Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:18]([NH2:21])=[CH:19][CH:20]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(O)(=O)C.[N:36]([O-])=O.[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]4[N:21]=[N:36][N:22]([C:23]5[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=5)[C:17]=4[CH:16]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nnc3ccc(-c4nnc(CCc5cccc(F)c5)o4)cc32)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a mixture of 4-[5-[2-(3-fluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl]-N2-(4-methoxyphenyl)benzene-1,2-diamine (0.20 g, 0.49 mmol), 6 M hydrochloric acid (2.5 mL) and acetic acid (2.5 mL) was added an aqueous solution (0.25 mL) of sodium nitrite (41 mg, 0.59 mmol) at 0° C., and the obtained mixture was stirred at 0° C. for 30 min and at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) and recrystallized from hexane/ethyl acetate to give the title compound (51.2 mg, yield 25%) as colorless crystals.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10]1([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]2[C:26](OCC)=[O:27])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+].[Cl-].[Na+]>C1(C)C=CC=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:26]([N:17]1[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:27])[CH2:2]2
Reactant: CCOC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Reactant: OC1CN2CCC1CC2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OC1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 12.5 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
(RS)-3-Quinuclidinol (7.23 g) was added to a solution of (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (10 g) in toluene (50 ml) at 25-30° C. under nitrogen atmosphere. Sodium hydride (60% w/w, 0.27 g) was added to the mixture and the reaction mass was heated to reflux for 24 h. The by-product ethanol was removed azeotropically with toluene and fresh toluene was added to maintain volume of reaction mass. The reaction mass was cooled to 10-15° C. and 10% w/w sodium chloride solution (30 ml) was added slowly at 10-25° C. Then the reaction mass was stirred for about 10 min and toluene layer was separated. The organic layer was then extracted with ˜18% w/w aqueous hydrochloric acid (100 ml) at 10-30° C. The aqueous layer was cooled to 5-10° C. and pH was adjusted to 7.0-7.5 using 40% w/w aqueous sodium hydroxide solution (36 ml). Thereafter, the pH was further adjusted to 9.5-10 using 10% w/w aqueous sodium hydroxide solution (11 ml). The product was extracted with ethyl acetate (100 ml) at 25-30° C. Then the organic layer was washed with water (30 ml) and then it was treated with carbon (0.5 g) at 25-30° C. for 30 min. The carbon was removed by filtration through hyflo and the residue was washed with ethyl acetate (20 ml). Thereafter, the filtrate was concentrated under reduced pressure at 40-50° C. to produce 12 g of (1S)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylic acid (3RS)-1-azabicyclo[2.2.2]oct-3-yl ester (Solifenacin and its diastereomer) as a pale yellow oil.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[Na].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[N:8]=1>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:4][CH:1]([CH3:3])[CH3:2])[N:8]=1
Reactant: CC(C)O
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Product: CC(C)Oc1cccc(Br)n1
Temperature: 80 °C

Procedure:
The compound was prepared in a manner similar to that described in WO 02/076983 (page 80). Dry isopropanol (25 mL, 42.2 mmole) was placed in an oven-dried 250 ml 3 necked flask under nitrogen, sodium spheres (0.5 g, 21.1 mmol) were added and the reaction was heated to 80° C. to dissolve the sodium. 2,6 dibromopyridine (10 g, 42.2 mmole) was added as a solid and the reaction was heated at 95° C. After heating for ˜2.5 hr the reaction was cooled and partitioned between ether and water. The organic layer was evaporated to give a solid plus oil, the mixture was suspended in hexanes, cooled, and filtered to remove the solid. The filtrate was evaporated carefully and chromatographed on silica eluting with hexanes to give the product as a clear, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:42]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][Br:42])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(Oc2ccc(CCBr)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of 2-(4-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethanol (300 mg, 0.947 mmol) and triphenylphosphine (300 mg, 1.144 mmol) in dichloromethane (5 mL) was added carbon tetrabromide (350 mg, 1.055 mmol) in portions. The reaction mixture was stirred at rt for 2 h, then concentrated. Purification via ISCO system afforded the title product (335 mg) as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@H:7]([NH:11][CH2:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]2[N:20]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:21]=[C:22]([C:23]([OH:25])=O)[C:14]=12)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[F:19][C:18]1[C:13]2[CH2:12][N:11]([C@H:7]([CH:8]([CH3:10])[CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:36])[C:23](=[O:25])[C:22]3=[CH:21][N:20]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=4)(=[O:28])=[O:27])[C:15]([C:14]=23)=[N:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@@H](C(=O)OC(C)(C)C)C(C)C)c(F)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(F)cnc42)CN([C@@H](C(=O)OC(C)(C)C)C(C)C)C3=O)cc1

Procedure:
Crude (R)-4-((l-tert-butoxy-3-methyl-1-oxobutan-2-ylamino)methyl)-5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid was heated in HATU (2.60 g, 7.19 mmol) and 4-methylmorpholine (1.091 g, 10.79 mmol) at reflux for 3 h. The reaction was incomplete by LC-MS. HATU (1.37 g, mmol, 3.79 mmol) and 4-methylmorpholine (1.091 g, 10.79 mmol) were added and the reaction mixture was stirred at reflux for 16 h. Following reaction, the mixture was washed with aqueous NaHCO3 (sat.) and extracted with DCM. The organics were washed with brine, dried over Na2SO4, and concentrated to a brown oil. Purification by silica column chromatography (EtOAc/DCM, 0-20%) afforded the title compound as a white foam. (0.933 g, 51.7%). 1H NMR (400 MHz, DMSO-d6) δ 0.80 (d, J=6.57 Hz, 3 H) 1.02 (d, J=6.57 Hz, 3 H) 1.39 (s, 9 H) 2.31-2.39 (m, 4 H) 4.77 (d, J=10.61 Hz, 1 H) 5.02 (d, J=7.58 Hz, 2 H) 7.46 (d, J=7.83 Hz, 2 H) 8.08 (d, J=8.34 Hz, 2 H) 8.29 (s, 1 H) 8.44 (d, J=2.78 Hz, 1 H). [M+H] calc'd for C25H28FN3O5S, 502; found, 502.3.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:12][C:4]1[CH:3]=[C:2]([OH:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: Oc1cc(O)c2ccccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cc(O)c2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A mixture of 1.5180 g of 1,3-dihydroxynaphthalene and 1.70 g of anhydrous potassium carbonate in 10 ml of anhydrous acetone was stirred at room temperature for 1 hour. Methyl bromoacetate (0.91 ml) was added and stirring at room temperature was continued for 50 hours. The solvent was removed in vacuo and the residue was acidified and extracted with ethyl acetate. The dried (magnesium sulfate) extract was concentrated in vacuo and the product was purified by high pressure liquid chromatography using 20% ethyl acetate-toluene to give 0.419 g (19% yield) of [(4-hydroxy-2-naphthalenyl)oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
4-Nitrobenzenesulfonyl chloride (4.4 g) was added to a stirred solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (4.0 g) and pyridine (2.25 ml) in methylene chloride (80 ml) and stirred at ambient temperature for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate solution. The organic layer was separated, washed with brine and dried over sodium sulfate. The solution was evaporated under vacuum and triturated with diethylether and filtered to remove undesired solids. The diethylether liquors were evaporated under vacuum and dissolved in methylene chloride before purification by column chromatography on silica eluting with ethyl acetate/isohexane (20/80). The fractions containing the expected product were combined and evaporated under vacuum to give tert-butyl 3-[(4-nitrophenyl)sulfonyloxy]piperidine-1-carboxylate as a yellow crystalline solid (6.77 g); 1H NMR Spectrum: (CDCl3) 1.43 (s, 9H), 1.40-1.54 (m, 1H), 1.70-1.94 (m, 3H), 3.22-3.60 (m, 4H), 4.67 (m, 1H), 8.11 (s, 2H), 8.40 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[N:21][C:22]#[N:23])SC)=[CH:13][CH:12]=1)#[N:10]>O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:22]([N:21]=[C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)[NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])#[N:23]
Reactant: CSC(=NC#N)Nc1ccc(C#N)cc1
Reactant: NCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CN=C(NCCC(=O)O)Nc1ccc(C#N)cc1
Yield: 63.4 %

Procedure:
A mixture of 12.3 g (0.138 mol) of β-alanine and of 5.52 g (0.138 mol) of sodium hydroxide in 100 cm3 of water is added to a solution of 20 g (0.092 mol) of N-(4-cyanophenyl)-N'-cyano-S-methylisothiourea in 300 cm3 of 95% ethanol. The mixture is heated to reflux for 4 hours. After cooling, the solution is filtered then concentrated to dryness in vacuo. The residue obtained is dissolved in 200 cm3 of a 2% sodium carbonate solution. The resulting solution is washed by dichloromethane (3×50 cm3) then acidified by a 3N HCl solution until a pH close to 2 is obtained. The white solid formed is filtered, then washed with water (2×10 cm3) and dried in vacuo. After recrystallization in water, 15 g (yield 63%) of N-[cyanoimino(4-cyanophenylamino)methyl]-3-aminopropanoic acid, which is a solid having a melting point of 158°-162° C., are obtained.
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:7][C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:4][C:5]1[C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:7][C:8]([O:13][CH2:2][CH3:3])=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: CCI
Reactant: N#Cc1cc(Br)c(-c2ccc(F)cc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc(-c2ccc(F)cc2)c(Br)cc1C#N

Procedure:
Iodoethane (1.43 mL) was added to a mixture of 5-bromo-6-(4-fluorophenyl)-2-hydroxynicotinonitrile (3.49 g), potassium carbonate (3.29 g), and DMF (30 mL), and the resultant mixture was stirred at 80° C. for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.00 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=2[C:18]#[N:19])[CH2:5][CH2:4]1)[CH3:2].N#N>CCO.CCOC(C)=O.[Pd]>[NH2:15][C:11]1[C:10]([C:18]#[N:19])=[C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCN1CCN(c2cccc([N+](=O)[O-])c2C#N)CC1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN1CCN(c2cccc(N)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-Ethylpiperazinyl)-6-nitrobenzenecarbonitrile (1.0 eq) was dissolved in EtOH and EtOAc. The flask was purged with N2, and 10% Pd/C (0.1 eq) was added. The flask was evacuated and purged with H2 three times. The resulting mixture was stirred overnight at room temperature. The mixture was filtered through Celite, and the filter pad was washed with EtOAc. The solvent was removed in vacuo to provide the desired product as a yellow solid. LC/MS m/z 231.2 (MH+), Rt 1.42 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=1)[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2.[BH4-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=1)[O:8][CH:7]([C:21]([F:24])([F:22])[F:23])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2
Reactant: O=Cc1ccc(Cc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(Cl)c(Cc3ccc(CO)cc3)cc2OC1C(F)(F)F
Reaction time: 0.25 h

Procedure:
The 6-chloro-7-(4-formylbenzyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid (Example 604 g) (210 mg, 0.49 mmole) was dissolved in MeOH:THF (1:1) (3 mL). NaBH4 (20 mg, 0.49 mmole) was added to the above solution portionwise. After stiring for 15 min, the reaction was finished. The reaction was quenched with (sat.) NH4Cl, the organic layer was extracted with EtOAc and dried over MgSO4 and filtered. The filtrate was concentrated to give the title compound as an oil, which solidify upon standing as a white solid 200 mg (95% yield): ESHRMS m/z 397.0457 (M−H, C19H13O4F3Cl, Calc'd 397.0449). 1H NMR (acetone-d6/400 MHz) 7.87 (s, 1H), 7.57 (s, 1H), 7.31 (d, 2H, J=8.2 Hz), 7.22 (d, 2H, J=8.2 Hz), 6.92 (s, 1H), 5.80 (q, 1H, J=7.2 Hz), 4.59 (s, 2H), 4.09 (d, 2H, J=4.3 Hz).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1.C(N(CC)CC)C.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>>[CH3:15][C:6]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=[C:2]1[O:1][Si:25]([CH3:27])([CH3:26])[CH3:24]
Reactant: CCCCCCCCC1(C)SC(=O)C=C1O
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCC1(C)SC(=O)C=C1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(66, 67). To 32 (247 mg, 1.02 mmol) dissolved in hexanes was added triethylamine (0.23 mL, 1.68 mmol) and trimethylsilylchloride (0.21 mL, 1.64 mmol) and the solution was allowed to stir at room temperature for 4 h. The mixture was filtered over celite and evaporated to provide 5-methyl-5-octyl-4-trimethylsilanyloxy-5-H-thiopen-2-one. To a solution of TiCl4 (0.7 mL, 0.7 mmol) in CH2Cl2 (1.95 mL) at −78° C. was added acetaldehyde (54 μL, 0.97 mmol) and this solution was allowed to stir for 5 min at −78° C. Then, 5-methyl-5-octyl-4-trimethylsilanyloxy-5-H-thiopen-2-one dissolved in CH2Cl2 (0.4 mL) was cannulated into TiCl4/acetaldehyde solution giving a bright orange color. This mixture was allowed to warm and stir for 20 min at 0° C. The mixture was poured into NH4Cl(sat) (15 mL) and extracted with CH2Cl2 (3×15 mL). The organics were combined, dried (MgSO4), filtered and evaporated. Flash chromatography (10% EtOAc/Hexanes) provided pure 66 (34 mg) and 67 (24 mg) (50%). (66) 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J=6.9 Hz, 3H), 1.05-1.08 (m, 1H), 1.24 (bs, 11H), 1.49 (d, J 6.5 Hz, 3H, rotamer) 1.55 (d, J=5.2 Hz, 3H, rotamer), 1.62 (s, 3H), 1.78-1.82 (m, 2H), 4.68 (q, J=6.5 Hz, 1H, rotamer), 5.04 (q, J=5.2 Hz, 1H, rotamer). HRMS (ES) m/z calculated for C16H28O3SNa+ (M+CH2+Na+) 323.1660 obsd. 323.1660.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:28][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=[O:29])[C:10]=2[CH:30]=1)(=[O:4])=[O:3].N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:28][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([NH:27][C:37](=[O:39])[CH3:38])=[CH:25][CH:26]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=[O:29])[C:10]=2[CH:30]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(N)cc3)CC1)O2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(NS(C)(=O)=O)ccc2O3)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A suspension of 6-methanesulfonamido-3,4-dihydro-1'-(2-(4-aminophenyl)ethyl)-spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one (0.50 g, 1.2 mmol), and pyridine (0.09 mL, 1.2 mmol) in 25 mL of methylene chloride was cooled in an ice bath and treated dropwise with acetyl chloride (0.09 mL, 1.2 mmol). The mixture was stirred at 0° C. for 2 hours, and then filtered. The tan solid was washed with methylene chloride and dried in the air. The solid was found to be a mixture by thin layer analysis, and was chromatographed on silica gel using 10% methanol in methylene chloride eluant. The pure oil was dissolved in 20 mL of absolute ethanol and was treated with excess 4.8N ethanolic HCl. The solution was then concentrated to 10 mL. The resulting ivory colored solid was collected, washed with diethyl ether, and dried 3 hours at 100° C. under vacuum to give 0.10 g (18%) of product, mp 294° C. (dec).
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].N1C=CC=CC=1.[NH:14]1[CH:18]=[C:17]([CH:19]2[CH2:28][CH2:27][CH2:26][C:25]3[C:24]([NH2:29])=[CH:23][CH:22]=[CH:21][C:20]2=3)[N:16]=[CH:15]1.C(O)C(N)(CO)CO>ClCCl>[NH:16]1[C:17]([CH:19]2[CH2:28][CH2:27][CH2:26][C:25]3[C:24]([NH:29][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:23][CH:22]=[CH:21][C:20]2=3)=[CH:18][N:14]=[CH:15]1
Reactant: Nc1cccc2c1CCCC2c1c[nH]cn1
Reactant: CCCS(=O)(=O)Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1cccc2c1CCCC2c1cnc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
To a solution of 1-propanesulfonyl chloride (20.5 mg, 0.14 mmol) in dichloromethane (250 mL) was added pyridine (78 mL, 0.96 mmol) followed 5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenamine (30 mg, 0.096 mmol) dissolved in CH2Cl2 (1 mL). The CH2Cl2 was removed under vacuum and the reaction gently shaken at ambient temperature overnight. To the reaction was added 1.0 mL of CH2Cl2 followed by 200 mg of polymer supported trisamine (Argonaut laboratories). The reaction was shaken at room temperature for 30 minutes, the filtrate collected and the volume brought to 5 mL with dichloromethane. The organic layer was extracted with 10% aqueous citric acid (3×4 mL), brine (2×4 mL), filtered (Varian CE1000M)® and the solvent removed under vacuum. The resulting oil was dissolved in 2 mL of acetonitrile and 0.5 g of Amberlyst resin was added. The reaction was shaken at room temperature for 72 hours and filtered. The resin was washed with acetonitrile (2×2 mL), methanol (2×2 mL), and suspended in 2 M methanolic ammonia (2 mL) for 2 hours. The resin was filtered, washed with 0.5 mL of methanol and then retreated with ammonia as described. The ammonia and methanol filtrates were combined and the solvent removed under vacuum. The crude material was purified using reverse phase preparative HPLC. (6.7 mg, 21.9% yield).
Reaction SMILES: [OH:1][C@@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[NH2:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15]>>[OH:1][C@@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([NH:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15])=[O:5]
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: C[C@](O)(C(=O)O)c1ccccc1
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)[C@](C)(O)c2ccccc2)c2cccc(N)c2-c2ccccc21

Procedure:
Following one or more of the general procedures outlined above, using (R)-(−)-2-hydroxy-2-phenylpropionic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 458 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]([CH2:17][CH:18]3[O:23][CH2:22][CH2:21][NH:20][CH2:19]3)[C:7]=2[CH:24]=1)[CH3:2].[CH2:25]=O.Cl>C(O)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]([CH2:17][CH:18]3[O:23][CH2:22][CH2:21][N:20]([CH3:25])[CH2:19]3)[C:7]=2[CH:24]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)N(CC1CNCCO1)c1ccccc1CC2
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CCc1ccc2c(c1)N(CC1CN(C)CCO1)c1ccccc1CC2
Reaction time: 8 h

Procedure:
A mixture of 3-ethyl-5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.3 g), 90% formic acid (0.7 g) and 37% formalin (0.58 ml) was stirred at 90°-100° C for 8 hours. After cooling, 4N hydrochloric acid was added to the reaction mixture. The resulting mixture was evaporated to dryness under reduced pressure. Water was added to the residue, neutralized with aqueous ammonia, and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 3-ethyl-5-(4-methyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. M.P. 168°-170° C (oxalate).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40]>>[OH:40][CH2:39][CH:38]([NH:37][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH2:41][OH:42]
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: NC(CO)CO
Product: O=C(NC(CO)CO)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 52.5 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl} benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol, 1.0M in DMF) were combined (reaction time 3 days at room temperature) to give 30 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 572 [M+H]+.