Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].CO.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[C:16]([N:20]=[N:21][C:22](Cl)([CH2:24][C:25]([CH3:33])([O:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:26])[CH3:23])([CH3:19])([CH3:18])[CH3:17]>O>[C:16]([N:20]=[N:21][C:22]([S:15][C:12]1[CH:11]=[CH:10][C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])=[CH:14][CH:13]=1)([CH2:24][C:25]([CH3:26])([O:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:33])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N=NC(C)(Cl)CC(C)(C)OOC(C)(C)C
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)N=NC(C)(CC(C)(C)OOC(C)(C)C)Sc1ccc(C(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a stirred solution of 1.38 g (0.021 moles) of 85% potassium hydroxide in 25 ml. of methanol in a 125 ml. erlenmeyer flask was added dropwise 3.66 grams (0.022 moles) of p-t-butylthiophenol. The reaction was stirred an additional 30 minutes and then 6.0 grams (0.0205 moles) of 2-(t-butylazo)-2-chloro-4-methyl-4-(t-butylperoxy)pentane from Example 23 was added dropwise over 30 minutes, holding the reaction temperature at 15° C with a cold water bath. The reaction was stirred an additional hour at room temperature and poured into 100 ml. of water. The product was extracted with 50 ml. of pentane, the pentane solution washed with water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated on a flash evaporator. The residue weighed 8.65 g (72% yield) and its infrared spectrum was in agreement with that of the desired product.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:9][C@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:3]1[CH2:2][NH:1][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C=CCOC(=O)N1CCC[C@H](C)[C@@H]1CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CCC[C@H](C)[C@@H]1CNc1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of rac-cis-Allyl 2-(aminomethyl)-3-methylpiperidine-1-carboxylate (1.36 g, 6.43 mmol), 2-chloro-5-(trifluoromethyl)pyridine (1.75 g, 9.645 mmol), and Cs2CO3 (4.2 g, 12.86 mmol) in DMF (20 mL) was stirred at 80° C. for 2 days. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound. ESI-MS (m/z): 358, [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](OCC)=[O:11])=[CH:7][C:6]=2[CH:15]=1.CC(C[AlH]CC(C)C)C.O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 5-bromo-benzofuran-2-carboxylate (5 g; 18.6 mmol) in 65 mL THF under nitrogen, was added DIBAL (46 mL, 46 mmol) dropwise over 30 minutes, then stirred overnight at room temperature. After dropwise addition of 25 mL of water, the mixture was evaporated, extracted with ethyl acetate, filtered, washed, dried (MgSO4) and evaporated to yield 4.2 g of crude product which was further purified by chromatography to afford (5-bromo-benzofuran-2-yl)-methanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([CH3:14])[C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][O:21]1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:20]([OH:21])([CH3:22])[CH2:19][N:6]2[C:7]3[CH:8]=[C:9]([CH3:14])[C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:16][CH2:15][C:5]2=3)[CH:24]=1
Reactant: CC1(c2cccnc2)CO1
Reactant: Cc1cc2[nH]c3c(c2cc1C)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c3c(n(CC(C)(O)c4cccnc4)c2cc1C)CCN(C)C3
Temperature: 0 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
2,7,8-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400 mg, 1.86 mmol) was dissolved in DMF (4 mL), cooled to 0° C. and sodium hydride (224 mg, 5.60 mmol) was added portionwise at the same temperature. 3-(2-methyloxiran-2-yl)pyridine (504 mg, 3.73 mmol) in DMF (1 mL) was added to the reaction mixture and allowed to stir at RT for 12 h. After complete consumption of starting material, the reaction mixture was poured in to ice water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was crystallized with ether and hexane to obtain 400 mg 2-(pyridin-3-yl)-1-(2,7,8-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol. 1H NMR (DMSO, freebase) δ (ppm): 8.60 (s, 1H), 8.4 (d, 1H), 7.7 (d, 1H), 7.28 (t, 1H), 7.06 (s, 1H), 7.01 (s, 1H), 4.11 (dd, 2H), 3.41 (m, 2H), 2.53 (m, 2H), 2.44 (m, 2H), 2.35 (s, 3H), 2.22 (s, 6H), 1.5 (s, 3H). Separation by chiral HPLC provides enantiomers II-220a-b.
Reaction SMILES: C(O)(C)C.C[O:6][C:7](=O)[CH2:8][CH2:9][SH:10].[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[CH2:12]([NH:20][C:7](=[O:6])[CH2:8][CH2:9][SH:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)CCS
Reactant: CCCCCCCCN
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCCCCCCNC(=O)CCS
Reaction time: 19.5 h

Procedure:
In a small multi-necked reaction vessel equipped with a magnetic stirrer and gas inlet was placed isopropanol (2 ml), methyl-3-mercaptopropionate (2.0 g, 16.64 mmol), and n-octylamine (2.19 g, 16.94 mmol). The reaction vessel was connected to a trap containing bleach to trap mercaptan vapors, and the reaction was stirred for 19.5 hours while the reaction temperature was held at 30°-35° C. Methylene dichloride was added and the crude product was transferred to a round bottom flask. Evaporation of the solvent under reduced pressure yielded crude N-(n-octyl)-3-mercaptopropionamide as an oily white solid in essentially quantitative yield.
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 0 °C
Yield: 386.9 %

Procedure:
The starting amine (5) (0.15 g, 0.12 mmol) and fluorescein isothiocyanate (FLITC) (0.056 g, 0.14 mmol) were dissolved in a mixture of DMF and CH2Cl2 (6 mL, 1:5 ratio) at room temperature. The reaction was cooled to 0° C., and then an excess amount of Et3N (66 μL, 0.48 mmol) was added dropwise. An orange colored precipitate was immediately formed and remained during the entire period of the reaction. After completion of the reaction, the insoluble precipitate was filtered off; and the solvent was removed under reduced pressure. The residue was diluted with CH2Cl2 (15 mL), washed with 1N HCl (2×15 mL) and H2O (2×15 mL). The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford 0.18 g (92%) of fluorescein-labeled guanidine (17) as an orange colored foam-shaped solid. 1H NMR (CD3OD): δ 8.20 (s, 1H, ArH), 7.86 (m, 1H, ArH), 7.22 (m, 2H, ArH), 6.64 (m, 3H, ArH), 6.56 (m, 2H, ArH), 3.86 (m, 2H, CH2NHCS), 3.66 (m, 12H, CH2O), 3.46 (m, 6H, CH2NHCO), 3.38 (m, 6H, CH2NH), 2.58 (m, 2H, CH2CO), 2.42 (m, 6H, CH2CO), 1.48 (s, 27H, t-Bu), 1.46 (s, 27H, t-Bu).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18].O>C(Cl)(Cl)Cl>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][Cl:18])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1)N1CCC(CCl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
In 20 ml of chloroform was dissolved 2.19 g (10 mmol) of N-benzoyl-4-hydroxymethylpiperidine (C) and to the resulting solution was added 2.08 g (10 mmol) of phosphorus pentachloride. The resulting mixture was stirred at room temperature for 1 hour. After the completion of the reaction, thereto was added 20 ml of chloroform and the resulting mixture was poured into 50 ml of iced water to separate an organic layer. The organic layer was washed with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate and dried over 4 g of anhydrous magnesium sulfate. Then, the solvent was removed by distillation to obtain 3.03 g of an oily matter. The oily matter was subjected to silica gel column chromatography (stationary phase: 50 g of Silicagel 60 available from Merck KGaA). The fraction eluted with a hexane/ethyl acetate mixture (1:1 (v/v)) was collected. The solvent was removed by distillation from the obtained fraction to obtain 1.33 g of N-benzoyl-4-chloromethylpiperidine (D) as a colorless crystal. The NMR spectrum of this compound coincided with that of the product in Example 3.
Reaction SMILES: [OH:1][CH:2]1[C:7](/[CH:8]=[CH:9]/[C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:6]([CH3:23])[CH2:5][CH2:4][CH2:3]1.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[C:24]([O:1][CH:2]1[C:7](/[CH:8]=[CH:9]/[C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:6]([CH3:23])[CH2:5][CH2:4][CH2:3]1)(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1ccc(C#C/C=C/C2=C(C)CCCC2O)cc1
Reactant: CC(C)C(=O)Cl
Product: CCOC(=O)c1ccc(C#C/C=C/C2=C(C)CCCC2OC(=O)C(C)C)cc1

Procedure:
The title compound, a colorless oil, was prepared from ethyl (+)-(E)-4-(4-(6-hydroxy-2-methylcyclohex-1-enyl)but-3-en-1-ynyl)benzoate (Compound 1b, 25 mg, 0.081 mmol) and iso-butyryl chloride (0.084 mL, 0.81 mmol) as described in General Procedure C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([N:20]=CN(C)C)[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CO>[C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([NH2:20])[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N=CN(C)C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
(Z)-N-(2-Phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide (130 mg, 0.36 mmol) was dissolved in 4 ml of methanol, followed by the addition of 1 ml of 2N hydrochloric acid. The mixture so obtained was stirred at 60° C. for 3 hours and 30 minutes. The reaction mixture was then added with 20 ml of a saturated aqueous solution of sodium hydrogencarbonate and 20 ml of ethyl acetate. The resulting mixture was then allowed to separate into an organic phase and an aqueous phase. The aqueous phase was further extracted twice with 10 ml portions of ethyl acetate. All the organic phases were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, whereby 107 mg of the title compound were obtained (yield: 97.5%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C1(=O)O[CH2:13][CH2:12][O:11]1.[C:16](=O)([O-])[O-].[K+].[K+]>>[OH:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:16])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1OCCO1
Reactant: O=Cc1ccc(O)cc1
Agent: [K+]
Product: C=Cc1ccc(OCCO)cc1

Procedure:
Woods et al. (U.S. Pat. No. 5,019,629) describe a two-step procedure for preparing p-(2-hydroxyethoxy)styrene starting with p-hydroxybenzaldehyde. In the first step, p-(2-hydroxyethoxy)benzaldehyde is formed by reacting p-hydroxybenzaldehyde with ethylene carbonate in the presence of potassium carbonate. In the second step, p-(2-hydroxyethoxy)styrene is formed by reacting the isolated p-(2-hydroxyethoxy)benzaldehyde with methyltriphenylphosphonium bromide in the presence of sodium amide.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20]I>CN(C)C=O.O>[CH3:20][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:10])=[CH:12]1
Reactant: O=S(c1ccccc1)c1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(S(=O)c2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
Sodium hydride in mineral oil (60% suspension, 0.036 g, 0.90 mmol) was suspended in dry dimethylformamide (10 ml) and a solution of 3-phenylsulfinylindole (0.200 g, 0.82 mmol) in dry dimethylformamide (10 ml) was added dropwise thereto with stirring. After 0.5 hours at room temperature, methyl iodide (0.057 ml) was added and fifteen minutes thereafter the mixture was diluted with water. The product was extracted into benzene, the extract dried and evaporated in vacuo. Crystallization of the residue from ethyl acetate-ether gave the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH:31](O)=O>C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[C:10]([CH:17]3[CH2:18][CH2:19][N:20]([CH3:31])[CH2:21][CH2:22]3)[C:9]=2[C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2c(-c3ccncc3)c(-c3ccc(F)cc3)nc3[nH]ncc23)CC1
Temperature: 75 °C
Yield: 19 %

Procedure:
To a suspension of 6-(4-fluorophenyl)-4-(4-piperidyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.24 g, 0.6 mmol, obtained in example 170) in formic acid (0.64 mL), 35-40% aqueous formaldehyde (0.96 mL) was added. It was heated to 70-80° C. for 24 h. It was allowed to cool and 1 N NaOH was added. It was extracted with CHCl3 and the combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using CHCl3—MeOH—NH3 mixtures of increasing polarity as eluent, to afford 47 mg of the desired compound (yield: 19%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
To a solution of (6-bromo-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester (1.636 g, 5 mmol), prepared as described in Example 1B, in DCE (16 mL) at RT was added benzaldehyde (1 mL, 10 mmol), followed by NaBH(OAc)3 (2.97 g, 14 mmol) and AcOH (0.6 mL, 10 mmol). The reaction mixture was stirred at RT for 16 h, then quenched with aqueous NaHCO3 (40 mL) and extracted with CH2Cl2 (50 mL×3). The combined extracts were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with 0-20% of EtOAc in hexanes to give the title compound (1.70 g, 81%) as a white foam.
Reaction SMILES: [B-](F)(F)(F)F.C[CH2:7][O:8][C:9]([C:11]([C:21]#[N:22])=NOC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[Br:32][C:33]1[S:37][C:36]([C:38]([OH:40])=O)=[C:35]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:34]=1.CONC1C=C[C:55]([O:58][CH2:59][CH2:60][N:61]2[CH2:65][CH2:64][CH2:63][CH2:62]2)=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)(=O)C>[C:45]([O:44][C:42](=[O:43])[NH:41][C:35]1[CH:34]=[C:33]([Br:32])[S:37][C:36]=1[C:38](=[O:40])[NH:22][C:21]1[CH:53]=[CH:54][C:55]([O:58][CH2:59][CH2:60][N:61]2[CH2:62][CH2:63][CH2:64][CH2:65]2)=[C:9]([O:8][CH3:7])[CH:11]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: CONc1ccc(OCCN2CCCC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)sc1C(=O)O
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)c2sc(Br)cc2NC(=O)OC(C)(C)C)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TOTU (327.3 mg) and N,N-diisopropylethylamine (122.8 mg) were added to a mixture of 5-bromo-3-tert-butoxycarbonylaminothiophene-2-carboxylic acid (306.1 mg), methoxy-4-(2-pyrrolidin-1-ylethoxy)phenylamine (224.5 mg) in DMF (3.8 mL). The reaction mixture was stirred at room temperature overnight. Ethyl acetate was then added, and the organic phase was washed with 10% strength citric acid and saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated. The product with the molecular weight of 539.11 (C23H30BrN3O5S) was obtained in this way; MS (ESI): 540, 542 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[C:13]1([C:23](Cl)=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:23]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[O:24])[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: NC1CCN(C2CCCCC2)C1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1cccc2ccccc12

Procedure:
To 9.69 gm. (0.06 mole) of 3-amino-1-cyclohexylpyrrolidine in 50 ml. of chloroform was added dropwise a solution of 8.4 gm. (0.046 mole) of 1-naphthalenecarbonyl chloride in 50 ml. of chloroform. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate containing 10% isopropyl ether and dilute hydrochloric acid. The separated acid layer was made basic with dilute sodium hydroxide solution and extracted with chloroform. The chloroform solution was dried over sodium sulfate, concentrated and the residue crystallized from ethyl acetate. The product weighed 3.8 gm. (25%) and melted at 119°-120° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=2)[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>C1COCC1.CO>[CH2:1]([C:5]1[O:6][C:7]2[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=2)[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCc4ccc(C(=O)OC)cc4)ccc3c2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCc4ccc(C(=O)O)cc4)ccc3c2)o1
Yield: 891.6 %

Procedure:
A mixture of methyl 4-[({6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)methyl]benzoate (51 mg, 0.0096 mmol), prepared in the previous step, and 1 N NaOH (145 μL, 0.145 mmol) in 10 mL of THF plus 10 mL of methanol, plus 5 mL of water was refluxed under nitrogen. The reaction was monitored by LC/MS. An additional three aliquots of 145 μL of 1 N NaOH were added over approximately three days of reflux. After cooling to room temperature 1 mL of 1 N HCl was added. The solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (44.3 mg, 89%) as a white solid, mp 251-254° C. Elemental Analysis for C33H27NO5. 0.10 H2O Calc'd: C, 76.31; H, 5.28; N, 2.70. Found: C, 72.79; H, 5.11; N, 2.47.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH3:12][C:13]1([CH3:16])[CH2:15][S:14]1.O>C1C=CC=CC=1>[CH3:12][C:13]([SH:14])([CH3:16])[CH2:15][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: CC1(C)CS1
Reactant: CCOC(=O)C1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1CCN(CC(C)(C)S)CC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
Ethyl piperidine-4-carboxylate (3.6 g, 22.9 mmol) was dissolved in benzene (5 mL), and 2,2-dimethylthiirane (5.04 g, 57.3 mmol) was added. The reaction mixture was stirred at 80° C. for 20 hours, poured into water and extracted several times with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The volatiles were evaporated and the residue was dried under vacuum to afford 5.45 g (97%) of the title compound. 1H NMR (300 MHz, CD3OD) δ 4.12 (q, J=7.1 Hz, 2H), 2.92-2.96 (d, J=11.9 Hz, 2H), 2.19-2.40 (m, 6H), 1.61-1.86 (m, 4H), 1.29 (s, 6H), 1.25 (t, J=7.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Oc1ccc(F)cc1
Product: CCN1c2ncc(COc3ccc(F)cc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 57 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 143°-144° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 4-fluorophenol. The yield was 57% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1C.[C:13](=[O:16])([O-])[O-:14].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].C(O)=O>O>[NH2:12][S:9]([C:4]1[CH:5]=[CH:6][C:7]([C:13]([OH:14])=[O:16])=[C:2]([F:1])[CH:3]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(N)(=O)=O)cc1F
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: NS(=O)(=O)c1ccc(C(=O)O)c(F)c1

Procedure:
To a stirred solution of 3-fluoro-4-methyl-benzenesulfonamide (prepared above) in 50 mL of water was added sodium carbonate (0.53 g, 5 mmol) and potassium permanganate (3.16 g, 20 mmol) portionwise over three hours at 50˜60° C. The resulting mixture was stirred for further 8 hours at this temperature before 0.2 mL of formic acid was added to quench the excess of potassium permanganate. The mixture was then filtered through celite while it was still hot and further washed with the hot water. The filtrate was concentrated to ˜30 mL and adjusted to pH 9˜10. The filtration was applied again to remove non-oxidized starting material. The final filtrate was acidified with HCl (conc.) to ˜pH 1 and 4-(aminosulfonyl)-2-fluorobenzoic acid was precipitated and collected by filtration as white solid (1.10 g, 50%).