Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:14][S:13][C@@H:9]2[CH2:10][C:11](=[O:12])[N:8]2[C:7]=1[C:15]([OH:17])=[O:16])=O.C[N:19]1[C:23]([SH:24])=[N:22][N:21]=[N:20]1.[C:25](=O)(O)[O-].[Na+]>O.CC(C)=O>[CH3:25][CH:5]([S:24][C:23]1[NH:22][N:21]=[N:20][N:19]=1)[C:6]1[CH2:14][S:13][C@@H:9]2[CH2:10][C:11](=[O:12])[N:8]2[C:7]=1[C:15]([OH:17])=[O:16]
Reactant: Cn1nnnc1S
Reactant: O=C([O-])O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Yield: 44.1 %

Procedure:
A solution of 7-[D-N-[2-{2-N-methyl-N-phenylcarbamoyl)phenoxy}acetyl]-2-phenylglycinamido]cephalosporanic acid (3 g.), 1-methyl-1H-tetrazole-5-thiol (0.58 g.) and sodium bicarbonate (0.76 g.) in water (100 ml.) and acetone (50 ml.) was stirred at 65° to 70° C. for 6 hours, meanwhile the solution was kept at pH 7 to 7.2. After removing the insoluble substance by filtration, water was added to the filtrate to a total volume of 300 ml., treated with activated charcoal, adjusted to pH 2.0 with 10% hydrochloric acid under cooling and then extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and then evaporated under reduced pressure the residue was crystallized with a small amount of ethyl acetate and collected by filtration to give 7-[D-N-[2-}2-(N-methyl-N-phenylcarbamoyl)phenoxy}acetyl]-2-phenylglycinamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem- 4-carboxylic acid (0.69 g.).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:30](=[O:32])[CH3:31])=[C:24]([OH:33])[CH:23]=1.C([O-])(O)=O.[Na+]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:30](=[O:32])[CH3:31])=[C:24]([OH:33])[CH:23]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)c(O)cc1OCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(C(C)=O)c(O)cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 13.1 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.2 g, 19 mmol), 1-[4-(3-chloropropoxy)-2-hydroxy-5-methoxyphenyl]ethanone (5.0 g, 19 mmol), NaHCO3 (1.8 g, 20 mmol) and acetonitrile (120 mL) was stirred and refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to a dark oil. The oil was taken up in anhydrous ether and ethereal HCl was added to precipitate 8.7 g of an off-white hydrochloride salt. A 2.0 g sample of the salt was converted to its free base and chromatographed by preparative HPLC (silica gel with 5% MeOH/CH2Cl2 as eluent). Concentration of the desired fractions gave 1.1 g of a white solid, which was recrystallized from EtOH to yield 0.85 g of the product, m.p. 122°-124° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[C:15](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]2)=[O:9])=[N:6][CH:7]=1
Reactant: O=C(c1ccc(Br)cn1)C1CCNC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C(=O)c2ccc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
To a solution of (5-bromo-pyridin-2-yl)-pyrrolidin-3-yl-methanone (0.35 g, 1.35 mmol) in methanol (68 mL), add acetic acid (0.15 mL, 2.7 mmol), and formaldehyde (0.33 g, 4.1 mmol, 37% aqueous solution). After 15 min, add sodium triacetoxyborohydride (0.86 g, 4.1 mmol) and allow the mixture to stir at RT for 1 h. Concentrate the reaction mixture, dissolve in CH2Cl2, and wash with saturated NaHCO3. Back-extract the aqueous with CH2Cl2. Wash the combined organic layer with water, dry over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography, eluting with 5-10% MeOH (2N NH3)/CH2Cl2 to give 0.17 g (47%) of the title compound. LC-MS/ES m/z (79Br) 270 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:3]([CH2:2][NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CBr
Reactant: NCCCN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCCCN1CCCC1=O
Reaction time: 12 h

Procedure:
Methyl bromoacetate (1.35 mL, 14.3 mmol) was added dropwise to a solution of 3-aminopropyl-2-pyrrolidinone (2.0 mL, 14.3 mmol) and diisopropylethylamine (2.7 mL) in CH2Cl2. The reaction was stirred for 12 hours and was then concentrated in vacuo, and carried forward without further purification.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:19][CH:18]=1
Reactant: COc1ccc(NN=C(Cl)C(C)=O)cc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(NN=C(Sc2ccc(Cl)cc2)C(C)=O)cc1

Procedure:
A suspension of 31.7 g (0.139 mol) of 1-chloro-1-[(4-methoxyphenyl)hydrazono]-2-propanone in 400 ml of ethanol was treated with 23.4 g (0.161 mole) of 4-chlorothiophenol followed by 23.4 ml of triethylamine. The suspension was heated at reflux for 2 hours and cooled. The resultant suspension was filtered and the precipitate was washed with 1 portion of cold ethanol. The solids were dried in vacuo to yield 1-[(4-chlorophenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, mp 111.5-113.5° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C(N(CC)CC)C>ClCCl>[CH:12]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1)=[O:11]
Reactant: N#Cc1ccc(CO)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1ccc(C=O)nc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (936 mg, 7.38 mmol) is dissolved in dichlormethane (8 ml) under an argon atmosphere and cooled to −78° C. in an acetone dry-ice bath. Dimethylsulfoxide (1.153 g, 14.76 mmol) is added dropwise and the mixture is stirred for 20 minutes at −78° C. The compound of Example 32A (900 mg, 6.71 mmol) is added dropwise as a dichloromethane (7 ml) solution. The reaction is stirred for an additional two hours at −78° C. Triethylamine (3.05 g, 30.19 mmol) is added and the reaction is kept at −78° C. for 10 minutes, then allowed to warm to room temperature. The reaction is quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate phase is washed with bicarbonate and brine, dried over magnesium sulphate monohydrate, filtered and concentrated to afford a yellow oil. The crude oil is purified by column chromatography on silica gel with dichloromethane as eluent.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:12]([CH2:13]O)=[CH:11][C:10]=1[CH2:20][CH2:21][CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:23][C:24]1[N:29]=[C:28]2[N:30]=[C:31]([CH2:33][CH3:34])[NH:32][C:27]2=[C:26]([CH3:35])[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Si:1]([O:8][C:9]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:12]([CH2:13][N:30]2[C:28]3=[N:29][C:24]([CH3:23])=[CH:25][C:26]([CH3:35])=[C:27]3[N:32]=[C:31]2[CH2:33][CH3:34])=[CH:11][C:10]=1[CH2:20][CH2:21][CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: CCCc1cc(CO)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of 4.2 g (13.0 mmol) of the product of Step E, 2.5 g (14.0 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine and 5.62 (20.0 mmol) of triphenylphosphine dissolved in 40 mL of THF, was added 3.396 g (20.0 mmol) of diethyl azodicarboxylate and the mixture was stirred for 1 hour. The reaction mixture was then concentrated in vacuo and the residual oil was purified on a silica gel flash chromatography column eluted with 25-40% ethyl acetate/hexane to afford 5 g (80%) of the title compound.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]=1.[CH2:18]([N:20]([CH2:32][CH3:33])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[O:22])[CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH2:32]([N:20]([CH2:18][CH3:19])[C:21](=[O:22])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]=1)[CH3:33]
Reactant: CCN(CC)C(=O)c1ccccc1B(O)O
Reactant: COc1ccc(Cl)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccccc1-c1ccc(OC)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
Under an argon atmosphere, a mixture of tripotassium phosphate (6.24 g) and water (15 ml) was added to a mixture of 2-chloro-5-methoxy-pyridine (2.05 g), 2-(diethylcarbamoyl)benzeneboronic acid (4.65 g), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (0.584 g) and toluene (30 ml), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, water (20 ml), citric acid (2.2 g) and ethyl acetate were added and the mixture was stirred and filtered through celite. The filtrate was partitioned in a separatory funnel. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1 to 1/2) to give a roughly purified product (1.144 g) of the title compound. This product was directly used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([NH:19][C@@H:20]2[CH2:24][CH2:23][C:22](=O)[CH2:21]2)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.Cl.[NH2:27][OH:28].C(=O)(O)[O-].[Na+]>C(O)C.C(O)C.ClCCl>[Cl:1][C:2]1[C:3]([C:17]([NH:19][C@@H:20]2[CH2:24][CH2:23][C:22](=[N:27][OH:28])[CH2:21]2)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: NO
Reactant: O=C1CC[C@@H](NC(=O)c2noc(-c3ccc(C(F)(F)F)cc3)c2Cl)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: O=C(N[C@@H]1CCC(=NO)C1)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl

Procedure:
A suspension of (R)-4-chloro-N-(3-oxocyclopentyl)-5-(4-(trifluoromethyl)phenyl) isoxazole-3-carboxamide (20 mg, 0.054 mmol), hydroxylamine hydrochloride (5 mg, 0.064 mmol), and sodium bicarbonate (7 mg, 0.083 mmol) in ethanol (2 mL) was heated to reflux overnight. The reaction mixture was diluted with ethanol/dichloromethane, filtered through a cotton plug and evaporated in vacuo. Purification by silica gel chromatography, eluting with 8% methanol in dichloromethane gave the title compound as a mixture of cis and trans isomers (10.5 mg, 0.027 mmol). MS (ESI) m/z (M+H+): 388.2/390.3
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[N:7]([CH3:10])[CH:8]=[O:9])=[O:4].[C:15]([OH:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([O:23][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[N:7]([CH3:10])[CH:8]=[O:9])=[O:4])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C=O)c1ccccc1C(=O)CCl
Reactant: O=C(O)c1ccccc1
Product: CN(C=O)c1ccccc1C(=O)COC(=O)c1ccccc1

Procedure:
The solution of 2'-(2-chloroacetyl)-N-methylformanilide may be reacted with benzoic acid by a method analogous to that of Example 2(d) to give the novel compound 2-[2-(N-methylformamido)phenyl]-2oxoethyl benzoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:21]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[CH2:24][CH2:23][CH2:22]1
Reactant: C1CNC1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(benzyloxy)-2-methoxyphenyl]acetic acid (1.8 g, 6.61 mmol) was dissolved in DMF (5 ml) and azetidine (0.566 g, 9.92 mmol), DIEA (3.46 ml, 19.8 mmol), and HATU (4.02 g, 10.6 mmol) added. The mixture was stirred at RT for 1 hr. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 312 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4](=[S:21])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Nc1ccccc1C(=O)NCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ccccc1C(=S)NCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47 %

Procedure:
A mixture of 2-amino-N-(3,4-dichlorobenzyl)benzamide (3.5 g) and phosphorus pentasulfide (4.74 g) in dioxane (56 ml) was stirred at room temperature for 5 hours. The reaction mixture was poured into an aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water and dried. Evaporation of the solvent gave a residue, which was chromatographed on silica gel. Elution with chloroform followed by recrystallization from isopropyl ether gave 2-amino-N-(3,4-dichlorobenzyl)benzenecarbothioamide (1.56 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:23]=[CH:22][S:21][C:11]=4[C:12](=[O:20])[NH:13][C:14]=3[CH:15]=[CH:16][C:17]=2[O:18]C)[CH:5]=[CH:4][C:3]=1[CH:24]([CH3:34])[CH2:25][NH:26]C(=O)OC(C)(C)C.B(Br)(Br)Br>C(Cl)Cl>[ClH:1].[NH2:26][CH2:25][CH:24]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[C:9]3[C:10]4[CH:23]=[CH:22][S:21][C:11]=4[C:12](=[O:20])[NH:13][C:14]=3[CH:15]=[CH:16][C:17]=2[OH:18])=[CH:7][C:2]=1[Cl:1])[CH3:34]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(CN)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1Cl
Product: Cl
Temperature: 25 °C
Yield: 79.1 %

Procedure:
Following General Procedure F, tert-butyl 2-(2-chloro-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (120 mg, 0.24 mmol) in CH2Cl2 at 0° C. was added BBr3 (1.0 M in CH2Cl2, 15 mL, 15 mmol) and the reaction was warmed to room temperature for 4 h. The reaction was quenched by pouring onto water or ice-water and the resulting mixture was concentrated and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired product was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product as a brown solid (40 mg, 43%): 1H NMR (500 MHz, CD3OD) δ 7.65 (ddd, J=9.9, 9.3, 6.1 Hz, 2H), 7.46-7.36 (m, 2H), 7.33-7.27 (m, 1H), 7.18 (t, J=9.0 Hz, 1H), 6.10 (dd, J=28.8, 5.4 Hz, 1H), 3.86-3.66 (m, 1H), 3.29-3.12 (m, 2H), 1.44-1.28 (m, 3H); ESI MS m/z 385 [C20H17ClN2O2S+H]+; HPLC >99% (AUC), tR=9.07 min.
Reaction SMILES: [I:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]=O.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][N:25]([CH2:13][CH2:12][C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[I:1])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CCc1ccc2c(c1I)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2I)COC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (4-iodo-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (1.2 g) was dissolved in DCM (40 mL). Boc-piperazine (1.1 g, 5.9 mmol) was added into the solution, followed by addition of sodium triacetoxyborohydride (4.2 g, 20 mmol). The reaction was allowed to stir at RT overnight. The reaction was diluted with DCM, washed with sodium bicarbonate and brine, dried over MgSO4, and purified by silica gel chromatography to furnish tert-butyl-4-[2-(4-iodo-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate. LC-MS (IE, m/z): 473 [M+1]+.
Reaction SMILES: [C:1]([Br:4])(=[O:3])[CH3:2].[CH2:5]([NH:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>FC(F)(F)C(O)=O.O>[BrH:4].[C:1]([O:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([NH:21][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:29][CH:28]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CO)cc1
Reactant: CC(=O)Br
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Br
Product: CCCCCCCCCCCCCCCCNc1ccc(COC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetyl bromide (0.33 ml.) is added to a solution of p-hexadecylaminobenzyl alcohol (1.0 g.) in trifluoroacetic acid (5 ml.), and the solution is stirred at room temperature for 0.5 hours. Two drops of water are added, and the solution is stirred at room temperature for 0.5 hours. Two drops of water are added, and the solution is evaporated in vacuo. The residue is dissolved in hexanes, and re-evaporated. The residue is treated with anhydrous diethyl ether, and the white solid is collected by filtration, washed with anhydrous diethyl ether, and dried to give 1.01 g. of the product of the Example, m.p. 80°-82° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([OH:19])[C@@H:11]([OH:18])[C@H:12]([OH:17])[C:13](=[O:16])[CH2:14][OH:15])=O)(C)(C)C.O.[ClH:21]>C(O)CC>[ClH:21].[NH2:8][CH2:9][C@H:10]([OH:19])[C@@H:11]([OH:18])[C@H:12]([OH:17])[C:13](=[O:16])[CH2:14][OH:15]
Reactant: CC(C)(C)OC(=O)NC[C@H](O)[C@@H](O)[C@H](O)C(=O)CO
Agent: Cl
Solvent: CCCO
Solvent: O
Product: NC[C@H](O)[C@@H](O)[C@H](O)C(=O)CO

Procedure:
20 g of N-tert.-butoxycarbonyl-6-amino-6-desoxy-L-sorbose were introduced in portions into a mixture of 6.4 ml of H2O and 13.2 ml of concentrated hydrochloric acid, whilst stirring and cooling. The batch was subsequently stirred for 2 hours, without cooling, and 120 ml of n-propanol were then added in the course of 2 hours. The resulting suspension of crystals was then stirred at 0° C. for 1 hour and filtered on a suction filter. The crystals were washed with a little n-propanol and dried at room temperature in a vacuum drying cabinet.
Reaction SMILES: CC1(C)[O:6][C@H:5]2[C@H:7]([NH:12][C:13]3[N:18]4[N:19]=[C:20]([C:22]5[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[CH:25]=[CH:24][CH:23]=5)[CH:21]=[C:17]4[N:16]=[CH:15][CH:14]=3)[CH2:8][C@H:9]([CH2:10][OH:11])[C@H:4]2[O:3]1.Cl[S:34]([NH2:37])(=[O:36])=[O:35].Cl.O>CN(C)C=O>[S:34](=[O:36])(=[O:35])([O:3][CH2:4][C@H:9]1[CH2:8][C@@H:7]([NH:12][C:13]2[N:18]3[N:19]=[C:20]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[CH:21]=[C:17]3[N:16]=[CH:15][CH:14]=2)[C@H:5]([OH:6])[C@@H:10]1[OH:11])[NH2:37]
Reactant: NS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3ccnc4cc(-c5cccc6ccccc56)nn34)[C@@H]2O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2ccnc3cc(-c4cccc5ccccc45)nn23)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
To a vial charged with (s.e.)-((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (1.76 g, 4.09 mmol) in N,N-dimethylformamide (7.20 mL) is added chlorosulfonamide (1.42 g, 12.3 mmol; obtained by the method described in J. Am. Chem. Soc. 2005, 127, 15391). After 1 hr, the reaction is quenched with methanol (5 mL). 6.0 M hydrochloric acid in water (3.41 mL, 20.4 mmol) is added and the mixture is stirred for 1 hr. Solvent is removed in vacuo and the crude material is purified by preparative HPLC to provide (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methyl sulfamate. LCMS: (AA) M+1 470; 1H NMR (400 MHz, MeOD) δ 8.48-8.40 (m, 1H), 8.19 (d, J=5.5 Hz, 1H), 7.99-7.90 (m, 2H), 7.81-7.75 (m, 1H), 7.60-7.47 (m, 3H), 6.69 (s, 1H), 6.37 (d, J=5.6 Hz, 1H), 4.24-4.06 (m, 3H), 4.04-3.99 (m, 1H), 3.96-3.89 (m, 1H), 2.55-2.45 (m, 1H), 2.45-2.35 (m, 1H), 1.60-1.48 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30])([CH3:23])[CH3:22].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)([CH3:23])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: CC(C)c1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccccc2C(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (example 284, Step 2) and 2-isopropyl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (example 285, Step 1), to produce a colorless oil. MS (ES) for C22H28O5 [M+NH4]+: 390.4.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[N:7]([C:12](Cl)=[O:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>CCOCC>[CH2:15]([N:17]([CH2:18][CH3:19])[C:12]([N:7]1[C:8]([S:10][CH3:11])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]1)=[O:13])[CH3:16]
Reactant: CCNCC
Reactant: CSc1cc(C(C)(C)C)nn1C(=O)Cl
Solvent: CCOCC
Product: CCN(CC)C(=O)n1nc(C(C)(C)C)cc1SC
Yield: 54 %

Procedure:
3-t-butyl-1-chlorocarbonyl-5-(methylthio)pyrazole (4.0 g) in ether (25 ml) was added dropwise with stirring to a solution of diethylamine (3.9 g, 5.5 ml) in ether (25 ml) at room temperature. The reaction mixture was refluxed for 1/2 hour and then filtered, and the ether layer washed with water, dried and evaporated to give crude product. Recrystallisation from petrol gave 1-(diethylcarbamoyl)-3-t-butyl-5-(methylthio)pyrazole, melting point 55°-6°. Yield 54%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C(C(=CNC1C=CC(CCCC)=CN=1)C(OCC)=O)#N>>[C:19]([C:13](=[CH:12][NH:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:20]
Reactant: Nc1ncccc1Cl
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: CCCCc1ccc(NC=C(C#N)C(=O)OCC)nc1
Product: CCOC(=O)C(C#N)=CNc1ncccc1Cl
Yield: 44 %

Procedure:
The title compound (m.p. 139.5°-141.5°, 44% yield) was prepared from 2-amino-3 -chloropyridine and ethyl ethoxymethylenecyanoacetate in a manner similar to that described for the preparation of ethyl 2-cyano-3-(5-n-butyl-2-pyridylamino)acrylate in Preparation D3 of U.S. Pat. No. 4,122,274.