Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:12][C:11]([CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])=[N:10]2)=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[C:21]([C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)(=[O:22])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc(-n2nc(C(O)c3ccccc3)cc2-c2ccc(C)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)c3ccccc3)cc2-c2ccc(C)cc2)cc1
Reaction time: 0.5 h

Procedure:
Compound 77 (3.7 g, 10 mM) was dissolved in CH2Cl2 (100 ml) and pyridinium chlorochromate (3.44 g, 16 mM) was added with vigorous stirringand stirred for 30 min. Et2O (150 ml) was added and the mixture was sonicated for 5 min and filtered through florisil (100-200 mesh), the Florisil washed with additional Et2O and the combined Et2O layer evaporated in vacuo to yield the title compound of sufficient purityfor subsequent steps.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1.[C:13]([O-:16])(=[S:15])[CH3:14].[K+].O>CN(C=O)C>[C:13]([S:15][CH2:2][CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1)(=[O:16])[CH3:14]
Reactant: CC([O-])=S
Reactant: ClCCc1ncc2cnccn12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SCCc1ncc2cnccn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution of 3-(2-chloroethyl)imidazo[1,5-a]pyrazine (1.51 g) in DMF (10 ml) was added potassium thioacetate (1.23 g). The mixture was stirred for 4 hours at room temperature. To the reaction mixture was added water. The mixture was subjected to extraction with ethyl acetate (50 ml×4). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (carrier: silica gel, 60 g, developing solvent: ethyl acetate) to give the title compound (1.65 g) as colorless solid product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].OS(O)(=O)=O.[CH3:21]O>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH3:21])=[O:14]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1Br

Procedure:
A solution of 2-bromo-4-trifluoromethylphenylacetic acid (2.00 g, 7.07 mmol) and concentrated aqueous H2SO4 (1 mL) in MeOH (30 mL) was heated at reflux for 16 hours. The volatiles were removed under reduced pressure then the residue taken up in EtOAc. The resulting solution was washed with 10% NaHCO3, dried (MgSO4) and evaporated under reduced pressure to give the title compound A57 as a clear liquid (2.07 g, 98%); 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=1.1 Hz, 1H), 7.53 (dd, J=8.0, 1.1 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 3.84 (s, 2H), 3.72 (s, 3H). LCMS-A: rt 6.236 min; m/z 297/299 [M+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:15]([CH3:16])=[C:14]([OH:17])[C:13]([CH3:18])=[CH:12][C:10]=1[OH:11].C(O[CH:23]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=O)C>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(O)C>[CH3:18][C:13]1[C:14](=[O:17])[C:15]([CH3:16])=[C:9]([CH3:8])[C:10](=[O:11])[C:12]=1[CH:23]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CCCCC(OC(C)=O)c1cccs1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1cccs1
Temperature: 60 °C
Yield: 74.8 %

Procedure:
D-Camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (50 ml) of 2,3,5-trimethylhydroquinone (3.1 g, 0.02 mole) and ethyl 6-acetoxy-6-(2-thienyl)hexanoate (5.6 g, 0.02 mole), and the mixture was heated at 60° C. for 6.5 hours, with stirring. After cooling, ethanol (100 ml) and a 10% aqueous solution (20 ml) of ferric chloride were added to the reaction solution, followed by stirring for 10 minutes. The reaction product was extracted with isopropyl ether, and the organic layer was washed with water, dried (over magnesium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl etherhexane (1:1) to give ethyl 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-(2-thienyl)hexanoate (5.6 g, 76%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 2 to 8 were prepared.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[CH:9]([C:15]1([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[CH2:18][CH2:17][CH2:16]1)[NH:8][CH2:7][CH2:6]2.C=O.[C:31]([BH3-])#N.[Na+].Br>C(O)(=O)C.C(#N)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[CH:9]([C:15]1([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[CH2:16][CH2:17][CH2:18]1)[N:8]([CH3:31])[CH2:7][CH2:6]2
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1OC)C(C1(c3ccc4ccccc4c3)CCC1)NCC2
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCc2cc(O)c(O)cc2C1C1(c2ccc3ccccc3c2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6,7-dimethoxy-1-[1-(2-naphthyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline (4.74 g prepared as described in Example RB20), 37-40% aqueous formaldehyde solution (5.1 ml), acetonitrile (120 ml) and sodium cyanoborohydride (1.3 g) was stirred at ambient temperature for 15 minutes. The mixture was neutralised by addition of glacial acetic acid and stirred for 45 minutes. The mixture was concentrated by evaporation and basified with 2N aqueous potassium hydroxide solution. The resulting mixture was extracted with ether. The extracts were washed with aqueous potassium hydroxide solution and extracted with aqueous hydrochloric acid. The acid extract was basified and extracted with ether. The ether extract yielded a residue, a portion (3.86 g) of which was mixed with 48% aqueous hydrobromic acid (40 ml) and glacial acetic acid (40 ml) and heated at 100° C. for two days. The solvent was removed by evaporation and the residue dried by azeotropic distillation with propan-2-ol. The residue was washed with ether and decolourised with charcoal in propan-2-ol. The mixture was filtered and yielded 6,7-dihydroxy-2-methyl-1-[1-(2-naphthyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline 1.1 hydrobromide (m.p. 150°-153° C.) which was dried in vacuo.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][P:11]([O-:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30]Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][P:11](=[O:20])([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCCCCc1ccccc1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=P(CCCCc1ccccc1)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride 50% oil dispersion (1.01 g., 20.8 mmole) is added to a solution of dibenzylphosphite (5.25 g., 20.0 mmole) in dry dimethylformamide (30 ml.) under argon. The resulting mixture is stirred at room temperature for one hour and at 40° (bath temperature) for 30 minutes. The resulting clear, yellow solution is allowed to cool to room temperature and treated with a solution of 4-phenylbutyl chloride (4.0 g., 23.7 mmole) in dimethylformamide (3 ml.). The resulting mixture is stirred at room temperature for 18 hours and at 40° for 2 hours. The mixture is partitioned between ethyl acetate-1% potassium bisulfate. The organic phase is washed successively with water (twice), saturated sodium bicarbonate (twice), and saturated sodium chloride (twice), dried over sodium sulfate, and evaporated. The residue is purified by flash chromatography (silica gel, 100 g. of LPS-1) eluting with ethyl acetate:hexane (3:7) to give (4-phenylbutyl)phosphonic acid, dibenzyl ester as a colorless, somewhat viscous oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1.[OH:30][C:31]1[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:36]([C:35]1[C:31]([O:30][CH2:2][C:3]2[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]4)[S:12][C:13]=3[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=2)=[N:32][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]=1)=[O:37]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: CCOC(=O)C1CCN(c2nc(COc3ccc(CCl)cc3OC)c(C)s2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCN(c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)s2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
A mixture of ethyl 1-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate (0.40 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.18 g), anhydrous potassium carbonate (0.13 g), and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give ethyl 1-(4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate as colorless crystals (0.37 g, yield 69%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-127° C.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:3][C:2]#[CH:1])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C#CCBr
Reactant: Oc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccccc1-c1ccccc1
Temperature: 65 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
To a solution of propargyl bromide (80% solution in toluene, 500 δ 3.36 mmol) in acetone (15 ml) at 23° C. was added 2-phenyl phenol (316 mg, 1.86 mmol) and potassium carbonate (1.05 g, 7.61 mmol). After being stirred in a sealed reaction vial at 65° C. for 14 hours, the reaction was concentrated in vacuo, the residue purified by flash chromatography (ethyl acetate:hexane: 9:1) to afford compound 5 in 95% yield. 1H NMR(CDCl3) δ 2.45-2.55 (m, 1H), 4.60-4.70 (m, 2H), 6.99-7.43 (m, 9H).
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CCN(CC)CC>C(Cl)Cl>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])(=[O:4])=[O:3])[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A 100 mL round bottom flask equipped with magnetic stirring bar and N2 inlet was charged with 5.2 g benzyl 3-chlorosulfonyl-2(R)-methylpropionate in 50 mL CH2Cl2. The flask was cooled to 0° C. and charged with 3.5 g N-Boc-piperazine and 2.9 mL (1.1 eq.) NEt3. The reaction was stirred 30 minutes at 0° C., concentrated in vacuo and partitionned between ethyl acetate/water. The combined organics were washed with 5% aqueous. citric acid, saturated aqueous sodium bicarbonate, brine, and concentrated in vacuo to yield a yellow liquid. Purification via flash chromatography on silica gel (30% ethyl acetate/hexane) yielded 7.2 g (90%) product as a clear oil.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.S(Cl)(Cl)(=O)=O.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][C:2]1([C:22]2[CH:23]=[CH:24][C:19]([OH:25])=[CH:20][CH:21]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: Oc1ccccc1
Reactant: CC1Sc2ccccc2N(C)C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CN1C(=O)C(C)(c2ccc(O)cc2)Sc2ccccc21
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a stirred solution of 3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzothiazine (4.8 g) in methylene chloride (25 ml), sulfuryl chloride (3.5 g) is added under ice-cooling. The mixture is stirred for 30 minutes, and added into a solution of phenol (2.4 g) and aluminum chloride (3.3 g) in methylene chloride (20 ml) with stirring under ice-cooling. The mixture is stirred for 1 hour under ice-cooling, and washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution is dried over anhydrous sodium sulfate and concentrated in vacuo. A mixture of benzene and n-hexane (1:1) is added to the residue and the separated crystals are collected by filtration to give 6.4 g (90.2%) of the titled compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].Br[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25](=[O:26])[O:24]1>>[F:17][C@@H:16]1[C@@:11]2([C:10](=[O:21])[O:9][CH2:8][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:12]2[C@H:14]([C@@H:13]2[C:18]([O:20][C@@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:25](=[O:26])[O:24]2)=[O:19])[CH2:15]1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Product: C=CCOC(=O)N1COC(=O)[C@]12C1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O[C@H]1OC(=O)c2ccccc21
Yield: 41.2 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 640 mg) and 3-bromophthalide (456 mg) were treated in the same manner as in Example A-1 (3) to give (1S,2S,3S,5R,6S)-3′-allyl 6-(3-oxo-1,3-dihydroisobenzofuran-1-yl) 3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-3′,6-dicarboxylate (A-17-1, 380 mg) as a pale yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13]O)=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][Cl:18])=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Solvent: c1ccccc1
Product: Cc1nnn(-c2ccc(F)cc2)c1CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-fluorophenyl)-4-methyl-5-hydroxymethyl-1,2,3-triazole (871 mg; 4.20 mmol), prepared as described in example 6, and thionyl chloride (400 ml; 5.46 mmol) in benzene (14 ml) was heated under reflux for 4 hours. The reaction mixture was kept under stirring at room temperature overnight, thionyl chloride and benzene were evaporated and the resultant crude compound was collected several times with benzene. After evaporation of the solvent, the crude compound was purified by chromatography on silica gel (230-400 mesh), eluent methylene chloride:acetone=95:5, giving the title compound (m.p. 70°-71° C.).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:11]([C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
To a stirred mixture of N-acetyl-4-hydroxypiperidine (7.1 g, 0.050 mol), 4-nitrophenol (7.1 g, 0.050 mmol, (PPh3 (16.3 g, 0.062 mol), and THF (50 mL) was added a solution of diethyl azodicarboxylate (10.8 g, 0.062 mol) in THF (16 mL). The mixture was stirred at room temperature for 48 hours, and then concentrated. The crude mixture was purified by flash chromatography (1% MeOH/EtOAc) to give 4.5 g (30%) of N-acetyl-4-(4-nitrophenoxy)piperidine as a yellow oil: 1H NMR (DMSO-d6): δ8.10 (d, 2H) 7.05 (d, 2H), 4.80 (m, 1H) 3.80 (m, 1H), 3.65 (m, 1H), 3.15 (m, 1H), 3.00 (m, 1H), 2.00 (s, 3H), 1.90 (m, 2H), 1.65 (m, 1H), 1.50 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:11]([N+:15]([O-:17])=[O:16])=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(F)cc(Cl)c2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
The Method of Cheeseman, supra. was adapted. 5-Chloro-7-fluoro-1,4-dihydro-2,3-quinoxalinedione (30 mg, 0.14 mMol) was dissolved in concentrated H2SO4 (0.5 ml) at 0° C. for 30 min, and KNO3 (17 mg, 0.17 mmole, Baker) was added in one portion to this solution. The mixture was stirred at 0° C. for 3 h, then at room temperature for 30 h. It was poured into ice water (5 g) and the precipitate was collected by filtration. The precipitate was dissolved in 1N NaOH (5 mL), then was acidified to pH=2 with 4N HCl to give a cream precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h, affording the pure (by NMR) title compound 5-chloro-6-nitro-7-fluoro-1,4-dihydro-2,3-quinoxalinedione (31 mg, 85.4%), as a white amorphous solid. mp: decomposed from 280° C. IR (KBr, cm-1): 3600, 3462, 3131, 1712, 1612, 1550. NMR (1H, DMSO-d6): δ7.106 (d, J=10.2 Hz, 1H), 11.800 (s, 1H), 12.371 (s. 1H). HRMS: calcd. for C8H3N3O4ClF (M+)m/z: 258.9795, found: 258.9790.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[C:25]([C:29]3[N:30]=[N:31][N:32]([CH3:34])[N:33]=3)[CH:26]=[CH:27][CH:28]=2)OC1>>[CH3:34][N:32]1[N:31]=[N:30][C:29]([C:25]2[CH:26]=[C:27]([C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]4)[CH:28]=[CH:23][CH:24]=2)=[N:33]1
Reactant: Cn1nnc(-c2cccc(B3OCC(C)(C)CO3)c2)n1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: Cn1nnc(-c2cccc(-c3ccnc4nc(C(F)(F)F)ccc34)c2)n1
Yield: 6.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 5-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-2-methyl-2H-tetrazole (76 mg, 0.28 mmol) as described in Example 7 part g), affording 5-[3-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-trifluoromethyl[1,8]naphthyridine (5 mg, 7%). δH (360 MHz, CDCl3) 4.43 (3H, s), 7.59-7.65 (2H, m), 7.73 (1H, t, J 7.7), 7.83 (1H, d, J 8.4), 8.29 (1H, s), 8.34 (1H, d, J 7.4), 8.56 (1H, d, J 8.1), 9.30 (1H, d, J 3.9). m/z (ES+) 357 [MH]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([Cl:15])=[C:13]([Cl:16])[N:12]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([Cl:15])=[C:13]([Cl:16])[N:12]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([Br:23])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Cl)c(Cl)n2CCC(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Cl)c(Cl)n2CCC(C)C
Yield: 49.6 %

Procedure:
A suspension of 2,3-dichloro-4-hydroxy-1-(3-methyl-butyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (2.23 g, 6.46 mmol), N-bromosuccinimide (1.38 g, 7.75 mmol), and benzoyl peroxide (156 mg, 0.646 mmol) in 50 mL of benzene was heated at reflux temperature for 5 hours. The reaction mixture was washed successively with saturated sodium bicarbonate, brine, saturated ammonium chloride solution, and brine. The organic solution was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-2% ethyl acetate in hexanes to produce 1.36 g of a white solid. MS: (+) m/z 423.1 (M+1).
Reaction SMILES: [N:1]([C:4]([F:16])([F:15])[C:5]([F:14])([O:9][C:10]([F:13])([F:12])[F:11])[C:6]([O-:8])=[O:7])=[N+:2]=[N-:3].[Na+].S(OC)(O[CH3:22])(=O)=O>>[N:1]([C:4]([F:15])([F:16])[C:5]([F:14])([O:9][C:10]([F:12])([F:13])[F:11])[C:6]([O:8][CH3:22])=[O:7])=[N+:2]=[N-:3]
Reactant: COS(=O)(=O)OC
Reactant: [N-]=[N+]=NC(F)(F)C(F)(OC(F)(F)F)C(=O)[O-]
Agent: [Na+]
Product: COC(=O)C(F)(OC(F)(F)F)C(F)(F)N=[N+]=[N-]
Yield: 84 %

Procedure:
The resulting solution, which contained sodium 3-azido-2-trifluoromethoxytrifluoropropionate, was stirred with 69.3 g (0.55 mole) of dimethyl sulfate for 3 hr. until an initial exothermic reaction subsided. Volatiles were removed at 50° (2 mm, 2.6×10-1 kPa), and the resulting crude ester was fractionated to yield 111.8 g (84%) of methyl 3-azido-2-trifluoromethoxytrifluoropropionate, bp 38°-41° (24 mm, 2.1 kPa). IR (CCl4): 3010, 2960, and 2850 (sat'd CH); 2150 (N3), 1780 (C=O), and 1100-1250 cm-1 (C--F). NMR (CCl4): 1H 3.89 ppm (s, OCH3); 19F -56.0 (d, JFF 8.6 Hz, 3F, OCF3) and -131.6 ppm (q of t, JFF 8.6, 5 Hz, 1F, CF) with an AB for CF2N3 at -8333 and -8521 Hz (d, JFF 5.0 Hz, 1F) and -8548 and -8763 Hz (d, JFF 5.6 Hz, 1F).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:28][CH3:29])=[C:16]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:15]([O:28][CH3:29])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1N1CCCC1=O
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1N1CCCC1=O
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (8.5 mg, 0.043 mmol), 1-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]pyrrolidin-2-one (11 mg, 0.039 mmol), and N,N-diisopropylethylamine (0.014 mL, 0.078 mmol) in isopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C19H22ClN6O2 (M+H)+: m/z=401.1. found: 401.1.