Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10](Cl)=[O:11].[CH2:14]([OH:16])[CH3:15]>>[CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:16][CH2:14][CH3:15])=[O:11]
Reactant: CC1(C)[C@H](C=C2CCC2)[C@H]1C(=O)Cl
Reactant: CCO
Product: CCOC(=O)[C@@H]1[C@@H](C=C2CCC2)C1(C)C

Procedure:
A solution of 12 g of (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid chloride and 25 ml of ethanol was stirred at room temperature for 8 hours and was evaporated to dryness at 45° C. under reduced pressure. The residue was taken up in isopropyl ether and the solution was washed with water, dried and evaporated to dryness under reduced pressure at 45° C. The residue was chromatographed over silica gel and was eluted with a 9-1 petroleum ether (b.p.=60°-80° C.)--isopropyl ether mixture. The fraction with an Rf=0.35 was evaporated to dryness under reduced pressure at 45° C. and the product was rectified to obtain 8 g of ethyl (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate with a boiling point of 78°-79° C. at 0.1 mm Hg and a specific rotation of [α]D20 =-18° (c=2% in chloroform).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH2:12][C:9]=3[CH:10]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:4]([C:22]([O:24]CC)=[O:23])[C:3]1=[O:27].[OH-].[K+].C(O)C>O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH2:12][C:9]=3[CH:10]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:4]([C:22]([OH:24])=[O:23])[C:3]1=[O:27]
Reactant: CCOC(=O)c1c(-c2ccccc2C)c2cc3c(cc2n(C)c1=O)CCC3
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-c1c(C(=O)O)c(=O)n(C)c2cc3c(cc12)CCC3
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
A mixture of ethyl 1-methyl-4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (2.0 g), potassium hydroxide (1.55 g) and 80% ethanol (20 ml) was stirred at 80° C. for 20 minutes. The mixture was diluted with water and acidified with 2N NCl to give crystals of 1-methyl-4-(2-methylphenyl) -2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylic acid (1.85 g, 99.6%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([NH2:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:10]([NH:19][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: NC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-phenyl-pyrrolidin-3-ylamine (0.25 g, 1.0 mmol) in THF (5 ml) was added a solution of K2CO3 (0.25 g, 1.8 mmol) in H2O (2 ml). After 10 minutes, ethyl chloroformate (0.119 g, 1.1 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (5 ml) and a solution of borane in THF (1M) was added (3.5 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (0.5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (20 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.21 g (82%) of rac-((3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methyl-amine as a colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[CH:18].C(N(CC)CC)C.C1C=CC=CC=1>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][N:9]=1
Reactant: NNc1ccccc1I
Reactant: C#Cc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1ccccc1Cc1n[nH]c2ccccc12

Procedure:
Under argon, 200 mg (0.86 mmol) of 2-iodophenylhydrazine, 133 mg (1.11 mmol) of 2-fluoro-phenylacetylene, 30 mg (0.04 mmol) of bis(triphenylphosphine)palladium(II) chloride and 8 mg (0.04 mmol) of copper(I) iodide are introduced into a mixture of 1.5 ml of triethylamine and 3.5 ml of benzene. The mixture is heated to reflux for 4 h and then diluted with ethyl acetate and filtered. The filtrate is concentrated and the residue is purified by preparative HPLC. 36 mg (18% of theory) of the desired product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:23][CH:24]([F:35])[C:25]1[CH:26]=[C:27]([CH3:34])[C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31](=[O:32])[C:28]3[C:27]([CH3:34])=[CH:26][C:25]([CH:24]([F:23])[F:35])=[CH:30][N:29]=3)[CH:3]=[C:4]([CH3:22])[C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: Cc1cc(C(F)F)cnc1C(=O)O
Reactant: Cc1cc(N)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Product: Cc1cc(C(F)F)cnc1C(=O)Nc1cc(C)c(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
To a solution of (4S,6S)-4-(5-amino-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.075 g, 0.232 mmol) and 5-(difluoromethyl)-3-methylpicolinic acid (0.048 g, 0.255 mmol) in DMF (2 mL) at 0° C. was added 1-propanephosphonic acid cyclic anhydride (0.177 ml, 0.278 mmol) and the resulting mixture was stirred at 0° C. for 2 h, the ice bath was removed and stirred at rt for 1 h. The reaction was diluted with EtOAc, washed with water, sat. NaHCO3, and chromatographed on silica gel using 0-4% MeOH/DCM to afford a white solid as N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-5-methylphenyl)-5-(difluoromethyl)-3-methylpicolinamide (0.0145 g, 0.029 mmol, 12.69% yield). MS m/z=492.9 [M+H]+. Calculated for C21H19F7N4O2: 492.14.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][Cl:15]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCCl)c(Br)c1
Temperature: 100 °C
Yield: 75.6 %

Procedure:
A mixture of 2-bromo-4-cyanophenol (3.96 g), 3-bromopropyl chloride (3.46 g), dimethylformamide (20 ml) and anhydrous potassium carbonate (3 g) was heated at 100° C. for 0.5 hour. The inorganic salt was filtered off, and the filtrate was concentrated. The residue was chromatographed on a column of silica gel (90 g), and eluted with a solution of n-hexane-chloroform-acetone (20:10:1) to give 3-(2-bromo-4-cyanophenoxy)propyl chloride as a colorless oil (4.15 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[Li]CCCC.B(OC)(OC)[O:21]C.OO.[NH4+].[Cl-]>C1COCC1.CCCCCC.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:6]=1[OH:21]
Reactant: COB(OC)OC
Reactant: COCOc1ccc(C(F)(F)F)cc1
Agent: OO
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C(F)(F)F)cc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methoxymethoxy-4-trifluoromethyl-benzene (4.6 g, 22.31 mmol) in 60 mL dry THF cooled to −78° C., BuLi (21 mL of a 1.6 m sol. in hexane, 1.5 eq.) was added drop-wise via a syringe and the mixture was stirred at low temperature for 2 h, then the cooling bath was removed and the mixture was allowed to gradually warm to 0° C. during 30 min. After cooling again to −78° C., B(OCH3)3 (3.95 g, 38 mmol, 1.7 eq.) was added to the reaction and the stirring was continued for another 1.5 h at −78° C., then the solution was allowed to warm to −10° C. during 20 min. Re-cooling to −78° C. was followed by addition of H2O2 (5.82 mL of a 30% solution in H2O, 2 eq.) and NaOHaq (5.8 mL of a 5 m aqueous solution, 1.3 eq.). This solution was stirred 16 h at r.t., then saturated NH4Cl-solution was added and the mixture was extracted twice with 30 mL EtOAc. The pooled organic fractions were washed with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 4:1) to yield the desired product as a yellowish oil.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=O)(C)(C)C.[ClH:21]>O1CCOCC1>[CH3:6][NH:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.[ClH:21]
Reactant: CN(CC[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A solution of 17.24 g (60.4 mmol) of trans-4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexanecarboxylic acid was dissolved in 150 mL of dioxane, cooled to 10° C. and treated with 151 mL (604.1 mmol, 10 eq) of 4M HCl in dioxane, then warmed to RT and stirred for 3 h. The solution was evaporated to ca. 15 mL, precipitated with ˜100 mL of Et2O and cooled to 0° C. The solid precipitate was filtrated, washed with Et2O (×3) and dried under reduced pressure to yield 13.55 g (quantitative) of trans-4-(2-methylamino-ethyl)-cyclohexanecarboxylic acid·HCl, MS: 186 (MH+), MP: 212-214° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:31]>CO>[IH:31].[N:22]1([CH2:21][CH2:20][N:19]2[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=[C:15]2[N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCn2ccnc2)CC1
Agent: I
Solvent: CO
Product: c1ccc2c(c1)nc(N1CCCNCC1)n2CCn1ccnc1
Reaction time: 20 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.22 g, 0.54 mmol), 57% hydriodic acid (0.25 mL, 1.13 mmol), methanol (10 mL) and heat to reflux. After 20 hours, cool the reaction mixture and evaporate in vacuo to give a residue. Triturate the residue with diethyl ether to give a solid. Repeatedly, decant and add diethyl ether before collecting the solid by filtration, rinse with diethyl ether, and dry in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C@@:2]([NH:15][NH2:16])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.O.C(=O)(O)[O-].[Na+].O.[CH2:24]([O:31][C:32](ON1[C:39](=O)[CH2:38][CH2:37][C:36]1=[O:41])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(OC)(C)C.C1COCC1>[CH2:24]([O:31][C:32]([NH:16][NH:15][C@@:2]([CH3:1])([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1)[C:12]([OH:14])=[O:13])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:37]1[CH2:36][O:41][CH2:39][CH2:38]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: C[C@@](Cc1ccc(O)c(O)c1)(NNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
A slurry of carbidopa monohydrate (20.0 g, 82 mmol), sodium bicarbonate (7.57 g, 90 mmol), water (200 mL), and THF (100 mL) was cooled to 5° C. to 10° C. and N-(benzyloxycarbonyloxy)succinimide (20.4 g, 82 mmol) was added. The mixture was warmed to ambient temperature and became a nearly homogeneous solution over 5 hours, when LC-MS showed nearly complete reaction. The solution was diluted with MTBE (100 mL), the layers separated, and organic layer extracted with saturated aqueous NaHCO3 (100 mL). The aqueous layers were acidified with 2 N HCl (160 mL) and the acidic aqueous layer was extracted with MTBE (2×100 mL). During the second back-extraction, a small amount of product began to precipitate. The combined organic layers were washed with brine (20 mL) and residual solid rinsed out of the separatory funnel with MTBE (20 mL). The resulting mixture was concentrated to 43 g total mass and 10% THF/MTBE (60 mL) was added. The mixture was too thick to stir, so additional MTBE (60 mL to 6 vol 5% THF/MTBE) was added. The resulting white slurry was then heated to 50° C. The slurry was cooled to ambient temperature over one hour and then stirred for 14 hours. The white solid was filtered, washed with 5% THF/MTBE (20 mL), and dried in a vacuum oven (50° C.), giving (S)-2-(2-((benzyloxy)carbonyl)-hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid compound with THF (4:3) (31.1 g, 71.9 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J=9.0 Hz, 2H), 8.18 (br s, 1H), 7.49-7.17 (m, 5H), 6.59 (dd, J=5.0, 3.0 Hz, 2H), 6.44 (dd, J=8.0, 2.0 Hz, 1H), 5.04 (s, 2H), 2.73 (d, J=13.4 Hz, 1H), 2.59 (d, J=13.3 Hz, 1H), 1.07 (s, 3H); MS (ESI) m/z 361 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C>>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:10]3)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Product: OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Yield: 57.8 %

Procedure:
The title compound (66 mg yield) was prepared in analogy to the procedure described in Preparation 4 and Preparation 5 starting from (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (97 mg, 0.4 mmol), and [(3-bromopropyl)oxy](1,1-dimethylethyl) dimethylsilane (152 mg, 0.6 mmol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:18]=2)[NH:15][C:14]([C:26](O)=[O:27])=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.C[N:33](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>CCCCCC.C(OCC)(=O)C.CO.O>[CH3:1][S:2]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:18]=2)[NH:15][C:14]([C:26]([NH2:33])=[O:27])=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.9 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylic acid (1.95 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.73 g), 1-hydroxybenzotriazole ammonium salt (1.37 g), and N,N-dimethylformamide (50 mL) was stirred at room temperature for 12 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (methanol:ethyl acetate:hexane=0:85:15 to 10:90:0, volume ratio) to give the title compound (2.06 g, yield 100%) as a white solid.
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:11][CH:12]=O.[C:14]([NH:17][CH2:18][CH2:19][NH2:20])(=[O:16])[CH3:15].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[N:20]1([CH2:19][CH2:18][NH:17][C:14](=[O:16])[CH3:15])[C:2]2[C:3](=[CH:4][CH:5]=[C:6]3[S:7][CH:8]=[CH:9][C:10]3=2)[CH:11]=[CH:12]1
Reactant: O=CCC1CCc2sccc2C1=O
Reactant: CC(=O)NCCN
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CC(=O)NCCn1ccc2ccc3sccc3c21

Procedure:
A 4.20 g of sodium periodate was added gradually to a mixture of 1.80 g of 5-allyl-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene, 25 mg of osmium tetraoxide, 15 ml of water and 45 ml of dioxane, while keeping the reaction mixture at 24 to 26° C., and then the mixture was stirred at room temperature for 3 hours. After extraction of the reaction mixture with ethyl acetate, the organic layers were combined, washed with 2% sodium thiosulfate aqueous solution, water and brine in that order and then dried with anhydrous magnesium sulfate. After removal of the drying agent, the solvent was concentrated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography to give 1.33 g of (4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophen-5-yl)acetaldehyde. A 1.32 g of the aldehyde compound and 1.39 g of N-acetylethylenediamine were dissolved in 50 ml of toluene. Then, 10 mg of camphorsulfonic acid was added, and the mixture was heated under reflux for 3 hours while removing the produced water. After cooling, the reaction solution was poured into ice-cooled saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layers were combined, the drying agent was removed by filtration and then the solvent was concentrated under a reduced pressure to give 1.38 g of N-(2-(4,5-dihydro-1H-thieno[2,3-g]indol-1-yl)ethyl]acetaamide. From this compound, N-[2-(1H-thieno[2,3-g]indol-1-yl)ethyl]acetamide was obtained in the similar manner as described in Reference Example 60.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][NH2:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH2:15]([O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH:20]=O)[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH:20]1[N:14]([CH2:13][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([F:1])[CH:3]=2)[C:7](=[O:8])[CH:2]([F:1])[CH2:3]1)[CH3:16]
Reactant: NCc1ccc(OC(F)(F)F)c(F)c1
Reactant: CCOc1cccc(F)c1C=O
Product: CCOc1cccc(F)c1C1CC(F)C(=O)N1Cc1ccc(OC(F)(F)F)c(F)c1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B), 10F (GP10F), and 10I (GP10I) using commercially available (3-fluoro-4-(trifluoromethoxy)phenyl)methanamine and synthesized 2-ethoxy-6-fluorobenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 433.92 g/mol.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8](=O)(OCC)[O:9]CC>C(O)C>[OH:4][CH2:3][C:2]1([CH3:7])[CH2:5][O:6][C:8](=[O:9])[NH:1]1
Reactant: CCOC(=O)OCC
Reactant: CC(N)(CO)CO
Solvent: CCO
Product: CC1(CO)COC(=O)N1
Temperature: 25 °C

Procedure:
A Dean-Stark trap was fitted to a flask containing 2-amino-2-methyl-1,3-propanediol (21.62 g, 205.6 mmol) suspended in diethyl carbonate (40 ml, 330 mmol). The suspension was heated to 150° C. for 6 h, during which time approximately 12 ml of ethanol was distilled. The solution was cooled to RT overnight, and the resulting crystals were filtered and washed with cold ethanol. The crude material (˜90% purity) was used without further purification (24.82 g, 189.0 mmol, 92%). 1H NMR (CDCl3, 400 MHz) δ 1.36 (s, 3H), 2.2 (br s, 1H), 3.57 (m, 2H), 4.06 (d, 1H, J=8.8 Hz), 4.33 (d, 1H, J=8.8 Hz), 5.2 (br s, 1H). LRMS (ESI/APCI): 132 [M+H]+.
Reaction SMILES: C(Cl)CCl.Cl.[CH3:6][N:7]1[C:14](=[O:15])[CH2:13][CH2:12][NH:11][C:10]2[N:16]=[CH:17][C:18](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:19][C:9]=2[CH2:8]1.C1C=CC2N(O)N=NC=2C=1.[CH3:35][NH:36][CH2:37][C:38]1[S:42][C:41]2[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=2[C:39]=1[CH3:47].C(N(C(C)C)C(C)C)C>COCCOC.C(#N)CC.C(OCC)(=O)C>[CH3:35][N:36]([CH2:37][C:38]1[S:42][C:41]2[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=2[C:39]=1[CH3:47])[C:22](=[O:24])/[CH:21]=[CH:20]/[C:18]1[CH:17]=[N:16][C:10]2[NH:11][CH2:12][CH2:13][C:14](=[O:15])[N:7]([CH3:6])[CH2:8][C:9]=2[CH:19]=1
Reactant: CN1Cc2cc(/C=C/C(=O)O)cnc2NCCC1=O
Reactant: CNCc1sc2ccccc2c1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: COCCOC
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(C)C(=O)CCN3)sc2ccccc12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
EDC (54 mg, 0.28 mmol) was added to a suspension of (E)-3-(5-methyl-4-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-b][1,5]diazocin-8-yl)acrylic acid hydrochloride (70 mg, 0.23 mmol), HOBt (34 mg, 0.25 mmol), N-methyl(3-methylbenzo[b]thiophen-2-yl)methanamine (48 mg, 0.25 mmol) and (i-Pr)2EtN (0.20 mL, 1.2 mmol) in 5 mL of DME:propionitrile (4:1). The mixture was allowed to stir for 1 h at 40° C. The mixture was cooled to room temperature and diluted with ethyl acetate (40 mL) and washed with water (50 mL) and NaHCO3 (50 mL), dried over MgSO4 and dried under high vacuum. The solid was then subjected to purification on Prep HPLC to obtain the product as a fluffy white solid. Yield 54 mg (54%); 1H NMR (400 MHz, CDCl3) δ10.41 (bs, 1H), 8.08 (s, 1H), 7.79-7.68 (m, 3H), 7.59 (d, J=15.2 Hz, 1H), 7.40 (m, 2H), 6.95-6.86 (m, 1H), 4.96 (s, 2H), 4.72 (bs, 2H), 3.90 (s, 2H), 3.15 (m, 5H), 2.84 (s, 3H), 2.46 (s, 3H); ESI MS m/z 435 [C24H26N4O2S+H]+
Reaction SMILES: [F:1][C:2]([F:34])([CH2:31][CH2:32][CH3:33])[CH:3]([OH:30])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:10][C@H:9]([OH:19])[C@@H:8]1[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C.Cl>C(Cl)Cl>[F:34][C:2]([F:1])([CH2:31][CH2:32][CH3:33])[C:3](=[O:30])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:10][C:9](=[O:19])[C@@H:8]1[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: CCCC(F)(F)C(O)CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(F)(F)C(=O)CCC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Reaction time: 1 h

Procedure:
To the above solution was added a solution of methyl (Z)-7-[(1 R)-(2 R,3 R,5 S)-2-{5,5-difluoro-4(RS)-hydroxy-octyl}-5-hydroxy-3-tetra-hydropyranyloxycyclopentyl]hept- 5-enoate (18) (0.244 g) in methylene chloride. The resultant mixture was warmed to -25° C. and stirred for 1 hour. Triethylamine (0.60 ml) was added thereto and the reaction mixture was stirred for additional 30 minutes, poured into 1N hydrochloric acid, and then worked up with the conventional procedure. The obtained product was subjected to silicagel column chromatography to give the titled compound (19).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1.[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:10]2[N:11]=[N:12][C:8]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=3)=[N:9]2)=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: Brc1cncc(-c2nn[nH]n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2nnc(-c3cncc(Br)c3)n2)cc1

Procedure:
The tetrazole (27.3 g, 104 mmol) from Step (a) was treated with 4-bromomethyl-benzoic acid tert-butyl ester (31.0 g, 114 mmol) and cesium carbonate (74.3 g, 228 mmol) in dimethylformamide (400 mL) at room temperature for 5.5 hours. The solvent was evaporated in vacuo and the residue passed through a pad of silica gel eluting with CH2Cl2:THF 19:1, to give a 9:1 mixture of regioisomers (40.07 g, 93%). 1H NMR (DMSO-d6) δ 9.16 (s, 1H), 8.87 (s, 1H), 8.54 (s, 1H), 7.91 (d, J=8 Hz, 2H), 7.51 (d, J=9 Hz, 2H), 6.13 (s, 2H), 1.57 (s, 9H).