Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][S:15]2(=[O:20])=[O:19])[CH:11]=[CH:10][C:9]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[CH3:36])[CH2:25][CH2:24]1)=[O:22])(C)(C)C.[H-].[Na+].CI.O>CN(C)C=O>[CH3:36][C:30]1[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:29]=1[N:26]1[CH2:25][CH2:24][N:23]([C:21]([C:9]2[CH:10]=[CH:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][S:15]3(=[O:20])=[O:19])=[CH:13][C:8]=2[NH:7][CH3:6])=[O:22])[CH2:28][CH2:27]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3NC(=O)OC(C)(C)C)CC2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.2 %

Procedure:
[2-Amino-4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (210 mg) described in Example 103 was dissolved in dichloromethane (2 mL), 4-dimethylaminopyridine (0.3 mg) and di-tert-butyl dicarbonate (110 mg) were added, and the mixture was stirred at room temperature. After completion of the reaction, the solvent was evaporated, and the obtained residue was purified by column chromatography (chloroform:methanol) to give {2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl}carbamic acid tert-butyl ester (283 mg). The obtained {2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl}carbamic acid tert-butyl ester (282.6 mg) was dissolved in N,N-dimethylformamide (8 mL), sodium hydride (26 mg) was added, and the mixture was stirred at room temperature for 10 min. Methyl iodide (0.04 mL) was added, and the mixture was stirred at room temperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in 1,4-dioxane (1 mL), 4N hydrogen chloride/1,4-dioxane (2.6 mL) was added, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by HPLC (ODS, 0.05% TFA aqueous solution-acetonitrile) to give the title compound (17 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH:13](OS(C)(=O)=O)[CH3:14])[CH2:9]2)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.ClC1C=CC(N2CCC(C(OS(C3C=CC(C)=CC=3)(=O)=O)C)C2)=C([N+]([O-])=O)C=1.[N-:51]=[N+:52]=[N-:53].[Na+]>CN(C)C=O.O>[N:51]([CH:13]([CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N+:20]([O-:22])=[O:21])[CH2:9]1)[CH3:14])=[N+:52]=[N-:53]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)C1CCN(c2ccc(Cl)cc2[N+](=O)[O-])C1
Agent: Cc1ccc(S(=O)(=O)OC(C)C2CCN(c3ccc(Cl)cc3[N+](=O)[O-])C2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])C1CCN(c2ccc(Cl)cc2[N+](=O)[O-])C1
Temperature: 80 °C
Yield: 88.3 %

Procedure:
A mixture of methanesulfonic acid 1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl ester (285.9 mg), toluene-4-sulfonic acid 1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl ester (55.2 mg) and sodium azide (185 mg) in N,N-dimethylformamide (ca. 5 mL) was heated at 80° C. overnight. The reaction mixture was cooled, diluted with water and extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 90/10) to give 214 mg (76% yield) of 3-(1-azido-ethyl)-1-(4-chloro-2-nitro-phenyl)-pyrrolidine.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[Cl:36][C:37]1[CH:42]=[C:41](B(O)O)[CH:40]=[CH:39][N:38]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:41]4[CH:40]=[CH:39][N:38]=[C:37]([Cl:36])[CH:42]=4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-c4ccnc(Cl)c4)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 120 using (1R,2R,4R)-4-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 117) and 2-chloropyridine-4-boronic acid. Light brown solid. MS (EI): 617.1 (M+H)+.
Reaction SMILES: O=O.[CH:3]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>[Pt].O>[C:3]1(=[O:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCCCCC1
Agent: [Pt]
Agent: O=O
Solvent: O
Product: O=C1CCCCCCC1
Yield: 87 %

Procedure:
In an ambient pressure oxygen atmosphere, 26.4 mg of cyclooctanol and 34.1 mg of the platinum catalyst obtained in Example 1 were agitated for twelve hours at 60° C. in 2 ml of water. The reaction mixture was subsequently extracted using ethyl acetate, and the organic layer was dried using magnesium sulfate, filtered and concentrated to obtain 22.6 mg (87% yield) of cyclooctanone. The reaction equation and the analytical results of the product are shown below.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C@H:14]([C:22](O)=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C@@H:59]([CH2:80][C:81]1[N:82]=[CH:83][NH:84][CH:85]=1)[C:60]([NH:62][C@@H:63]([CH2:73][CH:74]1[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]1)[C@@H:64]([OH:72])[CH2:65][C@@H:66]([CH:69]([CH3:71])[CH3:70])[CH:67]=[CH2:68])=[O:61].CCN(C(C)C)C(C)C>C(#N)C>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C@H:14]([C:22](=[O:23])[NH:58][C@H:59]([C:60](=[O:61])[NH:62][C@@H:63]([CH2:73][CH:74]2[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79]2)[C@@H:64]([OH:72])[CH2:65][C@@H:66]([CH:69]([CH3:70])[CH3:71])[CH:67]=[CH2:68])[CH2:80][C:81]2[N:82]=[CH:83][NH:84][CH:85]=2)[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:12])=[CH:5][CH:6]=1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: O=C(NCCOc1ccc(-c2ccccc2)cc1)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)NCCOc1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
A solution of 103 mg of N-[[2-(4-biphenyloxy)ethyl ]carbamoyl]-3-phenyl-L-alanine and 113 mg of BOP in acetonitrile was added to 100 mg (0.256 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide 0.052 ml of Hunig base in 5 ml of acetonitrile, and the mixture was subsequently stirred at room temperature for 12 hours. Subsequently the reaction mixture was poured onto 1N hydrochloric acid/ice, extracted with ethyl acetate, the extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by chromatography on silica gel with a 10:1 mixture of methylene chloride and methanol, to obtain 90 mg (45%) of 1-[2-(4-biphenyloxy)ethyl]-3-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]- carbamoyl]phenethyl]urea as an amorphous powder. MS: 777 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][C:24]=1[CH2:25]Br>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:25][C:24]1[CH:27]=[C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:29]=[CH:30][C:23]=1[F:22]
Reactant: Fc1ccc(Oc2ccc(F)c(CBr)c2)cc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2ccc(F)c(COc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)c2)cc1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a mixture of 0.51 g of 2,6-dichloro-4-(3,3,-dichloro-2-propenyloxy)phenol, 0.17 g of potassium carbonate and 20 ml of N,N-dimethylformamide was added dropwise a solution of 0.34 g of 2-fluoro-5-(4-fluorophenoxy)benzyl bromide dissolved in 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.50 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(2-fluoro-5-(4-fluorophenoxy) benzyloxy)benzene (68% yield), nD26.0 1.5871.
Reaction SMILES: Cl.[NH2:2]O.C(=O)([O-])[O-].[Na+].[Na+].C[O:11][C:12](=O)[C:13](=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:42])[C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)=[CH:28][N:27]=2)=[CH:21][CH:20]=1)[C:14]([O:16]C)=[O:15].CO>O.C1COCC1>[Cl:41][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[Cl:40])[C:33]([NH:32][C:29]1[CH:28]=[N:27][C:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([CH:18]=[C:13]3[C:14](=[O:15])[O:16][NH:2][C:12]3=[O:11])=[CH:24][CH:23]=2)=[CH:31][CH:30]=1)=[O:42]
Reactant: NO
Reactant: COC(=O)C(=Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1)C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C1NOC(=O)C1=Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of hydroxylamine hydrochloride (500 mg, 1.0 mmol) in water (0.2 mL) were added sodium carbonate (1.05 g, 9.91 mmol) and a solution of 2-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylidene}malonic acid dimethyl ester (500 mg, 1.0 mmol) in THF (5 mL). To the resulting solution was subsequently added methanol (5 mL) and stirred for 8 hours at 60° C. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). To the resulting white precipitate was added ethyl acetate, filtered, and the filtrate was washed with diethyl ether, to thereby yield 105 mg of the title compound.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>>[F:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:42][CH:43]=1
Reactant: Fc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Product: O=c1[nH]nc(CCc2ccc(F)cc2)cc1O

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)ethynyl]pyridazine (Intermediate 3).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH2:3]1>CCOC(C)=O.[Pd]>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: N#Cc1ccc(C2=CCC(=O)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2CCC(=O)CC2)cc1
Reaction time: 7 h

Procedure:
To a solution of the crude mixture of 4-(4-oxo-cyclohex-1-enyl)-benzonitrile and 4-(4-oxo-cyclohex-1-enyl)-benzonitrile prepared above in step c (36.6 mmol) in EtOAc (120 mL) was added 10% Pd—C (900 mg) and the reaction was degassed (3× vacuum and H2). After being stirred 7 hours under H2 atmosphere, additional 10% Pd—C (500 mg) was added and the resulting reaction was stirred for an additional 12 h under H2 atmosphere. The catalyst was removed by filtration through Celite and the filtrate was concentrated under reduced pressure to give 4-(4-oxo-cyclohexyl)-benzonitrile as a white solid. The product was used for next step without further purification.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:9]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O>[CH2:15]([C:9]1[CH:10]=[CH:11][C:12]([C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCc1ccccc1
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCCCCCCc1ccc(C(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Glutaric anhydride (77.6 g) is added in one portion to a stirred mixture of 1-phenylheptane (400 ml) and anhydrous aluminum chloride (200 g). The mixture is stirred at room temperature for 1 hour, then cooled in an ice bath and carefully treated with a mixture of water (300 ml) and conc. HCl (100 ml). After the addition is complete, the mixture is allowed to return to room temperature and then extracted with ether (3×500 ml). The combined ether extracts are dried over MgSO4, filtered and concentrated on a rotary evaporator. The solid precipitate is separated from the phenyl heptane solution, and then mixed with water (600 ml) and heated under reflux for 15 min. After cooling to room temperature the product is extracted with methylene chloride (2×300 ml). The extract is dried over MgSO4, filtered and concentrated. The residue is recrystallized from heptane to provide 4-(4-n-heptylbenzoyl)butanoic acid (34.86 g) as a white crystalline solid, m.p. 101°-103.5°0 C.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[CH:24]([C:26]1([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=O.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([CH2:24][C:26]5([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1cc(OCC2CCC2)c2c(OCC3CCNCC3)noc2c1
Reactant: COC(=O)C1(C=O)CCOCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC5CCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclobutylmethoxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 17, Step 4) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[NH:8][CH2:7][CH2:6][C:5]=2[N:4]=1>Br.CC(O)=O>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[NH:8][CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COc1ccc2c(n1)CCNC2=O
Agent: Br
Solvent: CC(=O)O
Product: O=C1NCCc2nc(O)ccc21
Temperature: 60 °C
Reaction time: 16 h
Yield: 102.4 %

Procedure:
2-Methoxy-7,8-dihydro-6H-[1,6]naphthyridin-5-one (18 g, 101.1 mmol) was added to a mixture of HBr/CH3CO2H (60 mL). The mixture was stirred at 60° C. for 16 h. The solvent was evaporated in vacuo to yield 2-hydroxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one (17 g, 68%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])=[C:4]([CH2:15][CH3:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:12](=[O:13])[CH2:11][CH2:10][C:9]=3[OH:14])=[C:4]([CH2:15][CH3:16])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: CCc1cc(Br)ccc1C1C(=O)CCC1=O
Reactant: Oc1ccc(Cl)cc1
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1cc(Oc2ccc(Cl)cc2)ccc1C1=C(O)CCC1=O
Temperature: 16 °C

Procedure:
To a mixture of 2-(4-bromo-2-ethylphenyl)cyclopentane-1,3-dione (0.20 g, 0.0007 mol), 4-chlorophenol (0.180 g, 0.0014 mol), cesium carbonate (0.460 g, 0.0014 mol), copper triflate (10 mg, 0.00003 mol) and activated 4 Å molecular sieves (0.30 g) is added anhydrous toluene (7 ml). The mixture is then heated at 16° C. for 1 hour under microwave irradiation, followed by dilution with ethyl acetate (50 ml) and 2M hydrochloric acid (50 ml). The organic phase is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product is purified by preparative reverse phase HPLC to afford 2-[4-(4-chlorophenoxy)-2-ethylphenyl]-3-hydroxycyclopent-2-enone as a cream solid.
Reaction SMILES: ClCC(O)=[O:4].[CH:6]([C:9]1[N:14]=[C:13](S)[N:12]=[C:11]([OH:16])[CH:10]=1)([CH3:8])[CH3:7].Cl>O>[CH:6]([C:9]1[N:14]=[C:13]([OH:4])[N:12]=[C:11]([OH:16])[CH:10]=1)([CH3:8])[CH3:7]
Reactant: CC(C)c1cc(O)nc(S)n1
Reactant: O=C(O)CCl
Agent: Cl
Solvent: O
Product: CC(C)c1cc(O)nc(O)n1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Chloroacetic acid (22 g, 0.23 mol) and 6-isopropyl-2-mercaptopyrimidin-4-ol (10 g, 59 mmol) were suspended in water (150 mL). The reaction mixture was refluxed for 6 hours. Concentrated HCl (0.36 mL) was added carefully, and the reaction was returned to reflux for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 6-isopropylpyrimidine-2,4-diol (9.0 g, yield: 100%), which was used in the next step without further purification. LCMS (ESI) m/z: 155.0 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[OH:27][CH2:28][C:29]([NH:38]C(=O)OC(C)(C)C)([CH2:36][OH:37])[CH2:30][C:31]1[CH:35]=[CH:34][S:33][CH:32]=1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]>C(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[NH2:38][C:29]([CH2:30][C:31]1[CH:35]=[CH:34][S:33][CH:32]=1)([CH2:28][OH:27])[CH2:36][O:37][CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)Cc1ccsc1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cc(COCC(N)(CO)Cc2ccsc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of intermediate A 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (50 mg, 0.11 mmol) in 1 mL CH2Cl2 cooled to 0° C. was added intermediate m tert-butyl 2-hydroxy-1-(hydroxymethyl)-1-(thien-3-ylmethyl)ethylcarbamate (81 mg, 0.28 mmol), silver triflate (72 mg, 0.28 mmol) and 2,6-ditert-butylpyridine (76 μL, 0.34 mmol). The reaction mixture was stirred at 0° C. for 40 min and purified by flash chromatography (20 g silica, 30→80% EtOAc/hexanes) and by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) to afford tert-butyl 2-({3-({[(1R)-1-(4-fluorophenyl)ethyl]amino}carbonyl)-5-[methyl(methylsulfonyl)amino]benzyl}oxy)-1-(hydroxymethyl)-1-(thien-3-ylmethyl) contaminated with 2,6-ditert-butylpyridine. Treatment with 10% TFA in CH2Cl2 for 30 min, followed by concentration under a stream of nitrogen, and purification by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) afforded 3-{[2-amino-3-hydroxy-2-(thien-3-ylmethyl)propoxy]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide as a TFA salt. 1H NMR (400 MHz, d4-MeOH) δ 8.86 (d, J=7.9 Hz, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 7.48-7.36 (m, 3H), 7.17 (s, 1H), 7.10-7.00 (m, 2H), 6.95 (d, J=5.0 Hz, 1H), 5.30-5.20 (m, 1H), 4.68 (A of AB, d, J=12.0 Hz, 1H), 4.63 (B of AB, d, J=12.0 Hz, 1H), 3.57 (s, 2H), 3.51 (A of AB, d, J=11.0 Hz, 1H), 3.45 (B of AB, d, J=11.0 Hz, 1H), 3.09 (s, 3H), 3.04 (A of AB, d, J=13.6 Hz, 1H), 3.45 (B of AB, d, J=13.6 Hz, 1H), 2.94 (s, 3H), 1.58 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].OO.CC(C)=[O:56]>CO.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N+:41]([O-:56])([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC(C)=O
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: OO
Solvent: CO
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H]([N+](C)(C)[O-])[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
220.2 g(0.3 mol) of erythromycin A was dissolved in a mixture of 1,500 ml of methanol and 1,000 ml of water. 79 ml(0.9 mol) of 35% hydrogen peroxide was added dropwise to the solution at a temperature ranging from 15 to 20° C. and stirred at room temperature for 20 hours in a similar method described in E. H. Flynn et al., J. Am. Chem. Soc., 76, 3121(1954) and P. H. Jones et al., J. Org. Chem., 33, 665(1968). The resulting mixture was concentrated to a half volume under a reduced pressure and extracted successively with 1,000 ml and 500 ml portions of chloroform. The combined chloroform extract was washed with brine, dried over anhydrous magnesium sulfate, and then, concentrated under a reduced pressure to obtain a foamy residue. 1,000 ml of acetone was added to the residue and stirred at room temperature for 3 hours. The crystalline material formed was filtered and dried overnight at 45° C. to obtain 220 g of erythromycin a N-oxide in a yield of 98%.