Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[CH2:25][CH2:26][CH2:27][S:28]2(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCN2CCCS2(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-Boc-4-(2-aminoethyl)-piperazine (1.26 g, 6.8 mmol) and triethylamine (1 mL) in THF (10 ML), 3-chloro-propylsulfonyl chloride (Aldrich, 0.68 mL, 6.94 mmol) was added slowly at room temperature. The mixture was stirred for 30 minutes at and the reaction was quenched with water. The new mixture was extracted with ethyl acetate and the extracts were combined and dried (Na2SO4). The solution was concentrated and the residue was dissolved in THF (20 mL) and Cs2CO3 (500 mg), NaI (80 mg) were added and the mixture was stirred at reflux overnight. The mixture was cooled to room temperature and poured into water. The new mixture was extracted with ethyl acetate (3×15 mL) and the extracts were combined and dried (Na2SO4). Removal of the solvent on a rotary evaporator gave a solid. 2.01 g.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([N:22](S(CCC)(=O)=O)[S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.[CH3:36][O:37][CH2:38][CH2:39][OH:40].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:35][C:15]1[C:14]([C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([O:40][CH2:39][CH2:38][O:37][CH3:36])=[N:11]3)=[O:13])=[C:19]([F:20])[C:18]([F:21])=[CH:17][C:16]=1[NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24]
Reactant: COCCO
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(OCCOC)nc3c2)c1F
Temperature: 90 °C
Reaction time: 7.5 h
Yield: 0.6 %

Procedure:
To a solution of N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 9.6 mmol, 1.0 eq.) in DMF (2 mL) was added 2-methoxyethanol (17.5 mg, 24 mmol, 2.5 eq.) and Cs2CO3 (87 mg, 24 mmol, 2.0 eq.). The resulting mixture was stirred at 90° C. for 7.5 h, then cooled, washed with water and extracted with EA (20 mL×3). The combined organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford N-(2,4,5-trifluoro-3-(3-(2-methoxyethoxy)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (28 mg, 61%). LRMS (M+H+) m/z calculated 484.1, found 483.9. 1H NMR (DMSO-d6, 400 MHz) δ10.12 (s, 1 H), 8.81 (s, 1 H), 8.26 (s, 1 H), 8.22 (d, 1 H), 8.15 (d, 1 H), 7.79 (m, 1 H), 4.58 (brs, 2 H), 3.75 (brs, 2 H), 3.33 (s, 3 H), 3.23 (m, 2 H), 1.75 (m, 2 H), 0.97 (s, 3 H).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]([O:11][CH:12]([Cl:14])[CH3:13])=[O:10].[Cl-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:9](=[O:10])([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:11][CH:12]([Cl:14])[CH3:13]
Reactant: OC1CCCCC1
Reactant: CC(Cl)OC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.15 g of cyclohexanol was dissolved in 150 mL of methylene chloride, to which 7.4 mL of pyridine was added followed by dropwise addition of 10 mL of 1-chloroethyl chloroformate in an ice bath, and this mixture was stirred for 2 hours at room temperature. Then, a sodium chloride solution was added to the reaction mixture and the organic phase was separated therefrom. After the resultant organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled out under reduced pressure to yield 18.6 g of 1-chloroethyl cyclohexyl carbonate as colorless oil. 5.00 g of this 1-chloroethyl cyclohexyl carbonate was dissolved in 150 mL of acetonitrile, to which 16.3 g of sodium iodide was added, and this mixture was stirred for one hour at 60° C. The mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out therefrom by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 5.90 g of cyclohexyl 1-iodoethyl carbonate as red oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[N+:22]([O-])=O)=[CH:7][CH:6]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[NH2:22])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cc2N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
A mixture of [4-(2-nitro-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester (1.31 g, 3.54 mmol) and 10% Pd/C (377 mg, 0.354 mmol) in 17 mL of methanol was allowed to stir at room temperature under hydrogen atmosphere for 12 h. Upon completion, the mixture was filtered through a short column of celite and the filtrate was concentrated in vacuo to give 920 mg of [4-(2-Amino-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester. 1H NMR (CDCl3): δ 7.24-7.33 (m, 3H), 6.80-7.06 (m, 4H), 4.01 (br s, 2H), 3.71 (s, 3H), 3.61 (s, 2H). LCMS (ESI+) 326 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=O)[C:11]([O:13]CC)=O.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>CCO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([OH:13])=[N:23][C:18]2[C:17]([N:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CCOC(=O)C(=O)c1nc2ccccc2s1
Reactant: Nc1ccccc1N
Solvent: CCO
Product: Oc1nc2ccccc2nc1-c1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a solution of ethyl 2-(benzo[d]thiazol-2-yl)-2-oxoacetate (Example 13a, 655 mg, 2.78 mmol) in EtOH (5.6 mL) was added o-phenylenediamine (300 mg, 2.78 mmol). The reaction mixture was heated with stiffing at 90° C. for 1 hr (a yellow/green solid appeared quickly), cooled to 0° C., and the solid filtered and rinsed with cold EtOH. The solid was dried under vacuum overnight to provide the title compound (3-(benzo[d]thiazol-2-yl)quinoxalin-2-ol, 313 mg, 40% yield) as a yellow green solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1/C=C\CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1/C=C\CCN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
A solution of tert-butyl 4-((Z)-4-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-enyl)piperazine-1-carboxylate (0.0672 g, 0.127 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[(Z)-4-(piperazin-1-yl)but-1-enyl]benzofuran-3(2H)-one (0.0412 g, 75%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][S:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[CH3:11][C:9]1[CH:8]=[CH:7][C:3]([CH:4]=[O:6])=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([S:13][CH3:12])[CH:15]=2)[N:10]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CSc1cccc(N)c1
Product: CSc1cccc(Nc2nc(C)ccc2C=O)c1

Procedure:
The procedure of Synthetic Example 1 was repeated using 2-chloro-6-methylnicotinic acid and 3-methylthioaniline to obtain 6-methyl-2-(3-methylthiophenylamino)nicotinaldehyde.
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8].CN1C(=O)N(C)CCC1.I[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][CH2:23][CH2:22][C:11]#[C:10][Si:7]([CH3:9])([CH3:8])[CH3:6])=[CH:27][CH:28]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(CCCCI)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(CCCCC#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.2 %

Procedure:
12.4 ml (19.8 mmol) of 1.6 M butyllithium in n-hexane was added dropwise at −78° C. to a solution of 1.94 g (2.80 ml, 19.8 mmol) trimethylsilylacetylene and 2.39 ml(19.8 mmol) DMPU in 30 ml THF. After stirring for 1 h at −78° C. a solution of 28.7 g (9.89 mmol) 1-(4-Iodo-butyl)-4-methoxy-benzene in ml THF was added at −78° C. and stirring continued for 30 min. The reaction mixture was allowed to warm to r.t. overnight and then hydrolyzed by a saturated ammonium chloride solution. The water phase was extracted with ether and the combined organic phases were dried over sodium sulphate. Removal of solvents in vacuo gave 3.20 g yellow liquid, which still contained solvent and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:18]([S:21][CH2:22][CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24](Cl)=[O:25])(=[O:20])[CH3:19].Cl>C(Cl)(Cl)Cl.O>[C:18]([S:21][CH2:22][CH:23]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:25])(=[O:20])[CH3:19]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Yield: 41.3 %

Procedure:
3-Aminobenzoic acid (1.4 g) is suspended in chloroform (50 ml), and thereto is added triethylamine (2.06 g), and to the mixture is added 2-acetylthiomethyl-3-phenylpropionyl chloride (2.61 g) with stirring under ice cooling, and the mixture is stirred for 30 minutes and further at room temperature three nights. To the reaction mixture is added water, and the mixture is acidified with hydrochloric acid and extracted with chloroform. The extract is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure. The precipitates are separated by filtration and recrystallized from 50% aqueous ethanol to give the title compound (1.5 g).
Reaction SMILES: O[CH:2]([C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1)[C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3CCCC[O:19]3)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=2[N:6]=[CH:5][C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1>C(O)=O.[Zn]>[CH:18]([O:17][CH2:16][CH2:15][CH2:14][N:10]1[C:11](=[O:13])[C:12]2[C:3]([CH2:2][C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=3)=[C:4]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=3)[CH:5]=[N:6][C:7]=2[N:8]([CH3:25])[C:9]1=[O:24])=[O:19]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(C(F)(F)F)cc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(C(F)(F)F)cc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Temperature: 100 °C
Yield: 84.3 %

Procedure:
To a solution of 5-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, crude) in HCOOH (5 mL) was added Zn dust (100 mg, 1.54 mmol). The reaction was heated at 100° C. for 1 h, cooled to RT and filtered. The filtrate was concentrated to give 3-(1-methyl-2,4-dioxo-5-(4-(trifluoromethyl)benzyl)-6-(3-(trifluoromethyl)phenoxy)-1,2-dihydro pyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (150 mg, 58.9 yield) as an oil. LCMS: MH+ 582 and TR=1.746 min. Used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[NH2:14])=[O:5].C([O-])(=O)C.[Na+].[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH:23]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:14][CH2:23][CH2:22][C:21]([CH3:26])([CH3:25])[CH3:20])=[O:5]
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)[C@@H]1CCCCCC[C@@H]1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCCCC[C@@H]1NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
cis-2-Amino-cyclooctanecarboxylic acid methyl ester hydrochloride (0.25 g, 1.35 mmol) was dissolved in methanol (10 mL). Sodium acetate (0.22 g, 2.70 mmol) was added followed by 4 Å powdered molecular sieves (0.20 g) and 3,3-dimethyl-butyraldehyde (0.17 mL, 1.35 mmol). Sodium cyanoborohydride (0.17 g, 2.70 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, cis-2-(3,3-dimethyl-butylamino)-cyclooctanecarboxylic acid methyl ester (0.34 g, 1.26 mmol, 93%), as a clear oil. LC-MS (ESI) calcd for C16H31NO2 269.42, found [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:10]Br>C(O)(=O)C>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1ccccc1N
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1N
Reaction time: 1 h
Yield: 57 %

Procedure:
At room temperature, 3.4 ml (30 mmol, 1.25 eq) of 2-methoxyaniline is diluted in 10 ml of acetic acid. Over approximately 1 hour, 1.2 ml (24 mmol, 0.8 eq) of bromine dissolved in 10 ml of acetic acid is added dropwise. A purple precipitate is formed. When all the bromine has been added, the hydrobromide is filtered on a Buchner funnel and rinsed with acetic acid. Take up the solid in a H2O/CH2Cl2 mixture. A slight excess of KOH pellets is added, the aqueous phase is extracted with CH2Cl2 and the organic phase is dried on MgSO4. Concentration under reduced pressure gives a brown oil which is purified by column chromatography (eluent CH2Cl2). The expected product (3.46 g) is a colorless oil (yield: 57%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH:14]=[CH2:15])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:24]>ClCCl.C1(C)C=CC=CC=1>[O:24]1[CH:14]([CH:13]([O:12][C:11]2[CH:17]=[CH:18][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:9][CH:10]=2)[CH3:16])[CH2:15]1
Reactant: C=CC(C)Oc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C1CO1
Reaction time: 140 h
Yield: 87.9 %

Procedure:
A solution of (3R and 3S)-3-[4-(tert-butoxycarbonyl)phenoxy]-1-butene (3.78 g, 15.2 mmol) in dry dichloromethane (50 ml) was treated at 22° C. with 3-chloroperoxybenzoic acid (4.8 g, 28.0 mmol) and the resulting mixture was stirred for 140 hours. The mixture was then diluted with toluene, washed with 5% sodium thiosulfate, sodium bicarbonate and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 2%) gave 3.53 g (87%) of the title material as an oil. 1H NMR indicated a 6:4 diastereoisomeric mixture which was used as such for the next step.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][N:9]([C:12]3[S:13][C:14]([C:18]([NH:20][CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[O:19])=[C:15]([CH3:17])[N:16]=3)[C:8]2=[O:28])=[CH:4][CH:3]=1.[CH2:31]([Zn]CC)C.ICI.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]3[CH:10]([CH2:31]3)[N:9]([C:12]3[S:13][C:14]([C:18]([NH:20][CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[O:19])=[C:15]([CH3:17])[N:16]=3)[C:8]2=[O:28])=[CH:29][CH:30]=1
Reactant: CC[Zn]CC
Reactant: Cc1nc(-n2ccn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: C1CCOC1
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C3CC32)sc1C(=O)NCc1cccnc1
Yield: 7 %

Procedure:
To a 25-mL two-neck round bottom flask under argon was charged with 2-(3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.10 g, 0.24 mmol) and tetrahydrofuran (5 mL). Diethylzinc in hexanes (0.35 mL of 1 M solution, 0.35 mmol) was added slowly with a syringe. The solution was stirred and maintained at ambient temperature while diiodomethane (0.10 g, 0.35 mmol) was added slowly with a syringe. The reaction mixture was stirred at 60° C. for 8 hours and cooled in an ice-water bath, followed by the addition of saturated aqueous ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (80 mL) and washed with saturated aqueous ammonium chloride (2×8 mL), water (3×8 mL), dried over sodium sulfate and filtered. The filtrate was concentrated and purified by preparative thin layer chromatography eluted with dichloromethane/methanol (20/1) to afford the title compound in 7% yield (7 mg). 1H NMR (300 MHz, CDCl3) δ 8.57 (br, 2H), 7.66-7.63 (m, 1H), 7.35-7.26 (m, 2H), 7.20-7.18 (m, 1H), 7.06-7.00 (m, 2H), 6.31-6.29 (m, 1H), 4.87 (br s, 2H), 4.74 (br s, 2H), 3.00 (br s, 2H), 2.39 (s, 3H), 0.92-0.81 (m, 2H); MS (ES+) m/z 437.9 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C@@H:15]2[O:32][C@H:31]([CH2:33][O:34]C(=O)C)[C@H:26]([O:27]C(=O)C)[C@H:21]([O:22]C(=O)C)[C@H:16]2[O:17]C(=O)C)=[CH:10][CH:9]=1.C[O-].[Na+]>CO>[CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C@@H:15]2[O:32][C@H:31]([CH2:33][OH:34])[C@H:26]([OH:27])[C@H:21]([OH:22])[C@H:16]2[OH:17])=[CH:10][CH:9]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(OCOCC[Si](C)(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCOc1ccc(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the SEM protected thioglycoside 79 (1.60 g, 2.73 mmol) in 15 mL of methanol is added sodium methoxide (300 mg, 5.56 mmol). The mixture is stirred at room temperature for 12 h, then neutralized with Amberlite resin (acid form), filtered, concentrated and run through a short column of silica gel (10% MeOH/EtOAc) to provide crude 1-deoxy-1-{4-[2-(trimethylsilyl)ethoxymethoxy]phenylthio}-β-D-galactopyranose 80 as an oil: Rf 0.15 (EtOAc). The material is taken up in 10 mL of DMF, and dimethoxypropane (0.59 mL, 4.8 mmol), and p-toluenesulfonic acid hydrate (90 mg, 0.48 mmol) are added. The mixture is stirred at room temperature for 12 h, pyridine (0.04 mL, 0.48 mmol) is added, and the reaction mixture is concentrated and purified by flash chromatography (60% EtOAc/hexane) to give 0.5 g (41%) of 1-deoxy-3,4-O-isopropylidene-1-{4-[2-(trimethylsilyl)ethoxymethoxy]phenylthio}-β-D-galactopyranose 81 as a colorless oil: Rf 0.5 (67% EtOAc/hexane); 1H NMR (CDCl3, 300 MHz) δ 7.48 (d, J=8.6 Hz, 2H), 6.99 (d, J=8.6 Hz, 2H), 5.21 (s, 2H, SEM), 4.35 (d, J=10.2 Hz, 1H, H-1), 4.17 (dd, J=1.7, 5.4 Hz, 1H), 4.09 (dd, J=6.5 Hz, 1H), 3.94 (m, 1H), 3.85 (m, 2H), 3.73 (t, J=8.1 Hz, 2H, SEM), 3.52 (m, 1H), 2.49 (d, J=1.8 Hz, 1H), 2.17 (d, J=9.1 Hz, 1H), 1.40 (s, 3H, Me), 1.33 (s, 3H, Me), 0.93 (t, J=8.1 Hz, 2H, CH2 --TMS), 0.01 (s, 9H, SiMe3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14]([OH:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([O:16][CH:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10](=[O:27])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15]1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(OC(C)=O)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one (previously described, 1.0 g) in acetic anhydride (20 ml) was maintained at 80° for 3 hours. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. Ether (100 ml) was added, and the resulting solution washed with water (50 ml) and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 5-acetoxy-3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as a pale yellow oil which was used without further purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=O)[CH2:2]1.Cl[C:13]([CH3:21])([CH2:15][CH2:16][C:17](Cl)([CH3:19])[CH3:18])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCl.C1COCC1>[CH3:18][C:17]1([CH3:19])[CH:16]=[CH:15][C:13]([CH3:21])([CH3:14])[C:8]2[C:9]1=[CH:10][C:5]1[NH:4][CH2:3][CH2:2][O:1][C:6]=1[CH:7]=2
Reactant: O=C1COc2ccccc2N1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)C=CC(C)(C)c2cc3c(cc21)NCCO3
Temperature: 80 °C
Yield: 70 %

Procedure:
To a solution of 6-6-9-9-tetramethyl-6,9-dihydro-4H-naphtho[2,3-b][1,4]oxazin-3-one (400 mg, 1.5 mmol) [prepared by Friedel Crafts alkylation/annulation of 2H-1,4-benzoxazin-3-(4H)-one with 2,5-dichloro-2,5-dimethyl hexane in the presence of aluminum chloride at ambient temperatue (24° C.) in dichloromethane]in THF at ambient temperature was added LiA1H4 (4.6 ml, 4.6 mmol). The reaction mixture was allowed to stir and then was heated to 80° C. for 30 min. The reaction mixture was poured over saturated sodium potassium tartrate solution (100 ml), extracted with EtOAc (100 ml), dried with anhydrous MgSO4 (0.5 g), and concentrated to give 6,6,9,9-tetramethyl-3,4,6,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazine (300 mg, 70% yield of theory): 1H NMR (400 MHz, CDCl3) δ 6.70 (s, 1H, benzylic), 6.52 (s, 1H, benzylic), 4.23 (t, 2H, J=2.8, 1.6 Hz, ring CH2), 3.39 (t, 2H, J=4.4, 6.8 Hz, ring CH2), 1.63 (s, 4H, 2 CH2), 1.22 (s, 12H, 4 CH3).