Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl.[C:3]([NH2:10])(=[NH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>CC(C)=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:9][C:3](=[NH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCCC(=N)NC(=O)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 3.2 g. sodium in 200 ml. dry acetone, 21. g. hexanamidine hydrochloride, and 21.4 g. 4-chlorophenyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from acetone 13.9 g. of the hydrochloride of 1-(4-chlorophenyl)-3-(hexanimidoyl)urea; m.p. 175°-179°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][O:9][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)cc1COC1CCCCO1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of 25 parts of 5-chloro-2-nitrobenzenemethanol, 13.3 parts of 3,4-dihydro-2H-pyran, 0.28 parts of dichloromethane and 300 parts of 4-methylbenzenesulfonic acid was stirred and for 2 hours at reflux temperature. After cooling, there was added Na2CO3 and the whole was stirred for 10 min. The reaction mixture was filtered and the filtrate was evaporated. The residue was co-evaporated with methylbenzene and was further purified by column chromatography (silica gel; CHCl3). The eluent of the desired fraction was evaporated and the residue was co-evaporated with methylbenzene, yielding 36 parts (99.6%) of 2-[(5-chloro-2-nitrophenyl)methoxy]-tetrahydro-2H-pyran (interm. 54).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOCCOC1.Cl[CH:22](Cl)[C:23]([OH:25])=[O:24].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([C:35]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[OH:36])[CH:29]=1>O1CCOCC1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH:22]([C:23]([OH:25])=[O:24])[O:36][C:35]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:30]=2[CH:29]=1
Reactant: Oc1ccc(Cl)cc1C(O)(C1CCCCC1)C1CCCCC1
Reactant: O=C(O)C(Cl)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a suspension of 1.6 g of NaH (60% dispersion in mineral oil) and 131 mg of 18-crown-6 ether in 60 ml of anhydrous dioxane, a solution of 16.4 ml of a solution of dichloroacetic acid (1 M) in anhydrous dioxane was slowly added at room temperature. The reaction mixture was heated to 60° C. and a solution of 3.2 g of 4-Chloro-2-(dicyclohexyl-hydroxy-methyl)-phenol in 42 ml anhydrous dioxane was added and stirred at 90° C. for 6 h. After cooling to 0° C., the reaction mixture was quenched with 8 ml of isopropanol and poured on ice. The aqueous phase was extracted with ether, then acidified with HCl (2 M, to pH 1), and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was recrystallized from n-heptane to yield a bright yellow product. Yield: 2.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].[CH3:23][O:24][C:25]1[N:30]=[C:29](S(C)(=O)=O)[N:28]=[C:27]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:26]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][C:29]1[N:28]=[C:27]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:26]=[C:25]([O:24][CH3:23])[N:30]=1
Reactant: COC(=O)COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OC)nc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a mixture of 400 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, 359 mg of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylsulfonylpyrimidine and 3 ml of N,N-dimethylformamide, 196 mg of potassium carbonate was added, and the mixture was stirred for 1 hour at 80° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 620 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-4-(methoxycarbonyl)methoxypyrimidine [present compound 1-45].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>N1C=CC=CC=1>[CH:18]1([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCCCC4)nc23)CC1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A solution of 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 1.0 mL pyridine was heated to 50° C. To this solution were then added 0.0064 mL (0.048 mMol) cyclohexanecarbonyl chloride and the reaction mixture stirred for 1 hour. The reaction mixture is concentrated under reduced pressure and a solution of the residue in methanol passed over a VARIAN BOND ELUT SCX™ (Varian, Harbor City, Calif., U.S.A.) ion exchange column which had been preactivated with 10% acetic acid in methanol. The column was washed thoroughly with methanol and then the desired product eluted with 2M ammonia in methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.013 gm (87.2%) of the title compound.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[CH3:7][C:2]1([CH2:5][OH:6])[NH:1][C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:4][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: CC(N)(CO)CO
Solvent: Cc1ccccc1
Product: CC1(CO)COC2(CCCCC2)N1

Procedure:
The procedure of Example 1 was employed utilizing 2-amino-2-methyl-1,3-propanediol (42.05 grams; 0.4 mole) and cyclohexanone (39.26 grams; 0.4 mole) in 250 mls of toluene. After removing the toluene, the residue was distilled to obtain 37.7 grams (50.8% of theoretical; b.p. 120° C. at 2.0 mm.) of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:13]([N:15]1[CH2:19][CH:18]=[CH:17][C@H:16]1[C:20](=O)[NH2:21])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:13]([N:15]1[CH2:19][CH:18]=[CH:17][C@H:16]1[C:20]#[N:21])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CC=C[C@H]1C(N)=O)C(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CC=C[C@H]1C#N)C(C)(C)C
Temperature: 0 °C
Yield: 84.3 %

Procedure:
(175 mg, 0.54 mmol) of (2) was dissolved in 4 ml of pyridine and the mixture was cooled to 0° C. Phosphorus oxychloride (0.2 ml, 2.15 mmol) was added dropwise and after 10 minutes of stirring the reaction mixture was poured into 20 ml of ice water and the organic material was extracted into 5×10 ml of ethyl acetate. The combined organic extract was washed with 2×20 ml of water, 1×20 ml of brine and dried over magnesium sulphate. The solvent was evaporated to afford 140 mg of (S,S) [1-(2-Cyano-2,5-dihydro-pyrrole-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester (3). Oil, 85% yield. 1H-NMR (CDCl3, 200 MHz) δ: 1.05 (s, 9H); 1.42 (s, 9H); 4.22 (d, 1H); 4.39-4.53 (m, 1H); 4.65-4.77 (m, 1H); 5.30 (d, 1H); 5.41-5.48 (m, 1H); 5.83-5.90 (m, 1H); 6.09-6.15 (m, 1H).
Reaction SMILES: Cl.[CH2:2]1[O:13][C:12]2[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][C:4]=2[O:3]1.[Cl:14][CH2:15][C:16](Cl)=[O:17]>ClCCCl>[O:13]1[C:12]2[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH:9][C:16](=[O:17])[CH2:15][Cl:14])=[CH:5][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: NCCc1ccc2c(c1)OCO2
Agent: Cl
Solvent: ClCCCl
Product: O=C(CCl)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.5 %

Procedure:
3,4-Methylenedioxyphenethylamine hydrochloride (101 mg, 0.5 mmol) was dissolved in DCE (2 mL) and TEA (70 μL). Next, chloroacetyl chloride (48 μL, 0.6 mmol) was added and the reaction was allowed to stir at room temperature for 16 hours. After this time, the solution was concentrated down under N2. The residue was redissolved in DCM, washed with sat. NaHCO3 (aq) and dried over Na2SO4. The crude residue was purified by Prep-LCMS to afford 32 mg (27%) of N-(2-benzo[1,3]dioxol-5-yl-ethyl)-2-chloro-acetamide. 1H-NMR (400 MHz, CDCl3) δ 6.75-6.62 (m, 3H), 5.92 (s, 2H), 4.01 (s, 2H), 3.52-3.47 (m, 2H), 2.79-2.72 (t, 2H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[F:16][C:17]([O:22][CH2:23][CH:24]1[O:26][CH2:25]1)([F:21])[CH:18]([F:20])[F:19]>>[F:16][C:17]([F:21])([O:22][CH2:23][CH:24]([OH:26])[CH2:25][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=1)[CH:18]([F:19])[F:20]
Reactant: FC(F)C(F)(F)OCC1CO1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)CC(C)(C)c1ccc(OCC(O)COC(F)(F)C(F)F)cc1
Temperature: 100 °C
Yield: 107.8 %

Procedure:
A 250 mL 2-neck flask was charged with 20.6 g (0.10 mol) of 4-tert-octylphenol obtained from Aldrich Chemical Co., a catalytic amount of dry, ground potassium carbonate obtained from EM Science, Inc. (1.38 g, 0.010 mol), a stir bar, and 95% ethanol (75 mL) under argon. The side arm was then stoppered with a rubber septum, and a condenser with an argon inlet was attached to the center neck. The system was evacuated and backflushed with argon three times. Stirring was commenced to dissolve the phenol, then glycidyl 1,1,2,2-tetrafluoroethyl ether (27.0 mL, 19.15 g, 0.11 mol) obtained from Aldrich Chemical Co., was added through the septum in two portions using a 20 mL glass syringe. The reaction was monitored by thin layer chromatography (TLC) while it refluxed for 24 hours in an oil bath at 100° C. The mixture was then allowed to cool and the ethanol removed by rotary evaporation. The product was obtained by dissolving the reaction mixture in 100 mL hexanes and extracting with 1×50 mL 5% NaOH in 15:85 v/v water/methanol followed by 2×50 mL deionized water washes. The methanol-water layers were back-extracted with 50 mL hexanes. After drying over anhydrous MgSO4, the combined hexanes were evaporated off to give 41.0 g (108% yield) of a pale yellow oil. The product was purified by fractional distillation under vacuum with 31.96 g (84%) of spectroscopically pure product being collected at 145-153° C. (0.2 mm Hg). The structure and purity of the compound were corroborated by proton (1H) and carbon-13 NMR spectrometry.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH3:13].C1C=C(O[C:22](OC2N=CC=CC=2)=[S:23])N=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[N:1]([C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH3:13])=[C:22]=[S:23]
Reactant: Cc1cc(N)c(C)c2c(C)ccnc12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1cc(N=C=S)c(C)c2c(C)ccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-amino-4,5,8-trimethylquinoline (0.37 g), di-2-pyridyl thionocarbonate (0.494 g) (DPT) (Aldrich), dimethylaminopyridine (0.052 g) and methylene chloride (4 mL) is stirred at room temperature for 2 hours. An additional 100 mg of DPT is added, and stirring is continued for one hour. Another 100 mg portion of DPT is added, and the reaction is stirred at room temperature for one more hour. The mixture is concentrated by evaporation and purified by chromatography through a short column consisting of layers of sand/flash silica gel/sand, using 20% ethyl acetate in hexane as the eluting solvent, providing 6-isothiocyanato-4,5,8-trimethylquinoline.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]=[O:7])=[C:8]([CH3:10])[CH:9]=1)[CH3:18]
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C)c(C=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-hydroxy-2,6-dimethyl-benzaldehyde (87 mg), ethyl chloroacetate (85 mg) and Cs2CO3 (375 mg) in acetone (4 mL) was stirred at room temperature for 16 h. The mixture was concentrated, diluted with water, and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give (4-formyl-3,5-dimethyl-phenoxy)-acetic acid ethyl ester: MS (m/z) 237 (M+1); 1H NMR (CDCl3, 400 MHz) δ 10.48 (s, 1H), 6.59 (s, 2H), 4.66 (s, 2H), 4.29 (q, 2H), 2.60 (s, 6H), 3.29 (t, 3H).
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@H:32]1[CH2:34][O:33]1.C(O)C>C(Cl)Cl>[OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:34][C@@H:32]([OH:33])[C:23]2[CH:24]=[CH:25][C:26]3[C:27](=[O:31])[O:28][CH2:29][C:30]=3[C:22]=2[CH3:21])[CH2:6][CH2:5]1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Solvent: ClCCl
Product: Cc1c([C@H](O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a 20 mL microwave tube charged with 5-[(1R)-1-hydroxy-2-piperazin-1-ylethyl]-4-methyl-2-benzofuran-1(3H)-one (166 mg, 0.600 mmol) and a stir bar was added 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (171 mg, 0.900 mmol) and ethanol (10 mL). The mixture was heated in a microwave apparatus to 150° C. for 90 minutes. After the reaction cooled down, DCM (5 mL) was added to the tube. The mixture was allowed to sit at RT overnight. A lot of solids precipitated during that time; these were collected by filtration. Chiral HPLC analysis showed the material was over 95% ee pure 5-((1R)-1-hydroxy-2-{4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one. 1H-NMR (500 MHz, DMSO-d6) δ ppm 7.74 (s, 4H), 5.43 (m, 4H), 6.60-5.80 (broad, 2H), 5.33 (s, 2H), 3.40 (broad, 8H), 3.09 (broad, 4H), 2.32 (s, 6H); LCMS M+1 (calc. 467, found 467).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([CH3:13])[N:7]=[CH:6][N:5]=1>CC(O)=O>[Br:1][CH2:13][C:8]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:4]([Cl:3])[N:5]=[CH:6][N:7]=1
Reactant: CCCc1c(C)ncnc1Cl
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCc1c(Cl)ncnc1CBr
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Br2 (0.153 ml, 3 mmol) is added dropwise to a solution of 4-chloro-6-methyl-5-propyl-pyrimidine (3 mmol) heated at 85° C. in HOAc (10 ml). After the addition, the mixture is stirred at 85° C. for 1 hour. The solvent is removed in vacuo and the residue dissolved in EtOAc (15 ml), washed with Na2S2O3 solution (sat. 5 ml), followed by NaHCO3 (10 ml), and brine (10 ml). The organic phase is dried (Na2SO4) and evaporated. The resulting yellow oil is purified by flash column chromatography, which provides the title compound.
Reaction SMILES: C([O-])(=O)C.[C:5]([NH:8][CH:9]1[CH2:14][CH2:13][NH2+:12][CH2:11][CH2:10]1)(=[O:7])[CH3:6].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>CN(C=O)C>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:5](=[O:7])[CH3:6])[CH2:10][CH2:11]1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(=O)NC1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 5 %

Procedure:
To a flask was added 4-acetylamino-piperidinium acetate (as prepared in the previous step) (800 mg, 4.00 mmol), DMF (40 mL), 2-fluoro-1-nitrobenzene (422 μL, 4.00 mmol), triethylamine (836 μL, 6.00 mmol) and the mixture stirred at RT for 17 h. The solvents were removed in vacuo and the residue was purified by silica gel preparative TLC eluting with dichloromethane/hexane/acetonitrile (47.5/47.5/5 v:v:v) yielded 55 mg (5%) of the title compound as a crystalline orange solid. 1H-NMR (400 MHz, CDCl3): δ 8.18 (m, 1H), 8.09 (br d, 1H, J=7.2 Hz), 7.45 (m, 1H), 6.88 (m, 1H), 6.67 (m, 1H), 4.38 (m, 1H), 3.86-3.74 (m, 1H), 3.32 (m, 1H), 3.07 (m, 1H), 2.14 (s, 3H), 1.67-1.52 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>CO.[Pd]>[C:12]1([C@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][CH2:20]2)[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Palladium (10 wt. %) on carbon (50 g) and triethylamine (90 mL, 0.65 mol) were added sequentially, each in one portion, to a stirred solution of 4-(4-chlorophenyl)cyclohexanecarboxylic acid (150 g, 0.63 mol) in MeOH (1.5 L). The reaction mixture was stirred under a hydrogen atmosphere for 4 h at 50° C. at a pressure of 5 bar then cooled, filtered and then concentrated in vacuo to give the title compound (160 g, 83%) as a solid, which was contaminated with triethylamine hydrochloride (0.65 mol) and used with no further purification; 1H NMR δ 1.23 (9H, t), 1.44-1.53 (4H, m), 1.8-1.9 (2H, m), 1.96-2:05 (2H, m), 2.22-2.32 (1H, m), 2.45-2.58 (1H, m), 3.05 (6H, q), 7.1-7.35 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N+:6]([O-:29])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ncc(Cl)cc32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2cc(Cl)c[n+]3[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of 6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine (8.5 g, 27.7 mmol) in CH2Cl2 (150 mL) in an ice bath was added m-chloroperbenzoic acid (85%, 8.4 g, 41.6 mmol). The mixture was stirred at RT for two h. The reaction mixture was quenched by saturated sodium thiosulphate solution. The organic layer was washed with saturated NaHCO3 solution and water, dried (Na2SO4) filtered, and concentrated under reduced pressure to afford 8.75 g (90%) of 6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-4-oxide as a yellow solid. MS (ESI): m/z=323.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:33][S:34][C:35]1[O:36][C:37]2[CH:43]=[C:42]([CH:44]=O)[CH:41]=[CH:40][C:38]=2[N:39]=1>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:44][C:42]2[CH:41]=[CH:40][C:38]3[N:39]=[C:35]([S:34][CH3:33])[O:36][C:37]=3[CH:43]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CSc1nc2ccc(C=O)cc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccc(CNc3ccc(Br)cc3[N+](=O)[O-])cc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 4-bromo-2-nitroaniline (400 mg, 1.84 mmol) and TFA (1.89 mL) in DCM (8 mL) at −5° C. was added NaBH(OAc)3 (1.17 g, 5.52 mmol). Then to the mixture at 0° C. was added a solution of 2-(methylthio)benzo[d]oxazole-6-carbaldehyde (391 mg, 2.03 mmol) in DCM (7 mL), and the mixture was stirred at 0° C. for 2 h. The mixture was diluted with DCM and washed with H2O, aq NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20:1 to 10:1 petroleum ether/ethyl acetate to give 4-bromo-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline as a yellow solid (704 mg, 97.4%). 1H NMR (300 MHz, DMSO-d6) δ 8.80 (t, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 7.50-7.60 (m, 2H), 7.35 (d, J=8.4 Hz, 1H), 6.90 (d, J=9.3 Hz, 1H), 4.72 (d, J=6.6 Hz, 1H), 2.73 (s, 3H). LCMS (ESI) m/z 394 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:5]=34)[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OC[C@@H]4C)C[C@H]1NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of (3S)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (0.5 g), anhydrous dimethyl sulfoxide (10 ml) and cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.54 g) was stirred for 2 hours at 90°-100° C. and then concentrated. The resulting residue was dissolved in chloroform and the solution was washed with 10% aqueous citric acid solution further washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The resulting precipitate was triturated in methanol and collected by filtration to give the title compound (0.67 g) as yellowish powder, mp 206°-207° C.