Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].[C:3]([N:6]1[C:15]2[C:10](=[C:11]([O:29][CH2:30][CH2:31][CH3:32])[C:12]([C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]=3)=[CH:13][CH:14]=2)[CH2:9][CH2:8][C@@H:7]1[CH3:33])(=[O:5])[CH3:4]>CO.[OH-].[OH-].[Pd+2]>[C:3]([N:6]1[C:15]2[C:10](=[C:11]([O:29][CH2:30][CH2:31][CH3:32])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[CH2:9][CH2:8][C@@H:7]1[CH3:33])(=[O:5])[CH3:4]
Reactant: CCCOc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCOc1c(C2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Balloon pressured hydrogen gas was charged into a round bottom flask containing a suspension of (S)-tert-butyl 4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (500 mg, 1.17 mmol) and 20% palladium hydroxide on carbon (30 mg, 0.21 mmol) in methanol (10 mL). The reaction was stirred under balloon pressure for 2 hours. The reaction was vented to nitrogen and filtered through a pad of Celite. The filtered solution was concentrated in vacuo and purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 20-40% ethyl acetate-hexane) to afford tert-butyl (S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate (500 mg, 100%) as a colorless oil. MS (ESI, pos. ion) m/z 432 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH2:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[Cu]C#N.C([Li])CCC.[CH3:21][Si:22](Cl)([CH3:32])[CH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.[Cl-].[NH4+]>C(OCC)C>[CH3:21][Si:22]([CH3:32])([CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH:1]([CH3:3])[CH3:2])[CH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: CC(C)C1=Cc2ccccc2C1
Reactant: C[Si](C)(Cl)C1C=Cc2ccccc21
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)C1=Cc2ccccc2C1[Si](C)(C)C1C=Cc2ccccc21
Temperature: -30 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
In a 100-ml flask, 3.0 g (19.0 mmol) of 2-i-propylindene and 47 mg (0.523 mmol) of copper (I) cyanide were suspended in 40 ml of diethyl ether, to which was dripped down 13.0 ml of n-butyllithium (1.6 M hexane solution) at -70° C. and the mixture was slowly elevated to room temperature and stirred for 1 hour. Again the mixture was cooled to -30° C. and 40 ml of a diethyl ether solution of 4.36 g (20.9 mmol) of dimethyl(1-indenyl)silyl chloride was added thereto to obtain a dark brown suspension. Stirring was continued at room temperature for 48 hours. The reaction mixture was poured in a saturated aqueous solution of ammonium chloride under ice cooling and the organic layer was washed with 300 ml of saline three times, dried over anhydrous magnesium sulfate, and removed of the solvent by distillation to obtain the reaction mixture as a yellow oil. The reaction mixture was purified by column chromatography (silica gel, development solvent: n-hexane) to separate unreacted raw material, 2-i-propylindene, to fractionate the target compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:3]1.C(O[CH:23](OC(C)(C)C)[N:24]([CH3:26])[CH3:25])(C)(C)C>CN(C=O)C>[CH3:23][N:24](/[CH:26]=[C:8]1\[CH2:9][CH2:10][CH2:11][C:5]2[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:3][N:2]([CH3:1])[C:6]=2[C:7]\1=[O:12])[CH3:25]
Reactant: CCOC(=O)c1nn(C)c2c1CCCCC2=O
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1CCC/C(=C\N(C)C)C2=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 1-methyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylate (210 mg, 0.94 mmol) in DMF (2 mL), N,N-dimethylformamide di-tertbutyl acetal (0.68 mL, 2.82 mmol) was added. The mixture was stirred at 80° C. for 3 h. Solvent was removed under reduced pressure and the residue used without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:15]([O:17]C)=[O:16])=[C:8]([C:11]([O:13]C)=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+].S(=O)(=O)(O)O>CC(C)=O.C(OC(=O)C)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]3[C:15](=[O:16])[O:17][C:11](=[O:13])[C:8]=3[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2cccnc2cc1C(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc3ncccc3cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of dimethyl 6,7-quinolinedicarboxylate (3.00 g, 12.2 mmol), methanol and 10% aqueous sodium hydroxide (25 mL, 62.5 mmol) is stirred overnight at room temperature, cooled, acidified to pH 4-5 with concentrated sulfuric acid, diluted with acetone and filtered. The filtrate is concentrated in vacuo to give a tan solid, which is suspended in acetic anhydride (100 mL), stirred overnight at 56° C. and cooled. The solvent is removed in vacuo to afford the title product as a tan solid (1.20 g, 49.4%) identified by 1HNMR and IR spectral analyses.
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([NH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][C@@H:9]3[CH3:24])[CH2:6][CH2:5]1)[CH3:3].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:24][C@H:9]1[CH2:10][C@@H:11]2[C@:16]([CH3:17])([CH2:15][CH2:14][C:13](=[O:23])[NH:12]2)[C@@H:18]2[C@@H:8]1[C@H:7]1[C@:21]([CH3:22])([CH2:20][CH2:19]2)[C@@H:4]([C:2](=[O:1])[CH3:3])[CH2:5][CH2:6]1
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 20-hydroxy-7β-methyl-5α-4-azapregnan-3-one (22.3 gms, 67 mmol, product of Step 10) in dry methylene chloride under nitrogen (110 mL) was added 4-methyl morpholine N-oxide (11.8 gms, 100 mmol) followed by 4 Å molecular sieves (33 gm). To this mixture was added tetrapropylammonium perruthenate (1.2 gm). After stirring at room temperature for 4 h, the reaction mixture was poured through pad of silica gel in a 300 mL sintered glass funnel which was subsequently eluted with 4:1 ethyl acetate/methylene chloride (5 L). The solvent was removed by rotoevaporation and the title compound recrystallized.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:50])[CH2:10][C:11]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1>C(Cl)Cl>[F:49][C:47]1[CH:46]=[CH:45][C:12]([CH2:13][CH2:14][C:15]2[C:20]([C:21]([F:23])([F:24])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[N:16]=2)=[C:11]([CH2:10][C:9]([NH2:8])=[O:50])[CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccc(F)cc4CC(N)=O)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1cc(F)ccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
TFA (0.825 mL, 10.8 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)-4-fluorophenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A37) (0.162 g, 0.269 mmol) in DCM (20 mL) under nitrogen and the resulting solution stirred for 24 hours at room temperature. The volatiles were removed in vacuo and the residue was taken up in MeOH and loaded onto an SCX cartridge (10 g). The column was eluted with 5 column volumes of MeOH and then 6 column volumes of 5% v/v aqueous ammonia in MeOH. The volatiles from the ammoniacal eluent were evaporated under reduced pressure to give the title compound 9 as a yellow solid (0.117 g, 87%); 1H NMR (400 MHz, d6-DMSO) δ 10.12 (s, 1H), 8.65 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.48 (s, 1H), 7.23-7.13 (m, 3H), 7.08 (dd, J=10.2, 2.8 Hz, 1H), 7.04-6.95 (m, 2H), 3.50 (s, 2H), 3.14-2.95 (m, 6H), 2.63-2.52 (m, 3H), 1.67 (d, J=10.8 Hz, 2H), 1.49 (qd, J=12.4, 3.9 Hz, 2H). LCMS-A: rt 4.853 min; m/z 502 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Na+]>CO.O>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:19])=[O:20])=[CH:14][CH:13]=2)[C:4]([OH:25])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)CC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of the title C compound, 3-cyclopentyl-2-[4-(2-oxo-propylsulfonyl)-phenyl]-propionic acid ethyl ester (5 g, 0.013 mol) in 40 mL of methanol and 60 mL of water is treated with 1 g (0.027 mol) of sodium hydroxide and the reaction is stirred at 25° C. for 6 h. The reaction mixture is concentrated under vacuum, and the residue is re-dissolved in water and extracted with diethyl ether (50 mL). The aqueous layer is then acidified to pH 1 with 1 N aqueous hydrochloric acid solution. This solution is extracted with ethyl acetate (2×100 mL). The organic layer is washed with water and brine, dried over sodium sulfate and then filtered and evaporated under vacuum to give 3-cyclopentyl-2-[4-(2-oxo-propylsulfonyl)-phenyl]-propionic acid as a white solid.
Reaction SMILES: [N:1]1[N:2]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:4][CH:5]=1.[F:10][C:11]1[CH:39]=[CH:38][CH:37]=[CH:36][C:12]=1[CH2:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[O:20])[CH2:15]1>>[N:3]1[N:2]([CH2:6][C:7]([N:17]2[CH2:18][C@H:14]([CH2:13][C:12]3[CH:36]=[CH:37][CH:38]=[CH:39][C:11]=3[F:10])[CH2:15][C@H:16]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)=[O:20])=[O:9])[N:1]=[CH:5][CH:4]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1C(=O)Cn1nccn1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid and (2S,4R)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 107, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 7.71 (s, 2H), 7.44-7.40 (m, 2H), 7.27-7.17 (m, 3H), 7.12-6.86 (m, 7H), 5.30 (d, 2H), 4.83 (d, 1H), 3.59-3.53 (m, 1H), 3.23 (t, 1H), 2.98-2.76 (m, 3H), 2.62 (dd, 1H), 1.78-1.69 (m, 1H). MS (EI) for C28H25F2N5O3 found 518 (MH+).
Reaction SMILES: [F:1][C:2](F)(F)[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1.OC1C=C2C(CCC2=O)=CC=1.FCCCO>>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1
Reactant: O=C1CCc2ccc(OCCC(F)(F)F)cc21
Agent: O=C1CCc2ccc(O)cc21
Agent: OCCCF
Product: O=C1CCc2ccc(OCCCF)cc21
Reaction time: 8 h
Yield: 94 %

Procedure:
The title compound (7.90 g, 94% yield) was prepared following the procedure for Intermediate 16, starting from 6-hydroxy-2,3-dihydro-1H-inden-1-one (5.98 g, 40.4 mmol) and 3-fluoropropan-1-ol (3.34 mL, 44.4 mmol). Additional 3-fluoropropan-1-ol (1.0 mL, 13.3 mmol) was added after stirring overnight to drive the reaction to completion. 1H NMR (500 MHz, CDCl3) δ ppm 2.20 (m, 2 H) 2.73 (m, 2 H) 3.08 (m, 2 H) 4.14 (t, 2 H) 4.61 (t, 3 H) 4.70 (t, 1 H) 7.21 (m, 2 H) 7.38 (d, 1 H); MS (ES+) m/z 208 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH2:5]Cl)[CH3:3].[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH2:5][O:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)[CH3:3]
Reactant: CC(C)(C)C(=O)CCl
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)COc1ccc(F)cc1
Temperature: 25 °C
Yield: 17.2 %

Procedure:
418.3 g (3.11 mol) of 2,2-dimethyl-4-chloro-butan-3-one were added dropwise to a suspension, heated to the boil, of 315 g (2.8 mol) of 4-fluorophenol and 386.4 g (2.8 mol) of potassium carbonate in 1,500 ml of acetone. The mixture was stirred under reflux for 4 hours. After cooling to room temperature, the salt which had separated out was filtered off and the filtrate was concentrated in vacuo. The oil which remained was distilled in vacuo. 101.5 g (86.2% of theory) of 2,2-dimethyl-4-(4-fluorophenoxy)-butan-3-one of boiling point 83°-84° C./0.05 mm Hg (nD20 =1.4919) were obtained. ##STR75##
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1N=CN(C(N2C=NC=C2)=O)C=1.CO>C1COCC1>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:9]=[CH:10][C:2]=1[OH:1]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(S(N)(=O)=O)ccc1O
Temperature: 50 °C

Procedure:
To 62 mmol 2-hydroxy-5-sulfamoyl-benzoic acid in 80 ml THF was added 80 mmol CDI and the mixture heated at 50° C. for 1 h. 616 mmol methanol was then added, and the mixture was heated at 50° C. for 16 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the residue chromatographed on silica gel (eluant: dichloromethane/methanol 20:1). The product containing fractions were concentrated in vacuo and the residue suspended in ethyl acetate and washed with aq NaHCO3 solution. The organic phase was dried with Na2SO4 and concentrated in vacuo to afford the title compound. MS (m/e): 230.2 ([M−H]−, 100%)
Reaction SMILES: [CH3:1][C:2]([CH3:35])=[CH:3][C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[O:10][C@@:9]([O:33]C)([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2CC2C=CC(OC)=CC=2)[CH2:8]1)=[O:5].CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[CH3:1][C:2]([CH3:35])=[CH:3][C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[O:10][C@@:9]([OH:33])([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[NH:19]2)[CH2:8]1)=[O:5]
Reactant: C=CCCC[C@@H]1C[C@@H](OC(=O)C=C(C)C)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: C=CCCC[C@@H]1C[C@@H](OC(=O)C=C(C)C)C[C@](O)([C@@H]2CSC(=O)N2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl 3-methylbut-2-enoate is substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][CH2:8][C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)[CH2:4][O:3]1.C(=O)([O-])[O-].[Br:25]Br>C(Cl)Cl>[Br:25][C:10]1[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][NH:13][C:9]=1[CH2:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:20])([CH3:1])[O:6]1
Reactant: BrBr
Reactant: CC1(C)OC[C@@H](CCc2cc(-c3ccccc3)n[nH]2)O1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC1(C)OC[C@@H](CCc2[nH]nc(-c3ccccc3)c2Br)O1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of (R)-5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-phenyl-1H-pyrazole (2.3 g, 8.45 mmol) and MP-carbonate (26 g, 84.5 mmol) in CH2Cl2 (100 mL), was added bromine (1.350 g, 8.45 mmol) dropwise at 0° C. After stirring for 1 h, MP-carbonate was filtered off and washed with CH2Cl2. The combined organic layer was poured into water, extracted with CH2Cl2, dried over MgSO4, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (2.81 g) as an oil. LCMS m/z=351.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Cl.Cl[CH2:25][C:26]1[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[C:29]([CH3:35])=[CH:28][N:27]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[C:29]([CH3:35])=[CH:28][N:27]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: Cl
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ncc(C)c(OC)c3C)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][NH:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2.O.[OH-].[Li+]>CO.O>[C:17]1([CH2:16][CH2:15][C:14]([NH:13][C@@H:10]2[C:11](=[O:12])[N:5]([CH2:4][C:3]([OH:28])=[O:2])[C:6]3[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=3[NH:8][CH2:9]2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CNc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CNc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
(3(S)-(3-Phenylpropionylamino)-2-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)acetic acid methyl ester (104a) was dissolved in 90% methanol. Lithium hydroxide hydrate was added to the reaction and the reaction was stirred at room temperature for 4 h. The reaction was evaporated in vacuo to give a white solid. This was dissolved in 20 ml of water and acidified to pH 5 and extracted with ethyl acetate to afford 304 mg (88%) of the title compound as a white solid. 1H NMR (CDCl3) δ7.5-6.9 (11H, m), 4.92-4.8 (1H, m), 4.7-4.58 (1H, d), 4.38-4.25 (1H, d), 3.88-3.78 (1H, m), 3.45-3.25 (1H, m), 3.05-2.85 (2H, m), 2.55-2.45 (2H, m)
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:10]=4[C:11]=3[CH2:12][CH2:13][S:14][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[C:21]([Si:24]([CH3:26])([CH3:25])[O:19][C:16]1[CH:17]=[CH:18][C:9]2[NH:8][C:7]3[C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:14][CH2:13][CH2:12][C:11]=3[C:10]=2[CH:15]=1)([CH3:23])([CH3:22])[CH3:20]
Reactant: Oc1ccc2[nH]c3c(c2c1)CCSc1ccccc1-3
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CCSc1ccccc1-3

Procedure:
Following the procedure described in Example 80, using 6,7-Dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulen-9-ol (350 mg, 1.31 mmol) and TBSCl (225 mg, 1.50 mmol) as the starting material, the title compound was prepared as a white solid.
Reaction SMILES: [F:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:9].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Br)C1C=CC=CC=1>[CH2:22]([N:13]1[CH2:14][CH:15]=[C:10]([CH:8]([OH:9])[CH2:7][C:6]2[CH:5]=[CH:4][S:3][C:2]=2[F:1])[CH2:11][CH2:12]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cc1ccsc1F)c1ccncc1
Reactant: Cc1ccccc1
Agent: BrCc1ccccc1
Product: OC(Cc1ccsc1F)C1=CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
After dissolving 304 mg of 2-(2-fluoro-3-thienyl)-1-(4-pyridyl)ethanone in 2 ml of toluene, 0.20 ml of benzyl bromide was added, the mixture was stirred at 100° C. for 8 hours and the precipitate was filtered out. The filtered substance was dissolved in 10 ml of methanol, 157 mg of sodium borohydride was added thereto in small portions at a time while cooling on ice, and the mixture was stirred for 1 hour. The reaction solution was distilled off under reduced pressure, water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (384 mg, 88% yield).
Reaction SMILES: [I-].C[N+]([CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)=[O:9])(C)C>O.C(OCC)(=O)C>[CH3:21][O:20][C:12]1[CH:11]=[C:10]([C:8](=[O:9])[CH:7]=[CH2:6])[CH:15]=[C:14]([O:16][CH3:17])[C:13]=1[O:18][CH3:19]
Reactant: COc1cc(C(=O)CC[N+](C)(C)C)cc(OC)c1OC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(=O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 2.5 h

Procedure:
The above iodide (355.9 g, 0.87 mol) was suspended in a mixture of water (3.56 L) and ethyl acetate (2.54 L) and heated under reflux with rapid stirring for 2-3 hours. The mixture was cooled and the pale yellow organic layer was removed. Fresh ethyl acetate (2 L) was added and the mixture was again heated under reflux for 1 hour and the process was repeated once again. The organic extracts were combined, washed with brine, dried (MgSO4), and evaporated to a yellow oil which was crystallized from hexane-ethyl ether to give 1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one: mp 46°-47° C.; NMR (CDCl3) δ 3.94 (s, 3 OCH3), 5.92 (2 d, J=1.5 & 9.0 Hz, CH=CH2), 6.44 (2 d, J=1.5 & 16 Hz, CH=CH2), 7.18 (2 d, J=9.0 & 16 Hz, CH= CH2), 7.28 (ArH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:16](=O)[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH2:19][C:20]1[N:21]=[N:22][C:23](=[O:25])[CH:24]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[N:21]2[NH:22][C:23](=[O:25])[CH:24]=[C:20]2[NH:19][C:16]([CH3:17])=[C:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: NC1=CC(=O)N=N1
Reactant: CCOC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2cc(=O)[nH]n2C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A solution of 2-[(2,3-dichlorophenyl)methylene]-3-oxobutanoic acid, ethyl ester (2.8 g; 10.0 mmole) in dimethylformamide (7 ml) was treated with 3-amino-5-pyrazolone (990 mg) and the resulting mixture was heated at 65° C.±5° for 15 hours. The reaction mixture was allowed to cool to room temperature and then diluted with ethyl acetate. The solution was washed with water, brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent provided a foam which was purified by flash chromatography (7% methanol in dichloromethane). The product was crystallized from acetonitrile-isopropyl ether to provide the title compound as a solid (1.42 g; melting point 213°-218° C.; sinters above 155° C.).