Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[C:8]1([CH:14]([N:16]2[CH2:19][CH:18](O)[CH2:17]2)[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CS(Cl)(=O)=O.[H-].[Na+].[C:28]1(C)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1C=CC=CC=1>[C:8]1([C:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([CH:18]2[CH2:19][N:16]([CH:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:15])[CH2:17]2)[C:6]#[N:3])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccccc1
Reactant: CCN(CC)CC
Reactant: CC(c1ccccc1)N1CC(O)C1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(c1ccccc1)N1CC(C(C#N)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 67.9 g. (0.67 mole) of triethylamine and 114 g. (0.64 mole) of 1-(1-phenylethyl)-3-azetidinol in 800 ml. of dry benzene was added dropwise 73.6 g. (0.65 mole) of methane sulfonylchloride while cooling in an ice bath. After stirring two hours at room temperature the mixture was filtered. The filtrate was added dropwise over a 40-minute period to a refluxing suspension of the sodium salt of diphenylacetonitrile prepared by refluxing 123.5 g. (0.64 mole) of the nitrile and 28.2 g. (0.7 mole) of 57% sodium hydride in 1 liter of dry toluene for 2.5 hrs. The toluene solution was extracted with dilute hydrochloric acid. The toluene-organic layer was treated with water and a volume of isooctane equal to the toluene layer. The oily layer and aqueous layer were separated together. The toluene layer was washed several times with water. All aqueous layers (and the oil) were combined and basified with dilute sodium hydroxide and extracted with chloroform. The chloroform layer was dried over sodium sulfate and concentrated by distillation. The residue was crystallized from isooctane isopropyl ether to give 94 g. (42%) of product melting 122°-130° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[Br:7][C:4]1[S:3][C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1cnc(N2CCNCC2)s1
Temperature: 160 °C
Yield: 94 %

Procedure:
A mixture of 2.06 mmol 2,5-dibromothiazole, 6.17 mmol piperazine and 6.17 mmol triethylamine in 6 ml tetrahydrofuran in a sealed tube was heated at 160° C. for 10 min under microwave irradiation. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to afford the title compound as a white crystalline solid (yield 94%). MS (m/e): 250.0 ({81Br}M+H+, 100%), 248.0 ({79Br}M+H+, 76%).
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][C:7]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:16]O>>[ClH:3].[NH2:6][C:7]1([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CO
Reactant: NC1(C(=O)O)CCOCC1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)C1(N)CCOCC1

Procedure:
Thionyl chloride (4.02 mL, 55.1 mmol) was added in the dehydrated methanol (100 mL) solution of 4-amino-4-carboxytetrahydro-pyran monohydrochloride (5.00 g, 27.5 mmol) in an ice bath, and the mixture was heated and refluxed for 2.5 hours. The solvent was removed by distillation under reduced pressure, and the obtained crude product was washed with ethyl acetate and then dried under reduced pressure to give a colorless solid (BB04, 5.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1nc(-c2ccc(Cl)cc2)co1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-oxazoleproprionic acid (0.5 g), benzyl bromide (0.25 ml), potassium carbonate (0.33 g) and dimethylformamide (DMF)(10 ml) was stirred for 3 hours at room temperature. The reaction mixture was poured into water to obtain crystals of benzyl 4-(4-chlorophenyl)-2-oxazolepropionate (0.664 g, 98%). Recrystallization from ether-hexane gave colorless prism crystals of mp 66°-67° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH3:28])[CH2:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][C@H:3]1[OH:29].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>O.ClC(Cl)Cl.C(N(CC)CC)C>[OH:29][C@H:3]1[C@H:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=2)[CH2:7][CH2:6][N:5]([CH:8]([CH3:28])[CH2:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](N)[C@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2cccc(C(F)(F)F)c2)[C@H](O)C1
Yield: 86.3 %

Procedure:
To a stirred and cooled solution of 4 parts of trans-4-amino-3-hydroxy-N,N,γ-trimethyl-α,αdiphenyl-1-piperidinebutanamide in 120 parts of trichloromethane were added 1.26 parts of N,N-diethylethanamine. A solution of 2.3 parts of 3-(trifluoromethyl)benzoyl chloride in 75 parts of trichloromethane was added dropwise. Upon completion, the reaction mixture was stirred overnight at room temperature. A solution of sodium carbonate in water was added. The separated organic layer was washed with water, dried, filtered and evaporated. The residue was taken up in 2,2'-oxybispropane. The precipitated product was filtered off and dried in vacuo at 60° C., yielding 4.9 parts (86.3%) of trans-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-4-[[3-(trifluoromethyl)benzoyl]amino]-1-piperidinebutanamide; mp. 140.7° C. (compound 1).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:10]=O.[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][SH:24]>C(O)(C)C>[CH2:1]([N:5]([CH2:10][S:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: C=O
Reactant: CCCCNCCCC
Reactant: CCCCCCCCCCCCS
Solvent: CC(C)O
Product: CCCCCCCCCCCCSCN(CCCC)CCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dibutylamine (129 gms.; 0.1 mole) was dissolved in isopropanol (25 gms). The solution was cooled in an ice bath and stirred during addition of aqueous formaldehyde (9 ml of 37% solution; 0.11 mole). To the solution there was added dodecylthiol (20.2 gms; 0.1 mole) in one portion and the mixture was stirred for 1 hour at room temperature. Di(butyl) aminomethyl dodecylsulfide was obtained as a clear, homogeneous solution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2([Cl:15])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[H][H]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([C:12]2([Cl:15])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1ccc(Cl)cc1)C1(Cl)CC1
Solvent: Cc1ccccc1
Product: O=C(CCc1ccc(Cl)cc1)C1(Cl)CC1
Temperature: 50 °C
Yield: 90.5 %

Procedure:
460 mg (0.5 mmol) of tris-triphenylphosphine rhodium chloride (=1 mol %, with reference to the reaction components) is added to a 100 ml autoclave. After purging with nitrogen, an air-free solution of 12 g (0.05 mol) of 1-chlorocyclopropyl 4-chlorophenylethenyl ketone in 40 ml of toluene is added and heated at 50° C. under a hydrogen pressure of 30 bar. The hydrogen pressure is kept between 40 and 50 bar until the absorption of gas is complete (after about 1 hour). The mixture is subsequently allowed to react for 1 hour. For working up, the solvent is removed under reduced pressure and the residue which remains is purified on silica gel using dichloromethane as the eluant. 11 g (90% of theory) of 1-chlorocyclopropyl 4-chlorophenylethyl ketone are obtained in the form of an oily product.
Reaction SMILES: [CH2:1]([O:16][C:17]1[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:25](OC1OC(C(O)=O)=CC=1)CCCCCCCCCCCCC>>[CH2:1]([O:16][C:17]1[O:21][C:20]([C:22]([CH3:25])=[O:24])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CCCCC/C=C\CCCCCCCCOc1ccc(C(=O)O)o1
Product: CCCCC/C=C\CCCCCCCCOc1ccc(C(C)=O)o1

Procedure:
When in the procedure of Example 1(B) an appropriate amount of 5-(cis-9-pentadecenyloxy)-2-furoic acid is substituted for 5-(tetradecyloxy)furoic acid, methyl 5-(cis-9-pentadecenyloxy)-2-furyl ketone is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:16])[C:9](=[O:15])[N:10]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[CH:4][CH:3]=1.[CH:17]([B-](F)(F)F)=[CH2:18].[K+].[C:24]([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>O>[CH3:24][C:12]([CH3:13])([CH3:14])[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([CH:17]=[CH2:18])=[CH:3][CH:4]=2)[N:8]([CH3:16])[C:9]1=[O:15]
Reactant: C=C[B-](F)(F)F
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)n(CC2CC2)c2ccc(Cl)nc21
Agent: [Cs+]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 100 °C
Reaction time: 18 h

Procedure:
5-Chloro-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-4, 3 g, 11.8 mmol, 1.0 equiv), potassium vinyltrifluoroborate (31-1, 3.2 g, 23.7 mmol, 2.0 equiv), Cs2CO3 (11.6 g, 35.5 mmol, 3.0 equiv) and 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (0.97 g, 1.2 mmol, 0.10 equiv) were added to 1,4-dioxane (19.7 mL) and water (3.9 mL). The resulting reaction mixture was heated to 100° C. and stirred for 18 h. Following this duration, LCMS showed complete consumption of 1-4. The contents were filtered through Celite and washed with ethyl acetate (10 mL). The filtrate was diluted with saturated NaHCO3 (50 mL) and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3×20 mL) and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a brown semi-solid. Purification by normal-phase HPLC (0-40% EtOAc:hexane) afforded 31-2 as a yellow solid. MS m/z (M+H): calculated=246.1601; observed=246.1608.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][N:10]([C:26]2[C:27]([N+:31]([O-:33])=[O:32])=[CH:28][N:29]=[C:24]([Cl:23])[N:25]=2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CNC2CCCCC2)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
To a solution of ethyl1-[(cyclohexylamino)methyl]cyclopropane-1-carboxylate (Intermediate 273; 7.175 g, 34 mmol) in acetone (200 mL) was added potassium carbonate 7.05 g, 51 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 9.235 g, 47.6 mmol). The reaction mixture was stirred at room temperature for 5 hours. A further addition of 2,4-dichloro-5-nitropyrimidine (4.62 g, 23.8 mmol) and potassium carbonate (3.5 g, 25.5 mmol) was made and the reaction stirred overnight at room temperature. The reaction mixture was then concentrated in vacuo and partitioned between EtOAc and water. The EtOAc layer was separated, dried over sodium sulphate and purified on a silica column eluting with EtOAc/isohexane 10:90, to yield the title compound as a yellow oil (12 g, 92%).
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[NH2:15])[C:9]([OH:11])=[O:10].[CH3:16]O>>[ClH:3].[CH3:16][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([NH2:15])=[C:6]([OH:5])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1O
Product: COC(=O)c1ccc(N)c(O)c1
Product: Cl
Reaction time: 0.25 h

Procedure:
To an anhydrous methanol (100 ml) was added thionyl chloride (14.0 ml) at −10° C. during 20 minutes. After stirring the mixture for 15 minutes, 3-hydroxy-4-aminobenzoic acid (10.0 g) was added at the same temperature. The appeared suspension was stirred at room temperature overnight. The mixture was concentrated and then azeotroped with methanol (50 ml, twice). To the residue was added diethyl ether, and the residue was collected by suction filtration in washing with diethyl ether to give the title compound (12.8 g) having the following physical data.
Reaction SMILES: [OH:1][CH:2]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>CCOCC>[CH2:13]([N:12]([CH2:11][CH:2]([OH:1])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCCCCCNCC(O)CNCCCCCC
Solvent: CCOCC
Product: CCCCCCCCCCCCN(CC(O)CN(CCCCCC)C(=O)CCC(=O)O)C(=O)CCC(=O)O
Yield: 103.8 %

Procedure:
A reactor was charged with 20 g (0.053 mole) of 9-hydroxy-7,11-diaza-tricosane, 13 g (0.130 mole) of succinic anhydride and 300 ml of anhydrous ether, and the contents were refluxed for 5 hours. After completion of a reaction, insoluble succinic anhydride in an excess amount was removed by filtration, and an ether layer was washed with water. The ether was distilled off under reduced pressure, thereby obtaining 30 g (0.055 mole) of 4-dodecyl-8-hexyl-3,9-dioxo-6-hydroxy-4,8-diaza-1,11-undecanedicarboxylic acid as a viscous transparent liquid. After adjusted to pH 10 with sodium hydroxide, this compound gave a single peak in HPLC measurement [column: RP-18 (product of Merck Co.), eluent: methanol/water=80/20]. The 1 H-NMR data of the compound will be shown below.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[CH:14]=1)=O)(=O)[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C([NH2:27])(=O)C.B(F)(F)F.CCOCC>C(OCC)(=O)C>[Cl:23][C:15]1[CH:14]=[C:13]([C:11]2[N:27]=[C:1]([CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[O:9][CH:10]=2)[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: CC(N)=O
Reactant: COC(=O)CCC(=O)OCC(=O)c1cc(Cl)cc(C(F)(F)F)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A stirred solution of 2-(3-chloro-5-(trifluoromethyl)phenyl)-2-oxoethyl methyl succinate (Reference Example 35, 1.10 g, 3.12 mmol), acetamide (0.921 g, 15.59 mmol) and boron trifluoride diethyl etherate (0.565 g, 3.98 mmol) was heated at 140° C. for 2 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 4:1) to provide methyl 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.401 g, 39%) as a yellow viscous oil.
Reaction SMILES: [C:1]([O:4]CC)(=[O:3])[CH3:2].[NH2:7][C:8](=[N:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][NH:20]C(=O)[O:22][CH2:23][C:24]1C=CC=CC=1.C([OH:40])C>[Pd]>[C:23]([OH:40])(=[O:22])/[CH:24]=[CH:2]\[C:1]([OH:4])=[O:3].[NH2:20][CH2:19][CH2:18][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:8](=[NH:7])[NH:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:10]=2)[NH:14][CH:13]=1
Reactant: NC(=Nc1ccccc1)c1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reactant: CCOC(C)=O
Reactant: CCO
Agent: [Pd]
Product: N=C(Nc1ccccc1)c1ccc2[nH]cc(CCN)c2c1
Product: O=C(O)/C=C\C(=O)O
Reaction time: 3 h

Procedure:
The product of Stage (i) (0.8 g) was stirred in ethanol (50 ml) under a hydrogen atmosphere and over 10% palladium on carbon catalyst (0.8, 50% aqueous paste). After 3 h, the catalyst was filtered off [hydrogen uptake=250 ml] and the filtrate evaporated to dryness, to give an oil which was evaporated to a foam (0.5 g), m.p. 80°-92°. A portion of the foam (0.3 g) in hot ethyl acetate was added to an equivalent amount of maleic acid in hot ethyl acetate. The mixture was cooled and the solid collected, washed with ethyl acetate and dried in vacuo at 60° for 2 days to give the title compound, m.p. >110° (decomposes).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([NH:42][C:43]([O:45][C:46]([CH3:49])(C)[CH3:47])=[O:44])[C@H:22]([OH:41])[CH2:23][N:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:25]([C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)[C:52]([OH:54])=[O:53].[CH2:57](N(C(C)C)C(C)C)[CH3:58]>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([NH:42][C:43]([O:45][C@H:46]3[C@H:47]4[C@H:52]([O:54][CH2:57][CH2:58]4)[O:53][CH2:49]3)=[O:44])[C@H:22]([OH:41])[CH2:23][N:24]([CH2:37][CH:38]([CH3:39])[CH3:40])[S:25]([C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)(=[O:27])=[O:26])=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 4-((2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxy-4-{isobutyl[(4-nitrophenyl)sulfonyl]-amino}butyl)phenyl 4-nitrobenzenesulfonate (0.21 mg, 0.29 mmol) in 10 mL of dichloromethane was added dropwise trifluoroacetic acid (2 mL). The mixture was stirred for 1 hour at room temperature. The solvents were removed under reduced pressure; the residue was redissolved in 50 mL of dichloromethane and 20 mL of 5% aqueous sodium carbonate was added. The aqueous phase was separated and extracted with dichloromethane (2×20 mL). The combined organic phases were dried over sodium carbonate, filtered, and concentrated under reduced pressure. The residue was redissolved in 10 mL of acetonitrile. N-Ethyldiisopropylamine (80 uL, 0.05 mmol) and (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-4-nitrophenylcarbonate (0.11 g, 0.37 mmol) were added, and the solution was stirred for 12 hours. The solvents were removed under reduced pressure. The residue was redissolved in ethyl acetate (30 mL), and the organic phase was extracted with water (20 mL) followed by 5% aqueous sodium carbonate solution (5×20 mL). The organic phase was dried with sodium carbonate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes as eluent to provide 0.12 g (55%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]([NH:5][N+:6]([O-:8])=[O:7])=[NH:4].[OH-].[Na+].[Cl:12][C:13]1[S:14][C:15]([CH2:18]Cl)=[CH:16][N:17]=1>CN(C=O)C>[Cl:12][C:13]1[S:14][C:15]([CH2:18][NH:4][C:3]([N:2]([CH3:9])[CH3:1])=[N:5][N+:6]([O-:8])=[O:7])=[CH:16][N:17]=1
Reactant: CN(C)C(=N)N[N+](=O)[O-]
Reactant: ClCc1cnc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reaction time: 13 h

Procedure:
To a mixture of 13.0 g of N,N-dimethyl-N'-nitroguanidine, 5.90 g of powdery sodium hydroxide and 200 ml of dry DMF was dropwise added a solution of 2-chloro-5-(chloromethyl)thiazole in 15 ml of DMF over 2 hours while cooling with ice. The bath was removed, and stirring continued at room temperature for 13 hours followed by removal of the DMF by distillation under reduced pressure. To the residue was added 200 ml of acetonitrile followed by separation of insoluble materials by filtration on celite. The filtrate was purified by column chromatography (eluted with dichloromethane-acetonitrile 2:1-1:2). There was obtained 6.45 g of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-2-nitroguanidine (reference compound No. 1), mp 155°-160° C. Crystallization from ethanol raised mp to 165.5°-166.5° C. NMR (DMSO-d6): 2.96(6H, s), 4.50(2H, d, J=5.8 Hz), 7.56(1H, s), 8.53(1H, br t, J=5.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28].O>C(Cl)(Cl)Cl>[C:27]([O:13][C:11]1[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH:12]=1)(=[O:29])[CH3:28]
Reactant: Oc1cc(-c2ccc(Br)cc2)nn1-c1ccccn1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1cc(-c2ccc(Br)cc2)nn1-c1ccccn1

Procedure:
3-(4-bromophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol (3 mmol, 1 equivalent) was dissolved in 10 mL of CHCl3 and 1.2 equivalents of triethylamine were added thereto at 0° C. Then, 1 equivalent of acetyl chloride was added thereto, followed by refluxing for 10 minutes. After the reaction was completed, H2O (10 mL) was added to the solution which was then extracted with CHCl3. The organic layer was dried over anhydrous MgSO4, filtered, concentrated, and then separated by column chromatography (n-hexane:EA=5:1 (v/v)) to afford the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH:27]=C)[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:29]=[O+][O-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl.C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][OH:29])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:17])([CH3:18])[N:13]1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: O=[O+][O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 340 %

Procedure:
A solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (15 g) in dry CH2Cl2 (250 mL) was treated with a stream of O3 until the reaction mixture turned blue at −78° C. The system was then flushed with O2 to remove excess ozone. Me2S was added and the mixture was allowed to warm to rt. Solvents were removed in vacuo to give the crude product (12 g). The crude product was dissolved in 250 mL of dry THF. The resulting mixture was cooled to 0° C. before LiAlH4 was added. After being stirred for 30 min, the reaction was quenched with 40 mL of H2O followed by 120 mL of 1 N NaOH. The resulting white slurry was filtered through celite, and the clear, colorless filtrate was dried over anhydrous Na2SO4. Filtration followed by concentration in vacuo gave the crude product, which was purified by flash column to give the pure product (S)-tert-butyl 4-((S)-2-((tert-butyldimethylsilyloxy)methyl)-4-hydroxybutyl)-2,2-dimethyloxazolidine-3-carboxylate (5.2 g, 340%). 1H NMR (CDCl3, 400 MHz) δ 0.06 (s, 6H), 0.89 (s, 9H), 1.46 (s, 12H), 1.50 (m, 3H), 1.53 (m, 3H), 3.09 (m, 1H), 3.49 (m, 2H), 3.50 (m, 2H), 3.7 (m, 2H), 3.90 (m, 1H).