Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:29])[C:13]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:29])[C:13]([CH2:17][NH2:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN3C(=O)c4ccccc4C3=O)ccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN)ccc21
Temperature: 100 °C
Yield: 73.2 %

Procedure:
To a stirred suspension of 318 (10.75 g, 0.026 mol) in EtOH (200 mL) was added hydrazine hydrate (2.52 mL, 0.052 mol), and the resulting reaction mixture was heated at 100° C. for 1 h. The cooled reaction mixture was diluted with water and thrice extracted with DCM. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The solid was suspended in hexane (100 mL) and ethyl acetate (5 mL) and filtered. The filtrate was concentrated under reduced pressure to afford 5.34 g (73%) of tert-butyl-5-(aminomethyl)-4-chloro-1H-indol-1-carboxylate (320) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=8.5 Hz, 1H), 7.73 (s, 1H), 7.50 (d, J=8.5 Hz, 1H), 6.71 (d, J=3.7 Hz, 1H), 2.09 (s, 2H), 1.63 (s, 9H); 2H not seen; MS (ESI) m/z=281.5 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:4]3[N:5]([C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=3)[CH:6]=[CH:7][C:2]=2[C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(Cl)cc2)cc1
Temperature: 150 °C
Yield: 43.4 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-(4-chlorophenyl)-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.05 g, 0.13 mmol), 4-methoxyphenylboronic acid (0.06 g, 0.39 mmol), and tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (0.04 g, 0.26 mmol) in water (0.34 mL). The resulting reaction mixture was heated in a microwave reactor at 150° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 23 mg of the title compound as a yellow solid. MS: [M+H]+=408.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]3[CH2:16][CH2:15]3)[O:12][C:11](=[O:17])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.CCCCCC.[CH:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31]([Cl-]C([O-])=O)[CH:30]=1.[C:42](=O)([OH:44])[O-:43].[Na+]>C1COCC1>[N+:35]([C:34]1[CH:29]=[CH:30][C:31]([O:44][C:42]([N:10]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[CH:13]([CH:14]3[CH2:15][CH2:16]3)[O:12][C:11]2=[O:17])=[O:43])=[CH:32][CH:33]=1)([O-:37])=[O:36]
Reactant: O=C([O-])O
Reactant: O=C1NC(c2ccc(F)c(F)c2)C(C2CC2)O1
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1C(=O)OC(C2CC2)C1c1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(3,4-difluorophenyl)-5-cyclopropyl-oxazolidin-2-one (2 g, 8.3 mmol) in 100 mL THF was added a solution of n-butyllithium in hexane (9.1 mmol) dropwise via a syringe under an argon atmosphere at -78° C. The resulting yellow solution was stirred at -78° C. for 10 min. To this solution was then added dropwise via syringe 4-nitrophenylchloroformate (1.03 g, 5.1 mmol) in 20 mL of THF. The reaction was stirred at -78° for 10 min. The reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate (2×200 mL). The organic extracts were washed with brine, and the organic layer was dried over Na2SO4. The solvent was removed after filtration, and the residue was purified by column chromatography on silica gel 30% ethyl acetate hexane. The material was rechromatographed on silica gel eluting with 2% acetone/methylene chloride to give 1.2 g the product as a thick syrup which solidified upon standing.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:19](Cl)[C:18]=1[CH2:27][CH2:28][OH:29])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]1.Cl>>[C:1]([O:5][C:6]([N:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)[C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:19]([NH:31][C@H:32]2[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]2)[C:18]=1[CH2:27][CH2:28][OH:29])=[O:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(Cl)nc3ccnn23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: Cl
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl[5-chloro-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (300 mg) and (S)-3-amino-1-tert-butoxycarbonylpiperidine (900 mg) was stirred at 90° C. for 16 hr. To the reaction solution, 1 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.O.Cl>C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COS(C)(=O)=O
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccnc1
Temperature: 72.5 °C
Reaction time: 7 h
Yield: 65.9 %

Procedure:
A mixture of (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-(methanesulfonyloxy)methylpyrrolidine (8.73 g) and imidazole (4.16 g) was stirred at 70-75° C. for 7 hours. After cooling, the reaction mixture was dissolved in ethyl acetate (30 ml), water (30 ml) and conc. hydrochloric acid (8.0 ml) with stirring. The aqueous layer was separated, adjusted to pH 9.0 with 10% aqueous sodium hydroxide and extracted twice with ethyl acetate (50 ml). The extract was dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-2-(imidazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (5.30 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:58]([NH2:76])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75]>CN(C)C=O>[Cl:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][Cl:23])[C:6]1[CH:5]=[CH:4][C:3]2[N:2]([CH3:1])[C:10]([CH2:11][CH2:12][CH2:13][C:14]([NH:76][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])=[O:16])=[N:9][C:8]=2[CH:7]=1
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 2 °C
Yield: 33.1 %

Procedure:
A 250 mL three neck round bottom flask equipped with a stir bar, thermocouple, cooling bath, 60 mL pressure equalizing dropping funnel and nitrogen in/outlet was charged with 10.0 g (25.3 mmol) of bendamustine hydrochloride, 10.6 g (27.8 mmol) of HATU and 100 mL of N,N-dimethylformamide (DMF). To this stirred yellow solution was added 4.41 mL (3.27 g, 25.3 mmol) of N,N-diisopropylethylamine (DIPEA). An exotherm to 27.1° C. was noted and the solution became a darker yellow. The reaction was cooled to 2.0° C. where a suspension of 6.2 mL (4.59 g, 35.5 mmol) of DIPEA, 7.65 g (25.6 mmol) of octadecyl amine in 0 mL of DMF was added via pipette. Once addition was complete the reaction became very thick and difficult to stir. It was warmed to room temperature and the magnetic stir bar was replaced with an overhead stirrer. The batch was stirred at RT overnight after which time an in process analysis indicated the reaction was complete. The batch was quenched onto 300 mL of DI water and extracted with dichloromethane (2×150 mL). The organic phases were combined, washed with 10% sodium hydrogen phosphate (1×300 mL), 8% aqueous sodium bicarbonate (1×300 mL) and brine (1×300 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo. The residue was purified by chromatography using 100 g of silica gel 60, 230-400 mesh, eluting with 1% MeOH/MDC (2 L), 2.5% MeOH/MDC (1 L) and 5% MeOH/MDC (1 L) collecting ˜100 mL fractions. The product containing fractions were combined and concentrated to dryness in vacuo to yield 5.11 g (8.38 mmol, 33%) of the desired product as a white solid with an HPLC purity of 90.9A %. The major impurity was shown to be the C-16 amide which results from an impurity in the starting amine 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, b, 1H), 7.33 (d, J=8.84 Hz, 1H), 6.91 (d, J=2.22 Hz, 1H), 6.80 (dd, J=2.36, 8.84 Hz), 3.71 (s, 8H), 3.70 (s, 3H), 3.01 (q, J=6.8, 12.68, 2H), 2.79 (t, J=7.44 Hz, 2H), 2.18 (t, J=7.36 Hz, 2H), 1.97 (m, 2H), 1.36 (m, 2H), 1.28 (s, b, 30H), 0.85 (t, J=6.32 Hz, 3H).
Reaction SMILES: CC[O:3][C:4]([C:6]1([CH3:14])[NH:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5].N[CH:16]([C:19](O)=[O:20])CS>>[C:19]([N:10]1[CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7][C:6]1([CH3:14])[C:4]([OH:3])=[O:5])(=[O:20])[CH3:16]
Reactant: CCOC(=O)C1(C)NC(C(=O)O)CS1
Reactant: NC(CS)C(=O)O
Product: CC(=O)N1C(C(=O)O)CSC1(C)C(=O)O

Procedure:
By an operation similar to that in Synthetic Example 13 and using 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester synthesized from DL-cysteine by a method similar to that in Reference Example 2, N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (trans form) was obtained as a white solid (yield 70%).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7].Cl.[C:42]([C:44]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)#[N:43].C(=O)([O-])[O-].[Na+].[Na+]>CO>[F:37][C:35]([F:36])([F:38])[C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([C:2]([F:39])([F:40])[F:1])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:47]2[CH2:48][CH2:49][C:44]([C:42]#[N:43])([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:45][CH2:46]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC1(c2ccccc2)CCN(CCCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)CC1
Reaction time: 2 h
Yield: 51.5 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (150 mg) and 4-cyano-4-phenylpiperidine hydrochloride (70 mg) in methanol (5 ml) was stirred at reflux temperature in the presence of sodium carbonate (100 mg). After 2 hours, the reaction mixture was evaporated under reduced pressure. The residue was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate-methanol (10:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[3-(4-cyano-4-phenylpiperidino)propyl]-2-(1H-indol-3-ylmethyl)piperazine (89 mg) as a powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:9][C:10]([F:25])([F:24])[C:11]1[CH:12]=[C:13]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:20]2[CH2:21][CH2:22][CH2:23][CH:18]([NH:17][C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:9])([F:25])[F:24])[CH:12]=3)[CH2:19]2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(NC2CCCNC2)c1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(NC2CCCN(c3ccc(Cl)nn3)C2)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
A mixture of 4.5 parts of 3,6-dichloropyridazine, 4.9 parts of N-[3-(trifluoromethyl)phenyl]-3-piperidinamine, 6.4 parts of sodium carbonate and 180 parts of N,N-dimethylformamide was stirred overnight at about 65° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue Was crystallized from 2-propanol. The product was filtered off (the filtrate was set aside) and dried, yielding 1.2 parts (16.8%) of 1-(6-chloro-3-pyridazinyl)-N-[3-(trifluoromethyl)phenyl]-3-piperidinamine: mp. 92.6° C. (compound 146). The filtrate, which was set aside, was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 2.6 parts (32.9%) of 1-(6-chloro-3-pyridazinyl)-N-[3-(trifluoromethyl)phenyl]-3-piperidinamine monohydrochloride; mp. 173.5° C. (compound 147).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:22]3[C:23]4[CH:44]=[CH:43][C:42]([O:45]CC5C=CC=CC=5)=[CH:41][C:24]=4[S:25][C:26]=3[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:29][CH:28]=3)=[O:21])=[CH:16][CH:15]=2)[CH2:5][CH2:4][O:3]1>[Pd].C1COCC1.CCO>[O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([C:22]3[C:23]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][C:24]=4[S:25][C:26]=3[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:29][CH:28]=3)=[O:21])=[CH:18][CH:19]=2)[CH2:5][CH2:4][O:3]1
Reactant: O=C(c1ccc(O[C@@H]2CCCC[C@H]2N2CCOC2=O)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(c1ccc(O[C@@H]2CCCC[C@H]2N2CCOC2=O)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(O)ccc12
Reaction time: 19 h
Yield: 62 %

Procedure:
A slurry of the (±)-6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 4-[trans-2-(2-oxooxazolidin-3-yl)cyclohexyloxy]phenyl ketone (Part C) and an equal weight of 10% Pd/C) in a 1:1 mixture of THF-EtOH was stirred under positive hydrogen pressure (from balloon) for about 19 h. The reaction mixture was filtered through a pad of diatomaceous earth and washed with THF. The filtrate was then concentrated under reduced pressure and the residue was flash chromatographed (silica gel, 10%[10% NH40H in MeOH]/CH2Cl2) to afford the title compound in 62% yield.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([N:19]1[CH2:26][CH:25]2[C:27]([CH3:29])([CH3:28])[CH:21]([CH2:22][NH:23][CH2:24]2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.O>[C:1]([N:23]1[CH2:24][CH:25]2[C:27]([CH3:29])([CH3:28])[CH:21]([CH2:20][N:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:26]2)[CH2:22]1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)C2CNCC1CN(Cc1ccccc1)C2
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC1(C)C2CN(Cc3ccccc3)CC1CN(C(=O)C=Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
3.9 g cinnamic acid chloride were dissolved in 20 ml dichloromethane, and to this solution a solution of 5.5 g 3-benzyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane in 10 ml dichloromethane was added with ice cooling. Subsequently the reaction mixture was stirred for 3 hours at room temperature. Then, for working up, the solvent was distilled off and the residue containing the 7-cinnamyl-3-benzyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane which had formed was dissolved in water. To remove non-basic fractions, extraction was carried out using ethyl acetate. Then the aqueous phase was made alkaline with dilute sodium hydroxide solution, and the reaction product was extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate, filtered, and the solvent was distilled off. 5 g 7-cinnamoyl-3-benzyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane were obtained as a residue.
Reaction SMILES: CO[CH:3]([CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])[CH:4]=[CH2:5].[CH3:11][OH:12]>[Pd](Cl)Cl>[CH3:11][O:12][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH2:3][CH:4]=[CH2:5]
Reactant: CO
Reactant: C=CCCCC(C=C)OC
Agent: Cl[Pd]Cl
Product: C=CCCCC=CCOC

Procedure:
A process for isomerizing 3-methoxy-1,7-octadiene comprising contacting 3-methoxy-1,7-octadiene with methanol and a catalytically effective amount of a catalyst selected from the group consisting of cupric chloride and a mixture of cupric chloride and palladium chloride at a temperature in the range of between about 115° C. and 135° C. and a pressure in the range of between about 75 psig and about 125 psig whereby 8-methoxy-1,6-octadiene is formed.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([OH:13])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[H-].[Na+].I[CH3:19]>O1CCCC1>[CH3:19][O:13][C:3]1([C:2]([F:1])([F:14])[F:15])[CH2:4][CH2:5][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:11][CH2:12]1
Reactant: OC1(C(F)(F)F)CCC2(CC1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(C(F)(F)F)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., 16.23 g (71.75 mmol) of 8-(trifluoromethyl)-1,4-dioxaspiro[4.5]decan-8-ol (Example 7A) were dissolved in 582 ml of tetrahydrofuran, 5.74 g (143.50 mmol) of sodium hydride (60% in paraffin oil) were added a little at a time and the mixture was stirred at room temperature for 1 hour. 50.92 g (358.76 mmol) of iodomethane were added dropwise to the resulting suspension, and the reaction mixture was stirred at room temperature overnight. For work-up, the mixture was poured into about 1 l of ice-water and the product was extracted with dichloromethane. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. Drying gave 17.34 g (100% of theory) of the title compound as a brownish oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[C:1]([NH:5][C:6]([C:8]1[C:9]([CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)NC(=O)c1ccccc1Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccccc1C(C(=O)C(C)(C)C)c1ccccc1
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube and maintained under a nitrogen atmosphere there is added at room temperature 59 g. (0.221 mole) of N-tert.butyl-α-phenyl-o-toluamide in 1000 ml. dry tetrahydrofuran. The flask is immersed in an ice bath and cooled to an internal temperature of 5° C. Stirring is initiated and 336.5 ml. (0.490 mole) of n-butyl lithium (15% in hexane) is added dropwise in about 1 hour maintaining the temperature below 8° C. The resulting solution is stirred 2 hours at room temperature, cooled to 5° C., and 26.6 g. (0.221 mole) of pivaloyl chloride in 250 ml. of dry tetrahydrofuran is added dropwise maintaining temperature below 8° C. After addition, the mixture is stirred 2 hours at room temperature and hydrolyzed with 150 ml. of saturated ammonium chloride, the resulting solution is filtered and the layers separated. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with ether to give N-tert.butyl-α-phenyl-α-pivaloyl-o-toluamide; m.p. 157°-161° C.
Reaction SMILES: [OH:1][CH:2]([CH2:27][CH2:28][CH2:29][OH:30])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12]([CH3:14])=[O:13])=[CH:8][C:7]1([OH:26])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[OH:1][CH:2]([CH2:27][CH2:28][CH2:29][OH:30])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12]([CH3:14])(=[O:39])=[O:13])=[CH:8][C:7]1([OH:26])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)C1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)C1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To a solution of 165 mg of 5-[(E)-4,7-dihydroxyheptenylidene]-4-hydroxy-2-methylsulfinyl-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 104 dissolved in 30 ml of dichloromethane was added a solution 117 mg of 3-chloroperbenzoic acid in 5 ml of dichloromethane, and the mixture was stirred for 2 hours. The reaction mixture was poured onto saturated aqueous sodium thiosulfate, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed twice with saturated aqueous sodium hydrogencarbonate and with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After filtration and concentration, the concentrate was subjected to chromatography to give 78 mg (yield 47%) of 5-[(E)-4,7-dihydroxy-2-heptenylidene]-4-hydroxy-2-methylsulfonyl-4-(4-phenoxybutyl)-2cyclopentenone
Reaction SMILES: [F:1][C:2]([F:17])([CH2:10][CH2:11][C:12]([O:14]CC)=O)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1>[F:17][C:2]1([F:1])[CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:12](=[O:14])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CCC(F)(F)CCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC(F)(F)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl 4,4-difluoroheptanedioate (4.3 g) in toluene (50 mL) was added potassium 2-methylpropan-2-olate (2.87 g) and the reaction stirred overnight at room temperature. The reaction was quenched with 1N aqueous HCl (100 mL) and extracted with diethyl ether (150 mL). The ether layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 40 g) eluting with a gradient of 1% to 5% ethyl acetate/hexanes gave the title compound.