Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]#[N:12].Cl.Cl[CH2:23][CH2:24][N:25]([CH:33]([CH3:35])[CH3:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O.CCCCCCC.O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH2:23][CH2:24][N:25]([CH:33]([CH3:34])[CH3:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]#[N:12]
Reactant: N#CC(CCN1CCCCC1)c1ccccc1Cl
Reactant: CC(C)N(CCCl)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCCCCCC
Product: CC(C)N(CCC(C#N)(CCN1CCCCC1)c1ccccc1Cl)Cc1ccccc1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
To a reaction vessel under a nitrogen atmosphere was charged 35.0 kg of pulverized potassium hydroxide (90%) and 34.0 L of dimethyl sulfoxide. A solution of 29.5 kg of α-(2-chlorophenyl)-1-piperidinebutanenitrile (product of Example 3) in 23 L of dimethyl sulfoxide was added while maintaining the temperature below 25° C. A solution of 30.7 kg of N-(2-chloroethyl)-N-(1-methylethyl)benzenemethanamine, monohydrochloride in 112 L of dimethyl sulfoxide was added while maintaining the temperature below 20° C. The mixture was stirred at 25° C. until the reaction was complete as indicated by gas chromatographic analysis (GC Method C). The mixture was cooled and diluted with 122 L of heptane and 200 L of water. The layers were separated, and the organic phase was filtered through a layer of diatomaceous earth. The filter cake was washed with 40 L of heptane. The combined organic phase was washed twice with 70 L of water and dried by azeotropic distillation. The solvent was removed by distillation under reduced pressure to give 49.4 kg (100.0%) of the title product α-(2-chlorophenyl)-α-[2-[(1-methylethyl)(phenylmethyl)amino]ethyl]-1-piperidinebutanenitrile as an oil. Analysis calcd for C27H36ClN3 : C,74.03; H,8.28; Cl,8.09; N,9.59. Found: C,73.35; H,8.36; Cl,7.27; N,9.15. The crude product (oil) was carried forward to the next step without purification. The purity of the title compound was estimated to be >85% based on GC Method C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:34]=[CH:33][C:25]2[O:26][C:27]([CH3:32])([CH3:31])[O:28][C:29](=[O:30])[C:24]=2[CH:23]=1.[BH4-].[Na+].[Na+].[Cl-]>C1(C)C=CC=CC=1.CO.C1COCC1.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:34]=[CH:33][C:25]4[O:26][C:27]([CH3:31])([CH3:32])[O:28][C:29](=[O:30])[C:24]=4[CH:23]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
A solution of 4-[(4-butylphenyl)ethynyl]benzaldehyde (5.43 g, 20.7 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one (4.00 g, 20.7 mmol) in toluene (60 mL) was heated at reflux for 3.5 hours with azeotropic removal of water. Then the mixture was cooled down to 0° C. and anhydrous THF (60 mL) and MeOH (60 1L) were added NaBH4 (1.65 g, 43.6 mmol) was added portionwise and the reaction mixture was stirred for 30 min at 0° C. and 45 min at rt. The reaction mixture was poured into a saturated solution of NaCl and extracted with Et2O. The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give the crude product. Precipitation from a mixture of EtOAc/MeOH gave 7.1 g (75%) of the title compound as a yellow powder. HPLC, Rt: 5.4 min (purity: 97.5%). 1H NMR (CDCl3) δ: 7.45 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.15-7.06 (m, 3H), 6.80-6.70 (m, 2H), 4.20 (m, 2H), 4.04 (brs, 1H), 2.57 (t, J=7.7 Hz, 2H), 1.65 (s, 6H), 1.61-1.49 (m, 2H), 1.37-1.23 (m, 2H), 0.88 (t, J=7.3 Hz, 3H).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][C:8]([Cl:19])=[CH:7][CH:6]=2.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:20]([NH:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][C:8]([Cl:19])=[CH:7][CH:6]=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Nc1c2c(nc3cc(Cl)ccc13)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3cc(Cl)ccc3c(NCc3ccccc3)c21
Reaction time: 1 h

Procedure:
In a biphasic solution comprised of 150 ml of toluene and 100 ml of 30% potassium hydroxide were added 3.00 g of 9-amino-6-chloro-3,4-dihydroacridin-1(2H)-one and 0.62 g of tetrabutylamonium hydrogen sulfate. The reaction was mechanically stirred and brought to reflux (b. p. 90° C.) with a steam bath. To the refluxing mixture was added a solution of 3.04 ml of benzyl bromide in 20 ml of toluene over 0.5 hour. Within 1 hour the reaction was complete by TLC. The toluene layer was separated and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to a solid. The solid was recrystallized from dichloromethane/hexane to yield 1.63 g of a solid, mp 141°-143° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C@H:4]([N:8]([CH3:14])[CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.[ClH:25].[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:34][CH2:35][CH2:36][NH2:37])=[CH:29][CH:28]=1.C(OCC)C>CN(C=O)C>[ClH:25].[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[CH2:34][CH2:35][CH2:36][NH:37][C:5](=[O:7])[C@@H:4]([N:8]([CH3:14])[CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:3][CH:2]([CH3:1])[CH3:15])=[CH:29][CH:28]=1
Reactant: CC(C)CCN(C)[C@@H](CC(C)C)C(=O)O
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)CCN(C)[C@@H](CC(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 66.8 %

Procedure:
(S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid (0.300 g, 1.39 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.728 mL, 4.18 mmol) and solid O-benzotriazol-1-yl-N,N,N″,N′-tetramethyluronium hexafluorophosphate (0.528 g, 1.39 mmol). The resulting reaction mixture was stirred at that temperature for 25 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.415 g, 1.39 mmol) was then added. After stirring for, sequentially, 20 minutes at 0° C. and 60 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.460 g (65%) of the pure titled compound as a white foam: mp 37-46° C. APCI-MS m/z 459.4 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19](=[O:21])[NH2:20].C(N(CC)CC)C>O1CCOCC1.O>[C:1]([NH:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19](=[O:21])[NH2:20])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.22 g lauroylchloride dissolved in 46 ml dioxane were slowly added to 6.72 g glutamine and 13.94 g triethylamin in 92 ml water and 92 ml dioxane, the temperature being 0° C. After stirring at room temperature for 1 hour, the dioxane was evaporated and the remaining solution was acidified to pH 1 with HCl. The crystals were filtered off and recrystallized from acetone and then from methanol: 9.9 g white needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][C@H:11]1[C:20]([O-:22])=[O:21].CO.[OH-].[Li+].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][C@H:11]1[C:20]([OH:22])=[O:21]
Reactant: O=C([O-])[C@@H]1CC2(CC[C@H]1c1cc(F)c(F)cc1F)OCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CC2(CC[C@H]1c1cc(F)c(F)cc1F)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of trans 8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]decane-7-carboxylate from Step E (1.82 g, 5.5 mmol) dissolved in tetrahydrofuran (11 mL) and methanol (22 mL) was treated with aqueous lithium hydroxide solution (1.0 M, 18.5 mL) and the mixture was stirred at room temperature overnight. The reaction solution was acidified with hydrochloric acid (1N) to pH 1 and extracted with ethyl acetate. The organic phase was washed by saturated brine solution, dried over anhydrous sodium sulfate and evaporated to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Br[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.O1CCOCC1>[Br:1][C:2]1[CH:10]=[C:6]([C:7]2[O:8][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Nc1ccccc1Br
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Brc1cncc(-c2nc3ccccc3o2)c1
Temperature: 120 °C
Yield: 45.8 %

Procedure:
A mixture of 5-bromonicotinoyl chloride (13.46 g, 61.04 mmol), 2-bromoaniline (10.00 g, 58.13 mmol), Cs2CO3 (37.88 g, 116.3 mmol), CuI (0.554 g, 2.907 mmol), 1,10-phenanthroline (1.048 g, 5.813 mmol) and anhydrous 1,4-dioxane (110 mL) was degassed with argon for 1 h while stirring. The reaction mixture was then maintained under argon at 120° C. while stirring until TLC (SiO2, 1:1 hexanes-dichloromethane) confirmed consumption of the starting material (48 h). Upon cooling to RT, dichloromethane (ca. 200 mL) was added to the reaction, the mixture filtered, the filtrant washed copiously with dichloromethane (ca. 200 mL) and ethyl acetate (ca. 200 mL) and the filtrate concentrated in vacuo. Purification of the crude product via flash chromatography (SiO2, 100% dichloromethane to 29:1-dichloromethane:acetone) afforded 2-(5-bromopyridin-3-yl)benzo[d]oxazole (7.32 g, 46%) as a light brown crystalline solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(#N)C>[OH:10][CH2:9][CH2:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCCC1CCCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCCCC1CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
3-(2-Piperidinyl)-1-propanol (8.69 g, 60.7 mmol) was stirred in acetonitrile (90 ml) with triethylamine (10.40 mL, 74.6 mmol) under N2 and cooled in an ice bath. Benzyl chloroformate (9.53 ml, 66.7 mmol) was added dropwise. After complete addition the reaction was allowed to warm to ambient temperature and stirring then continued overnight. The suspension was filtered and the filtrate evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, passed through a hydrophobic frit and evaporated to dryness. The residue was purified by chromatography on silica (330 g silica RediSep column, loaded in DCM) using a 0-50% ethyl acetate in cyclohexane gradient over 40 mins. with a 50-100% flush of ethyl acetate on an ISCO Companion. No peaks were detected (254 nm, 280 nm) so the waste was evaporated in vacuo to recover the material. The material was re-columned using identical conditions as before but detecting at 220 nm and collecting all the eluent. The main product peak was collected and evaporated in vacuo to give the title compound as a yellow oil (6.15 g). LCMS (System B): tRET=2.46 min; MH+ 278
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:14])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)Cl)cc1

Procedure:
Meanwhile, the 4-methylbenzoyl chloride acylating agent was prepared by suspending 3.314 g (24.3 mmol) of ρ-toluic acid in 200 ml benzene. To this solution was added 2.0 equiv. (4.25 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at O° C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.C1([C@H](N)C)C=CC=CC=1.[C@H:21]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH:24]=[CH:23][CH2:22]1.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Br:1][C@@H:24]1[C@@H:25]2[CH2:26][C@@H:21]([C:27](=[O:29])[O:28]2)[CH2:22][CH2:23]1
Reactant: O=C(O)[C@@H]1CC=CCC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: C[C@@H](N)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1O[C@H]2C[C@@H]1CC[C@@H]2Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
Under a nitrogen atmosphere, 1,3-dibromo-5,5-dimethylhydantoin (4) (11.6 g, 40.6 mol) was added to a solution of (S)-3-cyclohexene-1-carboxylic acid (R)-α-phenylethylamine salt (2-b) (10.0 g, 40.4 mmol) in acetonitrile (25 ml) that had been cooled on ice. The temperature of the reaction solution was increased to room temperature, and the reaction solution was then stirred for 2 hours. Thereafter, ethyl acetate (50 ml) and a 10% sodium thiosulfate aqueous solution (40 ml) were added to the reaction solution to separate it. The aqueous layer was extracted with ethyl acetate (50 ml), and the organic layers were gathered and were then washed with a 5% citric acid aqueous solution (40 ml). The resulting organic layer was washed with saturated saline (30 ml) and was then concentrated under reduced pressure. Thereafter, isopropyl alcohol (50 ml) was added to the residue, and the solvent was then concentrated under reduced pressure, so that the volume became 30 ml. The obtained slurry liquid was cooled to −10° C., and a precipitate was filtered and was then washed with ice-cooled isopropyl alcohol (10 ml) to obtain the title compound (6.9 g, yield: 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:31]=[CH:32][CH:33]=[CH:28][C:29]=2[S:34]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)(=[O:36])=[O:35])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCCCC1
Product: O=S(=O)(c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1)N1CCCCC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and 1-((2-bromophenyl)sulfonyl)piperidine. MS (ESI): mass calcd. for C24H24FN3O3S, 453.15; m/z found, 454.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.07-8.03 (m, 1H), 7.82 (d, J=1.0, 1H), 7.73-7.67 (m, 2H), 7.65-7.55 (m, 2H), 7.42-7.39 (m, 1H), 7.36-7.30 (m, 2H), 4.41-4.32 (m, 2H), 3.74-3.71 (m, 2H), 2.91-2.79 (m, 4H), 1.49-1.37 (m, 6H).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:18][C:19](OCC)=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:29][OH:30].C[O-].[Na+].[Na]>CO>[OH:30][NH:29][C:19](=[O:20])[CH2:18][N:17]([S:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=1)(=[O:16])=[O:15])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CCCCCCOc1ccc(S(=O)(=O)N(CC(=O)OCC)CC(C)C)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCOc1ccc(S(=O)(=O)N(CC(=O)NO)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Ethyl 2-[[4-hexyloxybenzenesulfonyl](isobutyl)amino]acetate (1.22 g, 3.05 mmol) is dissolved in methanol (15 mL). To this solution is added hydroxylamine hydrochloride (0.43 g, 6.11 mmol), followed by the addition of sodium methoxide, freshly prepared from sodium (0.35 g, 15.3 mmol) dissolved in methanol (5 mL). The reaction is stirred for 36 hours at room temperature. The reaction is worked up by partitioning between dilute hydrochloric acid (pH=~3) and ethyl acetate. The aqueous phase is extracted well with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is crystallized from hexnae/ethyl acetate and collected by filtration to give N-hydroxy-2-[[4-hexyloxybenzenesulfonyl](isobutyl)amino]acetamide, m.p. 108°-110° C.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.O.CC(C)=[O:49].Cl(O)(=O)(=O)=O>C(OCC)(=O)C>[OH:49][C@@H:43]([CH2:45][OH:44])[CH2:42][O:41][C:2]([CH3:40])([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:37])[CH3:38])[NH:13]2)=[O:11])=[N:5]1
Reactant: CC(C)=O
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H](O)CO)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (51.2 mg, 0.078 mmol), water (2 mL), and acetone (10 mL) was cooled to 0° C., then a solution of 35% perchloric acid (0.1 mL) was added dropwise. The reaction was stirred an additional 0.5 h. Then an additional 1 mL of the 35% perchloric acid solution was added at 0° C., the reaction was allowed to warm to rt for 12 h. The mixture was then diluted with ethyl acetate and washed with sodium bicarbonate (sat'd). The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-2,3-dihydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (22.1 mg, 42%) as an white powder. HRMS (ES+) m/z Calcd for C33H39Cl2F2N5O4S+H [(M+H)+]: 678.2420. found: 078.2416; C33H39Cl2F2N5O4+[(Na+H)+]: 700.2239. found: 700.2235.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[N:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.C(OCC)C>CN1C(=O)CCC1>[CH2:21]([O:20][C:18]([N:12]1[CH2:13][CH2:14][N:15]([CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:16][CH2:17]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Yield: 59 %

Procedure:
To a solution of 3-nitrobenzylbromide (2.2 g; 10.0 mmol) in NMP (5 ml) was added ethyl piperazine-1-carboxylate dropwise with stirring. At the end of the addition the temperature had reached 35° C. Triethylamine (1.39 ml) was added causing the temperature to rise to 40° C. The mixture was stirred for additionally 30 min. prior to dilution with diethyl ether (25 ml). The mixture was filtered and the filtrate was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The concentrate was suspended in diethyl ether and filtered. The filtrate was diluted with ethyl acetate and extracted with diluted hydrochloric acid. The aqueous phase was rendered alkaline by addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and evaporated to dryness to leave 6a (1.72 g; 59%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH2:26][CH2:27][CH3:28].C(O)(=O)C>CN(C=O)C>[CH2:25]([N:12]1[C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]=2[C:15](=[O:17])[NH:14][C:13]1=[O:18])[CH2:26][CH2:27][CH3:28]
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Yield: 44.9 %

Procedure:
7-benzyl-3,7-dihydro-1H-purine-2,6-dione (17.14 g, 70.8 mmol) [Synthetic Communications, 20 (16), 2459-2467, 1990] and potassium carbonate (11.43 g, 82.8 mmol) were suspended in DMF (400 mL) at 40° C. After stirring for thirty minutes, butyl iodide (8.76 mL, 77.0 mmol) was added, and the mixture was stirred at 40° C. overnight. 50% Aqueous acetic acid (60 mL) was added, and the solution was concentrated under reduced pressure. The residue was suspended in water (500 mL), and the products were extracted into chloroform. The organics were collected, concentrated, and product was isolated using flash chromatography eluting with 1% methanol in dichloromethane to provide the product (9.49 g, 45%); 1H NMR (400 MHz; CDCl3) δ: 0.95 (3H, t), 1.34-1.41 (2H, m), 1.70-1.78 (2H, m), 4.05 (2H, t), 5.46 (2H, s), 7.31-7.40 (5H, m), 7.56 (1H, s), 8.21 (1H, br.s); m/z 299[MH+].