Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:38])([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([C:24]2([C:29]#[N:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:23]=1)[C:16]([O:18]CC)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:38])([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([C:24]2([C:29]#[N:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:23]=1)[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C2(C#N)CCCC2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(COCc1cc(C(=O)O)cc(C2(C#N)CCCC2)c1)(Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 64 h

Procedure:
A solution of ethyl 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoate (0.13 g, 0.25 mmol) and LiOH.H2O (31 mg, 0.75 mmol) in 6.5 mL THF and 2.5 mL H2O was stirred at rt overnight. Additional LiOH.H2O (25 mg, 0.60 mmol) was added and the reaction was continued for 64 h. The mixture was concentrated, diluted with H2O, made acidic with 10% citric acid solution and extracted with EtOAc. The combined organic layers were washed with brine. Drying and solvent evaporation gave 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid. 1H NMR (500 MHz, CDCl3) δ 8.09 (app d, J=1.5 Hz, 1H), 8.04 (s, 1H), 7.74 (s, 1H), 7.28-7.20 (m, 3H), 7.17 (m, 2H), 4.62 (s, 3H), 3.58 (bs, 1H), 3.48 (d, J=8.5 Hz, 1H), 3.15 (d, J=12.9 Hz, 1H), 2.95 (d, J=13.2 Hz, 1H), 2.54 (m, 2H), 2.14-1.96 (m, 6H), 1.47 (s, 9H), 1.28 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]3=[O:25])=[C:12]([F:26])[CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH2:34]OS(C1C(C)=CC(C)=CC=1C)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[N:16]([NH2:34])[C:15]3=[O:25])=[C:12]([F:26])[CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CC(C)(C)c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)c2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 1.0 gram (2.5 mmole) of 3-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione (prepared in Example 1, Steps A-E), 0.41 gram (3.0 mmole) of potassium carbonate, and 50 mL of tetrahydrofuran was cooled in an ice bath. To this was added 1.1 grams (about 5 mmole) of 1-aminooxysulfonyl-2,4,6-trimethylbenzene. Upon completion of the addition the reaction mixture was stirred in the ice bath for ten minutes, then warmed to ambient temperature, where it stirred for an additional 18 hours. After this time the reaction mixture was poured into 150 mL of aqueous 10% ammonium chloride solution and extracted with two 75 mL portions of diethyl ether. The combined extracts were washed with two 50 mL portions of an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to an oil, which was subjected to column chromatography on silica gel. Elution was accomplished with 6:1 heptane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.75 gram of 3-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)-1-amino-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, m.p. 90°-92° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=O)[S:5][C:6]=1[Br:7].CN(C=O)C.N1C(Cl)=NC(Cl)=NC=1Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]#[N:10])[S:5][C:6]=1[Br:7]
Reactant: NC(=O)c1cc(Br)c(Br)s1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)c(Br)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
An oven-dried round-bottomed flask was charged with 4,5-dibromothiophene-2-carboxamide (4.28 g, 15.0 mmol) and 20 mL of DMF under an argon atmosphere. The solution was cooled on an ice-water bath, and cyanuric chloride (1.81 g, 9.8 mmol) was then added in one portion. After stirring at 0° C. for 1 h, the reaction mixture was warmed to room temperature, and stirred for a further 3 h. 100 mL of water was added. A white solid was formed, which was collected through suction filtration, washed with water, and dried together with phosphorous pentoxide under vacuum to afford 3.70 g (92%) of product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[O:9][N:8]=2)[CH:2]=1.C[Si](C)(C)[O-:22].[K+]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]([NH2:16])=[O:22])[O:9][N:8]=2)[CH:2]=1
Reactant: C[Si](C)(C)[O-]
Reactant: N#Cc1cccc(-c2nc(-c3cccnc3)no2)c1
Agent: [K+]
Solvent: C1CCOC1
Product: NC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the product of Example 1 (248 mg, 1 mmol) in THF (10 ml) was stirred with potassium trimethylsilanolate (257 mg, 2.000 mmol) at 65° C. for 10 hours. It was then quenched with water (20 mL) and stirred at ambient temperature for 2 hours. The precipitate was filtered and dried under vacuum to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.67 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 8.23 (dt, J=8.1, 1.4, 1.2 Hz, 1H), 8.30 [s (broad, 2H], 8.36 (dt, J=8.1, 1.3 Hz, 1H), 8.48 (dt, J=7.9, 2.0 Hz, 1H), 8.68-8.73 (m, 1H), 8.83 (dd, J=4.8, 1.6 Hz, 1H), 9.28 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCl/NH3) m/z 267 (M+H)+.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.C(N(CC)CC)C.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])#[N:21].O>O1CCCC1>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=[O:26])#[N:21]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CCOC(=O)c1csc(N)n1
Agent: Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(NC(=O)c2cccc(C#N)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
In 15 ml of dried tetrahydrofuran, 968 mg of 2-amino-4-ethoxycarbonyl-1,3-thiazolehydrobromide were suspended. To the suspension, 1.19 g of triethylamine were added. A solution of 3-cyanobenzoyl chloride dissolved in 3 ml of dried tetrahydrofuran was added dropwise to the resulting mixture under ice cooling, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (chloroform: methanol=10:1), whereby 980 mg of 2-[N-(3-cyanobenzoyl)amino]-4-ethoxycarbonyl-1,3-thiazole were obtained as white crystals. Yield: 83%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:14])[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=[O:13])[C:2]1=2.[OH-].[Na+].[CH2:17]([CH:23]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C.O.[Zn]>[CH2:17]([CH:23]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24][O:14][C:6]1[C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([O:13][CH2:24][CH:23]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[C:2]2[S:1][CH:5]=[CH:4][C:3]=12)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Reactant: CCCCCCCCC(CCCCCC)COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CCCCCCCCC(CCCCCC)COc1c2ccsc2c(OCC(CCCCCC)CCCCCCCC)c2ccsc12
Temperature: 25 °C

Procedure:
Benzo[1,2-b:4,5-b′]dithiophene-4,8-dione (1.0 g, 4.54 mmol) and Zn powder (0.659 g, 10.1 mmol) were suspended in ethanol (10 mL). A solution of NaOH (3 g) in water (15 mL) was added. The resulting mixture was heated to reflux for 1 hour, after which 2-hexyldecyl(4-methylbenzenesulfonate) (3.86 g, 9.73 mmol) was added. The reaction was heated to reflux overnight. The reaction was cooled to room temperature and water (50 mL) was added. The reaction was extracted with ether, followed by separation and drying of the organic layer over MgSO4. Solvent was removed and the residue was purified by chromatography (10% dichloromethane in hexanes as eluent). The yield of the 4,8-bis[(2-hexyldecyl)oxy]-benzo[1,2-b:4,5-b′]dithiophene was 0.80 g (26%). 1H NMR (CDCl3, 500 MHz) δ=7.47 (d, J=2.75, 2H), 7.36 (d, J=2.75, 2H), 4.16 (m, 4H), 1.86 (m, 2H), 1.38-1.65 (m, 48H), 0.86 (m, 12H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[OH-].[Na+].[CH2:10]([C:12]1([CH2:16]OS(C)(=O)=O)[CH2:15][O:14][CH2:13]1)[CH3:11]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[CH2:10]([C:12]1([CH2:16][O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6])[CH2:15][O:14][CH2:13]1)[CH3:11]
Reactant: OCCOCCO
Reactant: CCC1(COS(C)(=O)=O)COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(COCCOCCO)COC1
Temperature: 70 °C

Procedure:
Diethylene glycol (500 g (4.7 mol)), tetrabutylammonium bromide (5.0 g (15.5 mmol)) and 96% sodium hydroxide (50 g (1.2 mol)) were added to a glass flask having an inner volume of 1,000 ml equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and the mixture was warmed to 70° C. with stirring. Subsequently 3-ethyl-3-methanesulfonyloxymethyloxetane (216 g (1.0 mol)) having a purity of 90% (a value measured by 1H-NMR) was dropwise added and reacted for 2 hours while keeping the liquid temperature at 80-90° C. After the completion of the reaction, water (200 ml) was added to reaction liquid (a bisoxetane ether compound generated in the amount of only 9% (an analysis value by a gas chromatography)), and a liquid separation was performed to give an organic layer. Toluene (200 ml) and water (100 ml) were added to the resultant organic layer, and a liquid separation was performed. Subsequently a resultant aqueous layer was extracted with toluene (100 ml) twice. An extract (a toluene layer) and the previously obtained organic layer were mixed, and the mixture was concentrated under reduced pressure. A resultant concentrate was distilled under reduced pressure (142-145° C., 400 Pa) to give, as a colorless liquid, 3-ethyl-3-(2-hydroxyethyloxyethyl)oxymethyloxetane having a purity of 93% (an analysis value by a gas chromatography) (158 g) (an isolated yield based on 3-ethyl-3-methanesulfonyloxymethyloxetane: 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)[CH3:38]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 494 (0.039 g, 0.1 mmol) was suspended in dry CH2Cl2 (1 mL) under an argon atmosphere. K2CO3 (0.029 g, 0.21 mmol) was added followed by ethyl chloroformate (0.02 mL, 0.021 mmol). The suspension was stirred for 48 h at room temperature. Work up as described in the preparation of compound 277. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:2 as the eluent. This afforded the title compound as oil. 13C NMR (CDCl3) δ 196.0, 159.1 (dd), 155.6 (dd), 153.7, 147.9, 139.5, 135.6, 135.1, 133.6, 132.6, 131.9, 129.1, 124.4 (dd), 124.3 (dd), 121.3, 119.8, 116.2, 112.7, 111.6 (dd), 104.9 (dd), 61.3, 19.7, 14.5
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32](=[NH:35])[NH:33]O)=[CH:30][CH:29]=1.[H-].[Na+]>C1COCC1>[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]2[N:35]=[C:19]([C:18]3[CH:23]=[CH:24][C:15]([N:11]4[C:12](=[O:14])[NH:13][C:9]([C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])=[N:10]4)=[CH:16][C:17]=3[O:25][CH3:26])[O:21][N:33]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Reactant: N=C(NO)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1-c1nc(-c2ccc(Cl)cc2)no1
Yield: 11.7 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 4-chloro-N-hydroxybenzimidamide (Intermediate-19, 0.064 g, 0.38 mmol), sodium hydride (0.020 g, 0.50 mmol) and dry THF (5.0 mL) at RT to afford 0.015 g of desired product. 1HNMR (DMSO-d6): δ 4.00 (s, 3H), 7.66-7.72 (m, 5H), 7.81 (d, J=8.7 Hz, 1H), 7.89 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.22 (d, J=9.0 Hz, 1H), 12.82 (br s, 1H); MS (m/z): 515.84 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:31])[N:8]3[CH2:13][CH2:14][C:15]([CH3:30])([CH3:29])[CH2:16][CH2:17][N:18]1C(=O)C2=CC=CC=C2C1=O>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:31])[N:8]3[CH2:13][CH2:14][C:15]([CH3:29])([CH3:30])[CH2:16][CH2:17][NH2:18]
Reactant: Cc1nc2cccc3n(CCC(C)(C)CCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Solvent: CCO
Product: Cc1nc2cccc3n(CCC(C)(C)CCN)c(=O)c1n23

Procedure:
To a suspension of 1.25 g (3.0 mmol) of 1,2-dihydro-3-methyl-[3,3-dimethyl-5-(phthalimido)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 30 ml of ethanol was added, at room temperature, 0.44 ml (9.0 mmol) of hydrazinemonohydrate. The mixture was heated under reflux. The reaction mixture was cooled, and the resulting precipitates were filtered off. The solvent was distilled off. The residue was dissolved in chloroform. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate, dried, distilled off the solvent to give 1,2-dihydro-3-methyl-1-[3,3-dimethyl-5-(amino)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Li+].S([O-])(O)(=O)=O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reaction time: 2 h
Yield: 74.1 %

Procedure:
In tetrahydrofuran (5 ml) was dissolved methyl 3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]propionate (92 mg, 0.20 mmol). An aqueous solution (3 ml) of lithium hydroxide (23 mg, 0.5 mmol) was added to the resulting solution and the mixture was stirred for 2 hours. After addition of 10% sodium hydrogensulfate, the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue. The resulting residue was crystallized from ethanol to give the title compound (67 mg, 75%) as needle crystals.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH3:30][C:31](=[O:34])[CH:32]=[CH2:33]>C1C=CC=CC=1>[O:34]=[C:31]1[CH2:32][CH2:33][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:30]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=CC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 70 °C
Yield: 62.5 %

Procedure:
To a benzene (700 mL) solution of benzyl 4-formylpiperidine-1-carboxylate (90.0 g, 363.9 mmol) stirring in a 2 L 3-neck flask fitted with a Dean-Stark trap was added p toluenesulfonic acid (6.92 g, 36.4 mmol). The reaction was heated to 70° C. 3-buten-2-one (61.8 mL, 753 mmol) was added and mixture was heated at reflux for 24 hours collecting expelled water in the trap. The reaction was coded to room temperature and washed with 500 mL saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated. The resultant dark brown oil was taken up in 200 mL dichloromethane and filtered through a silica pad (600 mL silica), eluting with 2 L heptane followed by 3 L 50% ethyl acetate/heptane and then 3 L ethyl acetate, collecting by 1 L fractions. Fractions containing clean product were combined and concentrated to yield 68.1 g of the title compound as a thick brown oil. The fractions containing impure product were combined and concentrated and purified by flash chromatography (10-60% ethyl acetate/heptane, 340 g silica gel) to yield an additional 23.6 g of the title compound as a thick brown oil. Combined yield of 91.7 g, (94.1%) was realized. 1H NMR (400 MHz, CDCl3) δ ppm 7.27-7.43 (m, 5H), 6.79 (d, J=10.3 Hz, 1H), 5.95 (d, J=10.3 Hz, 1H), 5.13 (s, 2H), 3.58-3.71 (m, 2H), 3.39-3.55 (m, 2H), 2.38-2.50 (m, 2H), 1.96 (t, J=6.7 Hz, 2H), 1.70-1.52 (m, 4H).
Reaction SMILES: [CH:1]1([CH:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C@:23]3([CH3:29])[CH2:27][O:26]C(=O)[NH:24]3)[CH:17]=[CH:16]4)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O.[OH-].[Li+].O>>[NH2:24][C@@:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH:9]3[CH2:10][CH2:11][CH:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH2:8]3)[CH:14]=2)[CH:19]=1)([CH3:29])[CH2:27][OH:26]
Reactant: C[C@@]1(c2ccc3cc(OC4CCC(C5CCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2cc(OC3CCC(C4CCCC4)CC3)ccc2c1
Yield: 62 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(4-Cyclopentyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol), 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 114 mg the desired product as a white solid (90%). ESI-MS: 351 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ=7.87 (s, 1H), 7.81-7.55 (m, 3H), 7.31-7.21 (m, 1H), 7.18-7.00 (m, 1H), 4.98-4.59 (m, 3H), 4.43-4.27 (m, 0.63H), 3.57-3.14 (m, 4H), 2.19-0.84 (m, 17H)
Reaction SMILES: [Br:1][C:2]1[C:3]([SH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: Sc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCSc1ncccc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A mixture of 3-bromopyridine-2-thiol (0.04 g, 0.2 mmol), 1-bromo-3-chloropropane in DMF (0.424 mmol/mL, 2.0 mL), and K2CO3 (60 mg, 0.424 mmol) in DMF (2.0 mL) was stirred at rt for 10 minutes. The reaction mixture was then concentrated to dryness and the resultant residue diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated to dryness to give the title compound (0.05 g, 89% purity). MS (ESI): mass calcd. for C8H9BrClNS, 264.93; m/z found, 265.8 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][S:8][CH:7]([CH2:10][CH:11]([C:20]([O:22]CC2C=CC=CC=2)=O)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:6]1)=[O:4]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][S:8][CH:7]2[CH2:10][CH:11]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:20](=[O:22])[N:6]12)=[O:4]
Reactant: COC(=O)C1CSC(CC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)N1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)C1CSC2CC(NC(=O)OC(C)(C)C)C(=O)N21
Yield: 47.9 %

Procedure:
To a solution of 3 (1.4 g, 3.3 mmol) in 20 mL of pyridine was added 0.1 g DMAP and the mixture was refluxed overnight. After removal of the pyridine, the residue was partitioned between water and ethyl acetate. The organic phase was dried, concentrated and purified by column chromatography on silica gel to afford the pure product (0.5 g, 48%) 1H NMR (400 MHz, CDCl3) δ1.44 (s, 9 H), 2.01 (m, 1 H), 3.19 (m, 1H), 3.77 (d, 3 H), 4.12 (m, 1 H), 5.08-5.16 (m, 3 H).
Reaction SMILES: [I: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>>[I: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)c3ccccc3I)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3I)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-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 620.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:21])=[O:2])=[CH:9][CH:8]=1)[CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C/CCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC/C=C/CCCOc1ccc(C(=O)O)cc1
Yield: 85.1 %

Procedure:
The ester 35i (500 mg, 1.7 mmol) was dissolved in 50 ml methanol. Water (approximately 10 ml) was added until the solution remained cloudy, at which time lithium hydroxide monohydrate (723 mg, 17.0 mmol) was added. The reaction mixture was refluxed overnight and acidified with concentrated HCl. Water was added (approximately 30 ml), the mixture was cooled, filtered, washed with water and allowed to air dry yielding 400 mg (84%) of a white powder.