Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:13])[NH:7]1)=O)C.B.[Li].Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O1CCCC1>[OH:3][CH2:4][CH:6]1[NH:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)C1CCCCC(=O)N1
Agent: B
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CCCCC(CO)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
3.10 g of 7-oxo-azepane-2-carboxylic acid ethyl ester (compound G1) are dissolved in 150 ml of dichloromethane under an atmosphere of dry nitrogen. At room temperature, 8.45 ml of lithium boron hydride solution in tetrahydrofuran (strength 2.0 M) are slowly added to the solution in the course of 10 min. Thereafter, the reaction mixture is stirred for 17 hours overnight at room temperature. Subsequently, the mixture is cooled in an ice bath and acidified to pH 1 using hydrochloric acid (strength 3.0 M). Under stirring, the reaction mixture is allowed to warm up to room temperature. Thereafter, potassium carbonate is carefully added thereby re-adjusting neutral pH. The reaction mixture is filtered with suction and the filtrate is concentrated in vacuo. Purification is achieved by flash chromatography (eluent gradient: dichloromethane/0-10 vol. % ethanol) to yield 1.46 g of the title compound as colorless solid of m.p. 100° C. ESI-MS: 144.1 (MH+). TLC: Rf=0.47 (dichloromethane/ethanol 10:1 parts by volume; iodine staining).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OC(c1ccccc1)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(C(Cl)c2ccccc2)cc1
Yield: 95.2 %

Procedure:
In dichloromethane (30 mL), (±)-(4-fluorophenyl)phenylmethanol (2.1 g, 10 mmol) synthesized in Production Example 195 was dissolved, and thionyl chloride (5.1 g, 42 mmol) was added dropwise thereto at a room temperature. After the completion of the dropping, the mixture was heated under reflux, and the completion of the reaction was confirmed by TLC. After the completion of the reaction, the reaction mixture was concentrated, diluted with ethyl acetate, and washed with water. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. Thus the title compound (2.1 g, 94%) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(I)c(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCc1nc(I)c(C=O)[nH]1
Yield: 84.2 %

Procedure:
A stirred mixture of 174.1 g (0.62 mol) of 2-butyl-5-hydroxymethyl-4-iodoimidazole and 360 g (4.14 mol) of manganese dioxide in 3 liters of methylene chloride was refluxed for 24 hours using a trap to remove water. The hot reaction mixture was filtered through Celite® which was then washed with 4.5 liters of boiling methylene chloride. The combined filtrates were concentrated to dryness, the residue was dissolved twice in 150 mL of methanol and the solution was concentrated to dryness. The residue was dissolved in 130 mL of methanol and chilled. After crystallization had occurred, 700 mL of water was added slowly. The mixture was chilled, the solid was collected by filtration, and washed with water to give 145.2 g (84%) of product; mp 104°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:10]([CH3:12])[CH3:11].C([Li])CCC.C(OCC)C.[C:23](=[O:25])=[O:24]>O1CCCC1>[Cl:1][C:2]1[C:3]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: CC(C)Oc1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Oc1ccc(Cl)c(C(=O)O)c1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloro-1-isopropoxybenzene (3.53 g) in tetrahydrofuran (35 ml) was added n-butyl lithium solution (1.6 Mol solution in n-hexane, 11 ml) through a syringe at -78° C. After stirring for one hour at -78° C., the mixture was poured into dry diethyl ether (50 ml) containing pulverized dry ice in a few minutes. After warming to ambient temperature, the mixture was concentrated in vacuo. The residue was partitioned between diethyl ether (50 ml) and aqueous 10% sodium. hydroxide solution (100 ml). The aqueous layer was adjusted to pH 2 with 10% hydrochloric acid. The separated oil was extracted with dichloromethane. The extract was washed with water, dried, and evaporated under reduced pressure. The residue was crystallized from n-hexane to give 2,6-dichloro-3-isopropoxybenzoic acid (3.0 g).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].I[CH3:15]>C1COCC1>[F:1][CH2:2][CH2:3][N:4]([CH3:15])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCF)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
To a solution of tert-butyl 2-fluoroethylcarbamate (4.1 g, 25.1 mmol) in THF (100 mL) at 0° C. was added sodium hydride, 60 wt % in mineral oil (1.507 g, 37.7 mmol) portion-wise. The reaction was stirred under N2 for 15 minutes after which gas evolution ceased. Iodomethane (2.356 mL, 37.7 mmol) was added drop-wise and the reaction stirred under N2. After 6 h, the reaction was quenched with water (100 mL) and concentrated. The aqueous solution was washed with CH2Cl2 (3×50 mL). The CH2Cl2 extracts were combined, washed with water (2×100 mL), dried (MgSO4) and concentrated to afford the title compound (4.0 g, 90% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 4.58 (1H, brs), 4.47 (1 H, brs), 3.53 (1 H, brs), 3.47 (1 H, brs), 2.94 (3 H, s), 1.45 (9 H, s).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:21][C@H:22]1[CH2:26][CH2:25][NH:24][CH2:23]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:18]([N:24]1[CH2:25][CH2:26][C@H:22]([OH:21])[CH2:23]1)=[O:20])([CH3:5])([CH3:6])[CH3:7]
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (S)-N-Boc-4-fluorophenylalanine (5.08 g, 17.9 mmol) and (S)-3-hydroxypyrrolidine (1.05 mL, 19.7 mmol) in anhydrous DMF (200 mL), was added DIPEA (6.87 mL, 39.5 mmol) and HOBt.H2O (3.02 g, 19.7 mmol). The reaction mixture was stirred for 10 min at room temperature then EDCI (4.13 g, 21.5 mmol) was added and the resulting mixture stirred for 20 h at rt. The volatiles were removed in vacuo then the residue partitioned between water (200 mL) and ethyl acetate (200 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (3×50 mL). The combined organics were washed with aqueous sodium hydroxide solution (2M, 3×50 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The oily residue was purified via flash chromatography (SiO2, methanol/dichloromethane, 1:19, v/v) to give the title compound as a colourless oil which became a white solid on standing. m/z (ES+)=353 [M+H]+; RT=3.17 min.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)C1C=CC=CC=1.C(O)=O.N.[H][H]>CCO.[Pd].[OH-].[OH-].[Pd+2]>[C:17]1([CH2:16][CH2:15][CH2:14][C@H:10]2[CH2:9][NH:8][CH2:13][CH2:12][NH:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: C(=Cc1ccccc1)C[C@H]1CN(Cc2ccccc2)CCN1
Agent: [Pd+2]
Agent: [Pd]
Agent: N
Solvent: O=CO
Solvent: CCO
Product: c1ccc(CCC[C@H]2CNCCN2)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
Combine (S)-1-benzyl-3-(3-phenyl-allyl)-piperazine (1.45 g, 5.0 mmol), 10% Pd/C (265 mg, 0.025 mmol) and ammonia formate (1.57 g, 25.0 mmol) in EtOH (90 mL) and heat to reflux for 3 hours, cool to room temperature, remove the catalyst by filtration. Concentrate the solvent to a residue, which 1H NMR shows that the carbon-carbon double bond has been reduced, but the benzyl group remains. Subject the residue to the reaction with 10% Pd(OH)2/C (350 mg, 0.5 mmol) in EtOH with a balloon of hydrogen under reflux conditions. After refluxing for 3 hours, cool the reaction to room temperature, remove the catalyst, concentrate to a residue, and purification by silica gel chromatography using 2N NH3 in MeOH and dichloromethane (5%–15%) to give the title compound (950 mg, 93%): mass spectrum (Electrospray): m/z=205.2 (M+1); 1H NMR (CDCl3): δ7.29–7.15 (m, 5H), 2.97–2.59 (m, 6H), 2.35 (t, 1H, J=9.8 Hz), 1.70–1.45 (m, 6H), 1.38–1.25 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH:27][C:41]([CH:38]3[CH2:40][CH2:39]3)=[O:42])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:31]=[C:32]([CH3:37])[CH:33]=[C:34]([CH3:36])[CH:35]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(NC(=O)C4CC4)c(Cl)cc3[nH]c2=O)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (162 mg in 8 mL chlorobenzene) was added cyclopropanecarbonyl chloride (0.054 mL) and the mixture heated to 100° C. After 4 hours, the reaction was cooled and the solvent removed in vacuo. The residue was dissolved in methylene chloride and washed with saturated sodium bicarbonate. Concentration of the crude organics provided the title compound (80 mg).
Reaction SMILES: [CH2:1]([CH:4]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]2[C:6]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:7][C:8]3[C:13]2=[CH:12][CH:11]=[C:10]([O:19][CH2:20][O:21][CH3:22])[CH:9]=3)[CH2:5]1)C=C.[O:27]1[CH2:32][CH2:31][O:30]CC1>O>[CH2:23]([C:6]12[CH2:5][CH:4]([CH2:1][C:31](=[O:30])[CH2:32][OH:27])[C:16](=[O:17])[C:15]([CH3:18])=[C:14]1[C:13]1[C:8](=[CH:9][C:10]([O:19][CH2:20][O:21][CH3:22])=[CH:11][CH:12]=1)[CH2:7]2)[CH2:24][CH2:25][CH3:26]
Reactant: C=CCC1CC2(CCCC)Cc3cc(OCOC)ccc3C2=C(C)C1=O
Reactant: C1COCCO1
Solvent: O
Product: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(CC(=O)CO)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (2SR,9aSR)-2-allyl-9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (170 mg, 0.48 mmol) in dioxane (9 mL) was diluted with water (3 mL) and treated with a single crystal of OSO4 followed by NaIO4 (125 mg, 0.58 mmol). The mixture was stirred at room temperature for 15 minutes, treated with more NaIO4 (132 mg, 0.62 mmol), and stirred an additional 30 minutes at room temperature. Workup provided a gum which was purified by PLC on two 0.1×20×20 cm silica gel GF plates, developing twice with 4:1 hexanes-EtOAc. The minor UV visible band provided (2RS,9aSR)-9a-butyl-2-(3-hydroxy-2-oxopropyl)-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (26 mg) as an oil. The major UV visible band afforded (2RS,9aSR)-9a-butyl-7-methoxymethoxy-4-methyl-2-(2-oxoethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (85 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Br:14].[CH3:15][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[CH:4][C:3]=1[Br:14]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1c(Br)cc(C(=O)O)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 4-amino-3-bromo-5-nitrobenzoic acid (3.65 g, 14.0 mmol) in dichloromethane (35 mL) and methanol (35 mL) at 0° C. was slowly added trimethylsilyl-diazomethane (8.74 mL, 17.5 mmol). The mixture was allowed to warm to ambient temperature and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (1.54 g). LC-MS [M]=275.1.
Reaction SMILES: [S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.C1([C@]2(CO)CCCN2C2C=CC=CC=2)C=CC=CC=1.C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.B.B.CSC>C1COCC1>[S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C@@H:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCS(=O)(=O)c2sccc21
Agent: B
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Agent: OC[C@@]1(c2ccccc2)CCCN1c1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: O=S1(=O)CC[C@@H](O)c2ccsc21
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-one-7,7-dioxide (9) (1.00 g, 4.94 mmol) in dry THF (14 mL) was added (S)-diphenylprolinol--borane complex from Example 12 (132 mg, 0.494 mmol). The solution was cooled to -15° C. and a solution of borane-methyl sulfide (10M, 0.4 mL, 4.0 mmol) in dry THF (6.8 mL) was added at a rate to maintain the internal temperature at -15° C. The solution was stirred at -15° C. for 1 hour then at 22° C. for 6 hours. The product was isolated by the method decribed in Example 34 Step E. The enantiomeric ratio of the purified product was 95.5.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.[OH-].[Na+:25]>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][CH:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]([O-:22])=[O:21].[Na+:25]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])C(Cc1ccccc1)N=Cc1ccc(Cl)cc1Cl

Procedure:
A solution of 18.5 grams of 2,4-dichlorobenzaldehyde in 50 milliliters of ethanol was added to a solution of 16.5 grams of phenylalanine in about 50 milliliters of alcoholic sodium hydroxide (prepared from 4 grams of sodium hydroxide in 50 milliliters of 1:1 water:ethanol) to obtain sodium 2-(2,4-dichlorobenzalamino)-3-phenylpropionate (Schiff base) and water by-product in the reaction mixture. The solvent was evaporated and the residue was redissolved in ethanol and evaporatively distilled to remove the water in rotary evaporator. The vessel was flushed four times with 100 milliliter portions of toluene to obtain the Schiff base in a solid mixture.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=1)[CH2:12][N:13]1[CH2:17][CH2:16][N:15]([C@H:18]([CH:26]([CH3:28])[CH3:27])[C:19](OC(C)(C)C)=[O:20])[C:14]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.CCN(C(C)C)C(C)C.ClC(OCC)=O.C[Si](C)(C)[O:57][NH2:58].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=1)[CH2:12][N:13]1[CH2:17][CH2:16][N:15]([C@H:18]([CH:26]([CH3:27])[CH3:28])[C:19]([NH:58][OH:57])=[O:20])[C:14]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)ON
Reactant: CC(C)[C@H](C(=O)OC(C)(C)C)N1CCN(Cc2cccc(OCc3ccccc3)c2)C1=O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](C(=O)NO)N1CCN(Cc2cccc(OCc3ccccc3)c2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 8.7 %

Procedure:
t-Butyl (R)-2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (102 mg; 0.23 mmol) was dissolved in CH2Cl2 (2 ml) and cooled to 0° C. Trifluoroacetic acid (TFA; 1 ml) was added, and the mixture was stirred for 2 h. The solvents were removed under reduced pressure, and the residue was taken up in tetrahydrofuran (THF; 2 ml). DIEA (0.16 ml; 0.93 mmol) and ethyl chloroformate (67 μl; 0.69 mmol) were added. After stirring at RT for 2 h, O-trimethylsilylhydroxylamine (0.10 ml; 1.39 mmol) was added. The mixture was stirred for 15 h, HCl (6N, 0.30 ml) was added, and then the solvents were removed under reduced pressure. Purification of the residue by preparative HPLC resulted in (R)-2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyramide (8 mg, 0.02 mmol). MS: 398.15 (M+H); Rt: 1.46 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][O:5][C:4]([C:14]([NH2:16])=O)=[CH:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.C(N(CC)CC)C>[O:1]=[C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][O:5][C:4]([C:14]#[N:16])=[CH:3]1
Reactant: NC(=O)c1cc(=O)c(-c2ccccc2)co1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1cc(=O)c(-c2ccccc2)co1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of this amide (3.5 g) and triphenylphosphine (8.54 g) in carbon tetrachloride (10 ml), methylene chloride (20 ml) and triethylamine (2.3 ml) was stirred for 4 hours at room temperature. Ice (60 g) and 2 N hydrochloric acid (30 ml) were added, followed by sufficient chloroform to dissolve all the solid material. The solvent layer was washed with water, dried and evaporated, and the residue was crystallised from chloroform-petroleum spirit (60°-80° C.) and then from ethanol to give the title product (mp 177°-179° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[Se:19][C:18]([CH:20]=O)=[CH:17][CH:16]=3)=[C:11]([F:22])[C:10]=2F)=[CH:5][CH:4]=1)[CH3:2].[CH3:24][C:25](C)([O-])C.[K+].O.Cl>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[Se:19][C:18]([CH:20]=[CH:24][CH3:25])=[CH:17][CH:16]=3)=[C:11]([F:22])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccc(-c3ccc(C=O)[se]3)c(F)c2F)cc1
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC=Cc1ccc(-c2ccc(-c3ccc(CC)cc3)cc2F)[se]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.70 g (12.7 mmol) of ethyltriphenylphosphonium bromide are initially introduced together with 3.70 g (9.86 mmol) of 5-(4′-ethyl-2,3-difluorobiphenyl-4-yl)selenophene-2-carbaldehyde in 180 ml of THF, and a solution of 1.40 g (12.5 mmol) of potassium tert-butoxide in 20 ml of THF is added with ice-cooling. The mixture is stirred at RT for 1 h. Water and 2 N hydrochloric acid are added, and the batch is extracted with MTBE. The organic phase is washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=95:5). 2-(4′-Ethyl-3-fluorobiphenyl-4-yl)-5-propenylselenophene is obtained as a yellow solid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=1>ClCCl>[CH3:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([Cl:2])=[O:15])[N:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1nc(C(=O)O)cs1
Solvent: ClCCl
Product: Cc1nc(C(=O)Cl)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.2 %

Procedure:
Phosphorus pentachloride (13.35 g) was added in small portions to a suspension of 2-methyl-4-thiazolecarboxylic acid (7.65 g) in dry dichloromethane over a period of 10 minutes. The resulting mixture was vigorously stirred for 1.5 hours at room temperature and then concentrated under reduced pressure. The residue was dissolved in dry benzene (40 ml) and the mixture was concentrated under reduced pressure to give yellow powders of 2-methyl-4-thiazolecarbonyl chloride (9.0 g).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@@H:3]([OH:6])[CH2:4][OH:5].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](S([O-])(=O)=O)=[CH:13][CH:12]=1.C1C=C[NH+]=CC=1.COC(OC)C1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:9])[CH2:7][O:8][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C@H:3]1[CH2:4][OH:5]
Reactant: CC(C)(CO)[C@@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: COC(OC)c1ccccc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)COC(c2ccccc2)O[C@H]1CO
Yield: 220.4 %

Procedure:
Following the general procedure for the transacetalization reaction of Description 6, 6.6 g (49.2 mmol) of (2R)-3,3-dimethylbutane-1,2,4-triol (6) was reacted in 120 mL of dichloromethane (DCM) in the presence of 2.51 g (10.0 mmol) of PPTS with 11.3 mL (11.4 g, 75.0 mmol) of benzaldehyde dimethyl acetal. Purification by silica gel column chromatography using diethylether (Et2O) and hexane (Hxn) mixtures as eluent (Et2O/Hxn=2:3→Et2O/Hxn=1:1→Et2O/Hxn=3:2) provided 4.9 g (45% yield) of the title compound (7a) as a colorless liquid. Rf=0.44 (Et2O/Hxn=2:3). 1H NMR (400 MHz, CHCl3): δ=0.86 (s, 3H), 1.16 (s, 3H), 2.02-2.06 (m, 1H), 3.60-3.64 (m, 1H), 3.68-3.72 (m, 4H), 5.52 (s, 1H), 7.33-7.41 (m, 3H), 7.49-7.53 (m, 2H) ppm. MS (ESI) m/z: 223.0 (M+H)+, 245.0 (M+Na)+. The analytical data for the compound was consistent with that given in the literature.
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:23][N:22]([C:34](OCC2C=CC=CC=2)=O)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O-])([O-])=O.[K+].[K+].CC(OC)(C)C>C1COCC1>[CH3:34][N:22]1[CH2:23][C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C@H:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21]1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOC1CN(C(=O)OCc2ccccc2)CC1OCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C)C[C@@H]1OCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 100 mL RBF fitted with reflux condenser, compound 10 (4 g, 6.69 mmol) was dissolved in 26 mL THF for addition of the lithium aluminum hydride (13.38 ml, 13.38 mmol). Heated to reflux in a 85 C. oil bath. After 2 h, HPLC shows complete dissappearance of the SM. Cooled to RT and poured into 200 mL IM K2CO3 and 200 mL MTBE. Stirred for 30 min, separated layers and then extracted with 100 mL MTBE. Dried combined organics over Na2SO4, filtered through Celite and concentrated. Flash chromatography (10-30% IPA in DCM) provided compound 11 as a clear oil. 1H NMR (400 MHz, CDCl3) δ 5.39 (m, 4H), 3.93 (m, 2H), 3.50 (m, 4H), 3.04 (m, 2H), 2.79 (m, 2H), 2.48 (m, 2H), 2.39 (s, 3H), 2.08 (m, 4H), 1.62 (m, 4H), 1.40-1.25 (m, 26H), 0.91 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[C:27]([C:32](Cl)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.NC1C=CC(N2C(=O)CC(=O)NC3C(CC)=CC=CC2=3)=CC=1>>[CH3:25][C:26]1[C:27]([C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccnc1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CCc1cccc2c1NC(=O)CC(=O)N2c1ccc(N)cc1
Product: Cc1cccnc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 87 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 3-methylpicolinic acid chloride, the title compound (yield 87%) was obtained in the same manner as that of Example 1, (4).