Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7](=[O:17])[CH2:8][NH:9][C:10](=[O:16])OC(C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.NCC(C1CCCCC1)=O.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:41]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=3[Cl:49])[N:40]=[C:39](C(O)=O)[C:38]=2[CH3:53])=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.O1CCOCC1.CN(C=O)C>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[N:41]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=3[Cl:49])[N:40]=[C:39]([C:10]([NH:9][CH2:8][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:17])=[O:16])[C:38]=2[CH3:53])=[CH:35][CH:36]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NCC(=O)C1CCCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: Cc1c(C(=O)NCC(=O)C2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To a tert-butyl 2-cyclohexyl-2-oxoethylcarbamate (228 mg, 0.946 mmol) in DCM (5 mL) was added 4M HCl in 1,4-dioxane (5 mL) at room temperature. The reaction continued for an hour at room temperature. The volatiles were removed under vacuum. To the residue (2-amino-1-cyclohexylethanone hydrochloric acid), 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (361 mg, 0.946 mmol), EDCI (272 mg, 1.429 mmol), HOBt (192 mg, 1.429 mmol) in DMF (9 mL) was added NMM (1.0 mL, 9.46 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The residue was purified by reverse-phase prep HPLC to afford the title compound (232 mg, 49%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Li]CCCC.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][N:22]1[C:32]2[C:27](=[C:28]([Br:33])[CH:29]=[CH:30][CH:31]=2)[C:25](=[O:26])[C:23]1=[O:24])[CH3:18].[NH4+].[Cl-]>CCOCC>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][N:22]1[C:32]2[C:27](=[C:28]([Br:33])[CH:29]=[CH:30][CH:31]=2)[C:25]([OH:26])([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:23]1=[O:24])[CH3:35]
Reactant: Brc1cnc2ccccc2c1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCN(CC)CCN1C(=O)C(O)(c2cnc3ccccc3c2)c2c(Br)cccc21
Temperature: 25 °C
Yield: 4.7 %

Procedure:
To 3-bromoquinoline (56.3 mg, 1.1 eq) in anhydrous Et2O (1.0 mL) at −50° C. (internal temperature) and under a nitrogen atmosphere was added n-BuLi (0.18 mL, 1.1 eq, 1.53 M in hexanes). Stirring was continued for minutes and then to the resulting red/brown coloured precipitate was added 1-(2-diethylaminoethyl)-4-bromoisatin (80.0 mg, 2.46×10−4 mol) in anhydrous Et2O (2.0 mL) and the resulting dark blue coloured mixture was stirred for a further 8.5 hours at −50° C. Saturated aqueous NH4Cl (1.5 mL) was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration, the solvent was removed in vacuo. Purification was carried out by flash chromatography (silica gel, eluting 2% MeOH in CHCl3) to yield the title compound as a yellow oil (5.3 mg, 5%).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].[I:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[F:6][C:7]1[C:8]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:10]([OH:13])=[C:11]([I:18])[CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc(C(F)(F)F)c(F)cc1I
Reaction time: 1 h
Yield: 119.2 %

Procedure:
Concentrated sulfuric acid (0.78 mL. 15.0 mmol) was added to a mixture of 4-fluoro-3-(trifluoromethyl)phenol (8.00 g, 44.4 mmol) and N-iodosuccinimide (5.00 g, 22.2 mmol) in acetic acid (40 mL) at 0° C. After 1 hour, the ice bath was removed and an additional portion of N-iodosuccinimide (1.50 g. 6.67 mmol) added. After an additional 1 hour at ambient temperature, the final portion of N-iodosuccinimide (1.0 g, 4.4 mmol) was added. The reaction mixture was stirred for 1 hour then diluted with water (300 mL), treated with 20 wt % aqueous sodium thiosulfate, and extracted with ether (3×100 mL). The combined organic layers were washed with aqueous sodium thiosulfate then brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by automated silica gel flash chromatography (100% hexanes to 50% dichloromethane in hexanes gradient elution) to afford the title compound as a yellow oil (8.1 g).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH:18]=[CH:17]2.[N:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:45]3[CH2:46][CH2:47][N:42]([C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)[CH2:43][CH2:44]3)=[O:32])=[CH:34][CH:35]=1)(=[O:26])=[O:25])[CH:18]=[CH:17]2
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)cc1)N1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
1,1′-Carbonyldiimidazole (0.15 g) was added to a stirred solution of 4-(6-chloronaphth-2-ylsulphonyl)benzoic acid (0.29 g) in DMF (10 ml) which had been cooled to 0° C. and the mixture was stirred at 0° C. for 30 minutes. N-(4-Pyridyl)piperazine (0.164 g) was added, the cooling bath was removed and the mixture was stirred at ambient temperature for 16 hours. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was washed with water and with brine, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether to give 1-[4-(6-chloronaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine (0.085 g), m.p. 267-269° C.;
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[F:23][C:24]([F:29])([F:28])[S:25]([O-])=O.[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[C:3]=1[S:25][C:24]([F:29])([F:28])[F:23]
Reactant: O=S([O-])C(F)(F)F
Reactant: N#Cc1cc(N)n(-c2cc3c(cc2Cl)C(F)(F)OC3(F)F)n1
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: N#Cc1nn(-c2cc3c(cc2Cl)C(F)(F)OC3(F)F)c(N)c1SC(F)(F)F
Temperature: 55 °C
Reaction time: 10 h
Yield: 46.2 %

Procedure:
To a suspension wherein 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyanopyrazole (665 mg, 2.00 mmol), sodium trifluoro-methanesulfinate (624 mg, 4.00 mmol) and dimethylamine tosylate (1.086 g, 5.00 mmol) are in toluene (5 ml), thionyl chloride (476 mg, 2.00 mmol) was added dropwise under ice cooling over a period of about 10 minutes and stirred at 50 to 60° C. for 10 hours. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 400 mg of 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyano-4-trifluoromethylsulfenylpyrazole.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([I:1])=[N:3]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: IC1CCCC1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2C1CCCC1
Yield: 60 %

Procedure:
A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 1.53 mmol) and K2CO3 (1 g, 6 mmol) in DMF (5 ml) was stirred at room temperature under an argon atomosphere. Iodocyclopentane (1.0 g, 0.0084 mol) was added with a syringe. Reaction was refluxed under argon atmosphere for 2 hours. Solid K2CO3 was removed by filtration. Solvent was partially removed in vacuo. Sodium citrate (50 ml) was added and reaction was extracted with EtOAc. Organic phases concentrated in vacuo and purified using silica gel column chromatography [MeOH—CH2Cl2, 5:95] yielding BA80 (300 mg, 60% yield). ESI-MS (M+H)+ m/z calcd 330.0, found 330.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:10][C:11]1[N:16]=[CH:15][C:14]2[C:17](I)=[N:18][N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[Cl:10][C:11]1[N:16]=[CH:15][C:14]2[C:17]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=3[O:2][CH3:1])=[N:18][N:19]([C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:13]=2[CH:12]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1N
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: Cc1ccccc1
Product: COc1ccccc1Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 80 °C
Yield: 76.7 %

Procedure:
A mixture of 2-methoxyaniline (0.18 g), 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (0.50 g), Cs2CO3 (0.94 g), and (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride (0.071 g) in toluene (6 mL) was degassed and back filled with nitrogen (3 times) before it was heated at 80° C. for overnight. The reaction was cooled and diluted with ethyl acetate (15 mL) and water (10 mL). The mixture was filtered through celite and the filtrate was separated, the organic layer was wash with with brine (10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/isohexane=25% to give 6-chloro-N-(2-methoxyphenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (380 mg, 77% yield) as a brown solid.
Reaction SMILES: C([N:8]1[C:12]2[C:13](=[O:38])[N:14]([CH3:37])[C:15]([CH:28]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:29]([OH:31])=[O:30])=[C:16]([C:17]3[C:18]([CH3:27])=[C:19]4[C:24](=[CH:25][CH:26]=3)[O:23][CH2:22][CH2:21][CH2:20]4)[C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[C:33]([O:32][CH:28]([C:15]1[N:14]([CH3:37])[C:13](=[O:38])[C:12]2[NH:8][CH:9]=[CH:10][C:11]=2[C:16]=1[C:17]1[C:18]([CH3:27])=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][CH2:22][CH2:21][CH2:20]2)[C:29]([OH:31])=[O:30])([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccccc2)ccc2c1CCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Temperature: 50 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
An ice cold solution of 2-(1-benzyl-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetic acid (210 mg, 0.408 mmol) in Tetrahydrofuran (THF) (3 mL) was treated with KHMDS (8.16 mL, 4.08 mmol) and then heated to 50° C. for 2 hours. Additional KHMDS (8.16 mL, 4.08 mmol) was added and the mixture was stirred at 70° C. overnight. The mixture was quenched with HCl (1M) at 0° C. and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) to afford 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid (163 mg, 0.384 mmol, 94% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 11.20-11.38 (m, 1H) 7.28-7.40 (m, 1H) 6.93-7.05 (m, 1H) 6.70-6.82 (m, 1H) 5.84-6.01 (m, 1H) 5.25-5.57 (m, 1H) 4.15-4.28 (m, 2H) 3.74-3.90 (m, 3H) 2.61-2.78 (m, 2H) 2.04-2.19 (m, 2H) 1.87-2.06 (m, 2H) 0.94-1.26 (m, 9H); LCMS (m/z) ES+=425 (M+1).
Reaction SMILES: O1CCCC1.[N+:6]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH2:17]([O:19][P:20]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])([O:22][CH2:23][CH3:24])=[O:21])[CH3:18].CN1CCOCC1>[Ti](Cl)(Cl)(Cl)Cl.O>[CH2:23]([O:22][P:20](/[C:25](/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1)([O:19][CH2:17][CH3:18])=[O:21])[CH3:24]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CCOC(=O)/C(=C\c1ccc([N+](=O)[O-])cc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a mixture of titanium tetrachloride (20.0 g) and tetrahydrofuran (100 ml) were added 4-nitrobenzaldehyde (8.00 g) and ethyl diethylphosphonoacetate (11.9 g) under ice-cooling, and N-methylmorpholine (21.4 g) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated to give crystals of 4-[(E)-2-(diethylphosphono)-2-ethoxycarbonylethenyl]nitrobenzene (15.7 g, yield 83%), which were recrystallized from dichloromethane-isopropyl ether to give a colorless prism (14.0 g). melting point: 60–61° C. A mixture of this compound (5.00 g), iron (3.13 g), conc. hydrochloric acid (7 ml) and ethanol (30 ml) was stirred at room temperature for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was subjected to silica gel column chromatography to give crystals of 4-[(E)-2-(diethylphosphono)-2-ethoxycarbonylethenyl]aniline (2.40 g, yield 52%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v), which were recrystallized from acetone-isopropyl ether to give a pale yellow needle (1.75 g). melting point: 79–80° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)[CH3:2].Cl.[NH2:15][OH:16]>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCOCCCN1CCC(=NO)CC1

Procedure:
1-(3-Ethoxypropyl)-4-piperidone oxime is prepared from 1-(3-ethoxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH2:1]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[OH:11])[CH2:2][CH2:3][CH:4]=[CH2:5].[C:12](OC=C)(=[O:14])[CH3:13]>CCOCC>[C:12]([O:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])(=[O:14])[CH3:13]
Reactant: C=CCCC[C@@H]1CCC[C@H]1O
Reactant: C=COC(C)=O
Solvent: CCOCC
Product: C=CCCC[C@@H]1CCC[C@H]1OC(C)=O
Reaction time: 16 h
Yield: 42.8 %

Procedure:
AMANO LIPASE PS (7.0 g, 64.7 mmol) was added to a solution of trans-2-pent-4-en-1-ylcyclopentanol (10.0 g, 64.7 mmol) and vinyl acetate (19.5 g, 129.4 mmol) in Et2O (275 mL). The mixture was stirred for 16 hours, then filtered through CELITE. The filtrate was concentrated to afford a residue that was purified by column chromatography on SiO2 (gradient elution, 0-100% Et2O/petroleum ether) to afford in the first fractions the title compound (5.43 g, 43%). 1H NMR (300 MHz, CDCl3) δ 5.89-5.72 (m, 1H), 5.00 (d, J=18.1 Hz, 1H), 495 (d, J=11.0 Hz, 1H), 4.82-4.73 (m, 1H), 2.11-1.98 (m, 2H), 2.03 (s, 3H), 1.98-1.85 (m, 3H), 1.71-1.60 (m, 3H), 1.50-1.35 (m, 3H), 1.29-1.14 (m, 2H); [α]D=−36.1 (c=0.73 in CHCl3). The later fractions contained enantio-enriched (1S,2S)-2-pent-4-en-1-ylcyclopentanol.
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+]>CO>[CH2:18]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]([O:16][CH3:17])=[CH:15][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1c(/C=C/C(=O)OC)cc(OC)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1c(/C=C/C(=O)O)cc(OC)c2ccccc12
Yield: 99.7 %

Procedure:
As in Example 112, (E)-3-(1-butyl-4-methoxy-2-naphthalenyl)-2-propenoic acid methyl ester (4 g) in methanol (20 mL) was treated with 2N sodium hydroxide solution (5 mL) at reflux for 1 hour and the normal isolation procedure afforded 3.8 g of (E)-3-(1-butyl-4-methoxy-2-naphthalenyl)-2-propenoic acid. Crystallization of a sample from diethyl ether gave the analytical specimen, mp 166°-167° C. Anal. Calcd for C18H20O3 : C, 76.03; H, 7.09 Found: C, 75.89; H, 7.13
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1)#[N:26]>O1CCCC1>[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])[CH:30]=[CH:31][CH:32]=1)#[N:26]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-cyanophenyl isocyanate (176 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 204 mg (64.4%) of the desired product as a solid.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:18][C:19]([N:21]1[CH2:26][C@H:25]([CH3:27])[N:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:23][C@H:22]1[CH3:36])=[O:20])(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH2:18][C:19]([N:21]2[CH2:26][C@H:25]([CH3:27])[N:24]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:23][C@H:22]2[CH3:36])=[O:20])=[C:10]([CH:15]=1)[CH2:9][O:8][CH2:7][C:6]([OH:37])=[O:5]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1COCC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1COCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyloxy)-acetic acid tert-butyl ester (0.14 g, 0.25 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (0.5 mL). The resulting mixture was stirred at ambient temperature overnight, diluted with dichloromethane and treated with excess hydrogen chloride gas. The mixture was concentrated in vacuo to give the title compound as its hydrochloride salt (0.14 g).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].O[NH:26][C:27]([C:29]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1)=[NH:28].C[O-].[Na+]>CO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:28]=[C:27]([C:29]3([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:30][CH2:31][CH2:32][CH2:33]3)[N:26]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: N=C(NO)C1(c2ccccc2)CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCn1c(=O)n(CCCc2nc(C3(c4ccccc4)CCCC3)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 39 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol), N-hydroxy-1-phenylcyclopentanecarboximidamide (34 mg, 0.165 mmol) and sodium methoxide (20 mg, 0.37 mmol) in dry MeOH (0.75 ml) were heated at 140° C. in the microwave reactor for 10 min. The mixture was then partitioned between ethyl acetate and 2M HCl, the organic phase evaporated and the product purified by MDAP to give the title compound as a solid (29.1 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C.CCOC(C)=O>[Si:15]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Reaction time: 16 h
Yield: 61.9 %

Procedure:
(3) 4-Hydroxybenzaldehyde (20 g, 0.164 mol) was dissolved in DMF (60 ml) and stirred at RT as imidazole (22.3 g, 0.328 mol) and tert-butyldimethylsilyl chloride (32.1 g, 0.213 mol) were added. The reaction mixture was stirred for 16 h. The solution was diluted with EtOAc, washed with water, brine, then dried (MgSO4) and concentrated in-vacuo to afford 24 g of crude 4-(tert-butyldimethylsilanyloxy)benzaldehyde.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11]1.[H-].[Na+].[CH3:18]I>>[CH3:18][N:13]1[CH2:14][CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH2:11][C:12]1=[O:15]
Reactant: CI
Reactant: O=C1CC(c2cc3ccccc3o2)CN1
Agent: [H-]
Agent: [Na+]
Product: CN1CC(c2cc3ccccc3o2)CC1=O
Yield: 81 %

Procedure:
The compound is prepared from 4-(2-benzofuryl)-pyrrolidin-2-one, sodium hydride and methyl iodide, as described in Example 5. B.p.(0.3 mm Hg)=172° C. M.p. 73° C. Yield: 81%.
Reaction SMILES: [N+:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=2[O:19][CH3:20])[CH2:7][CH2:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].Cl>C1COCC1.CO>[N+:1]([CH:4]1[CH2:5][CH2:6][CH2:7][CH:8]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20])([O-:3])=[O:2]
Reactant: COc1ccc(C2CCC=C2[N+](=O)[O-])c(OC)c1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2CCCC2[N+](=O)[O-])c(OC)c1OC
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A stirred solution of 1.78 g (6.4 mmol) of 1-nitro-5-(2,3,4-trimethoxyphenyl)-cyclopentene in 40 mL of THF and 40 mL of methanol was cooled in an ice bath and a 0.35 g (9.2 mmol) portion of solid NaBH4 was added. The mixture was stirred for 1 h and 0.38 g (10.0 mmol) of solid NaBH4 was added. The mixture was stirred for 1 h and 0.37 g (9.8 mmol) of solid NaBH4 was added. After stirring for 1 h, 100 mL of 5% aqueous HCl was added and the bulk of the THF and methanol were removed in vacuo. The residue was extracted with two 100 mL portions of ether. The combined ether extracts were washed with 30 mL of brine, dried over MgSO4 and the solvent removed in vacuo to leave 1.37 g of an oil. The crude product was purified by flash chromatography on a column of 30 g of silica gel eluted successively with 100 mL portions of 0, 10, 20, 30, 40, 50 and 60% ether in hexanes to afford 0.68 g of a 1:1 mixture of cis- and trans-1-nitro-2-(2,3,4-trimethoxyphenyl)cyclopentane (Example 45).