Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH:24]([CH:27]1[NH:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]1=[O:34])([CH3:26])[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[CH:27]([CH:24]([CH3:25])[CH3:26])[C:28](=[O:34])[N:29]([CH3:33])[C:30]4=[O:32])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: CC(C)C1NC(=O)N(C)C1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C(C)C)cc3)CC2)c(C)c1
Yield: 52.7 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 5-isopropyl-3-methylimidazolidine-2,4-dione (69 mg) described in Preparation Example 216 and by the reaction and treatment in the same manner as in Example 536, the title compound (95 mg) was obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:1]([C:13]1[CH:14]=[CH:15][C:10]([CH3:16])=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
Dinitrotoluene is an important intermediate in producing toluenediisocyanate based polyurethanes. One of the conventional processes for producing dinitrotoluene is referred to as the mixed acid nitration process wherein toluene is reacted with nitric acid in the presence of sulfuric acid in a mononitration zone to produce the intermediate product, mononitrotoluene (MNT), which then is separated from the spent acid and the recovered mononitrotoluene contacted with nitric acid in the presence of sulfuric acid to form dinitrotoluene in a dinitration zone. Dinitrotoluene (DNT) then is separated from the aqueous phase and the spent sulfuric acid purified and concentrated. Typical, product specifications (weight %) for commercial grade dinitrotoluene generally will be greater than 98.5% dinitrotoluene, less than 0.1% mononitrotoluene, less than 0.1% trinitrotoluene, less than 0.1% by-products, less than 1.0% water and yield of toluene to dinitrotoluene greater than 98% at conversion levels of >99.9%. The isomer content of product DNT contains a minimum of 95% (on a water free basis) 2,4-plus 2,6-isomer with the balance of the DNT being made up of 2,3-; 3,4-; 2,5-; and 3,5-isomers. The normalized 2,4-plus 2,6-isomer content is between 79.0-81.0% 2,4-isomer and between 19.0-21.0% 2,6-isomer.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C@@H:6]1[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:28][C@H:29]([CH2:32][CH2:33][CH3:34])[CH2:30][CH3:31]>C1COCC1>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C@@H:9]([CH2:28][C@@H:29]([CH2:30][CH3:31])[CH2:32][CH2:33][CH3:34])[C:8](=[O:11])[N:7]([CH3:12])[C@@H:6]1[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4]
Reactant: COC(=O)N1CCC(=O)N(C)[C@@H]1C(C)(C)C
Reactant: CCC[C@H](CC)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC[C@H](CC)C[C@@H]1CN(C(=O)OC)[C@@H](C(C)(C)C)N(C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a −78° C. stirred solution of (S)-2-tert-butyl-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester (1.04 g, 4.57 mmol) in dry THF (15 mL) was added NaHMDS (5.03 mL, 1.0 M in THF) dropwise. The reaction was stirred at −78° C. for 1 hour and then a solution of (S)-3-Iodomethyl-hexane (1.24 g, 5.48 mmol) in dry THF (5 mL) was added dropwise. The reaction was stirred at this temperature for 2 hours and than was placed in a −10° C. refrigerator overnight. The reaction was quenched with sat. NH4Cl (20 mL) and was allowed to warm to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The organic extracts were combined and washed with brine (2×15 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified by chromatography using hexanes/EtOAc (10–>20%) to yield 0.185 g (12%) of pure product: 1H NMR (400 MHz, CD3OD) 8 ppm 0.9 (m, 6 H), 1.3 (m, 5 H), 1.4 (m, 3 H), 1.7 (m, 1 H), 2.5 (m, 1 H), 2.9 (d, J=6.6 Hz, 2 H). MS: M+1 (328).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C=C[S:48]C=3CCC2C)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[CH:21]=[CH:22][S:48][C:25]=3[CH2:24][CH2:23][C@H:19]2[CH3:20])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2c3ccsc3CCC2C)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccsc2CC[C@H]1C

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.35–7.30, 7.10, 6.90, 5.18, 4.60, 2.85, 2.66, 2.49, 2.05, 1.82, 1.29–1.12; HRMS (FAB) calcd for C23H25Cl2N3S+H 446.1224, found 446.1230. Anal. Calcd for C23H25Cl2N3S: C, 61.88; H, 5.64; N, 9.41; Cl, 15.88; S, 7.18. Found: C, 62.04; H, 5.77; N, 9.04.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:5][CH:3]2[CH2:4][O:1][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1COC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.5 %

Procedure:
To a stirred mixture of oxetan-3-ol (0.85 g, 11.5 mmol) in DCM (38 mL) were added TEA (3.3 mL, 23 mmol) and 4-methylbenzene-1-sulfonyl chloride (2.7 g, 13.8 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was partitioned between water and DCM. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 30% DCM in petroleum ether to 100% DCM to afford oxetan-3-yl 4-methylbenzenesulfonate (1.3 g, 50%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.7 Hz, 2H), 5.30 (m, 1H), 4.66-4.74 (m, 4H), 2.46 (s, 3H); LCMS (ESI) m/z 229 (M+H)+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[BrH:21]>O>[Br:21][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(N2CCC(O)CC2)cc1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1CCN(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1-(4-aminophenyl)piperidin-4-ol (600 mg, 3.12 mmol), HBr (14 mL, 48%), was mixed and cooled to 0° C., the solution of NaNO2 (215 mg, 3.12 mmol) in 2.3 mL water was added in. the mixture was stirred for 15 minutes, the solution of CuBr (246 mg, 1.72 mmol) in HBr (4.4 mL 4.8%) was added and reacted at 100° C. for 3 hours. 2M NaOH solution was added, extracted by EA, washed by 2M NaOH, dried over Na2SO4, concentrated and purified by flash chromatography. (PE:EA=3:1) to give 520 mg pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[C:13](OCC)(OCC)([O:15][CH2:16][CH3:17])[CH3:14].C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[C:8](=[C:13](/[O:15][CH2:16][CH3:17])\[CH3:14])/[C:9]#[N:10])=[O:7])=[CH:11][CH:12]=1
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1

Procedure:
A solution of 16.3 g. of p-fluorobenzoylacetonitrile and 18.3 ml. of triethyl orthoacetate in 35 ml. of acetic anhydride is heated on a steam bath for 2.5 hours. The solvents are removed in vacuo and the residue is distilled at 165°-167° C./300μ. Upon cooling, this distillate solidifies and is recrystallized from methylene chloride/hexane to give the desired 2-(p-fluorobenzoyl)-3-ethoxycrotononitrile, m.p. 77°/89° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccccc1OCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccccc2F)CC1
Temperature: 25 °C

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (2.79 g, 15 mmol) and 1-(2-bromoethoxy)-2-fluoro-benzene (3.28 g, 15 mmol) in DMF (6 mL) was added cesium carbonate (Cs2CO3, 9.75 g, 30 mmol). The mixture was stirred at room temperature for a day and then treated with water. The aqueous solution was extracted with ethyl acetate and the extract was washed with water and brine. The organic layer was concentrated and the residue was dried under the vacuum to yield the title compound quantitatively as an oil (5.1 g). 1H NMR (400 MHz, DMSO-d6): δ 1.39 (s, 9H), 2.44 (t, 4H), 2.73 (t, 2H), 3.29 (t, 4H), 4.45 (t, 2H), 6.93 (m, 1H), 7.11 (t, 1H), 7.18 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[OH-].[Na+].[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.Cl>O.CCO>[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1/[CH:17]=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([CH3:11])[CH:4]=1)=[O:10]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)/C=C/c2cccc(Cl)c2Cl)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a mixture of 1-(4-hydroxy-3-methylphenyl)ethanone (0.7 g, 4.66 mmol) (ICC, Indofine Chemical Company Inc.) and NaOH (0.36 g, 9.1 mmol) in 10 mL of 200 proof EtOH was added 2,3-dichlorobenzaldehyde (0.8 g, 4.66 mmol) (ACROS). The reaction mixture was stirred at rt for 18 h. Upon completion by LC/MS, 5 mL of H2O was added and the reaction mixture was acidified with conc. HCl to pH 5-6. The resulting precipitate was filtered, washed with water and dried to yield (E)-3-(2,3-dichlorophenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one, (0.45 g, 31%). MS (EI) for C16H12C2O2, 308.3 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:16][CH3:17])=[CH:11][CH:10]=3)=[CH:3][CH2:2]1.OOS([O-])=O.[K+].[OH2:33].O1CCCC1.[OH2:39]>>[O:1]1[CH2:6][CH2:5][C:4]([C:7]2[N:8]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:16]([CH3:17])(=[O:39])=[O:33])=[CH:11][CH:10]=3)=[CH:3][CH2:2]1
Reactant: CSc1ccc2c(c1)cc(C1=CCOCC1)n2S(=O)(=O)c1ccccc1
Reactant: O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2c(c1)cc(C1=CCOCC1)n2S(=O)(=O)c1ccccc1
Reaction time: 15 h

Procedure:
To a solution of the compound obtained in Example 14 (2) (33.7 mg) in a mixture of tetrahydrofuran/water (3:1, 4 ml), OXONE (registered trademark) (134 mg) was added at 15 to 30° C. and the mixture was stirred for 15 hours. The reaction solution was then poured into water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 28.8 mg of the desired product as a white powder.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([OH:9])=[O:8])[CH2:3]1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=1[N+:24]([O-:26])=[O:25]>>[C:14]([O:8][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([O:1][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=2[N+:24]([O-:26])=[O:25])[CH2:3]1)=[O:9])([CH3:20])([CH3:15])[CH3:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: O=C(O)N1CC[C@@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[N+](=O)[O-])C1

Procedure:
deprotonating (R)-3-Hydroxypyrrolidine-1-carboxylic acid tent-butyl ester, and reacting the resultant compound with 2-chloro-1,3-dinitro-5-trifluoromethylbenzene to form (R)-3-(2,6-dinitro-4-trifluoromethylphenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester;
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(Cl)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.90 g, 5.0 mmole), triethylamine (0.50 g, 5.0 mmole) and 4-(dimethylamino)pyridine (0.61 g, 5.0 mmole) in dry dichloromethane (100 mL) was added a solution of 3,4-dichlorophenyl isocyanate (0.94 g, 10.0 mmole) in dry dichloromethane (25 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 24 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (1.07 g, 58% yield), mp=89–91° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=+25.9° (c=1, EtOH).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:36][CH2:37][CH3:38])[CH:35]=1)[CH:31]=O)[CH3:26]>ClC(Cl)C.ClCCl>[Br:2][C:1]([Br:5])=[CH:31][C:30]1[CH:33]=[C:34]([O:36][CH2:37][CH3:38])[CH:35]=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=1
Reactant: CCOc1cc(C=O)cc(OCC)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(C=C(Br)Br)cc(OCC)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Carbon tetrabromide (4.78 g) was dissolved in dichloroethane (14 mL), and triphenylphosphine (7.56 g) was added thereto at 0° C. After stirring at 0° C. for 5 minutes, a solution of 3,5-diethoxybenzaldehyde (1.40 g) in dichloromethane (7 mL) was added thereto, followed by stirring for 20 minutes. Without performing further treatment, the reaction mixture was purified by silica gel chromatography (developing solvent: hexane/ethyl acetate) to obtain 1-(2,2-dibromovinyl)-3,5-diethoxybenzene. The obtained compound was used for the subsequent reaction without further purification. The compound obtained above was dissolved in THF (30 mL). A 1.63 M n-butyllithium solution in hexane (10.5 mL) was added thereto at −78° C. The resulting mixture was stirred at −78° C. for 30 minutes. After adding a saturated aqueous ammonium chloride solution, the reaction mixture was subjected to extraction using ethyl acetate. The resulting organic layer was washed with a saturated sodium chloride solution, and the organic layer was then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (1.31 g). Physical properties: m/z [M+H]+ 191.0
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[C:9](Cl)([Cl:11])=[O:10]>O1CCCC1>[Cl:11][C:9]([NH:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8])=[O:10]
Reactant: O=C(Cl)Cl
Reactant: NN1CC(=O)NC1=O
Solvent: C1CCOC1
Product: O=C(Cl)NN1CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.5 g. (0.1 mol.) of 1-amino-2,4-dioxoimidazolidine are thoroughly stirred into 150 ml. of absolute tetrahydrofuran. A solution of 15 g. (0.15 mol.) of phosgene in 25 ml. of absolute tetrahydrofuran is added dropwise at 0°-5° over 20 minutes. The mixture is then stirred for 3 hours at room temperature. An almost clear solution results. This is filtered and the solvent is evaporated in vacuum. The oily residue crystallizes on trituration with petroleum ether to obtain 1-(chlorocarbonylamino)-2,4-dioxoimidazolidine, yield 17.2 g., m.p. 126° (dec.).
Reaction SMILES: [NH2:1][CH:2]([P:10]([OH:12])[OH:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1.[OH-].[Na+]>[C:14]([NH:1][CH:2]([P:10]([OH:12])[OH:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: NC(CC1CCCCC1)P(O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NC(CC1CCCCC1)P(O)O)OCc1ccccc1
Reaction time: 48 h

Procedure:
A solution of 7.00 g (0.037 moles) of 1-amino-2-cyclohexylethylphosphonous acid in 105 ml of dioxane and 40 ml of 1N NaOH was cooled to 0° C. in an ice bath and stirred vigorously while 10.50 ml (12.53 g; 0.073 moles) of benzyl chloroformate and 80 ml of 1N NaOH were added rapidly and simultaneously over a period of approximately 1 minute. The pH was adjusted to the 8-9 range using 1N NaOH (hydrion paper) added in small increments. The reaction mixture was allowed to come to room temperature, and vigorous stirring was continued for 48 hours. The dioxane was removed in vacuo and the aqueous washed with 100 ml of ether. The ether layer was discarded and the aqueous solution acidified using 1N KHSO4 to approximately pH=1-2 (hydrion paper). The solution was extracted with 5 x 100 ml of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to afford N-CBZ-1-amino-2-cyclohexylethylphosphonous acid as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=1.Cl[CH2:17][C:18]1[CH:37]=[CH:36][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:28]=2[CH3:29])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:29][C:28]1[O:27][C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:25][C:24]=1[CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:7]2)=[CH:37][CH:36]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1c[nH]nc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-caboxylate (10.23 g), 4-(4-chloromethylphenoxy)methyl-5-methyl-2-phenyloxazole (14.66 g), potassium carbonate (13.09 g), and N,N-dimethylformamide (100 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (19.88 g, yield: 87%) from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 113˜114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:5]1[C:4](=[O:24])[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[C:7](=[O:11])[C:6]=1[CH3:12])(=[O:33])[CH3:32]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCOC(C)=O)=C(C)C1=O

Procedure:
2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-1,4-benzoquinone (3.38 g) was dissolved in dichloromethane (50 ml). Pyridine (1 ml) was added, and acetyl chloride (0.8 ml) was added with stirring under ice-cooling. After stirring for 1 hour at the same temperature, the mixture was washed with 0.1N hydrochloric acid (50 ml) followed by water (50 ml). The dichloromethane layer was concentrated under reduced pressure to obtain 6-(10-acetoxydecyl)-2,3-dimethoxy-5-methyl-l,4-benzoquinone as a red oil. This oil was dissolved in ether (50 ml), and a solution of sodium hydrosulfite (4 g) in water (50 ml) was added. Stirring was continued at room temperature until the red color of the ether layer disappeared. The ether layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired compound (3.8 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[NH4+].[NH4+].F[P-](F)(F)(F)(F)F.[N:30]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH3:16])[C:13]([NH2:30])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
A mixture of (2S)-2-[(benzyloxy)carbonyl]aminopropanoic acid (0.5 g, 0.002 mol), ammonium carbonate (0.43 g, 0.0045 mol), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (1.2 g, 0.0027 mol), N,N-diisopropylethylamine (980 μL, 0.0056 mol) in methylene chloride (3 mL) was stirred at RT overnight. The mixture was quenched with saturated NaHCO3 solution, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column to afford the desired product (0.54 g). Analytical LCMS: (M+H)+=223.1.