Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][C:7]([CH3:9])=[CH2:8]>CCCCC>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: C=C(C)C
Reactant: OCCCCl
Solvent: CCCCC
Product: CC(C)(C)OCCCCl
Yield: 98.06 %

Procedure:
A three-necked, 3-liter Morton flask was equipped with a mechanical stirrer, a Claisen adapter, a thermocouple, a dry-ice condenser with a gas inlet, and a dip tube. The glassware was dried in an oven at 125° C. overnight, assembled hot, and purged under argon until cool. The reaction flask was then charged with Amberlyst® 15 resin (42.0 grams), 3-chloro-1-propanol (4.65 moles, 1 equivalent, 440.0 grams), and pentane (3.7 equivalents, 2000 mL). These reagents were stirred at 500 RPMs. The alcohol was not completely soluble in the organic solvent. A cylinder of 2-methylpropene was attached to the dip tube and 261.16 grams (4.65 moles, 1 equivalent) was fed into the reaction vessel. The feed rate was approximately 2 grams/min. As the conversion of starting alcohol material into product proceeded, the reaction mixture became one liquid phase. The formation of the product was monitored via Gas Chromatography. After all the starting material was consumed, the solution was then pumped into a pressure filter where the Amberlyst® resin catalyst was separated from the product. The resin was washed with fresh pentane (2×100 ml.). The product was purified by distillation from 20 grams of potassium carbonate through a twelve inch Vigreaux column, under reduced pressure. This afforded a clear, colorless oil, yield=598.82 grams (83.75%). Boiling Point=64° C. at 60 mm Hg. GC assay=0.00% 2-methylpropene, 0.81% pentane, 1.13% 3-chloro-1-propanol, and 98.06% desired product. NMR(CDCl3): 3.63 (t, J=6 Hz, 2H), 3.46 (t, J=6 Hz, 2H), 2.28-1.62 (m, 2H), and 1.21 (s, 9H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:21])[C:5]2[O:20][C:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=3[C:6]=2[CH:7]=1.[C:22]1([S:28]([O-:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+]>>[Cl:21][C:4]1[C:5]2[O:20][C:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=3[C:6]=2[CH:7]=[C:2]([S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[CH:3]=1
Reactant: CCOC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2CC1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CCOC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2CC1
Yield: 62 %

Procedure:
The product of step D and sodium benzenesulfinate were coupled using the procedure of Example 29 step C. Purification by flash column chromatography (SiO2, 9:1 to 1:1 hexanes/ethyl acetate) afforded ethyl 7-chloro-9-(phenylsulfonyl)-4,5-dihydro-1H-benzofuro[2,3-d]azepine-3(2H)-carboxylate (35 mg, 62%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.00-7.92. (m, 3H), 7.80 (s, 1H), 7.62-7.48 (m, 3H), 4.20 (q, J=7.1 Hz, 2H), 3.80-3.68 (m, 4H), 3.22-3.11 (m, 2H), 2.96-2.82 (m, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1](OCC)(=[O:5])[C@H:2]([CH3:4])[OH:3].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[OH:3][C@@H:2]([CH3:4])[C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:5]
Reactant: C1COCCN1
Reactant: CCOC(=O)[C@H](C)O
Product: C[C@H](O)C(=O)N1CCOCC1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
A mixture of (S)-ethyl lactate (75 g) and morpholine (164 g) was heated at 80° C. for 64 hours. The reaction solution was concentrated and the residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=4/1 to ethyl acetate) to give 4-[(S)-2-hydroxypropionyl]-morpholine (69.4 g) as a pale yellow oily substance. p-Toluenesulfonic acid monohydrate (0.82 g) was added to a solution of 4-[(S)-2-hydroxypropionyl]morpholine (69.4 g) in dichloromethane (300 ml), to which 3,4-dihydro-2H-pyran (40.3 g) was added dropwise at ice-bath temperature. The reaction solution was stirred at 0° C. for 30 minutes and washed with a 5% aqueous solution of sodium bicarbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=8/1 to ethyl acetate) to give 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (89.1 g) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28](O)=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.[CH3:41][NH:42][CH3:43].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28](=[O:29])[N:42]([CH3:43])[CH3:41])([CH3:26])[CH3:27])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)N(C)C)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 23.3 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.07 mmol), dimethylamine hydrochloric salt (8.2 mg, 0.1 mmol), EDC.HCl (20 mg, 0.1 mmol), and HOBt (14 mg, 0.1 mmol) in THF (5 mL) was added DIPEA (0.018 mL, 0.2 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 10 mg).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[CH3:34][N:32]([CH3:33])[C:31]([CH:19]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)(=[O:22])=[O:23])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1)=[O:35]
Reactant: COC(=O)CCc1ccc(-c2ccc(CC(NS(=O)(=O)c3ccc(C)cc3)C(=O)N(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccc(-c3ccc(CCC(=O)O)cc3)cc2)C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
The sulfonamide compound 54 (1.1 g, 2.06 mmol) was dissolved in THF (30 mL) and diluted with water (30 mL). Lithium hydroxide (0.2 g, 8.26 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×25 mL). The organic layer was washed with water (1×25 mL) and brine (1×25 mL), dried and concentrated to yield the desired acid compound 55 (1.05 g, 98%). 1H NMR (400 MHz, DMSO-d6): 12.2 (br, 1H), 8.09 (d, J=9.2 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 4.33 (m, 1H), 2.81-2.87 (m, 3H), 2.75 (s, 3H), 2.61-2.67 (m, 1H), 2.56 (t, J=8.0 Hz, 2H), 2.53 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ccc(O)cc2)s1
Agent: Cl
Solvent: CCO
Product: Nc1ncc(Sc2ccc(O)cc2)s1
Yield: 83.1 %

Procedure:
A mixture of 2-acetylamino-5-(4-hydroxyphenylthio)thiazole (1.5 g) in a mixture of ethanol (40 ml) and aqueous 6N hydrochloric acid (6 ml) was refluxed for 4.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 10 using aqueous sodium hydroxide under ice cooling. The precipitates were collected by filtration and recrystallized from a mixture of ethanol and water (3:1) to give 2-amino-5-(4-hydroxyphenylthio)thiazole (1.05 g, yield: 84.0%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[CH:10]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:22])=O.O.[OH-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[CH:10]=2)=[C:6]([Cl:22])[N:7]=1
Reactant: Cn1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide (1.0 g) in DMF was added phosphoric trichloride (1.07 ml) at −40° C. for 20 minutes. This reaction mixture was warmed to −10° C. and stirred for 1 hour. To this solution was added water (40 ml) and stirred at 40° C. for 14 hours. The pH of the resulting suspension was adjusted to 4.5 with 30% The pH of the aqueous mixture was adjusted to 6-7 with 12% aq. NaOH. The precipitate was collected by filtration and washed with water to give 3-amino-5-chloro-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (263 mg) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.O[N:14]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N>>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([NH2:14])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: N
Product: NC(=O)c1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of 4-bromo-2,6-difluoro-benzoic acid (2.77 g, 11.7 mmol) and 1-hydroxybenzotriazole (1.74 g, 12.8 mmol) is added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.46 g, 12.9 mmol) and the solution is stirred at room temperature for 2 hours. After cooling at 0° C. is added aq. NH3 (1.74 mL) and the reaction mixture is stirred for an additional 20 hours. The solvent is evaporated in vacuo and the residue partitioned between diethyl ether and water. The aqueous phase is extracted several times with Et2O, the organic layers are then combined, washed with 1M HCl, sat. NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to afford the benzamide as a white solid (2.56 g, 93%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=O.[C:12](=[O:15])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH:12]([C:6]1[CH:7]=[CH:8][C:3]([C:1]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[CH:4][CH:5]=1)=[O:15]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccccc2)cc1
Reaction time: 24 h

Procedure:
The bromoresin 1-Scheme 10 (1 g, 1 mmol) was swelled in toluene (10 mL) and ethanol (4 mL). To this was added 4-formylphenylboronic acid (450 mg, 3 mmol), aqueous sodium carbonate (2M, 3 mL, 6 mmol) and tetrakistriphenylphosphine palladium (200 mg). The reaction mixture was heated under Argon ("Ar") with stirring for 24 h., cooled and filtered through a sintered glass funnel. Washed the resin with methylene chloride, methanol, methanol-water (1:1), methanol, methylene chloride and finally with methanol. Dried in vacuo to give colorless 4-formylbiphenyl resin 2-Scheme 10. IR (KBr) 1701 cm-1 (CHO).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[CH3:12]>>[CH2:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCO
Product: CCOC(=O)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
4-Aminobenzoic acid (5.0 g, 36.46 mmol) in 500 mL 3-neck round bottomed flask, fitted with a condenser, thermometer, addition funnel, stir bar, and nitrogen atmosphere, was dissolved in ethanol (100 mL). Next ethanol/HCl saturate (from bubbling concentrated HCl through ethanol) was added dropwise, by addition funnel. Then stirred at reflux for 1 h, cooled to room temperature, and stirred an additional 104 hours. Reaction mixture was then concentrated under reduced vacuum, and dissolved in ethyl acetate, and washed with water (2×50 mL), dried (K2CO3), filtered and concentrated under reduced vacuum, yielding 3.56 g of an off-white solid. This material was purified by silica gel chromatography, using a Waters HPLC Prep 2000, over one Prep-Pak, in a 1:1 hexanes:ethyl acetate solvent system, yielding the title compound as 2.35 g (39%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[O:8])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[CH:7]=[O:8])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(C=O)ccc1OC
Solvent: CCOCC
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1OC
Yield: 78 %

Procedure:
To a solution of 3-ethoxy-4-methoxybenzaldehyde (6.0 g, 33.3 mmol, 1.0 equiv; commercially available) in diethyl ether (50 mL) was added dropwise 65% nitric acid (4.12 mL, 5.81 g, 59.9 mmol, 1.8 equiv) over a period of 30 min at rt. After the addition was completed the reaction mixture was heated to reflux for 4 h. The reaction product precipitated out of solution, was filtered off, washed with cold diethyl ether (3×20 mL) and dried yielding 5.85 g (78%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.53 (t, J=7.0 Hz, 3H), 4.04 (s, 3H), 4.26 (q, J=7.0 Hz, 2H), 7.37 (s, 1H), 7.61 (s, 1H), 10.40 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.34, 56.68, 65.35, 107.31, 110.48, 125.52, 143.56, 152.54, 152.70, 187.60. MS (ISP): 225.9 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH:9]1[CH2:12][N:11]([C:13](=[O:21])[CH2:14][S:15][C:16]2[N:20]=[CH:19][NH:18][N:17]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1.S(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH:9]1[CH2:12][N:11]([C:13](=[O:21])[CH2:14][S:15]([C:16]2[N:20]=[CH:19][NH:18][N:17]=2)=[O:34])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1ccccc1OCC1CN(C(=O)CSc2nc[nH]n2)C1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1OCC1CN(C(=O)CS(=O)c2nc[nH]n2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A solution of 3-[(2-{3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl]-2-oxoethyl)sulfanyl}-1H-1,2,4-triazole (112 mg, 0.31 mmol) obtained in Example 243 and m-chloroperbenzoic acid (122 mg, 0.50 mmol) in ethyl acetate (6.2 mL) was stirred at 0° C. for 3 hr. Saturated aqueous sodium bisulfite solution (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative HPLC (device: Gilson Inc., High Throughput Purification system; column: YMC Combiprep ODS-A, S-5 μm, 50×20 mm; solvent: SOLUTION A; 0.1% trifluoroacetic acid-containing water, SOLUTION B; 0.1% trifluoroacetic acid-containing acetonitrile; gradient cycle: 0.00 min (SOLUTION A/SOLUTION B=90/10), 1.00 min (SOLUTION A/SOLUTION B=90/10), 4.20 min (SOLUTION A/SOLUTION B=10/90), 5.40 min (SOLUTION A/SOLUTION B=10/90), 5.50 min (SOLUTION A/SOLUTION B=90/10), 5.60 min (SOLUTION A/SOLUTION B=90/10); flow rate: 25 mL/min; detection method: UV 220 nm) to give 3-[(2-{3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl}-2-oxoethyl)sulfinyl]-1H-1,2,4-triazole (61 mg, 53%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([C:6]1([N:26]([CH3:28])[CH3:27])[CH2:11][CH2:10][CH:9]([CH:12]([O:20]C(OCC)C)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]>O1CCCC1.C(Cl)Cl>[CH2:2]([C:6]1([N:26]([CH3:27])[CH3:28])[CH2:11][CH2:10][CH:9]([CH:12]([OH:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC1(N(C)C)CCC(C(Cc2ccccc2)OC(C)OCC)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCC1(N(C)C)CCC(C(O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2 M hydrochloric acid (20 ml) was added to a solution of {1-butyl-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexyl}dimethylamine (1.09 g, 2.90 mmol) in anhydrous tetrahydrofuran (20 ml) and the mixture was stirred at room temperature for 3 d. The tetrahydrofuran was removed i. vac. and the acid aqueous solution was extracted with diethyl ether (3×10 ml) and thereafter rendered alkaline with 4 M sodium hydroxide solution. The alkaline phase was extracted with methylene chloride (4×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (646 mg) was purified by flash chromatography with methylene chloride/methanol (9:1→8:2→0:1). The product obtained in this way was in the form of the hydrochloride. It was taken up in methylene chloride and the suspension was washed with saturated potassium carbonate solution. The organic phase was dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[CH2:17]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Br)([Br:21])=O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[CH2:17][Br:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc2ccccc2c1-c1ccccc1
Reactant: O=S(Br)Br
Solvent: Cc1ccccc1
Product: BrCc1ccc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The above alcohol (2.3 g) was dissolved in toluene (10 ml) and thionyl bromide (1.0 ml) was added. The mixture was stirred at ambient temperature for 1 h, heated at reflux for 10 minutes and finally stirred at ambient temperature for 30 minutes. The reaction mixture was diluted with toluene (75 ml), washed with a 10% sodium bicarbonate solution and dried (MgSO4). The solvent was evaporated in vacuo to give crude (1-phenyl-2-naphtyl) methylbromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)=[O:6].[OH-].[K+].[C:24]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O>CS(C)=O>[C:27]([O:26][C:24](=[O:25])[NH:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:20]=[C:19]([Cl:21])[CH:18]=3)=[CH:9][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:36][CH:37]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
To a solution of Example 254a (2.0 g, 6.1 mmol) in DMSO (50 mL) was added KOH (1.4 g, 24.3 mmol) and N-Boc-4-aminophenol (1.3 g, 6.1 mmol). The mixture was heated at 80° C. for 4 h. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The residue was purified by silica gel chromatography eluting with hexanes/ethyl acetate/methanol (80:10:10) to give the desired product (1.6 g, 51%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[K+].C(=O)(O)[O-].[K+].[C:14]1([C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:23][CH2:24]Br)[C:21]#[N:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:26]1([C:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([CH2:23][CH2:24][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:21]#[N:22])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C1CCNCC1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: N#CC(CCN1CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66.6 %

Procedure:
1.96 Parts piperidine, 1.91 parts potassium iodide and 25 parts deionized water are combined and gently heated under a nitrogen atmosphere. To this slurry is then added 2.75 parts of potassium bicarbonate, followed by 7.51 parts of 2,2-diphenyl-4-bromobutyronitrile. The mixture is heated to reflux and maintained thereat for 4.5 hours. After cooling to room temperature, the reaction mixture is extracted three times with 14 part portions of ethyl ether. The ether extracts are combined, and extracted six times with 25 parts by volume portions of dilute acetic acid solution. The acid extracts are combined, basified to about pH 10 - 12 with 50% sodium hydroxide solution, and again extracted with ethyl ether. The ether extracts are combined, washed with water and saturated sodium chloride solution, and dried over anhydrous potassium carbonate. Removal of the solvent affords 2,2-diphenyl-4-piperidinobutyronitrile, identical to the product of Example 22, in a 66.6% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](Br)[CH2:8][CH2:9][CH3:10].[OH-].[Na+]>C(O)C>[CH2:7]([N:1]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:2][CH2:3][CH2:4][CH:5]=[O:6])[CH2:8][CH2:9][CH3:10]
Reactant: NCCCC=O
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN(CCCC)CCCC=O
Yield: 39 %

Procedure:
A! A solution of 4-aminobutyraldehyde diethylacetale (90 ml, 0.5 mole) and butyl bromide (121 ml, 1.1 mole) in ethanol (1.000 ml) was added with a 1N solution of sodium hydroxide (1.130 ml). The reaction mixture was refluxed for 8 hours. The reaction solvent was evaporated off and the aqueous solution was extracted with diethyl ether. The organic phases were combined and anhydrified over sodium sulfate, then evaporated under vacuum. The resulting crude was purified by fractionated distillation to yield 54 g of 4-dibutylaminobutyraldehyde diethylacetale (yield: 39%). B.p.: 95°-06° C. (0,05 mmHg).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:14]([C:32]2[CH:36]=[CH:35][O:34][C:33]=2[CH:37]=[O:38])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:42]([O:41][C:39]([N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:14]([C:32]2[CH:36]=[CH:35][O:34][C:33]=2[CH2:37][OH:38])=[CH:13][CH:12]=1)=[O:40])([CH3:44])([CH3:45])[CH3:43]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccoc2C=O)c1OS(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccoc2CO)c1OS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
Sodium borohydride (0.304 g) was added to a solution of methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-(2-formylfuran-3-yl)-2-(4-methylbenzenesulfonyloxy)-benzoate (Intermediate 6, 3.9 g) in ethanol (50 mL) and the mixture was stirred for 15 minutes. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-(2-hydroxymethylfuran-3-yl)-2-(4-methylbenzene-sulfonyloxy)benzoate (3.82 g) as a white solid.