 ml) was then added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-ethyl-2-thiophenecarboxylic acid (1.48 g) as crystals.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:40][C:39]([CH3:41])=[N:38][C:37]=2[C:42](O)=[O:43])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[S:40][C:39]([CH3:41])=[N:38][C:37]=2[C:42]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]2[CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[O:43])=[CH:34][CH:35]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.3 %

Procedure:
To a solution of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (100 mg, 387 μmol) in DMF was added DIPEA (202 μL, 1.16 mmol) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (137 mg, 580 μmol) and HATU (176 mg, 465 μmol). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1 M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give 2-(((2S,3R)-1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione as a light yellow oil (130 mg, 71%). MS (ESI) 478 (M+H).
Reaction SMILES: C(O)C.Cl.[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[OH:19])([CH3:8])([CH3:7])[CH3:6].[N:20]([O-])=[O:21].[Na+]>O>[N:20]([C:13]1[CH:14]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:10]([OH:19])=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=1)=[O:21]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
Ethanol (75 ml) was cooled to 15° C and saturated with hydrogen chloride gas. This solution was diluted by addition of another 400 ml of ethanol. To this alcoholic solution was added 82.4 grams of 2,6-di-tert-butylphenol. After it was dissolved, a solution of 30.4 grams of sodium nitrite in 40 ml of water was added at 15°-20° C over a period of one hour with stirring. Stirring was continued for another two hours with the temperature allowed to rise to room temperature. The solution was diluted with 200 ml of water, and the product formed was collected by filtration and washed well with water. The filter cake was then slurried in 300 ml of petroleum ether, filtered, washed with another 100 ml of petroleum ether and dried in a vacuum oven at 70°-80° C to yield the desired intermediate 4-nitroso-2,6-di-tert-butylphenol, melting at 219° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([OH:17])[CH2:14][N:13]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])(=O)=O)=CC=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:18]([N:13]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:12]2[CH2:11][N:35]2[C:34](=[O:36])[C:33]3=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]3[C:31]2=[O:41])=[O:19])=[CH:27][CH:26]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxypyrrolidine-2-methanol p-toluenesulfonate (24 g: 55.1 mmole) in dimethylformamide (200 ml), potassium phthalimide (15.3 g) is added. The mixture is stirred at 80° C. for 4 hours. The reaction mixture is diluted with ethyl acetate, successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate=1:2) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxy-2-phthalimidomethylpyrrolidine (18.1 g). Yield: 80%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-]>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[CH2:9][C:10](=[O:12])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:5]=2[CH:4]=1
Reactant: COc1ccc(CC(=O)O)c(Oc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)Oc1ccccc1C(=O)C2
Reaction time: 2.5 h
Yield: 47.8 %

Procedure:
A solution of 2-(4-methoxy-2-phenoxyphenyl)acetic acid (594 mg, 2.3 mmole) in thionyl chloride (10 mL) was heated at reflux for 30 min, then was concentrated to dryness, and the residue was reconcentrated from toluene. The resulting residue was dissolved in dry CH2Cl2 (3 mL), and the solution was added dropwise at RT to a suspension of AlCl3 (673 mg, 5.06 mmole) in dry CH2Cl2 (4 mL) in a flame-dried flask under argon. After stirring for 2.5 hr, the mixture was diluted with CH2Cl2 (10 mL) and washed sequentially with 1.0 N NaOH and brine. Drying (MgSO4), concentration, and flash chromatography on silica gel (5% EtOAc/hexanes) gave the title compound (264 mg, 48%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ3.80 (s, 3 H), 4.02 (s, 2 H), 6.74-8.08 (m, 7 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:16]=[CH:17][CH:18]=[C:4]2[N:3]=1.O=P(Cl)(Cl)Cl.CN([CH:27]=[O:28])C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[N:5]2[N:16]=[CH:17][C:18]([CH:27]=[O:28])=[C:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc2ccnn12
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc2c(C=O)cnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To tert-butyl 5-chloropyrazolo[1,5-a]pyrimidin-7-ylcarbamate (3.7 g, 13.8 mmol) in DMF (36 mL), POCl3 (7.7 mL, 82.9 mmol) was added dropwise at 0° C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 8 hours. Then, the reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water then the solid was collected by filtration. The solid was washed several more times with water and dried under vacuum overnight. The product, tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-ylcarbamate, was collected as a solid in 27% yield. The product did not ionize on LCMS unless first deprotected using TFA/DCM (1:1). LCMS (M+1=197)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][C@@H:13]3[C@H:9]2[CH2:10][N:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:12]3)=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20].C(N(CC)CC)C>O1CCCC1>[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]3[CH2:14][C@@H:13]4[C@H:9]3[CH2:10][N:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:12]4)=[CH:6][CH:7]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc(N)cc3)[C@@H]2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(C(C)C)cc4)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 113.3 %

Procedure:
0.935 g of 1-((1R,5S,6R)-6-(4-amino-phenyl)-3-aza-bicyclo[3.2.0]hept-3-yl)-propan-1-one (3.83 mmol) were dissolved in 30 ml of tetrahydrofuran and 0.795 g of 4-isopropylbenzenesulfonyl chloride (3.64 mmol) and 1.6 ml of triethylamine (11.48 mmol) were added. After stirring for 18 h at room temperature, the solvent was evaporated under reduced pressure, the remaining material was partitioned between diethyl ether and water that was adjusted to alkaline pH with 1 N aqueous sodium hydroxide. The aqueous layer was reextracted three times with diethyl ether, and the combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated to yield 1.76 g of crude product that was used in the subsequent reaction step without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][NH:16][C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(OCC)(O[CH2:28][CH3:29])(=O)=O.C(O)(=O)C>C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]([CH2:28][CH3:29])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(C)=O)CC3)nc21
Temperature: 25 °C

Procedure:
To a solution of 0.45 g of 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid in 30 ml of sodium carbonate was added two 0.5 ml portions of diethyl sulfate with stirring at room temperature. After the completion of the reaction the mixture was neutralized with acetic acid. The precipitate resulted was collected and recrystallized from dimthylformamide to yield 0.4 g of the product, m.p. 298° - 300°C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[S:12][N:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].O1CCOCC1.Cl>O>[S:12]1[C:13]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=[N:11]1
Reactant: COC(=O)c1cccc2nnsc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc2nnsc12
Temperature: 40 °C
Reaction time: 4 h

Procedure:
100 g (0.51 mol) of 7-methoxycarbonylbenzo-1,2,3-thiadiazole are suspended in 1000 ml of water, and then 310 ml of 2N sodium hydroxide solution and 5 ml of dioxane are added. The reaction mixture is heated to 40° C., is stirred for 4 hours at that temperature and is then cooled to 10° C. A further 1000 ml of water are added and the batch is neutralised with 310 ml of 2N hydrochloric acid. The resulting precipitate is isolated by filtration, lightly dried in a current of air and then dissolved in tetrahydrofuran and the solution is dried over magnesium sulfate, filtered and concentrated. The crystals are suspended in hexane, isolated by filtration and dried.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([N+:13]([O-])=O)[CH:9]=[CH:10][C:11]=1[Cl:12]>C(O)C.Cl.O.[OH-].[Na+]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[Cl:12])[NH2:13]
Reactant: CN(C)CCOc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)CCOc1cc(N)ccc1Cl

Procedure:
A solution of 3-(2dimethylaminoethoxy)-4chloronitrobenzene (D57) (295 mg) in ethanol (5 ml) was heated to 60° C. and treated dropwise with a solution of stannous chloride (0.82 g) in concentrated hydrochloric acid (1.5 ml) with stiring. After heating to reflux for 1/2 h, the reaction mixture was cooled, diluted with water and basified with 40% NaOH, then extracted into dichloromethane. The dried (Na2SO4) organic phase was evaporated under reduced pressure to give the title compound as a yellow oil. (221 mg, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27](O)[CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][CH2:27][O:8][C:7](=[O:9])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(OCCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 9 h
Yield: 77 %

Procedure:
A mixture of 30 g 3,5-dinitrobenzoic acid, 0.8 g p-toluenesulfonic acid and 100 ml 1,3-propanediol was stirred 9 hours at 110° C. After cooling, a white product crystallized and was separated from solution by filtration after adding a large quantity of water. The product was recrystallized from methanol to provide 77% white crystals with m.p. 76° C. IR: 1712 cm-1 (carbozyl) 1535 cm-1 (nitro asymmetric), 1341 cm-1 (nitro symmetric). 1H-NMR (DMSOd6): 9.05 ppm (C4), 8.93 ppm (C2, C6), 4.47 ppm (CH2OCO, triplet) 3.62 ppm (CH2O, triplet), 1.94 ppm (CH2 multiplet).
Reaction SMILES: BrC1N2C=NC=C2C(=O)N(CC2C=CC(OC)=CC=2)C=1.[CH:21]([N:34]1[C:38]2[CH:39]=[C:40](Br)[CH:41]=[CH:42][C:37]=2[O:36][C:35]1=[O:44])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClC1C=CC(O)=C(B(O)O)C=1.[CH2:56]([O:63][C:64]1[CH:69]=[CH:68][C:67]([CH3:70])=[CH:66][C:65]=1B(O)O)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[CH:21]([N:34]1[C:38]2[CH:39]=[C:40]([C:69]3[CH:68]=[C:67]([CH3:70])[CH:66]=[CH:65][C:64]=3[O:63][CH2:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH:41]=[CH:42][C:37]=2[O:36][C:35]1=[O:44])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1oc2ccc(Br)cc2n1C(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(OCc2ccccc2)c(B(O)O)c1
Agent: COc1ccc(Cn2cc(Br)n3cncc3c2=O)cc1
Agent: OB(O)c1cc(Cl)ccc1O
Product: Cc1ccc(OCc2ccccc2)c(-c2ccc3oc(=O)n(C(c4ccccc4)c4ccccc4)c3c2)c1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations to replace 5-bromo-7-(4-methoxybenzyl)imidazol[1,5-a]pyrazin-8(7H)-one with 3-benzhydryl-5-bromobenzo[d]oxazol-2(3H)-one and (5-chloro-2-hydroxyphenyl)boronic acid with (2-(benzyloxy)-5-methylphenyl)boronic acid, 3-benzhydryl-5-(2-(benzyloxy)-5-methylphenyl)benzo[d]oxazol-2(3H)-one was obtained as a colorless solid in quantitative yield (1.05 g): 1H NMR (300 MHz, CDCl3) δ7.30-7.16 (m, 17H), 6.98 (dd, J=8.3, 1.7 Hz, 1H), 6.80-6.76 (m, 3H), 6.68 (s, 1H), 4.95 (s, 2H), 2.24 (s, 3H); MS (ES+) m/z 497.8 (M+1).
Reaction SMILES: [CH2:1]([C:6]1(C(C(OC)=O)C(=O)C)[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]>O>[CH2:1]([CH:6]1[CH:10]([CH2:6][C:7](=[O:11])[CH3:8])[CH2:9][CH2:8][C:7]1=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1(C(C(C)=O)C(=O)OC)CCCC1=O
Solvent: O
Product: CCCCCC1C(=O)CCC1CC(C)=O
Yield: 176 %

Procedure:
567 g of 2-n-pentyl-(1-carbomethoxy-2-oxopropyl)-1-cyclopentanone were mixed with an equal weight of water and heated according to the process described in Example 1 (b). There were obtained 391 g of 2-n-pentyl-3-(2-oxopropyl)-1-cyclopentanone (overall yield=80% based on the amount of 2-n-pentyl-cyclopent-2-en-1-one consumed) having the physical constants shown in Example 1 (b).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:6]([F:16])[C:5]([CH:17](Br)Br)=[CH:4][CH:3]=1.C([OH:23])(C)C.O>[N+]([O-])([O-])=O.[Ag+].ClCCl>[C:8]([C:7]1[C:6]([F:16])=[C:5]([CH:4]=[CH:3][C:2]=1[Cl:1])[CH:17]=[O:23])(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)O
Reactant: O=C(c1ccccc1)c1c(Cl)ccc(C(Br)Br)c1F
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(Cl)c(C(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Step 4 A mixture of (6-chloro-3-dibromomethyl-2-fluoro-phenyl)-phenyl-methanone (582 mg, 1.38 mmol), silver nitrate (469 mg, 2.76 mmol), isopropanol (10 ml) and water (2 ml) was stirred at room temperature overnight. Dichloromethane was added and the mixture was filtered under suction washing with isopropanol. The organic liquors were concentrated then purified by silica chromatography eluting with 0-20% ethyl acetate/petroleum ether furnishing 3-benzoyl-4-chloro-2-fluoro-benzaldehyde (222 mg oil, 90% clean). Analytical data as above
Reaction SMILES: [C:1]([CH:3]([N:14]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13])#[N:2].O.C(O)(=O)C>O1CCCC1>[NH2:14][C@H:3]([C:1]#[N:2])[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13]
Reactant: N#Cc1ccc(CC(C#N)N=C(c2ccccc2)c2ccccc2)c(F)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1ccc(C[C@H](N)C#N)c(F)c1

Procedure:
A solution of 4-{2-cyano-2-[(diphenylmethylene)amino]ethyl}-3-fluorobenzonitrile from step 2 (24.5 g) in tetrahydrofuran (190 ml) is treated with water (45 ml) then with acetic acid (90 ml) and let stir for 24 h at 40° C. Approximately 75% of the volatiles were then removed under reduced pressure. The residual solution is diluted with water (100 ml) and 1 N hydrochloric acid (25 ml), extracted with 2 portions (100 ml each) of diethyl ether then was made basic with 8N potassium hydroxide and aqueous potassium phosphate until pH 9-10 was reached. The aminonitrile was extracted with three portions (300 ml each) of ethyl acetate. The pooled organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The orange product gum was dissolved in ethanol (20 ml) and diluted with hexanes (20 ml). Aliquots of 500 mg were injected on chiralcel AD column using 50% ethanol:50% hexanes isocratic conditions. The faster nitrile is the wrong enantiomer (Rt=19 min) while after evaporation and coupling (step 4) the slower enantiomer (t=24 min) will lead to the potent diastereomer of the (2S)—N-[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-4-fluoro-4-methyl-2-({1(S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}amino) pentanamide that is assumed to be of S configuration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:37]2[C:38]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3F)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.