Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1>CC#N>[Br:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:2][CH3:1])=[CH:6][CH:5]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: CN
Solvent: CC#N
Product: CNCc1ccc(Br)nc1

Procedure:
To a mixture of 12.3 g of 40% aqueous methylamine solution and 40 ml of CH3CN was added 8.0 g of crude (6-bromo-3-pyridyl)methyl bromide with stirring. The mixture was further stirred at room temperature for 30 minutes. The reaction mixture thus obtained was concentrated and the residue was diluted with toluene and subjected to azeotropic distillation to remove the water. Then, the soluble fraction was extracted with Et2O. The Et2O layer was dried over MgSO4 and concentrated to recover 4.4 g of the title compound as a yellow oil.
Reaction SMILES: [OH:1]O.[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[N:9][CH:10]=1)[CH3:4].O>CC(O)=O>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[N+:9]([O-:1])[CH:10]=1)[CH3:4]
Reactant: OO
Reactant: CCc1ccc(NC(=O)C(C)(C)C)nc1
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(NC(=O)C(C)(C)C)[n+]([O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
H2O2 (30%, 34 mL, 0.33 mol) was added to a solution of N-(5-ethylpyridin-2-yl)pivalamide (22 g, 0.11 mol) in HOAc (200 mL). The mixture was stirred overnight at 80° C. The reaction mixture was poured into water and was extracted with EtOAc. The organics were washed with sat. Na2SO3 and NaHCO3 before being dried over MgSO4. The solvent was evaporated in vacuo to afford 5-ethyl-2-pivalamidopyridine 1-oxide (16 g, 67%), which was used for the next step without further purification.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC[N:11]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C.C1COCC1>CN(C)C1C=CN=CC=1.O>[C:5]([O:4][CH2:1][CH2:2][N:11]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])(=[O:7])[CH3:6]
Reactant: COC(=O)CCN(CCO)CCC(=O)OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCN(CCOC(C)=O)CCC(=O)OC
Reaction time: 5 h
Yield: 89.8 %

Procedure:
At 20 to 30° C., 2.56 g of acetic anhydride was added to a mixture of 5.00 g of N-(2-hydroxyethyl)bis[2-(methoxycarbonyl)ethyl]amine, 2.97 g of triethylamine, 50 mg of 4-dimethylaminopyridine and 25 g of THF. The resulting mixture was stirred for 5 hours. Water was added to terminate the reaction. The reaction mixture was then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by distillation under reduced pressure, whereby 5.30 g of N-(2-acetoxyethyl)bis[2-(methoxycarbonyl)ethyl]amine was obtained (boiling point: 120° C./15 Pa, yield: 92%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]([OH:31])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([OH:29])([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)[C:18]([F:21])([F:20])[F:19]>>[Cl:9][C:10]1[CH:11]=[C:12]([O:31][CH2:2][C:3]2[CH:7]=[C:6]([CH3:8])[O:5][N:4]=2)[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)([OH:29])[C:18]([F:19])([F:21])[F:20]
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: Cc1cc(CCl)no1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCc3cc(C)on3)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 3-chloromethyl-5-methylisoxazole and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=442.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=O)([O-:3])=[O:2].O=P(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][C:35]=1[C:42]([F:45])([F:44])[F:43]>ClCCCl>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:7]2[C:6]3[C:11](=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:10]=[CH:9][N:8]=2)=[CH:36][C:35]=1[C:42]([F:43])([F:44])[F:45]
Reactant: NCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c(=O)[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of methyl 6-nitro-4-oxo-3,4-dihydroquinazoline-8-carboxylate (250 mg, 1.0 mmol) in 5 mL of anhydrous DCE, POCl3 (110 μL, 1.2 mmol, 1.2 equiv.) was added followed by DIPEA (870 μL, 5.0 mmol, 5.0 equiv.). The resulting mixture was stirred at 90° C. for 1 h. After cooling down to rt, 4-chloro-3-(trifluoromethyl)benzylamine (230 mg, 1.1 mmol, 1.1 equiv.) was added. The reaction mixture was stirred at 80° C. for 3 h. After work-up, the crude was purified by flash chromatography to yield the title compound in 46% yield. 1HNMR (in DMSO): 3.91 (s, 3H), 4.88 (d, J=5.9 Hz, 2H), 7.65-7.71 (m, 2H), 7.91 (s, 1H), 8.64 (s 1H), 8.68 (d, J=2.2 Hz, 1H), 9.49 (d, J=2.4 Hz, 1H), 9.70 (t, J=5.7 Hz, 1H). Mass: M+H+: 441.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Cl)[N:11]=[C:10]([NH:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Cl)[N:9]=1)=[O:6].CN(C=O)C.CC(C)([O-])C.[K+]>C(Cl)Cl>[N:7]1([C:8]2[N:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[N:11]=[C:10]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:27])[N:9]=2)[CH2:2][CH2:3][CH2:4][C:5]1=[O:6]
Reactant: O=C(CCCCl)Nc1nc(NC(=O)CCCCl)nc(NC(=O)CCCCl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCN1c1nc(N2CCCC2=O)nc(N2CCCC2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
440 mg of N,N',N"-tris(4-chlorobutyryl)melamine was placed in a flask equipped with a magnetic stirring bar, a reflux condenser, an argon inlet and a rubber septum. To the flask was added 6 ml DMF followed by 450 mg potassium tert-butoxide, while stirring the reaction mixture at room temperature for about 30 minutes. It was then diluted with CH2Cl2 and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was then purified by column chromatography (silica gel) to give 180 mg of pure 2,4,6-tris(pyrrolidin-2-on-1-yl)-1,3,5-triazine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([N:15](CC)CC)C.[CH3:20][O:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[O:24][CH2:25][CH2:26]N>C1C=CC=CC=1>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([NH2:15])[N:3]=[C:2]2[CH2:26][CH2:25][O:24][C:23]1[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=1[O:21][CH3:20]
Reactant: COc1ccccc1OCCN
Reactant: CCN(CC)CC
Reactant: Cc1ccc2ncnc(Cl)c2c1
Solvent: c1ccccc1
Product: COc1ccccc1OCCc1nc(N)nc2ccc(C)cc12
Reaction time: 5 h
Yield: 29.1 %

Procedure:
To a solution of 1.8 g (0.01 mol) of 4-chloro-6-methylquinazoline in 50 ml of benzene were added 1.0 g (0.01 mol) of triethylamine and 1.7 g (0.01 mol) of 2-(0-methoxyphenoxy)ethylamine, and the mixture was heated, with stirring, at 60°~70° C. for 5 hours. After completion of the reaction, the benzene was evaporated under reduced pressure and the residue was dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure to leave crystals, which were recrystallized from ethanol, giving 0.9 g of 6-methyl-4-[2-(2-methoxyphenoxy)ethyl]-aminoquinazoline in the form of colorless plates.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([OH:16])(=[O:15])[C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9]>>[N+:1]([C:14]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[C:5]([OH:16])=[O:15])([O-:4])=[O:2]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: O=[N+]([O-])O
Product: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reaction time: 3 h

Procedure:
100 parts by weight and 150 parts by weight 99% by weight concentrated nitric acid are each added to a reaction vessel and brought to a temperature of 70° C. To each solution is added 10 parts by weight phthalic acid. Nitration is allowed to continue at 70° C. for three hours and produces yields of greater than 90% of theoretical yield consisting essentially of a mixture of 3- and 4- nitrophthalic acid. Table 1 shows the make-up of the reaction product mix in mole percent. The mole ratio of 4- to 3- nitrophthalic acid formed was approximately 1.1:1.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.O=[C:12]([CH2:20][CH3:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].OS(O)(=O)=O.[C:27]([O-])(O)=O.[Na+]>CC(O)C>[F:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]([CH2:13][CH2:14][C:15]([O:17][CH:18]([CH3:27])[CH3:19])=[O:16])=[C:20]2[CH3:21]
Reactant: NNc1ccc(F)cc1
Reactant: O=C([O-])O
Reactant: CCOC(=O)CCC(=O)CC
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(CCC(=O)OC(C)C)[nH]c2ccc(F)cc12

Procedure:
A mixture of 1-(4-fluorophenyl)hydrazine hydrochloride (1.03 g), ethyl 4-oxo-hexanoate (1.0 g), 2-propanol (25 ml) and H2SO4 is refluxed under nitrogen for 9 hours. After cooling the mixture is poured into a aqueous solution of NaHCO3, extracted with AcOEt and evaporated to dryness to yield 1.45 g of isopropyl 5-fluoro-3-methyl-1H-indole-2-propanoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:5])[CH3:2].[H-].[Na+].IC.[CH2:28](OCC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[N:8]([CH3:28])[C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOCC
Reactant: CCOC(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1N(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethoxycarbonyl-N-(4-nitrobenzoyl)aniline (3.15 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in oil, 442 mg) and the solution was stirred at ambient temperature for 30 minutes. Iodomethane (1.56 g) was added to the solution and the mixture was stirred at ambient temperature for 4 hours. The solution was diluted with ethyl acetate and the solution was washed with successively with 1N hydrochloric acid, water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The oil was solidified with diethyl ether to give 2-ethoxycarbonyl-N-methyl-N-(4-nitrobenzoyl)aniline (3.28 g) as a pale yellow powder.
Reaction SMILES: [C:1](=[S:12])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)SC.[CH3:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16].[NH2-].[Na+].Cl>C1(C)C=CC=CC=1.O>[CH3:13][CH:14]([CH3:18])[C:15](=[O:17])[CH2:16][C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[S:12]
Reactant: CSC(=S)OCc1ccccc1
Reactant: CC(=O)C(C)C
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C(=O)CC(=S)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
A solution of S-methyl O-benzyl dithiocarbonate (6.90 g) and 3-methylbutan-2-one (3.00 g) in toluene (20 mL) was added dropwise to a suspension of sodium amide (2.71 g) in toluene (60 mL) at 0° C. over a 5-minute period. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the mixture was acidified by addition of 1 mol/L hydrochloric acid. The resulting mixture was extracted with diethyl ether, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) to give the title compound (5.90 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH-].[K+].[F:13][C:14]([F:19])([F:18])[CH:15]([OH:17])[CH3:16].Cl>CS(C)=O>[F:13][C:14]([F:19])([F:18])[CH:15]([O:17][C:2]1[N:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=1)[CH3:16]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(O)C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(Oc1ccc(C(=O)O)cn1)C(F)(F)F
Reaction time: 8 h
Yield: 70.7 %

Procedure:
6-Chloronicotinic acid (0.500 g, 3.17 mmol), powdered potassium hydroxide (0.712 g, 12.69 mmol) and 1,1,1-trifluoropropan-2-ol (0.724 g, 6.35 mmol) were combined in DMSO (12 mL) and heated in a sealed tube to 100 C for 18 h. The mixture was acidified to pH 1 by adding 2M hydrochloric acid. The mixture was then left to stand at room temperature overnight and the resultant precipitate filtered off, washed with water and dried under vacuum to afford the title compound as a cream solid (0.527 g, 71%). 1H NMR (500 MHZ, MeOH-d4) δ ppm 8.82 (1H, d), 8.29 (1H, dd), 6.94 (1H, d), 5.96 (1H, m) and 1.52 (3H, d).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C.O>CN(C=O)C>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[N:7]3[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(S)cc1
Reactant: Cc1cn2c(Cl)cccc2n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn2c(Sc3ccc(N)cc3)cccc2n1
Yield: 67.9 %

Procedure:
A solution of 5-chloro-2-methylimidazo[1,2-a]pyridine (1.0 g) and 4-aminothiophenol (3.25 g) and triethylamine (1.7 ml) in DMF (10 ml) was stirred for 3 days at 90° C. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 2:1→ethyl acetate→ethanol:ethyl acetate 1:9), to give 5-(4-aminophenylthio)-2-methylimidazo[1,2-a]pyridine (1.04 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[OH:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN([CH:25]=[O:26])C>C1COCC1.CCOC(C)=O.CCCCCC>[CH2:14]([O:13][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[Br:3])[C:8]([O:26][CH2:25][C:4]1[CH:12]=[CH:11][CH:7]=[CH:6][CH:5]=1)=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(Br)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(Br)c(OCc2ccccc2)c1
Temperature: 9.5 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a stirred suspension of NaH (10.47 g, 60% by wt, 0.2616 mol) in THF (1.40 L), at 13.1° C. under argon, was added a solution of 4-bromo-3-hydroxybenzoic acid (28.11 g, 0.130 mol) in THF (400 ml) over 1.25 h maintaining the internal temperature in the range 4-15° C. After 1.5 h a solution of benzyl bromide (44.3 g, 0.2591 mol) in THF (70 ml) was added over 0.5 h. To the resulting suspension was added DMF (500 ml) and the mixture allowed to warm to room temperature. After a further 15 h extra DMF was added (1.5 L) to the suspension. After approximately 30 minutes the reaction mixture was essentially clear and TLC analysis (25% EtOAc/hexane) indicated that effectively all of the starting material had been consumed. The reaction mixture was quenched with dilute ammonium chloride (100 ml) and concentrated in vacuo. To the concentrate was added ethyl acetate (1.0 L) and dilute ammonium chloride (1.0 L) and the fractions separated. The aqueous fraction was back extracted with ethyl acetate (1×450 ml and 1×300 ml). The total organic fraction was dried over sodium sulphate, filtered and concentrated in vacuo. The resulting solid was crystallised from ethanol:water (9:1; vol:vol, 200 ml), heated at reflux, to which was added ethanol (65 ml) until all the material had dissolved. Water was then added dropwise (17 ml), followed by extra ethanol (8.0 ml). The resulting solution was allowed to slowly cool to ambient temperature. The resulting solid was filtered off and dried (44.54 g). This solid was then dissolved in hot ethanol (227 ml) and water (5.0 ml) added and then allowed to slowly cool to ambient temperature. The resulting crystals were filtered off, washed with cold ethanol (25 ml) and dried in a vacuum oven at 50° C. to give the title compound (36.79 g, yield 71.5%). mp=80.5-81.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[S:42]([Cl:45])(=[O:44])=[O:43])[CH:35]=[CH:34][CH:33]=1>>[ClH:45].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:42]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:41]=3[N:32]=[CH:33][CH:34]=[CH:35]4)(=[O:44])=[O:43])=[C:3]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: Cl
Product: O=S(=O)(Nc1cc(N2CCCNCC2)ccc1NS(=O)(=O)c1cccc2cccnc12)c1ccccc1

Procedure:
The compound was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)- phenyl}benzenesulfonamide and 8-quinolinesulfonylchloride (61 mg, 0.27 mmol) to give 34 mg of a purple solid. M+1 538.2 Calcd 538.15.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[N:10]([CH2:21][C:22]([CH3:24])=[CH2:23])[C:9]1=[O:25])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:11]([CH3:20])[N:10]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:9]1=[O:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@@H](c2ccccc2)[C@H]1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@@H](c2ccccc2)[C@H]1C

Procedure:
To a solution of tert-butyl[(3S,5S,6R)-6-methyl-1-(2-methylprop-2-en-1-yl)-2-oxo-5-phenylpiperidin-3-yl]carbamate (0.129 g, 0.364 mmol) in ethanol (15 mL) was added 10 wt. % palladium on carbon (39 mg, 0.036 mmol) and the mixture was stirred under a balloon of hydrogen at 23° C. for 1 h. The catalyst was removed by filtration through Celite® and washed thoroughly with ethanol and ethyl acetate. Concentration of the organics afforded the title compound which was used as is. MS: m/z=361.2 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:22])[C:20]=1F)[C:15]([OH:17])=[O:16].Cl>CN(C=O)C>[CH2:1]([O:8][C:20]1[C:19]([F:22])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzyl alcohol (22.0 mL) in DMF (100 mL) was added sodium hydride (60% oil, 8.52 g), and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added 3,4,5-trifluorobenzoic acid (15.0 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in DMF (100 mL) were added potassium carbonate (11.8 g) and methyl iodide (5.30 mL), and the mixture was stirred with heating at 60° C. for 15 min. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). To a solution of the obtained oil in a mixed solvent of THF (100 mL) and methanol (50 mL) was added 2 M aqueous sodium hydroxide solution (85 mL), and the mixture was stirred with heating at 60° C. for 40 min. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with diethyl ether/hexane to give the title compound (18.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:14][F:15])([CH2:12][F:13])[CH2:6][C@@H:5]2O.N12CCCN=C1CCCCC2.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CC(OC)(C)C>[N:42]([C@H:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[O:8][C:7]([CH2:14][F:15])([CH2:12][F:13])[CH2:6]1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@H]1CC(CF)(CF)Oc2ccc(F)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1CC(CF)(CF)Oc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
A solution of Example 65B (54.1 mmol) in THF (190 mL) was cooled to <5° C. To this solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (12.1 mL, 81.0 mmol) followed by diphenylphosphoryl azide (15.2 mL, 70.3 mmol), keeping the temperature ≦5° C. (no exotherm). After stirring for 2 hours at ≦5° C., the reaction mixture was warmed to ambient temperature and stirred for 14 hours. The reaction mixture was diluted with MTBE (250 mL), washed with 2N NaOH (2×125 mL), brine (50 mL), 2N HCl (2×125 mL), and brine (50 mL). The organic portion was dried (Na2SO4), filtered, and concentrated, giving (R)-4-azido-6-fluoro-2,2-bis(fluoromethyl)chroman (14.6 g, >100%) as a dark oil. The crude (R)-4-azido-6-fluoro-2,2-bis(fluoromethyl)chroman in MeOH (300 mL) was added to 5% Pd—C (4.38 g) in a 500 mL stainless steel pressure bottle. The mixture was stirred for 3 hours at 50° C. and 30 psi H2. Upon cooling, the reaction mixture was filtered through a nylon membrane and concentrated. The resulting residue was used without further purification. MS (DCI) m/z 232 (M+H)+.