Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[CH3:19][C@H:20]1[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][O:21]1.[Cl-].[NH4+]>C1COCC1>[Cl:13][C:14]1[S:15][C:16]([C@@:24]2([OH:26])[CH2:23][CH2:22][O:21][C@@H:20]([CH3:19])[CH2:25]2)=[CH:17][N:18]=1
Reactant: Clc1nccs1
Reactant: C[C@H]1CC(=O)CCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@H]1C[C@@](O)(c2cnc(Cl)s2)CCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 111.3 %

Procedure:
n-Butyl-lithium (2.5M in hexane, 57.5 ml) was dropwise added during 30 minutes to a solution of di-isopropylamine (19.3 ml) in THF (180 ml) which had been cooled to -78° C. The mixture was stirred at -78° C. for 1 hour. The reaction vessel was shielded from light and 2-chlorothiazole (15.0 g) was added dropwise during 20 minutes, whilst keeping the temperature of the reaction mixture below -70° C. The mixture was stirred at -78° C. for 1.5 hours. (2S)-2-Methyltetrahydropyran-4-one (12.9 g) was added during 20 minutes. The mixture was stirred and allowed to warm briefly to -25° C. to obtain a homogeneous solution. The mixture was recooled to -70° C. and stirred at that temperature for 1 hour. A 5% aqueous solution of ammonium chloride was added and the mixture was extracted with diethyl ether. The organic solution was washed with brine, dried (MgSO4) and evaporated. There was thus obtained a mixture (29.4 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 1:4. The mixture so obtained was dissolved in diethyl ether (250 ml) and the solution was cooled to 0° C. A concentrated (25% v/v) aqueous solution of sulphuric acid was added and the mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate (750 ml) and neutralised to pH3 by the addition of sodium bicarbonate. The organic solution was washed with brine, dried (MgSO4) and evaporated to give a mixture (26 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 9:1. The material was purified by column chromatography using a 1:1 mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluent. There was thus obtained (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran (21 g, 79%).
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27](O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:55][C@H:56]([C:58]([CH2:60][Cl:61])=[O:59])[CH3:57]>>[NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27]([NH:55][C@H:56]([C:58]([CH2:60][Cl:61])=[O:59])[CH3:57])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@H](N)C(=O)CCl
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)CCl
Temperature: -20 °C
Reaction time: 3 h

Procedure:
Boc-Ala-CH2Cl (2 g) in 5 equiv of HCl in dioxane was stirred at room temp for 1 h. After removal of solvent, the residue was triturated with diethyl ether to give crude H-Ala-CH2Cl (1.41 g). The Z-Leu-Asp(OtBu)-Leu-OH (2.68 g) and N-methylmorpholine (0.54 mL) were dissolved in ThF (25 mL), the cooled to −20° C. Isobutyl chloroformate (0.64 mL) was added to generate the mixed anhydride, which was transferred to the H-Ala-CH2Cl (1.41 g in 10 mL of DMF) solution at −20° C. The resulting mixture was allowed to come to room temp and reaction was completed in 3 h. The salt was removed by filtration. The filtrate was concentrated, redissolved in ethyl acetate (100 mL). The solution was washed with 0.2 N HCl, 5% NaHCO3, sat. NaCl; dried over Na2SO4, filtered, and concentrated to yield crude solid of 3.19 g. The crude Z-Leu-Asp(OtBu)-Leu-Ala-CH2Cl was purified by Sephadex IMO column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[CH2:23](I)[CH3:24]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:23][CH3:24])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reaction time: 1 h

Procedure:
To (2R)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.406 g) and Na2CO3 (2.59 g) was added dry EtOH (28 ml) then ethyl iodide (0.54 ml) and the mixture heated at reflux for 18 h under argon. The solvent was then removed under reduced pressure and 5% MeOH/DCM (40 ml) was added and stirred for 1 hour in a sealed flask. The solution was filtered and washed with dichloromethane (2×10 mL). The filtrate was then placed directly onto a 120 g-silica cartridge and was purified using eluent 10-70% MeOH/DCM. After evaporation, the product was isolated as a white foam (1.00 g), which was used without further purification.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C=O.Cl.NCCC[Si](OCC)(OCC)[O:20]CC.C[Si](C)(C)Cl.[N+](C1C=CC=CC=1)([O-])=O>C(N(CC)CC)C>[OH:20][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:2][CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: Oc1cccc2cccnc12
Agent: C=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1ccc2ccccc2n1

Procedure:
Preferably, Route A can be used. A chloromethylated ligand can be prepared, for example, by reacting 8-hydroxyquinoline with formaldehyde and hydrochloric acid. That derivative is further reacted with γ-aminopropyltriethoxysilane in the presence of trimethylchlorosilane and triethylamine and nitrobenzene. Next, the prepared organosilicon derivative is reacted with the support to obtain hydroxyquinoline modified silica gel. A sample of this sequence of reactions is described in further detail in Example 2 below.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6](=[O:8])[CH3:7])[CH2:5][CH2:4]1.[C:9]([S:13][CH3:14])([S:11][CH3:12])=S>CN(C=O)C>[CH:3]1([C:6](=[O:8])[CH:7]=[C:9]([S:13][CH3:14])[S:11][CH3:12])[CH2:5][CH2:4]1
Reactant: CSC(=S)SC
Reactant: CC(=O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(=CC(=O)C1CC1)SC

Procedure:
To a mixture of NaH (240 mg, 6.0 mmol, 60% in mineral oil) and 1-cyclopropylethanone (168.2 mg, 2.0 mmol) in DMF (1 mL) was added dimethyl carbonotrithioate (304.3 mg, 2.2 mmol) at rt. The reaction was quenched with water after 3 h and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to yield crude 1-cyclopropyl-3,3-bis(methylthio)prop-2-en-1-one 30 which was purified by flash chromatography on silica with 15% EtOAc in hexanes as eluant. 1H NMR (400 MHz, CDCl3) δ 6.14 (s, 1H), 2.41 (s, 3H), 2.40 (s, 3H), 1.81 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H). MS m/z 189.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[K].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[N:23]=1>O1CCOCC1>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:3]2[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]2([CH3:10])[CH3:1])[N:23]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: Brc1cccc(Br)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K]
Solvent: C1COCCO1
Product: CC1(C)CCCC(C)(C)N1c1cccc(N2C(C)(C)CCCC2(C)C)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a 1,4-dioxane solution (30 ml) of 2,2,6,6-tetramethylpiperidine (3.11 g, 22.0 mmol) and potassium-bis(trimethylsilyl)amide (4.39 g, 22.0 mmol)2 was added 2,6-dibromopyridine (2.37 g, 10.0 mmol). The reaction mixture was stirred vigorously at 100° C. overnight. After cooling down to room temperature, the reaction was quenched with water and extracted with diethyl ether/THF (1:1) mixtures. The combined extracts were washed with 1 M Na2CO3, dried over MgSO4, filtrated, and evaporated to dryness. The product was purified by flash chromatography on silica gel leading to colorless oil (Rf=0.5 in Ethylacetate:hexane=1:20, Yield=1.13 g (31.6%))
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[CH:12]=[CH:13][C:14]=1[CH2:15][O:16][CH2:17][C@@H:18]1[CH2:20][C@@H:19]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[O:31][N:30]=[C:29]([CH:32]([CH3:34])[CH3:33])[N:28]=2)[CH2:23][CH2:22]1>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH2:35][C:36]([OH:38])=[O:37])[CH:12]=[CH:13][C:14]=1[CH2:15][O:16][CH2:17][C@@H:18]1[CH2:20][C@@H:19]1[CH:21]1[CH2:22][CH2:23][N:24]([C:27]2[O:31][N:30]=[C:29]([CH:32]([CH3:34])[CH3:33])[N:28]=2)[CH2:25][CH2:26]1
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)OC(C)(C)C)cc3F)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)O)cc3F)CC2)n1
Temperature: 35 °C
Reaction time: 4 h
Yield: 158 %

Procedure:
A solution of 4 M HCl in dioxane (3.85 mL, 15.4 mmol) was added to a solution of tert-butyl 2-(3-fluoro-4-((((1R,2R)-2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)cyclopropyl)methoxy)methyl)phenyl)acetate (Step C product, 750 mg, 1.54 mmol) in DCM (4 mL). This mixture was stirred at 35° C. for 4 hrs. The reaction mixture was subsequently concentrated under reduced pressure to afford the title compound (1.05 g, 97%) as a crude product to be used for the next step. LC/MS (m/z): 432 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]([O:11][CH2:12]CCC)(=[O:10])[CH3:9]>CS(O)(=O)=O>[CH3:9][C:8](=[O:10])[O:11][CH2:12][CH:5]([CH2:6][O:4][C:1](=[O:3])[CH3:2])[O:4][C:1](=[O:3])[CH3:2]
Reactant: CCCCOC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Product: CC(=O)OCC(COC(C)=O)OC(C)=O

Procedure:
Comments—example 4 shows that from a high ester content glycerin, using butyl acetate as azeotropic agent, methanesulfonic acid as catalyst, in the presence of combined alkalinity and complementing the reaction with acetic anhydride, it is possible to obtain a food grade triacetin.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=3)=[N:7][C:6]=12.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>>[F:12][CH:11]([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[C:6]2[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOc1cccc(-c2cc(C(F)F)n3ncc(Br)c3n2)c1
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(C#C[Si](C)(C)C)c3n2)c1
Yield: 96.1 %

Procedure:
Prepared from 3-bromo-7-difluoromethyl-5-(3-ethoxy-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.19 step 3a) (20.0 g, 54 mmol) and commercially available trimethylsilylacetylene (15 mL, 109 mmol) as described in example C.1 step 3a to give the title compound (20 g, 95%) as a light brown solid. MS (ISP) 386 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:11](=[O:13])[CH:10]([CH3:14])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:19][CH:18]=1)#[N:15]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(CNC(=O)OC(C)(C)C)C(=O)NCc1ccc(C#N)cc1
Yield: 71 %

Procedure:
A solution of 3-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (200 mg, 0.98 mmol), 4-(aminomethyl)benzonitrile (130 mg, 0.98 mmol), HATU (486 mg, 1.28 mmol) and TEA (0.411 mL, 2.95 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20 to 67% ethyl acetate/hexane) to give tert-butyl (3-((4-cyanobenzyl)amino)-2-methyl-3-oxopropyl)carbamate (221 mg, 0.696 mmol, 70.8%) as a white powder.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][NH2:28])[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1)(=[O:3])[CH3:2].[C:46](Cl)(=[O:49])[CH:47]=[CH2:48]>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][NH:28][C:46](=[O:49])[CH:47]=[CH2:48])[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cccc(OCCN)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)NCCOc1cccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 101e (250 mg, 0.387 mmol) and TEA (78 mg, 0.77 mmol) in DCM (10 mL) was added dropwise a solution of acryloyl chloride (42 mg, 0.46 mmol) in DCM. This mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduce pressure to afford 101f as a yellow solid (crude), which was used in next step without further purification. MS-ESI: [M+H]+ 666.4
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12](O)[CH2:13][NH:14][C:15](=[O:21])[O:16]C(C)(C)C)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Cl>CN(C=O)C.O>[CH3:23][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:21])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)NC[C@H](O)c1ccc2c(c1)COC(C)(C)O2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Temperature: 21 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
tert-Butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate, (86.37 g) in DMF (600 ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 11.9 g) in DMF (160 ml) with cooling such that the internal temperature remained at 0° C. under nitrogen. The mixture was stirred at 21° C. for 2 h. The mixture was recooled to 0° C. and 2M HCl (134 ml) was added. The mixture was diluted with water and the product was extracted with ethyl acetate twice. The solution was washed with brine twice, dried (MgSO4) and evaporated to give the title compound (63.55 g) LCMS RT=2.66 min.
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccco2)CN(CC(=O)O)C1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1CC(c2ccco2)SCC(NC(CCc2ccccc2)C(=O)O)C1=O
Yield: 71.3 %

Procedure:
Following the procedure described in Example 44, 130 mg of α-[6-(1-ethoxycarbonyl-3-phenylpropylamino)-2-(2-furyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid (prepared as described in Example 57 above) were hydrolyzed with sodium hydroxide, to afford 87 mg of the title compound as a powder.
Reaction SMILES: [OH:1][CH2:2][C@:3]([OH:20])([CH3:19])[C:4](=[O:18])[C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH:7]([CH3:9])[CH3:8].Cl[S:22]([C:25]1[C:42]([CH3:43])=[CH:41][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[CH:27][C:26]=1[CH3:44])(=[O:24])=[O:23].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:13]([O:12][C:11]([NH:10][C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4](=[O:18])[C@@:3]([OH:20])([CH3:19])[CH2:2][O:1][S:22]([C:25]1[C:26]([CH3:44])=[CH:27][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])=[CH:41][C:42]=1[CH3:43])(=[O:24])=[O:23])=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)[C@](C)(O)CO
Reactant: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 34.7 %

Procedure:
Referring to FIG. 37, to a solution of the tert-butyl ((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)carbamate (0.72 g, 2.5 mmol) in DCM (30 mL) were added benzyl 2-(4-(chlorosulfonyl)-3,5-dimethylphenoxy)acetate (1.1 g, 3 mmol), Et3N (0.52 mL, 3.7 mmol) and DMAP (63 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 7 h (TLC analysis showed some starting material was left). DCM (50 mL) was added and the resulting mixture was washed with HCl solution (1 N, 30 mL) and saturated aqueous NaHCO3 (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc=10:1) to give product as a white powder (540 mg, 34.8%). LC-MS analysis confirmed the structure.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1.Cl[C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(Cl)Cl>ClCCCl>[O:25]=[C:18]([C:8]1[C:9]([O:15][CH3:16])=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=1[O:6][CH3:5])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CCC(=O)Cl
Reactant: COc1cc(OC)cc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1c(OC)cc(OC)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) suspension of AlCl3 (2.036 g; 15.27 mmol) in anh. DCE (10 ml) was treated with commercially available 1,3,5-trimethoxybenzene (1.675 g; 9.96 mmol), and stirring at 0° C., under nitrogen, was continued for 10 min. Commercially available methyl 4-chloro-4-oxobutanoate (1.000 g; 6.64 mmol) was then added, and the mixture was stirred at rt for 24 h. The resulting reaction mixture was poured onto crushed ice (30 g), and DCM (20 ml) was added. The separated aq. layer was further extracted with DCM (3×10 ml). The mixed organic layers were washed successively with water (15 ml) and brine (2×15 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording methyl 4-oxo-4-(2,4,6-trimethoxyphenyl)butanoate as a colorless oil. LC-MS (conditions D): tR=0.88 min.; [M+H]+: 283.02 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].Cl.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH:29]([OH:34])[C:30](=N)OC>C(O)C.C(=O)([O-])O.[Na+].O>[NH2:1][C:2]1[C:3]2[N:9]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:30]([CH:29]([C:23]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=3[Cl:21])[OH:34])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cccc1N
Reactant: COC(=N)C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Reaction time: 12 h
Yield: 99.5 %

Procedure:
To a stirred solution of tert-butyl {2-[(2,6-diaminophenyl)amino]ethyl}carbamate (5.00 g, 18.8 mmol) in ethanol (38 mL) was added methyl 2-(2,4-dichlorophenyl)-2-hydroxyethanimidoate hydrochloride (5.59 g, 20.7 mmol) at room temperature. After 12 h, the reaction mixture was diluted with aqueous sodium hydrogen carbonate and water. The resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate to give the title compound as a brown amorphous solid (8.46 g, 18.7 mmol, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:19])[CH2:11][NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.C(N(CC)CC)C.[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:19][C@H:10]([C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:31]([C:30]2[CH:29]=[C:28]([F:27])[CH:36]=[C:35]([F:37])[CH:34]=2)=[O:32])=[CH:5][CH:6]=1)[CH2:11][NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CC(C)S(=O)(=O)NC[C@H](C)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC[C@H](C)c1ccc(NC(=O)c2cc(F)cc(F)c2)cc1
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
A 500 mL three necked round bottom flask equipped with a magnetic stirrer, thermometer, addition funnel and a positive nitrogen was charged with [(2R)-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine (12.02 g, 46.85 mmol) and methylene chloride (200.0 mL). To this solution was added triethylamine (6.53 mL, 46.85 mmol) all at once. The solution was stirred for 10 minutes then added dropwise, neat 3,5-difluorobenzoyl chloride (5.9 mL, 46.85 mmol) over a period of 20 minutes. The reaction exothermed to reflux by the end of addition. Stirred to room temperature over the weekend for convenience. Quenched reaction with 1N HCl (100.0 mL) and separated lower organic layer. Washed the organic layer with 25% brine (70.0 mL) and dried with anhydrous magnesium sulfate. Filtered precipitates and concentrated filtrate to a tan oil (20.0 g). To this oil was added 1:1 ethyl acetate/hexane (125.0 mL) with stirring. A massive off white precipitate formed. The precipitate was then filtered and the cake washed with 1:1 ethyl acetate/hexane (50.0 mL). Precipitate was then dried in a house vacuum oven at 40° C. to provide N-[4-((1R)-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (15.02 g, 80.9%); 1H NMR (CDCl3, 300 MHz) δ 1.26-1.27 (d, 6H), 1.29-1.30 (d,2H), 2.92 (m, 1H), 3.10 (m, 1H), 3.20 (1H), 3.3-3.4 (m, 1H), 7.0 (triplet, 1H), 7.20 (d, 2H), 7.40 (d, 2H), 7.60 (m, 2H), 8.19 (s, 1H); 13C NMR (CDCl3, 300 MHz) δ 17.19, 17.30, 19.75, 41.03, 50.99, 54.15, 107.68, 107.86, 108.08, 111.12, 111.33, 121.81, 128.59, 136.97, 138.77, 140.51, 162.62, 162.71, 164.12, 164.61, 164.71.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][NH:5][CH2:6][C:7]([CH3:12])([N+:9]([O-])=O)[CH3:8]>CO.[Ni].O>[CH3:13][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][CH2:6][C:7]([CH3:8])([NH2:9])[CH3:12]
Reactant: CN(C)CCNCC(C)(C)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CN(C)CCNCC(C)(C)N
Reaction time: 24 h

Procedure:
To a solution of N1,N1-dimethyl-N2-(2-methyl-2-nitropropyl)ethane-1,2-diamine (23.2 mmol) in MeOH (20 ml) was added a slurry of Raney Nickel in H2O (1 ml). The vessel was pressurized with H2 (500 psi) and the suspension stirred for 24 h. The mixture was filtered through Celite, then 0.45 um PTFE, and concentrated in vacuo. ESI/APCI (pos) expected for C8H21N3: 159.17. Found: 160 (MH+).