Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH:23]([OH:26])[CH2:24][CH3:25].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CCC(O)c1cccc(F)c1Oc1ccnc2cc(OC)c(OC)cc12
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)c1cccc(F)c1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 1 %

Procedure:
1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml). Sulfur trioxide trimethylamine complex (70 mg) was added to the solution at 0° C., and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The reaction solution was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (2 mg, yield 1%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH3:46][C:38]1([N:32]2[C:31](=[O:47])[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([CH2:27][NH:26][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][N:8]=4)=[O:12])[CH:29]=3)[C:33]2=[O:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CCOc1ccc(C(=O)O)nc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A stirred mixture of 5-ethoxy-pyridine-2-carboxylic acid (0.33 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solids were filtered and dissolved in CH2Cl2 (10 mL). The crude product was purified by column chromatography (0-5% MeOH CH2Cl2, gradient, product eluted at 3% MeOH). The product fractions were combined and concentrated to give 5-ethoxy-pyridine-2-carboxylic acid[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.69 g, 77% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.98 min (95.90%); mp: 145-147° C.; 1H NMR (DMSO-d6) δ 1.37 (t, J=7.2 Hz, 3H), 1.88 (s, 3H), 2.01-2.07 (m, 1H), 2.54 2.71 (m, 3H), 4.19 (dd, J=6.9, 13.8 Hz, 2H), 4.61 (d, J=6.3 Hz, 2H), 7.53 (dd, J=3.0, 8.7 Hz, 1H), 7.77-7.82 (m, 3H), 7.99 (d, J=8.7 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 9.40 (t, J=6.3 Hz, 1H), 11.00 (s, 1H); 13C NMR (DMSO-d6) δ12.70, 19.30, 26.90, 27.40, 40.60, 57.00, 62.40, 119.60, 120.00, 121.40, 121.70, 127.80, 129.60, 131.80, 135.10, 14.050, 145.90, 155.30, 162.30, 166.10, 166.20, 170.40, 170.50; LCMS: MH=451; Anal Calcd for C23H22N4O6+0.5H2O: C, 60.13; H, 5.05; N, 12.19. Found: C, 59.95; H, 4.91; N, 12.04.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C@@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:6].C([O-])(=O)C.[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O)([O-:20])=[O:19].C([BH3-])#N.[Na+]>C(O)C>[CH3:2][O:3][C:4](=[O:12])[CH:5]([NH:6][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[N+:18]([O-:20])=[O:19])[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C[C@@H](N)C(=O)OC
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCO
Product: COC(=O)CC(NCc1ccccc1[N+](=O)[O-])C(=O)OC
Reaction time: 1.5 h
Yield: 99 %

Procedure:
A mixture of D-aspartic acid dimethyl ester hydrochloride (4.2 g, 21.25 mmol) and sodium acetate (1.46 g, 17.85 mmol) was stirred in 25 mL of warm ethanol for 10 min. 2-Nitrobenzaldehyde (1.35 g, 8.936 mmol) was added and stirring was continued at room temperature for 1.5 h. Sodium cyanoborohydride (333.88 mg, 5.31 mmol) was added in portions over 5 min. and stirring at room temperature continued overnight. The reaction mixture was concentrated in vacuo, the residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and sodium chloride solutions. The organic layer was dried (Na2SO4) and concentrated to give 2.62 g of the title compound as a light brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
Under nitrogen atmosphere in a 250 mL round bottomed flask containing 4-bromocinnamic acid (5.0 g, 22 mmoles) in 45 mL of N,N-dimethylformamide (0.5 M) was added benzenesulfonylhydrazide (7.6 g, 44 mmoles). The mixture was stirred at reflux for 12 hours. The solution was cooled at room temperature, aqueous saturated ammonium chloride was added and the aqueous layer was extracted with ethyl acetate 3 times. Combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuo. The resulting solid was purified by flash chromatography eluting with 5% methanol:95% dichloromethane to afford 3.66 g (73%) of beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[C:10]([Cl:15])=[N:11][CH:12]=[CH:13][N:14]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:15][C:10]1[C:9]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:14][CH:13]=[CH:12][N:11]=1
Reactant: Nc1ccccc1
Reactant: Clc1nccnc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1nccnc1Nc1ccccc1
Temperature: 90 °C
Yield: 18.1 %

Procedure:
Aniline (11.25 g, 121 mmol), dichloropyrazine (20 g, 134 mmol), sodium t-butoxide (15.48 g, 161 mmol) were stirred in toluene (300 mL) under nitrogen purging for 15 minutes. Pd2(dba)3 (1.23 g, 1.34 mmol) and BINAP (3.34 g, 5.47 mmol) were added. The reaction was heated to 90° C. for 5 h. After it cooled to room temperature, the reaction was filtered through Celite®. After solvent evaporation, the residue was purified with column chromatography using 30% ethyl acetate in hexanes as solvent to give 3-chloro-N-phenylpyrazin-2-amine (4.5 g, 16.3% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].N12CCCN=C1CC[CH2:11][CH2:10][CH2:9]2.BrCCCBr>CN(C)C=O>[CH3:7][O:6][C:4]([C:3]1([C:1]#[N:2])[CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)CC#N
Agent: BrCCCBr
Solvent: CN(C)C=O
Product: COC(=O)C1(C#N)CCC1
Temperature: -7.5 °C
Reaction time: 0.17 h

Procedure:
To methyl cyanoacetate (10 g, 0.1 mol) under N2, N,N-dimethylformamide (DMF, 10 mL) was added at room temperature. After 10 min, the solution was added 1,8-diazabicyclo [5,4,0]undec-7-ene (DBU, 33.4 g, 0.22 mol) at 10-20° C., and then reacted 15 min at 50° C. The mixture was cooled to −5 to −10° C., 1,3-dibromopropane (20.4 g, 0.1 mol) in DMF (10 mL) added by syringe, reacted 15 min at room temperature, rose up to 70° C., and then reacted 30 min. The mixture was evaporated and the residue taken up in H2O and extracted with CHCl3 (3×50 mL). The chloroform phase was evaporated under reduced pressure. The compound 1 was purified by column chromatography (SiO2, hexane/acetone 8:1), yielding 8.74 g (62.81%). MS (ESI): m/z: 140.08 [M+H]+. Anal. Calcd (Found) for C7H9NO2: C, 60.42 (60.74); H, 6.52 (6.58); N, 10.07 (10.21). 1H NMR (D2O, 400 MHz), δ ((ppm): 3.84 (s, 3H, —OCH3), 2.73-2.63 (m, 4H, —C—CH2—CH2—CH2—), 2.17-2.32 (m, 2H, —C—CH2—CH2—CH2—). 13C NMR (D2O, 400 MHz), δ (ppm): 169.17, 128.11, 53.50, 39.38, 31.22, 17.18.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]=[C:4]1[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2.CN(C)C=O.[H][H]>[Pd].CO>[CH2:3]([CH:4]1[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH:2]([CH3:21])[CH3:1]
Reactant: CC(C)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21

Procedure:
2.8 g of a mixture of 10-(2-methyl-1-propenyl)-5H,10H-imidazo[1,2-]indeno[1,2-e]pyrazin-4-one and 10-(2-methylpropylidene)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one are hydrogenated in the presence of 180 ml of dimethylformamide, 20 ml of methanol and 0.5 g of 10% palladium on charcoal for 22 hours at 50° C. and at a pressure of 54 bar of hydrogen. After filtration of the catalyst under inert atmosphere, the solvents are evaporated off and the grey solid obtained (2.1 g) is purified by chromatography on a column of silica (180 g partially deactivated with 3 ml of water), using a mixture of dichloromethane and methanol (90/10 by volume) as eluent. After trituration in 20 ml of ethyl ether, filtration and drying at 100° C., 1.2 g of 10-isobutyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, in the form of a cream-coloured solid melting above 260° C. (Analysis % calculated C: 73.10, H: 6.13, N: 15.04, O: 5.73, % found C: 72.9, H: 5.6, N: 14.8).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.CS([C:25]1[N:30]=[C:29]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:28]([C:44]([F:47])([F:46])[F:45])=[CH:27][N:26]=1)(=O)=O.C(O)(C(F)(F)F)=O.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(O)C(F)(F)F>[CH3:43][O:42][C:40](=[O:41])[CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][CH2:31][C:29]1[C:28]([C:44]([F:47])([F:45])[F:46])=[CH:27][N:26]=[C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[N:30]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)CCO3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
tert-Butyl 2-(4-aminophenyl)morpholine-4-carboxylate (I88) (50 mg, 0.18 mmol) and methyl 2-(2-(2-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I67) (72 mg, 0.18 mmol) were heated in trifluoroethanol (1.2 mL) and TFA (0.12 mL) under microwave irradiation (100° C./20 minutes). The mixture was concentrated, evaporated from toluene and loaded onto a 5 g SCX cartridge in methanol (1 mL). The cartridge was washed with methanol (50 mL), and then eluted with 1% methylamine/methanol (50 mL). The basic eluent was concentrated, and taken up in dichloromethane (5 mL). Boc anhydride (0.062 mL, 0.27 mmol) was added, and the mixture stirred at room temperature for 18 hours. The mixture was evaporated onto silica gel, and chromatographed (12 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I89) (46 mg, 42% yield) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) 8.55 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.47 (s, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.29-7.18 (m, overlaps with CHCl3), 4.41 (d, J=8.4 Hz, 1H), 4.08 (m, 3H), 3.76 (s, 2H), 3.73-3.64 (m, 4H), 3.16-2.98 (m, 5H), 2.85 (s, 1H), 1.51-1.47 (m, 9H). LCMS Method C: rt 6.88 min; m/z 601.1 [M+H]+, 545.1 [M−tBu+2H]+.
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][C:18](=[O:20])[CH3:19])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=O)[CH2:2][CH2:3][CH3:4]>[OH-].[K+].O>[CH2:1]([C:5]12[CH2:17][C:18](=[O:20])[CH:19]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC(C)=O)Cc2cc(OC)ccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCC12CC(=O)C=C1c1ccc(OC)cc1C2

Procedure:
Potassium hydroxide (8 g, 87% weight pure, 0.12 mol) was dissolved in 7:1 water-EtOH (80 mL) to give a 1.56M solution. A suspension of 2-butyl-5-methoxy-(2-oxopropyl)-1-indanone (83 mg, 0.3 mmol) in 5 mL of the KOH solution was stirred and heated at reflux for 23 hours. After cooling, the mixture was diluted with water (10 mL) and extracted with EtOAc (3×30 mL). The extracts were washed with 1N HCl, water, and brine (20 mL each), dried over MgSO4, filtered, and concentrated under vacuum to an oil. 1H NMR revealed a 65:35 mixture of desired product to starting material. The mixture was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing twice with 5:1 hexane-EtOAc. The product band was extracted with EtOAc and the extracts evaporated under vacuum to provide 8a-butyl-6-methoxy-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as an oil.
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.Cl.Cl.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16]([NH2:18])=[NH:17].C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:18][C:16]1[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][C:19]=2[F:23])[NH:13][C:2]2([CH2:5][N:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]2)[N:17]=1
Reactant: N=C(N)c1c(N)cccc1F
Reactant: CCOC(=O)N1CC(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC2(C1)N=C(N)c1c(F)cccc1N2
Yield: 38.3 %

Procedure:
Ethyl 3-oxoazetidine-1-carboxylate (Y. Nitta, T. Yamagouchi, T. Tanaka; Heterocycles, 1986, 24, 25) (175 mg, 1.22 mmol) and 2-amino-6-fluorobenzamidine dihydrochloride (Example C, 280 mg, 1.22 mmol) in dry DMF (10 ml) were heated at 80° C. for 4 hours. The resulting solution was cooled and poured into aqueous sodium bicarbonate solution and the resulting mixture was extracted with ethyl acetate. The extracts were concentrated and the residue purified by flash chromatography on silica eluting with dichloromethane/methanol (10:1) to give the title compound as a solid (0.13 g) m.p. 210°-212° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=4)[C:15]=3[CH:30]=2)=[N:9][N:10]=1)(=O)C.[OH-].[Na+].CO>C(OCC)(=O)C>[F:28][C:26]([F:27])([F:29])[O:25][C:21]1[CH:20]=[C:19]([C:16]2[C:15]3[CH:30]=[C:11]([C:8]4[O:7][C:6]([CH2:5][OH:4])=[N:10][N:9]=4)[CH:12]=[CH:13][C:14]=3[O:18][CH:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)OCc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A mixture of [5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazol-2-yl]methyl acetate (230 mg, 0.550 mmol), 1M aqueous sodium hydroxide solution (1 mL) and methanol (4 mL) was stirred at room temperature for 20 min. 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 recrystallized from hexane/ethyl acetate to give the title compound (yield 85%) as colorless crystals.
Reaction SMILES: N#[C:2][Br:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C[CH2:13][S:14][C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[CH:16]=1>C(Cl)(Cl)Cl.CO>[Br:3][CH2:2][CH2:13][S:14][C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[CH:16]=1
Reactant: CN(C)CCSC1=Cc2ccccc2Oc2ccccc21
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: BrCCSC1=Cc2ccccc2Oc2ccccc21

Procedure:
To a stirring solution of 0.36 g of cyanogen bromide, 2.28 g of potassium carbonate in 10 ml of chloroform is added dropwise a solution of 1.0 g of 10-[β-(dimethylamino)ethylthio]dibenz[b,f]oxepin, Example 8, in chloroform. After total addition the reaction mixture is refluxed for 2 hours and the solvent removed leaving an oil. The oil is dissolved in 10 ml of methanol and the methanolic solution refluxed for 10 minutes and again concentrated to recover the oil. The oil is chromatographed through a silica gel column with an eluant of ether. The top fraction is collected and concentrated leaving a white solid, mp 106°-107° C. of 10-[β-(bromo)ethylthio]dibenz[b,f]oxepin.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:12]1[C:17]([C:18]([CH2:20]Br)=O)=[CH:16][CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)C>[N+:22]([C:14]1[CH:15]=[CH:16][C:17]([C:18]2[N:1]=[C:2]3[N:6]([CH:20]=2)[C:5]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:4]=2[S:3]3)=[CH:12][CH:13]=1)([O-:24])=[O:23]
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1

Procedure:
2-Amino-6-hydroxybenzothiazole, 2-Bromo-4-nitroacetophenone and absolute Ethanol are added together and heated to reflux for approximately 24 hours. Tetrabutylammonium iodide is added and the reaction is refluxed an additional 12 hours. The resulting yellow suspension is cooled and the solids collected and washed with Ethanol and Diethyl ether. The solids are dried under vacuum to give Intermediate 2.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:22])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:22])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:26][CH2:25][CH2:23][OH:24])=[O:6]
Reactant: NCCO
Reactant: CC(=CC(=O)O)CCCC(C)CCCC(C)CCCC(C)C
Product: CC(=CC(=O)NCCO)CCCC(C)CCCC(C)CCCC(C)C
Yield: 95 %

Procedure:
The procedure of Example 1 was repeated except that 6.2 g of 3,7,11,15-tetramethyl-2-hexadecenoic acid and 1.8 ml of ethanolamine were used as starting materials. 6.7 g (yield 95%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:25][CH2:24][C@@H:23]([NH:26][C:27](=[O:42])[CH2:28][NH:29][C:30](=[O:41])[C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=5)[CH2:22]4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N)(=O)C1C=CC=CC=1>>[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:42])[CH2:28][NH:29][C:30](=[O:41])[C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=5)[CH2:22]4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc(C(=O)N4CCOCC4)cc3)CC2)C1
Agent: NC(=O)c1ccccc1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCN(C2CCN(c3ccc(C(=O)N4CCOCC4)cc3)CC2)C1

Procedure:
The title compound was synthesized in a similar fashion to N-{2-[((3R)-1-{1-[4-(morpholin-4-ylcarbonyl)phenyl]piperidin-4-yl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide, substituting (S)—N-(2-oxo-2-(pyrrolidin-3-ylamino)ethyl)-3-(trifluoromethyl)benzamide for (R)—N-(2-oxo-2-(pyrrolidin-3-ylamino)ethyl)-3-trifluoromethyl)benzamide. 1H-NMR (CD3OD) δ: 1.43-1.68 (m, 2H), 1.62-1.79 (m, 1H), 1.94-2.00 (m, 2H), 2.20-2.38 (m, 2H), 2.55-2.68 (m, 2H), 2.75-2.98 (m, 4H), 3.35-3.40 (m, 2H), 3.60-3.75 (m, 8H), 3.80-3.90 (m, 2H), 4.02 (s, 2H), 4.36-4.46 (m, 1H), 6.99 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.69 (t, J=7.8 Hz, 1H), 7.87 (t, J=7.5 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.22 (s, 1H). MS m/z: 588 (M+1).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C([O-])(O)=O.[Na+].Cl[C:28]([O:30][CH3:31])=[O:29]>C1COCC1.O.CCOC(C)=O>[C:18]([NH:17][CH2:16][C@@H:14]1[O:13][C:12](=[O:21])[N:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH2:1][N:2]([C:28]([O:30][CH3:31])=[O:29])[CH2:3][CH2:4]3)[CH2:15]1)(=[O:20])[CH3:19]
Reactant: COC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N1CCc2cc(N3C[C@H](CNC(C)=O)OC3=O)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A mixture of N-[[(5S)-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Step 6, 450 mg, 1.55 mmol) and NaHCO3 (260 mg, 3.10 mmol) in THF (15.5 mL) under N2 is treated with methyl chloroformate (0.144 mL, 1.87 mmol) with vigorous stirring. A thick, white slurry results which is redissolved by the addition of H2O (approx. 2 mL). The mixture is stirred at ambient temperature for 1 hr and is then diluted with H2O (10 mL) and EtOAc (20 mL) and the layers are separated. The aqueous phase is reextracted with CH2Cl2 (20 mL), and the combined organic phase is washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product is chromatographed on silica gel (45 g, 230-400 mesh), eluting with MeOH/CHCl3 (2/98), and those fractions with an Rf=0.51 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 475 mg (88%) of the title compound as a glassy solid. 1H NMR (400 MHz, CDCl3) δ 7.32 (m, 2H), 7.11 (m, 1H), 6.19 (m, 1H), 4.76 (m, 1H), 4.59 (s, 2H), 4.05 (t, 1H), 3.78 (dd, 1H), 3.75 (s, 3H), 3.75-3.50 (m, 4H), 2.85 (m, 2M), 2.02 (s, 3H); MS (ESI+) for C17H21N3O5 m/z 348 (M+H)+; [α]25D=−20° (c 1.04, DMSO).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:12]([O:14][CH3:15])=[O:13])[C:10](=[O:11])[C:4]=2[CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]([OH:11])[C:4]=2[CH:3]=1
Reactant: COC(=O)C1CCCc2ccc(Br)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCc2ccc(Br)cc2C1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a solution of the crude methyl 3-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-carboxylate from step A2 (350 mg, 1.18 mmol) in MeOH (5 mL) was slowly added NaBH4 (44.6 mg, 1.18 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. The solvent was removed in vacuo at rt. EtOAc (100 mL) was added and the organic layer was washed with water. The organic layer was concentrated, and the residue was purified using silica gel column chromatography (hexanes-60% EtOAc) to give methyl 3-bromo-5-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-carboxylate (230 mg, 0.769 mmol, 65% yield). 1H NMR (500 MHz, chloroform-d) δ 7.81-7.39 (m, 1H), 7.35-7.23 (m, 1H), 7.01-6.87 (m, 1H), 5.13-4.96 (m, 1H), 3.77-3.65 (m, 3H), 3.39-3.22 (m, 1H), 3.20-2.56 (m, 3H), 2.47-1.86 (m, 3H), 1.65-1.30 (m, 1H).