Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:24])[CH2:19][CH2:20][C:21](Cl)=[O:22]>>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([O:1][C:18](=[O:24])[CH2:19][CH2:20][C:21]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])=[CH:16][CH:17]=2)=[O:22])=[CH:3][CH:4]=1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Product: O=C(CCC(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)Oc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 22.8 g of benzyl p-hydroxybenzoate and 7.7 g of succinic acid dichloride to yield di(p-benzyloxycarbonylphenyl)succinate, m.p. 106°-107° C., as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[CH3:24][O:25][C:26]([C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1)=[O:27]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(O)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cccc(-c2ccc(-n3cc(C(C)(C)O)nc3-c3ccccc3Cl)cc2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
To a 50 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 2-[1-(4-Bromo-phenyl)-2-(2-chloro-phenyl)-1H-imidazol-4-yl]-propan-2-ol (275 mg, 702 μmol), 3-methoxycarbonylphenyl boronic acid (164 mg, 913 μmol), PdCl2dppf (51 mg, 10 mol %), K2CO3 (290 mg, 2.11 mmol), 1,2-dimethoxyethane (13 mL) and H2O (1.5 mL). The reaction solution was allowed to stir at 70° C. for approximately 2 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4 Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 90% EtOAc to afford 122 mg (39% yield) of product. MS (ES): 446.3, 448.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH3:27])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C(O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH3:27])[CH2:2][CH2:3][CH:4]2[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]=3[O:5]2)=[CH:21][CH:20]=1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Reactant: CNCc1ccc(OC)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C)CCC2CN(C)C(=S)c3cccnc3O2)cc1
Reaction time: 4 h

Procedure:
To 40 ml of absolute ethanol was added 5.0 g (0.0194 mole) of 2-(2-chloroethyl-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione, 3.53 g (0.021 mole) of 4-methoxy-N-methylbenzenemethanamine and 2.75 g (0.021 mole) of diisopropylethylamine and the reaction solution heated to reflux for 18 hr. Another 1.0 g (0.006 mole) of 4-methoxy-N-methylbenzenemethanamine was added and heating continued for 4 hr. An additional 1.0 g (0.006 mole) of 4-methoxy-N-methylbenzenemethanamine was added and heating continued overnight. Still an additional 0.6 g (0.0036 mole) of 4-methoxy-N-methylbenzenemethanamine was added and heating continued for 24 hr. The ethanol was removed by rotary evaporation. The residue was taken up in 100 ml of methylene chloride and treated with ~8 ml of acetic anhydride overnight. The methylene chloride was extracted with 3×100 ml of 1N hydrochloric acid. The combined aqueous extracts were washed with 2×100 ml of chloroform, cooled, basified with concentrated sodium hydroxide, and extracted into 3×100 ml of chloroform. The combined organic extracts were dried over sodium sulfate, filtered, concentrated by rotary evaporation, and triturated with isopropyl ether. Because the crystals were still impure, they were dissolved in 100 ml of methylene chloride, washed with 2×50 ml of 4N sodium hydroxide, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was crystallized from isopropyl alcohol to give 4 g (56%) of yellow analytically pure crystals, m.p. 128°-30° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1I>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[Cl:37])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccccc1I
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2Cl)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and l-chloro-2-iodobenzene according to the general procedure C. Obtained as a yellow oil (886 mg).
Reaction SMILES: C([C:3]1[CH:8]([CH3:9])[CH:7]=[CH:6][N:5]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:4]=1)=O.CN(C=O)C.P(Cl)(Cl)(Cl)=O.CN(C=O)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH3:9][CH:8]1[CH:7]=[CH:6][N:5]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:4]=[CH:3]1
Reactant: CC1C=CN(C(=O)Oc2ccccc2)C=C1C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1C=CN(C(=O)Oc2ccccc2)C=C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a dry 500 ml three neck flask under nitrogen, a solution of cuprous iodide (0.28 g, 1.5 mmol) and dimethyl sulfide (8 ml) in 30 ml of dry THF was stirred at room temperature for 10 minutes. Pyridine (2.43 ml, 30 mmol) in 120 ml of dry THF was added to the reaction, then cooled to -25° C. Phenylchloroformate (3.9 ml, 30 mmol) in 10 ml dry THF was added to the reaction via an addition funnel (a thick brown precipitate formed immediately upon addition). The mixture was stirred for 15 minutes. Methyl magnesium chloride (10 ml, 30 mmol) was added to the mixture via syringe whereupon the brown precipitate dissolved. The reaction was stirred at -25° C. for 20 minutes then stirred at room temperature for 20 minutes. 20% NH4Cl(aq) (70 ml) was added to the reaction. The mixture was then extracted with 150 ml diethyl ether. The organic extract was then washed with 40 ml portions of 20% NH4 Cl(aq) /NH4OH (1:1), water, 10% HCl(aq), water, and brine. The organic layer was then dried over NaCl/Na2SO4, filtered, and concentrated to yield 5.9 g of a yellow oil. Kugelrohr distillation (bp. 150°-170° C., 1 mmHg) to yield 4.9 g (77%) of the desired compound (A). B. 3-Formyl-4-methyl-1-(phenoxycarbonyl)-1,4-dihydropyridine To a dry 50 ml flask under nitrogen, DMF (7.44 ml, 97 mmol) in 10 ml of dichloromethane was cooled to 0° C. Phosphorus oxychloride (4.5 ml, 48 mmol) was slowly added to the solution. The solution was stirred at room temperature for 30 minutes. (A) (4.7 g, 22 mmol) in 40 ml of dichloromethane was stirred in a 100 ml two neck flask under nitrogen at 0° C. The DMF/Phosphorus oxychloride solution was transferred to an addition funnel via cannula then slowly added to the (A)/dichloromethane solution. The ice bath was then removed, and the reaction was stirred at room temperature for 20 hours. The reaction was cooled to 0° C. whereupon a solution of potassium acetate (15 g) in 50 ml of water was carefully added via the addition funnel. The mixture was then allowed to reflux for 20 minutes. The methylene chloride layer was separated then extracted once more with 100 ml methylene chloride. The organic phases were combined then washed with 40 ml portions of water, K2CO3(aq), water and brine, then dried over NaCl/Na2SO4. The organics were concentrated on a rotary evaporator to yield 4 g of a brown oil. Purified by flash chromatography over silica gel eluting with ethyl acetate/hexane. Yield 2.0 g (37%) of the desired compound (B).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[I:12]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[C:10]([I:12])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: ClCCl
Product: Clc1nc(Cl)c2c(I)c[nH]c2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.7 %

Procedure:
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 16.0 mmol) in CH2Cl2 (30 mL), N-iodosuccinimide (3.60 g, 16.0 mmol) was added. It was stirred at room temperature for 20 h. The fine precipitate was collected, dried on vacuum to give 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.80 g). MS 314.1 and 316.1 (M+H)
Reaction SMILES: [CH:1]([C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:2].[Br:22]Br>C(O)(=O)C>[Br:22][C:7]1[CH:8]=[C:3]([CH:1]=[O:2])[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:5][CH:6]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2C=O)CC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2C=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
tert-Butyl 4-(3-formylpyridin-2-yl)piperazine-1-carboxylate (1.88 g) was dissolved in acetic acid (20 ml), and bromine (1.03 g) was added dropwise thereto, followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. The obtained residue was subjected to liquid separation by the addition of CHCl3 and a 1 M aqueous NaOH solution. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 4-(5-bromo-3-formylpyridin-2-yl)piperazine-1-carboxylate (2.05 g).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Zn+2:10]>>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[Zn+2:10].[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Zn+2]
Product: C=CC(=O)[O-]

Procedure:
In this experiment, acrylic acid was reacted with zinc carbonate to form zinc acrylate prior to addition of the other components. The reagent systems was prepared to contain 8% acrylic acid, 6.9% zinc carbonate, 0.25% MBA, 8% DMDHEU, 2% polyethylene softener, 0.1% wetting agent, and 0.5% K2S2O8. Samples of fabric that were impregnated with this reagent solution to wet pickups of approximately 110% were placed on pin frames in heat-resistant plastic bags that were flushed with nitrogen and sealed. In these bags, fabrics were subjected to 3 different curing conditions: (a) 120° C for 10 minutes followed 160° C for 5 minutes, (b) 120° C for 10 minutes followed by removal from bag and 160° C for 5 minutes, and (c) at 160° C for 15 minutes. The samples of fabric were rinsed extensively in hot-running tap water and line dried. Weight increases due to reaction of reagents were (a) 22.2%, (b) 23.6%, and (c) 21.7%; the DP appearance ratings for these 3 samples were 4.2, 4.5, and 4.3, respectively. The textile performance properties are summarized in Table I. In all three cases attractive levels of resilience and Accelerotor abrasion resistance were obtained. Sample (a) was tested and found to be 100% effective against S. epidermidis in the modified Quinn test.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][NH:17]1>>[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][N:17]1[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C1Cc2c(OCCCl)ccc(F)c2N1
Product: O=C1Cc2c(OCCN3Cc4ccccc4C3)ccc(F)c2N1
Yield: 75 %

Procedure:
4-(2-Chloroethoxy)-7-fluoro-1,3-dihydro-indol-2-one was reacted with isoindoline in the same manner described for intermediate 16 to afford the title compound in 75% yield as a thick oil. The fumarate salt was prepared in ethanol: mp 210°-212° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][S:6][C:7](=[S:17])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)#[N:2].Cl.[OH2:19]>>[C:1]([CH2:3][CH2:4][CH2:5][S:6][C:7](=[S:17])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)(=[O:19])[NH2:2]
Reactant: N#CCCCSC(=S)NCc1ccc(Cl)cc1
Reactant: O
Agent: Cl
Product: NC(=O)CCCSC(=S)NCc1ccc(Cl)cc1

Procedure:
29.2 G. of 3-cyanopropyl(p-chlorobenzyl)dithiocarbamate were suspended in 150 ml. of concentrated hydrochloric acid and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. After washing, drying and concentration of the ethyl acetate phases, 18.1 g. of 3-carbamoylpropyl)p-chlorobenzyl)dithiocarbamate were crystallized from ethyl acetate/diisopropyl ether; melting point 123°-125° C.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[O:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1>C1COCC1>[OH:19][C:20]1([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24][CH2:25]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2cncc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
Isopropylmagnesium chloride-lithium chloride complex (1.0M in THF) (5.31 mL, 5.31 mmol) was added dropwise to 3-bromo-5-(trifluoromethyl)pyridine (1.20 g, 5.31 mmol) in THF (10 mL) cooled to 0° C. over a period of 10 minutes. The resulting solution was stirred at 0° C. for 1 hour then benzyl 4-oxo-1-piperidinecarboxylate (1.24 g, 5.31 mmol) in THF (5 mL) was added dropwise. The mixture was allowed to warm slowly to room temperature and stirred for a further 1 hour before quenching with aqueous ammonium chloride (25 mL). The mixture was then extracted with tert butyl methyl ether. The extract was washed with water followed by saturated brine, dried over MgSO4, concentrated by evaporation then purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford benzyl 4-hydroxy-4-[5-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxylate (1.32 g, 65%) as a pale yellow oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]([O:21][CH3:22])=[CH:12][CH:13]=[C:14]2[C:19]=1[C:18](=[O:20])[NH:17][CH2:16][CH2:15]2>CN(C)C=O>[NH2:9][C:10]1[C:11]([O:21][CH3:22])=[CH:12][C:13]([Cl:1])=[C:14]2[C:19]=1[C:18](=[O:20])[NH:17][CH2:16][CH2:15]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1N)C(=O)NCC2
Solvent: CN(C)C=O
Product: COc1cc(Cl)c2c(c1N)C(=O)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
N-chlorosuccinimide (20 g, 0.147 mol) was added to a solution of 8-amino-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (296c, 24 g, 0.125 mol) in N,N-dimethylformamide (250 mL) and stirred at room temperature overnight. The solution was partitioned between water (100 mL) and ethyl acetate (5×100 mL). The combined organic extracts were washed with brine (5×100 mL), dried over sodium sulfate, and concentrated to dryness. The residue was triturated with acetonitrile (200 mL), and the solids collected by filtration. After drying, 8-amino-5-chloro-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (296d, 12.5 g, 44% yield) was obtained as a blue solid. 1H NMR (400 MHz, DMSO-d6): δ 7.84 (s, 1H), 6.93 (s, 1H), 3.80 (s, 3H), 3.29-3.25 (m, 2H), 2.81-2.78 (t, J=6.6 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=1.[OH-:19].[Na+]>O.CS(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: O=Cc1ccc(-c2ncnc3ccc(Br)cc23)s1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
A solution of 2.19 g silver nitrate in 40 mL water and a solution of 1.96 g 5-(6-bromoquinazolin-4-yl)thiophen-2-carboaldehyde (compound in Production Example 381) in 20 mL dimethyl sulfoxide were added little by little successively to a solution of 1.0 g sodium hydroxide in 40 mL water under ice-cooling, and the mixture was stirred at room temperature for 24 hours. The reaction solution was filtered through Celite and acidified with hydrochloric acid, and the precipitated crystals were filtered. This product was recrystallized from dichloromethane/methanol/ether, to give 1.7 g of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([CH3:31])([CH2:22][O:23][Si](C(C)(C)C)(C)C)[CH:4]([NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[CH3:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCC>C1COCC1>[CH3:32][N:2]([CH3:1])[C:3]([CH3:31])([CH2:22][OH:23])[CH:4]([NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[CH3:20])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(C(=O)NC(c2ccccc2)C(C)(CO[Si](C)(C)C(C)(C)C)N(C)C)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)NC(c2ccccc2)C(C)(CO)N(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A solution of (±)-N-(2-(dimethylamino)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-1-phenylpropyl)-2,3-dimethylbenzamide D49 (56 mg; 0.12 mmol) in THF (5 ml) was treated with a solution of tetrabutylammonium fluoride (1.0M solution in THF; 0.2 ml, 0.2 mmol) and the mixture stirred at room temperature overnight. The mixture was poured directly onto a chromatography column (Flashmaster II; eluent 0-100% ethyl acetate/pentane) to afford the title compound (38 mg; 63%). 1H NMR (CDCl3) δ: 0.73 and 1.14 (3H, 2×s), 1.70-2.50 (1H, br s), 2.26 (6H, q), 2.38 and 2.48 (6H, 2×s), 3.17, 3.39, and 3.55 (2H, 3×d), 5.26 and 5.46 (1H, 2×d), 6.83 and 7.89 (1H, 2×br d), 7.07-7.46 (8H, br m). Mass spectrum (Electrospray LC/MS), API+: Found 341 (MH+), C21H28N2O2Si requires 340. Ret. time 1.71 and 1.76 min.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)C(C)C)(C)C>C(#N)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 94.6 %

Procedure:
A solution of 4-(2-keto-1-benzimidazolinyl)piperidine (10.0 g, 46 mmol), ethyl bromoacetate (5.1 mL, 46 mmol) and N,N-diisopropylethylamine (8.8 mL, 50.6 mmol) in acetonitrile (200 mL) was heated at reflux for 1 hour. The solvent was evaporated in vacuo, and the residue was suspended in water (˜200 mL). The suspension was made basic with the addition of a saturated aqueous solution of sodium bicarbonate. The resultant solid was collected by filtration, washed with water and dried in vacuo to give the ethyl (4-(2-keto-1-benzimidazolinyl)piperidin-1-yl)acetate as a colorless solid (13.2 g, 94%). MS m/z 304 (MH+); NMR(CDCl3): δ 1.32 (t, 3 H), 1.84 (br d, 2 H), 2.40-2.66 (m, 4 H), 3.13 (br d, 2 H), 3.31 (s, 2 H), 4.23 (q, 2 H), 4.45-4.49 (m, 1 H), 6.99-7.10 (m, 2 H), 7.12-7.19 (m, 1 H), 7.27-7.34 (m, 1 H) and 10.54 (brs, 1 H).
Reaction SMILES: [CH:1](=[C:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH2:2]C.[Na].[C:11](OC)(=O)[CH2:12]C(C)=O>CO>[CH2:11]=[CH:12][C:5](=[O:9])[CH2:6][CH2:7][CH2:8][CH2:4][CH2:1][CH3:2]
Reactant: COC(=O)CC(C)=O
Reactant: CCC=C1CCCC1=O
Agent: [Na]
Solvent: CO
Product: C=CC(=O)CCCCCC

Procedure:
The procedure of Example 1 is repeated with 19.5 g (0.16 mol) of propylidene cyclopentanone, 0.46 g (0.02 g-atom) of sodium, 21 g (0.18 mol) of methyl acetoacetate and 100 ml of methanol. Fractional distillation yields 14 g (bp 95°-102° C. at 0.5 mm) of 5-ethylbicyclo [4.3.0.] non-1-en-3-one having the structure: ##STR8##
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=3)[C:22]([OH:24])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH3:32]O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=3)[C:22]([O:24][CH3:32])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)ccc1C
Temperature: 25 °C
Yield: 90 %

Procedure:
To a stiffed mixture of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylbenzoic acid (compound 39.3, 1.392 g, 4.00 mmol, 1.00 equiv) in methanol (50 mL) was added sulfuric acid (784 mg, 7.99 mmol, 2.00 equiv), dropwise. The resulting mixture was heated to reflux overnight in an oil bath. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residue was diluted with 20 mL of EtOAc and was washed with 1×100 mL of saturated sodium bicarbonate(aq) followed by 1×100 mL of brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield 1.303 g (90%) of the title compound as a white solid.
Reaction SMILES: Br[CH:2]([CH2:15][CH2:16][CH2:17][CH2:18]Br)[C:3]([O:5][CH:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[Na+].[I-].C(N(CC)CC)C.Cl.[CH2:30]([NH2:33])[CH:31]=[CH2:32]>O1CCCC1>[CH2:30]([N:33]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:2]1[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4])[CH:31]=[CH2:32]
Reactant: CC(OC(=O)C(Br)CCCCBr)C(=O)N1CCCC1
Reactant: C=CCN
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN1CCCCC1C(=O)O[C@@H](C)C(=O)N1CCCC1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
TO 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2,6-dibromohexanoate (295 mg, 0.75 mmol), NaI (225 mg, 1.5 mmol), triethylamine (303 mg, 3.0 mmol) and tetrahydrofuran (4 mL) were added. Subsequently, allylamine hydrochloride (84.2 mg, 0.9 mmol) and tetrahydrofuran (4 mL) were added thereto. The mixture was stirred at 20° C. for 4 hours and then at 40° C. for 15 hours. It was confirmed with NMR analysis of the reaction solution that the conversion ratio was 100% and the diastereo ratio was 75:25.