Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1O)[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:16])=[CH:10][C:11]=2[OH:15])[O:6]1.[O:21]1C2C(=CC=CC=2)CCC1C1C=CC=CC=1.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH2:40]1[CH2:41][CH:42]([C:10]2[C:11]([OH:15])=[C:12]3[C:13]([CH:14]=[C:5]([C:4]4[CH:17]=[CH:18][CH:19]=[CH:2][CH:3]=4)[O:6][C:7]3=[CH:8][C:9]=2[OH:16])=[O:21])[NH:37][CH2:38][CH2:39]1
Reactant: c1ccc(C2CCc3ccccc3O2)cc1
Reactant: Oc1cc(O)c2c(c1)OC(c1ccc(O)c(O)c1)CC2
Reactant: C1CCNCC1
Product: O=c1cc(-c2ccccc2)oc2cc(O)c(C3CCCCN3)c(O)c12

Procedure:
The assistance of 2-D spectra, HSQC, COSY and HMBC, was required to connect the flavan skeleton and piperidine substituent in a manner reasonable to fit the data. According to the HSQC spectrum, the three protons (dd at 6.72 and 6.78 ppm and d at 6.85 ppm) correlated to the three aromatic carbons from 114 to 118 ppm. This, with the splitting pattern in the proton spectrum, indicated a 3,4-dihydroxy phenyl substituent. In keeping with the molecular formula C20H23NO5, a dihydroxy phenyl ring leaves three oxygens not yet accounted for as well as six more aromatic carbons and the structure is now comparable to 3′,4′,5,7-tetrahydroxyflavan. Due to the different chemical environment between C-6 and C-8 of the flavan and alkaloid NMR signals, a flavan structure with a nitrogen-containing substituent attached to ring A was explored. The COSY spectrum shows the saturated carbons between 20 and 30 ppm all seem to coordinate with each other but a closer look, combined with HSQC assignments, separates the three saturated carbons of the flavan from the five saturated carbons of the piperidine. The protons at 1.87 and 2.13 ppm (C-3) correlate to the protons at 2.62 ppm (C-4) as well as the proton at 5.0 ppm (C-2). Conversely, the protons of C-6″, 1.87 and 2.31 ppm, show correlations to protons at 1.62 and 1.87 ppm (C-4″ and C-5″) and the doublet at 4.54 ppm (C-1″). Additionally, C-4″ and -5″ protons correlate to C-3″ at 2.97 and 3.4 ppm. The HSQC spectrum corrected the assignment of an oxygenated methyl at 54.79 ppm to a nitrogenated methine and the downfield shift is explained by attachment to an aromatic ring. This nitrogenated methine and the nitrogenated methylene, at 46.82 ppm, can be connected to three of the five saturated 13C signals between 20 and 30 ppm (C-4″, -5″ and -6″) composing a 2-piperindinyl substituent attached to the aromatic ring A at the methine. A similar flavonoid alkaloid compound with a 2-piperidinyl substituent was used for comparison to confirm this piperidine moiety; Ahond et al. isolated N-demethylcapitavine (10). The reported 13C spectral data matches the piperidine assignments of the kinkéloids at 53.2, 46.5, 23.5, 22.6, and 27.9 ppm for C-1″-C-6″, respectively, confirming the piperidinyl moiety.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(O)CC>O>[Br:28][C:24]1[CH:23]=[C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc2ccc(-c3cccc(Br)c3)nc2n1
Reactant: O=C(O)c1cccc(Br)c1
Solvent: O
Solvent: CCCO
Product: O=C(Nc1ccc2ccc(-c3cccc(Br)c3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 56.9 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.2 g), N,N'-carbonyldiimidazole (1.8 g) and 2-amino-7-(3-bromophenyl)-1,8-naphthyridine (2.4 g). The product obtained by precipitation in water (3.1 g; m.p. approximately 140° C.) is dissolved in boiling propanol (100 cc). After cooling for 3 hours at 4° C., the crystallized solid is separated by filtration, washed with propanol (2×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(3-Bromophenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (2.2 g), m.p. 144°-146° C., is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]([O:18][C:19]([N:21]1[C@@H:25]([C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23][C@H:22]1[CH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[OH:33][C@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:25]1[CH2:24][CH2:23][C@@H:22]([CH2:34][C:35]2[CH:43]=[CH:42][C:38]([C:39]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:9][CH2:10]3)=[O:40])=[CH:37][CH:36]=2)[N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20]
Reactant: c1ccc(CN2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCN(Cc4ccccn4)CC3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 0.018 g (0.102 mmol) of (1-(pyridine-2-ylmethyl)piperazine and 0.035 g (0.085 mmol) of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid in 2 mL of N,N-dimethylformamide was added 0.074 mL (0.425 mmol) of N,N-diisopropylethylamine and 0.065 g (0.170 mmol) of HATU. The resulting mixture was stirred under an atmosphere of nitrogen for 3 h and then purified directly by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). LC/MS: m/z (ES) 571.2 (MH)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C(Cl)Cl>[OH:14][CH:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)CCC(=O)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)CCC(O)Cc1ccccc1
Yield: 60.4 %

Procedure:
A 100-ml stainless steel autoclave purged with nitrogen in advance was charged with 5 g (0.0261 mol) of 6-phenyl-2,5-hexanedione and 10 ml of methanol. A solution of 0.185 g (0.13 mmol) of RuI(p-cymene)((R)-T-BINAP)]I3 in 2 ml of methylene chloride was added thereto, thereby conducting reaction at a reaction temperature of 50° C. for 36 hours under a hydrogen pressure of 50 kg/cm2. After distilling off the solvent, the residue was purified by column chromatography on a silica gel using a developing solvent of hexane/ethyl acetate (5/1) to obtain 3.03 g of (-)-5-hydroxy-6-phenylhexane-2-one (yield: 60.2%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH4+].[Cl-]>C1COCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([OH:27])([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccnc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccnc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
Following the procedure of N. I. Carruthers et al. (J. Med. Chem. 2005, 48, 1857-1872), to a −78° C. solution of 2-bromo-3-methylpyridine (10.0 g, 7.1 mL, 57.1 mmol) in THF (150 mL) was added drop wise a solution of n-BuLi (2.5 M in hexanes, 25.1 mL, 62.8 mmol) over 10 min. After 1.5 h a solution of N-benzyl-4-piperidone (10.8 g, 57.1 mmol) in THF (20 mL) was added drop wise over 15 min and the mixture was allowed to slowly warm to room temperature overnight. After 18 h sat. NH4Cl solution (40 mL) was added and the mixture was concentrated. The resulting residue was diluted with 1N NaHCO3 (100 ml) and extracted with EtOAc. The combined organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography afforded the alcohol (8.1 g), an orange viscous oil, in 50% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[N:4][C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:13][C:14]([F:25])([F:24])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OC(C)C)=O)(C(OC(C)C)=O)=[N-]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[N:4][C:3]=1[O:12][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:14]([F:13])([F:25])[F:24]
Reactant: OC(c1ccc(F)cc1)C(F)(F)F
Reactant: Cc1nc(O)c(Br)cc1[N+](=O)[O-]
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(OC(c2ccc(F)cc2)C(F)(F)F)c(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 6 h
Yield: 62.5 %

Procedure:
To a stirred suspension of 3-bromo-6-methyl-5-nitro-pyridin-2-ol (0.10 g, 0.43 mmol) in THF (3 mL), 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol (0.13 g, 0.64 mmol, 1.5 equiv) and triphenylphosphine (0.17 g, 0.64 mmol, 1.5 eq) were added at room temperature under inert atmosphere (Ar). To this mixture, DIAD (diisopropyl diazodicarboxylate) (0.13 mL, 0.64 mmol, 1.5 eq) was added dropwise over 10 minutes while keeping the temperature below 40° C. The reaction mixture was stirred for 6 h under heating at 60° C. After this time, TLC indicted that the starting material had been consumed and the reaction mixture was allowed to reach room temperature before quenching with water (10 mL). The water phase was extracted with ethyl acetate (3×15 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give a brown residue, which was purified by combiflash column chromatography (silica gel, heptane/ethyl acetate, v/v=95/5). Fractions containing the pure compound were collected and concentrated in vacuo to give the title compound (0.11 g, 62% yield) as a yellow oil.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[O:27])=[CH:21][CH:20]=2)[CH:15]=[CH:14][N:13]=1)=[O:10])=[O:5])C.[OH-].[Na+].CO.Cl>CN(C)C=O>[C:4]([CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[O:27])=[CH:21][CH:20]=2)[CH:15]=[CH:14][N:13]=1)=[O:10])([OH:5])=[O:3]
Reactant: CCOC(=O)CCCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)CCCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1

Procedure:
N-{4-[2-(4-Ethoxycarbonylbutyryl)aminopyridin-4-yl]oxyphenyl}-N′-(4-fluorophenyl)urea (22 mg), 2N aqueous sodium hydroxide (1 ml), methanol (2 ml) and dimethylformamide (1 ml) were stirred together at 80° C. for 20 minutes. After returning the mixture to room temperature, 0.4 ml of 5N aqueous hydrochloric acid was added and the precipitated solid was filtered out to obtain 16 mg of the target substance as a white solid.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[C:12]([NH:15][C:16]1[N:20]([C:21]2[C:26]([F:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][C:22]=2[Cl:32])[N:19]=[CH:18][CH:17]=1)(=[O:14])[CH3:13]>C(O)(=O)C>[C:12]([NH:15][C:16]1[N:20]([C:21]2[C:26]([F:27])=[CH:25][C:24]([C:28]([F:30])([F:31])[F:29])=[CH:23][C:22]=2[Cl:32])[N:19]=[CH:18][C:17]=1[N+:8]([O-:11])=[O:9])(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccnn1-c1c(F)cc(C(F)(F)F)cc1Cl
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
2 ml (0.021 mol) of acetic anhydride and 0.9 ml (0.02 mol) of 98% strength nitric acid are successively added to 6 g (0.019 mol) of 5-acetamido-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole in 15 ml of glacial acetic acid at room temperature, and the mixture is stirred at room temperature for 15 hours. For working-up, the reaction mixture is added dropwise to 200 ml of ice-water, and the precipitate formed is filtered off, washed with water and dried in vacuo at 50° C. 5.8 g (85% of theory) of 5-acetamido-4-nitro-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole of melting point 129°-130° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:12][C:13](=[O:15])[CH3:14])[CH2:6][CH2:5]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.CCOC(C)=O>[C:27]([O:26][C:24](=[O:25])[C:23]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([NH:12][C:13](=[O:15])[CH3:14])[CH2:6][CH2:5][C:4]=2[CH:3]=1)([CH3:32])[CH3:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CC(=O)NC1CCc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NC1CCc2cc(OC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To a suspension of N-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (0.439 g; 2.1 mmol) in DMF (6 mL) is added Cs2CO3 (1.7 g; 5.2 mmol) and tert-butyl 2-bromoisobutyrate (2.1 mL; 9.4 mmol) and the reaction mixture was stirred at 100° C. for 18 h. The reaction was cooled to RT, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to provide a crude oil, which was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 0.51 g (69%) of 2-(6-acetylamino-5,6,7,8-tetrahydronaphthalen-2-yloxy)-2-methylpropionic acid tert-butyl ester as an oil.
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:6][C:5]=1[CH3:15].C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:3][C:4]1[C:5]([CH3:15])=[CH:6][C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:8][C:9]=1[I:1]
Reactant: ClI
Reactant: Cc1cc(-n2cncn2)ccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-n2cncn2)cc(I)c1N

Procedure:
Iodine monochloride (5.103 g) was added dropwise to a stirred solution of 1-(4-amino-3-methylphenyl)-1,2,4-triazole (5.22 g) and sodium acetate (2.583 g) in acetic acid (100 cm3). After 16 hours volatile material was removed in vacuo and the residue was partitioned between dichloromethane (100 cm3) and sodium carbonate solution (50 cm3). The organic phase was washed with sodium thiosulphate solution (10 g in 50 cm3 water), dried (MgSO4) and evaporated to give a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate. Combination and evaporaton of the appropriate fractions gave a solid which was recrystallised from ethyl acetate-ether to afford the title compound, m.p. 151°-154° (3.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O1CCCC1.CO.[OH-].[Li+]>O>[CH3:1][C:2]1[CH:11]=[C:10]([CH:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(C)N2CCCCC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(C)N2CCCCC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of methyl 2-methyl-4-(1-(piperidin-1-yl)ethyl)benzoate (283 mg, 1.1 mmol) in the mixture solution of tetrahydrofuran:methanol:water=3:1:1 (10 mL) was added lithium hydroxide (100 mg, 4.2 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo and quenched with hydrochloride acid aqueous (1N, 5 mL). To the residue was added water (50 mL). The mixture was extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give the product 2-methyl-4-(1-(piperidin-1-yl)ethyl)benzoic acid as pale solid (247 mg, 89%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:7]2>CCO.CO.[OH-].[OH-].[Pd+2]>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)[C@@H:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(OCCN2CCCC2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Reaction time: 68 h
Yield: 90.4 %

Procedure:
1-{2-[4-(6-Methoxy-2-phenyl-3,4-dihydronaphthalen-1yl)phenoxy]ethyl}pyrrolidine hydrochloride (nafoxidene hydrochloride) (75 g, 162 mmol) was dissolved in 1000 mL of EtOH and 300 mL of MeOH. Dry Pd(OH)2 on carbon was added and the mixture was hydrogenated on a Parr shaker at 50° C. and 50 psi for 68 h. The catalyst was filtered off with the aid of celite and the solvents were removed in vacuo. The resulting white solid was dissolved in CH2Cl2 and the solution was washed with satd NaHCO3 (aq). The organic solution was dried (MgSO4), filtered, and concentrated to yield an off-white solid (62.6 g, 90%).
Reaction SMILES: Cl.O1CCCC1.[CH2:7]([O:14][C@@H:15]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[S:18][C:16]1([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([CH:54]2OCC[O:55]2)[CH:48]=1)[OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH2:7]([O:14][C@@H:15]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[S:18][C:16]1([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([CH:54]=[O:55])[CH:48]=1)[OH:17])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC1(c2ccc(Cl)c(C3OCCO3)c2)S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
Then, 6M hydrochloric acid (120 mL) was added to a tetrahydrofuran (50 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-[4-chloro-3-(1,3-dioxolane-2-yl)phenyl]-5-thio-D-glucopyranose (6.01 g, 8.12 mmol) while ice-cooled, and stirred at room temperature for two days. The reaction mixture was added with an iced water and extracted with ethyl acetate and the organic phase was washed with a saturated sodium bicarbonate aqueous solution, brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain colorless amorphous 2,3,4,6-tetra-O-benzyl-1-C-(4-chloro-3-formylphenyl)-5-thio-D-glucopyranose (4.53 g, 80%).
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:17][CH:15]([CH2:16]2)[O:14][C:13](=[O:18])[NH:12]3)=[CH:7][CH:6]=1)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[N:28]=1.C(N(CC)CC)C>C(O)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]2[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]45[CH2:17][CH:15]([CH2:16]4)[O:14][C:13](=[O:18])[NH:12]5)=[CH:7][CH:6]=3)[N:33]=[C:29]2[N:28]=1
Reactant: COc1ccnc(N)n1
Reactant: O=C1NC2(c3ccc(C(=O)C(Br)c4ccccc4)cc3)CC(C2)O1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccn2c(-c3ccccc3)c(-c3ccc(C45CC(C4)OC(=O)N5)cc3)nc2n1
Temperature: 100 °C

Procedure:
A mixture of crude 5-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-2-oxa-4-aza-bicyclo[3.1.1]heptan-3-one (2.5 g), 4-methoxypyrimidin-2-amine (1.26 g), triethylamine (0.84 mL) and ethanol (62 mL), under argon, was heated at 100° C. (bath temperature) for 6 hours. On cooling the reaction was concentrated and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried and concentrated. Purification was achieved by chromatography on silica gel followed by preparative reverse phase HPLC to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:17](=[O:23])[N:18]([CH2:21]C)CC)=[C:9]([CH:16]=1)CNC(=O)OC)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Li+].Cl>CO>[C:1]([C:5]1[CH:16]=[C:9]2[C:8](=[CH:7][CH:6]=1)[C:17](=[O:23])[NH:18][CH2:21]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)C(=O)c1ccc(C(C)(C)C)cc1CNC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)CNC2=O
Temperature: 110 °C
Yield: 56.2 %

Procedure:
A 25-mL microwave vial equipped with a magnetic stirrer was charged with 103b (858 mg, 2.68 mmol), tetrahydrofuran (5 mL), methanol (5 mL) and 2 M aqueous lithium hydroxide (5 mL). The vial was loaded in a Biotage microwave and heated at 110° C. for 2.5 h. After this time, the solution was neutralized with 2 M hydrochloric acid to pH 7 and concentrated in vacuo. The resulting residue was partitioned between ethyl acetate (150 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 50% ethyl acetate to 100% ethyl acetate/hexanes) to afford a 56% yield (285 mg) of 103c as an off-white solid: mp=132-134° C.; 1H NMR (300 MHz, CDCl3) δ 7.80 (d, 1H, J=7.8 Hz), 7.52 (m, 2H), 6.71 (br s, 1H), 4.44 (s, 2H), 1.37 (s, 9H), MS (ESI+) m/z 190.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:5]([C:15]#[CH:16])[CH:4]=1.C(N(CC)CC)C.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([O:31][CH2:32][C:33](O)=[O:34])=[CH:27][CH:26]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1.CCOC(C)=O>[Cl:24][C:25]1[N:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([NH:1][CH2:2][C:3]2[CH:8]=[C:7]([F:9])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:5]([C:15]#[CH:16])[CH:4]=2)=[O:34])=[CH:27][CH:26]=1
Reactant: O=C(O)COc1ccc(Cl)nc1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#Cc1cc(CNC(=O)COc2ccc(Cl)nc2)cc(F)c1NS(C)(=O)=O
Reaction time: 0.17 h
Yield: 22.8 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide (74.3 mg, 0.266 mmol) was suspended in THF and treated with triethylamine (27 mg, 0.266 mmol) and then the resulting mixture was stirred for 10 mins. (6-chloro-pyridin-3-yloxy)-acetic acid (50 mg, 0.266 mmol) was added to the reaction mixture followed by DMTMM (62.5 mg, 0.266 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO3 (×3), and brine, and then dried over anh. MgSO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl2) to yield the title compound (25 mg, 25%).