Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:15]=[CH:14][C:13]=2[NH2:26])=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:5])[CH3:2].[CH:33](OCC)(OCC)OCC>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:12]3[CH:17]=[C:16]([CH2:18][N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)[CH:15]=[CH:14][C:13]=3[N:26]=[CH:33]2)=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2N)nc1-c1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(-n2cnc3ccc(CN4CCN(C)CC4)cc32)nc1-c1ccccc1

Procedure:
To a mixture of 2-[2-amino-5-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VII.1a) from previous step and 0.2 mL of acetic acid was added 0.2 mL of triethyl orthoformate. The reaction mixture was heated to 60 degrees for 1 hour, and then concentrated under reduced pressure. The residue was diluted with 10 mL of water and 2 mL of saturated sodium bicarbonate and then extracted three times with 5 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient 0:100-10:90) to give 0.041 g of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (I.1a) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9]CC=C)=[CH:5][CH:4]=1)#[N:2].C(OCC)C.[C:18]1(OC2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1>>[CH2:23]([C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[OH:9])[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc(C#N)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: C=CCc1cc(C#N)ccc1O
Temperature: 25 °C

Procedure:
A solution of allyl 4-cyanophenyl ether (12 g) in diphenylether (20 ml) was heated at 260° C. for 30 minutes. The reaction mixture was cooled to ambient temperature, diethyl ether was added and the mixture was extracted with 1M aqueous sodium hydroxide solution. The aqueous phase was separated, acidified with 2M aqueous hydrochloric acid solution and extracted with diethyl ether. The organic phase was separated, dried (MgSO4) and evaporated to give 2-allyl-4-cyanophenol as a solid (11.4 g), m.p. 70° C.; microanalysis, found: C, 73.7; H, 5.6; N, 9.2%; C10H9NO. 0.25H2O requires: C, 73.4; H, 5.8; N, 8.6%; NMR: 3.2-3.5(2H,d), 5.0-5.1(2H,m), 5.85-6.05(1H,m), 6.9-7.0(1H,d), 7.4-7.5(2H,m) and 10.6(1H,s).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:15])([F:14])[C:10](Br)([F:12])[F:11].N1C=CC=CC=1C1C=CC=CN=1.CS(C)=O.Cl>CC1CCCCC1.[Cu]>[F:14][C:9]1([F:15])[C:10]([F:12])([F:11])[C:2]2[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)(F)Br)c(Cl)c1
Agent: [Cu]
Agent: Cl
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CC1CCCCC1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)C(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 311.8 %

Procedure:
Into a pressure bottle was placed 10.0 g (0.028 mole) of the 3-chloro-4-(2-bromo-1,1,2,2-tetrafluoroethoxy)nitrobenzene prepared in (A) above, 9.0 g (0.14 mole) copper powder (200 mesh), 0.45 g (0.0028 mole) 2,2'-bipyridyl, and 40 ml of dimethyl sulfoxide (DMSO). The pressure bottle was sealed and the reaction mixture stirred at 190°-195° C. for two hours. The pressure bottle was cooled to room temperature, opened, and the contents poured into a separatory funnel. Approximately 200 ml of a 2N hydrochloric acid solution was added to the separatory funnel. The mixture was extracted with three 150 ml portions of diethyl ether. The extracts were combined and washed in succession with 200 ml of a 2N hydrochloric acid solution, 200 ml of a saturated aqueous sodium chloride solution, and 200 ml of a 2N sodium hydroxide solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure leaving an oil. The reaction described above was repeated six additional times. The residual oils from the seven runs were combined and subjected to column chromatography on silica gel, eluting with toluene, to yield a yellow oil. This oil was dissolved in 125 ml of methylcyclohexane and the solution placed in a freezer for approximately 18 hours. Crystals formed and were collected by filtration to yield 20.7 g 2,2,3,3-tetrafluoro-5-nitrobenzofuran. The filtrate was evaporated under reduced pressure leaving an oil. Distillation of this oil under reduced pressure provided an additional 3.0 g of product (bp 75° C./0.2 mm Hg).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(O)[CH2:9]1)(C)(C)C.COCCN(S(F)(F)[F:34])CCOC.CO>C(Cl)Cl>[F:34][C:10]1([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:11][CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCCC(O)(Cc2ccccc2F)C1
Solvent: CO
Solvent: ClCCl
Product: NC1CCCC(F)(Cc2ccccc2F)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl-3-(2-fluorobenzyl)-3-hydroxycyclohexylcarbamate (1 mmol, 323 mg) in DCM was added Deoxo-Fluor® (2 mmol, 370 μL) at room temperature. The reaction mixture was stirred for overnight. Methanol was added dropwise. The desired product was obtained after the removal of solvent by rotary evaporation.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[C:17]([O-:20])(O)=[O:18].[Na+]>C(Cl)Cl.O.CCOC(C)=O>[CH2:2]([O:4][C:5](=[O:16])[C@H:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[NH:7][C:17]([O:20][C:9]([CH3:14])([CH3:10])[CH3:8])=[O:18])[CH3:3]
Reactant: O=C([O-])O
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 180.9 %

Procedure:
To a mixture of L-tyrosine ethyl ester hydrochloride (55.08 g) and NaHCO3 (22.52 g) in CH2Cl2/H2O (280 ml/280 ml) was added di-tert-butyl bicarbonate (56.82 g) portionwise. The mixture was stirred for 2 hours at room temperature and diluted with AcOEt. The organic layer was washed with H2O, dried (Na2SO4) and evaporated. The residue was recrystallized from a mixture of diethyl ether and hexane to yield N-(tert-butoxycarbonyl)-L-tyrosine ethyl ester (62.71 g). mp. 87-88° C.; MS (APCI) m/z 327 (M+NH4), 310 (M+H).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C1(C([O-])=O)SC=CC=1.Cl>C1COCC1>[C:14]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: O=C1CCCC1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: O=C([O-])c1cccs1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 3.0 M solution of phenylmagnesium bromide in ether (49.7 mL, 149 mmol) was added THF (300 mL). To this solution cooled to 0° C. cyclopentanone (13.23 mL, 149 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, then—at reflux for 2 h. Ice (20 g) was added, followed by 6N HCl, until the precipitate dissolved. The product was extracted with ether. The combined etherial layers were washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give cyclopentenylbenzene (21.49 g, 149 mmol, 100% yield) as colorless oil. LC-MS (M+H)+=145.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.48 (2H, d, J=7.3 Hz), 7.35 (2H, t, J=7.8 Hz), 7.22-7.27 (1H, m), 6.22 (1H, t, J=2.1 Hz), 2.70-2.80 (2H, m), 2.52-2.64 (2H, m), 2.01-2.12 (2H, m).
Reaction SMILES: [F:1][C:2](I)([F:7])[C:3]([F:6])([F:5])[F:4].[C:9]([C@@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20]2[C:25](I)=[C:24]([CH2:27][CH3:28])[N:23]=[CH:22][N:21]=2)[CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C@@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:20]2[C:25]([C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])=[C:24]([CH2:27][CH3:28])[N:23]=[CH:22][N:21]=2)[CH2:17][CH2:18]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: FC(F)(F)C(F)(F)I
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1I
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1C(F)(F)C(F)(F)F

Procedure:
Prepared as in Example 43 from pentafluoroethyl iodide and 4-(cis-4-tert-butylcyclohexylamino)-6-ethyl-5-iodopyrimidine (Example 1), colorless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11].[C:16](=S)=[S:17].[OH-].[K+].C(OCC)(=O)C>CN(C)C=O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:16]=[S:17])(=[O:11])=[O:12]
Reactant: S=C=S
Reactant: NS(=O)(=O)c1ccccc1OC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(N=C=S)c1ccccc1OC(F)(F)F
Temperature: 35 °C

Procedure:
24.1 g (0.1 mole) of 2-trifluoromethoxy-benzene-sulphonic acid amide are dissolved in 100 ml of dimethylformamide. 7.6 g (0.1 mole) of carbon disulphide and 5.6 g (0.1 mole) of potassium hydroxide powder are added and the reaction mixture is stirred at 35° C. until a clear solution has formed. A further 5.6 g (0.1 mole) of potassium hydroxide powder are then added and stirring is continued until a clear solution is formed. 100 ml of ethyl acetate are then added dropwise at 20° C. The product thereby obtained as crystals is isolated by filtration with suction and dried under reduced pressure. The dried product is suspended in 100 ml of toluene; 20 g of liquid phosgene are added dropwise at 0° C. and the mixture is stirred at 5° C. to 10° C. for one hour and at 20° C. for two hours. After filtration, the filtrate is concentrated to give an oily residue, which essentially contains 2-trifluoromethoxy-phenylsulphonyl isothiocyanate. Because of its low stability, the product is reacted as quickly as possible--without further purification--in the process according to the invention.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=O)[CH2:10][CH2:9]1)=O)(C)C.[NH2:24][CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:32]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C@@H:40]([CH3:51])[CH2:39]3)[CH:34]=[CH:35][CH:36]=2)=[CH:28][CH:27]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH3:51][C@@H:40]1[NH:41][CH2:42][CH2:43][N:38]([CH2:37][C:33]2[CH:32]=[C:31]([C:29]3[S:30][C:26]([CH2:25][NH:24][C:18](=[O:20])[C:17]4[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:16]=4)=[CH:27][CH:28]=3)[CH:36]=[CH:35][CH:34]=2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)O)c2)CC1
Reactant: C[C@H]1CN(Cc2cccc(-c3ccc(CN)s3)c2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2cccc(-c3ccc(CNC(=O)c4cccc(CC5CCNCC5)c4)s3)c2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (128 mg, 0.40 mmol) in CHCl3 (2.0 mL) was added 1,1-dimethylethyl (2S)-4-({3-[5-(aminomethyl)-2-thienyl]phenyl)methyl)-2-methyl-1-piperazinecarboxylate (160 mg, 0.40 mmol), TEA (0.1 ml, 0.7 mmol), EDC (115 mg, 0.6 mmol) and HOBt (59 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 2 h, followed by addition of 0.5 mL of saturated Na2CO3. The organic layer was isolated via a hydrophobic frit followed by addition of 0.5 mL of TFA, and stirred at room temperature for 1 h. After removal of the solvent, the residue was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (100 mg, 50%). LC/MS: m/z, 503 (M+H), 1.22 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[C:5]([NH:15][C:16]2[C:17]([C:26](O)=[O:27])=[CH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[O:10][C:9]([CH3:14])([CH3:13])[CH:8]=[CH:7][C:6]2=[C:5]2[C:4]=1[C:26](=[O:27])[C:17]1[CH:18]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]3=[CH:25][C:16]=1[NH:15]2
Reactant: COc1cc(Nc2cc3ccccc3cc2C(=O)O)c2c(c1)OC(C)(C)C=C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(c3[nH]c4cc5ccccc5cc4c(=O)c13)C=CC(C)(C)O2
Reaction time: 2 h

Procedure:
1.02 mmol of the compound obtained in Step A in 14 ml of dichloromethane is treated with 1 ml of trifluoroacetic acid. After 2 hours at room temperature, the reaction mixture is evaporated. The residue is taken up in a mixture of dichloromethane and a saturated NaHCO3 solution, extracted with dichloromethane, washed with a 10% sodium hydroxide solution and then extracted again with dichloromethane. After conventional treatment, chromatography of the residue over silica gel (dichloromethane/methanol: 98/2) enables isolation of the expected product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([NH:1][CH2:2][C:3]1[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[C:5]([CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:29])=[O:28]
Reactant: CCOC(=O)c1cc(CN)cc(C(=O)OCC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CNS(C)(=O)=O)cc(C(=O)OCC)c1
Yield: 35 %

Procedure:
To a stirring solution of crude diethyl 5-(aminomethyl)isophthalate in 30 mL of CH2Cl2 at 0° C. was added 1.2 mL of Et3N and 0.7 mL of MsCl. The ice bath was removed, and after 2 h at r.t. the solution was concentrated, and EtOAc and H2O were added. The organic layer was washed with brine, the aqueous layer was extracted with EtOAc, the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1% MeOH/CHCl3) provided 901 mg of diethyl 5-(methylsulfonamidomethyl)isophthalate as a pale yellow solid in 35% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[Cl:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.0025 mole) in dry 1,2-dichloroethane (5 mL) (under an atmosphere of nitrogen for 10 minutes) was added, 2-chloroaniline (0.352 g, 0.0027 mole), acetic acid (0.125 g, 0.00209 mole) and sodium triacetoxyborohydride (0.442 g, 0.00209 mole). The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched in cold aqueous 1N NaOH solution and the product was extracted with dichloromethane. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was stirred with hexane. The hexane was then decanted and the residue was dried to afford 0.615 g (79%) of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a solid. 1H NMR (DMSO-d6): δ 7.6 (dd, 1H), 7.1 (t, 1H), 6.8 (d, 1H), 6.54 (t, 1H), 4.8 (d, 1H), 3.9 (d, 3H), 3.5 (m, 1H), 2.9 (bs, 2H), 1.8 (d, 2H), 1.4 (s, 9H), 1.3 (d, 1H). To a stirred, cooled (0° C.) solution of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.150 g, 0.00048 mole) in dioxane (0.5 mL) was added dioxane.HCl (1.5 mL). The stirring was continued at the same temperature for 10 minutes, then the mixture was gradually brought to ambient temperature with continued stirring for a further 15 minutes. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with dry ether and dried to afford 0.118 g (99%) of (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride.
Reaction SMILES: [C:1]1([C:11]2[S:12][C:13]3[CH:36]=[C:35]([O:37]C)[CH:34]=[CH:33][C:14]=3[C:15]=2[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:1]1([C:11]2[S:12][C:13]3[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:14]=3[C:15]=2[C:16]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[CH:22][CH:23]=2)=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccc4ccccc34)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cccc3ccccc23)sc2cc(O)ccc12
Yield: 53.4 %

Procedure:
A solution of the product of Example 1 (1.00 g, 1.92 mmol), ethanethiol (0.45 mL, 6.18 mmol), and aluminum chloride (1.54 g, 11.55 mmol) in anhydrous methylene chloride (40 mL) was stirred for 3.5 hours. The mixture was quenched with saturated potassium sodium tartrate (also known as Rochelle's salt) and extracted with ethyl acetate. The organic layer was washed with saturated sodium potassium tartrate and brine, dried (sodium sulfate), and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol in methylene chloride) to give 520 mg (53%) of the title product as a dark yellow/green foam: 1H NMR (300 MHz, CDCl3) δ1.46 (m, 2H), 1.65 (m, 4H), 2.54 (m, 4H), 2.73 (t, J=5.4 Hz, 2H), 3.96 (t, J=5.4 Hz, 2H), 6.37 (d, J=8.7 Hz, 2H), 6.88 (dd, J=1.9 Hz, 8.8 Hz, 1H), 7.23-7.29 (m, 2H), 7.37-7.51 (m, 5H), 7.62-7.70 (m, 3H), 8.02-8.05 (m, 1H), 8.28 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ23.3, 24.7, 54.4, 57.0, 64.5, 106.9, 113.0, 115.2, 124.2, 124.3, 125.2, 125.5, 126.1, 127.6, 128.7, 128.7, 130.3, 130.5, 131.2, 131.6, 131.8, 132.8, 133.4, 140.7, 141.1, 154.6, 161.6, 192.1; MS (FD) m/e 508 (MH+); Anal. calc'd. for C32H29NO3S: C, 75.71; H, 5.76; N, 2.76. Found: C, 75.43; H, 6.02; N, 3.03.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[OH:13].Cl[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=1>>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[O:13][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OCc1cccc2c(O)cccc12
Product: N#Cc1ccc(Oc2cccc3c(CO)cccc23)nc1

Procedure:
Using the procedure outlined in Preparation 15, 5-hydroxymethylnaphthalen-1-ol (Preparation 32) and 6-chloronicotinonitrile were converted to the title compound: RT=3.17 min; m/z (ES+)=277.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[F:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O.O.C(O)(=O)C(O)=O>C(O)(C)C.CN(C)C=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][CH2:8][C:7]4[CH:16]=[CH:17][CH:18]=[CH:19][C:6]3=4)[CH2:29][CH2:28]2)=[O:26])=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: ClCCCN1c2ccccc2CCc2ccccc21
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCN2c3ccccc3CCc3ccccc32)CC1
Yield: 32 %

Procedure:
A stirred mixture containing 4.5 gms. (0.017 mole) of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine, 3.4 gms (0.017 mole) of 4-(4-fluorobenzoyl)piperidine, 10.0 gms. of potassium carbonate and 75 ml. of dimethylformamide was heated at 90°-100°C. for 16 hours. The cooled suspension was filtered, the solvent removed at reduced pressure and the residual oil was taken up in ether and filtered to remove insoluble materials. The clear filtrate was treated with a solution of 2.1 gms. (0.017 mole) of oxalic acid dihydrate in isopropanol. The oxalate which separated on cooling was collected by filtration. The salt melted at 150°-155°C. and weighed 2.9 gms. (32% yield). After recrystallization from isopropanol the salt melted at 156°-159°C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1.Cl[CH2:17][C:18]1[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:20][O:21][C:22]=1[CH3:23].Cl>C1COCC1>[CH3:23][C:22]1[O:21][N:20]=[C:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]=1[CH2:17][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1
Reactant: Cc1onc(-c2ccccc2)c1CCl
Reactant: Cc1ccc(C(=O)O)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1CCc1ccc(C(=O)O)cn1
Temperature: -74 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
n-Butyllithium solution was added dropwise to a stirred suspension of 6-methylnicotinic acid (137 mg, 1.0 mmol) in THF (3 mL) over 30 min at −74° C. After 1 h a solution of 4-chloromethyl-5-methyl-3-phenyl-isoxazole (208 mg, 1.0 mmol) in THF (3 mL) was added dropwise such that the temperature did not exceed −68° C. The reaction mixture was stirred at −74° C. for 1 h, then HCl (1 N, 10 mL) added and the reaction mixture warmed to room temperature and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 9:1) afforded the title compound (20 mg, 6%) as a light yellow oil. MS: m/e=168.3 [M+H]+.
Reaction SMILES: [N:1]([C@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]1=[O:25])=[N+]=[N-]>[Pd]>[NH2:1][C@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:5]1=[O:25]
Reactant: CC(C)(C)OC(=O)CN1C[C@H](c2ccccc2)CC[C@H](N=[N+]=[N-])C1=O
Agent: [Pd]
Product: CC(C)(C)OC(=O)CN1C[C@H](c2ccccc2)CC[C@H](N)C1=O
Yield: 102.5 %

Procedure:
Reduction of 1.9 g of t-butyl α-[3(S*)-azido-2-oxo-6(S*)-phenylperhydroazepin-1-yl]acetate (Isomer B) [prepared as described in Example 1(i)] with 5% w/w palladium-on-carbon in a similar manner to that described in Example 1(j) gave 1.8 g of the title compound as a gummy substance.