Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]([C:26]([S:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:7][P:8]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)=[O:9])[CH3:2].ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]([C:26]([S:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:45])=[O:27])[CH2:7][P:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)=[O:9])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CN(CP(=O)(Oc1cccc(C)c1)Oc1cccc(C)c1)C(=O)SCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CN(CP(=O)(Oc1cccc(C)c1)Oc1cccc(C)c1)C(=O)S(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 5.25 h

Procedure:
To a solution of ethyl-N-[(benzylthio)carbonyl]-N-[bis(3-methylphenoxy)phosphinylmethyl]-glycinate (2.6 g.; 0.005 mol.) dissolved in 25 ml. of methylene chloride at 0° C. was added metachloroperbenzoic acid (1.02 g.; 0.005 mol.). The reaction mixture was stirred at 0° C. for 5.25 hours, filtered and the filtrate was washed with 5% sodium hydroxide, dried, and concentrated in vacuo. To remove any remaining solvent, the residue was concentrated at 25° C. and 0.05 mm. and yielded ethyl-N-[(benzylsulfinyl)carbonyl]-N-[bis(3-methylphenoxy)phosphinylmethyl]-glycinate as an oil (nD25 =1.5584) having the following analysis:
Reaction SMILES: CN(C)[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5](OCC)=[O:6].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:22])[NH2:21])[N:15]=1.O(C)[Na].Cl>CO>[N+:10]([C:4]1[C:5]([OH:6])=[N:22][C:20]([C:16]2[N:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[N:21][CH:3]=1)([O-:12])=[O:11]
Reactant: CCOC(=O)C(=CN(C)C)[N+](=O)[O-]
Reactant: N=C(N)c1cccnn1
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1cnc(-c2cccnn2)nc1O
Yield: 86 %

Procedure:
A mixture of ethyl 3-(dimethylamino)-2-nitroacrylate, 35i-f, (1 g, 5.3 mmol) and pyridazine-3-carboximidamide (0.8 g, 5.3 mmol) in CH3OH (30 mL) was added with NaOCH3 (3.4 g, 6.36 mmol) and refluxed overnight. The pH of reaction mixture was adjusted to 7 by addition of concentrated HCl. The solids were filtered to afford the product, 35i-g, (1 g, 86%). 1H NMR (300 MHz, DMSO) δ 7.77 (dd, J=4.8, 7.5 Hz, 2H), 8.29 (d, J=8.4 Hz, 1H), 8.77 (s, 1H), 9.26 (d, J=4.5 Hz, 1H). LC-MS (M+H)+ 220.1
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=[O:17])[CH2:14][NH:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](O)([CH3:23])([CH3:22])[CH3:21].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])[CH2:14][NH:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
5.1 g of (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylic acid (Liebich's Annalen der Chemie 529 (1937), page 1) are dissolved in 20 ml of pyridine, and 50 ml of tert.-butanol are added thereto. The solution is cooled to a temperature below -5° C., and 3.5 g of phosphorous oxychloride are added dropwise thereto. The mixture is stirred at the same temperature for about 30 minutes and then at room temperature for 3 hours. The reaction mixture is poured into 200 ml of ice-water, and extracted with ethyl acetate. The extract is washed with 1% hydrochloric acid, an aqueous sodium bicarbonate solution and water, successively. Then, the extract is dried and evaporated to remove solvent. The residue obtained is crystallized with a mixture of ether and n-hexane. 5.5 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 89.0%
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][O:5][CH2:6]Cl.Cl.[Cl:13][C:14]1[CH:15]=[N:16][C:17](=[O:20])[NH:18][CH:19]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][O:5][CH2:6][N:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[N:16][C:17]1=[O:20]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cc1ccccc1COCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1COCn1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of chloromethyl 2-methylbenzyl ether (see Preparation 3a and 3b) (10 mmol) in dichloromethane (20 ml) was added dropwise with stirring to a solution of 5-chloropyrimidin-2-one hydrochloride (10 mmol) and triethylamine (20 mmol) in dichloromethane (80 ml). The reaction mixture was stirred for 2 hours at room temperature. It was then washed with water and the dried (MgSO4) solution evaporated to yield a crude mixture (2.55 g, 96%) which was purified by trituration with ether. The yield of the title compound was 1.33 g (50%), m.p. 88° C. 1H NMR (CDCl3): δ2.26 (Me), 4.63 (CH2 -Ph), 5.30 (CH2O), 7.00 (Ph), 7.60 and 8.37 (H-4, H-6, J 4 Hz). IR(KBr): 1660 cm-1 (CO).
Reaction SMILES: C(OC(=O)[N:7]([CH:25]([CH3:27])[CH3:26])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>>[CH:25]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:29][CH:30]4[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:26])[CH3:27]
Reactant: CSc1nccc(-c2cnc3c(N(C(=O)OC(C)(C)C)C(C)C)nccn23)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Product: CC(C)Nc1nccn2c(-c3ccnc(NC4CCC(O)CC4)n3)cnc12

Procedure:
4-[4-(8-Isopropylamino-imidazo[1,2-a]pyrazin-3-yl)-pyrimidin-2-ylamino]-cyclohexanol was prepared by a process analogous to that described in Example 12 starting from isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 11 supra), and trans-4-amino-cyclohexanol. LC-MS: [M+H]+ 368.3.
Reaction SMILES: CO.[Li+].[BH4-].C([O:7][C:8]([C:10]1[CH:11]=[C:12]2[CH2:17][CH2:16][CH2:15][N:13]2[N:14]=1)=O)C>C1COCC1>[N:14]1[N:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[CH:11][C:10]=1[CH2:8][OH:7]
Reactant: CCOC(=O)c1cc2n(n1)CCC2
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc2n(n1)CCC2
Temperature: 40 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
MeOH (2.73 mL) was added to the THF (180 mL) solution of LiBH4 (1.63 g) under a nitrogen atmosphere at room temperature, and then 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid ethyl ester (8.11 g) was added to the suspension and stirred for 2 h at 40° C. The mixture was quenched with 1 mol/L HCl at pH 1 and stirred for 1 h at room temperature. Solid K2CO3 was added to the solution to adjust pH to 8 and the mixture was extracted with AcOEt. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as brown crystals (4.87 g, 78%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].[H-].[Na+].F[C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1>CN(C)C=O.O>[NH2:2][CH2:3][C:4]([S:6][C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:13][CH:12]=1)([CH3:7])[CH3:5]
Reactant: CC(C)(S)CN
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(SC(C)(C)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a suspension of 1-amino-2-methyl-2-propanethiol hydrochloride (75 mg) in N,N-dimethylformamide (2 mL) is added sodium hydride (60% dispersion in mineral oil, 50 mg) and the mixture is stirred at room temperature for 30 minutes. To the mixture is added tert-butyl 4-fluorobenzoate (50 mg) and the mixture is stirred at 70° C. for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is concentrated in vacuo and the resultant product is purified by flash column chromatography on NH-silica gel (solvent; ethyl acetate) to give tert-butyl 4-[(2-amino-1,1-dimethylethyl)thio]benzoate (54 mg, yield; 75%) as a colorless oil. MS (APCI) m/z: 282 [M+H]+
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:20]3[CH:21]=[CH:22][C:23]([CH2:24][NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)=[CH:26][CH:27]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccc(O)cc1
Reactant: O=Cc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1ccc(CNCc2ccc(-c3nc4ccn5cnnc5c4cc3-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-2 (0.05 g, 0.14 mMol) and 4-(aminomethyl)phenol (0.04, 0.35 mMol) in DMF (0.5 mL) was added acetic acid (0.04 mL, 0.7 mMol). After stirring for 2 hours at room temperature, sodium triacetoxyborohydride (0.06 g, 0.3 mMol) was added. After stirring overnight, the reaction was filtered through a syringe filter and purified on a C18 reverse phase HPLC to yield 19-1 as a solid. LC/MS (M+1) calculated: 458.5; observed: 458.3.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[C:29](#[N:32])[CH:30]=[CH2:31]>C(O)(C)C>[C:29]([CH2:30][CH2:31][N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17]1)#[N:32]
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Reactant: C=CC#N
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Product: N#CCCN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 95 °C

Procedure:
A solution of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (15 g, 0.049 mole) and acrylonitrile (5.2 g, 0.098 mole) in isopropanol (50 ml) was stirred at reflux (95° C.) for twenty hours. The reaction mixture was cooled then concentrated to an oil (17 g, 96%) of which 3.5 g was distilled to an oil of 3-(2-cyanoethyl)-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine (2.6 g, 235°-237° C./0.1 mm).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[NH2:17])[S:5][C:6]=1[CH3:7].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][S:23]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)(=[O:25])=[O:24])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(-c2cc3cccc(N)c3[nH]2)sc1C
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: Cc1nc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)sc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
To a mixture of 2-(4,5-dimethyl-1,3-thiazol-2-yl)-1H-indole-7-amine (0.10 g) and pyridine (8 mL) was added thiophene-2-sulfonyl chloride (0.090 g) at 4° C., and the mixture was stirred at room temperature for 15 hr. The reaction solution was concentrated. The obtained residue was diluted with ethyl acetate, washed with aqueous citric acid solution and saturated brine, dried over-anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate) to give the title compound (142 mg, yield 89%) as pale-purple crystals. melting point 210-211° C.
Reaction SMILES: [CH:1]1([C:4](=[O:16])[CH2:5][C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>O1CCOCC1>[CH:1]1([C:4](=[O:16])[C:5](=[CH:19][N:20]([CH3:22])[CH3:21])[C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(CC(=O)C1CC1)c1ncc(Cl)cc1Cl
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)C=C(C(=O)c1ncc(Cl)cc1Cl)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 3-cyclopropyl-1-(3,5-dichloropyridin-2-yl)propan-1,3-dione (1.3 g) and N,N-dimethylformamide dimethyl acetal (1.1 ml) in 1,4-dioxane was stirred at room temperature for 4 days and the solvent was evaporated to yield 3-cyclopropyl-1-(3,5-dichloropyridin-2-yl)-2-dimethylaminomethylenepropan-1,3-dione (1.73 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([NH:15][NH2:16])=[O:14])=[CH:7][CH:6]=2.[N:17]#[C:18]Br>CO.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[O:14][C:18]([NH2:17])=[N:16][N:15]=1)=[CH:7][CH:6]=2
Reactant: N#CBr
Reactant: NNC(=O)Cc1ccc2ncc(Br)cc2c1
Solvent: O
Solvent: CO
Product: Nc1nnc(Cc2ccc3ncc(Br)cc3c2)o1

Procedure:
A mixture of (3-bromo-quinolin-6-yl)-acetic acid hydrazide (prepared according to procedure described herein) (4.12 g, 14.7 mmol), cyanogen bromide (1.1 eq., 16.2 mmol, 1.7 g) and KHCO3 (1.25 eq., 18.3 mmol, 1.83 g) was stirred in methanol (30 mL) at ambient temperature for 18 hours. The was then diluted with water (40 mL) and the solid was collected via filtration and washed with cold methanol and dried to return the title compound as an off white solid (4.02 g, 13.2 mmol, 90%). 1H NMR (DMSO-d6): δ 4.27 (2H, s), 6.94 (s, 2H), 7.71 (dd, 1H), 7.86 (d, 1H), 8.02 (d, 1H), 8.73 (d, 1H); 8.93 (d, 1H); MS (m/z) 305 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH:3]=1.C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:3]=1
Reactant: CCOC(=O)COc1cc(Cl)c2c(=O)c(-c3ccccc3O)coc2c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(O)COc1cc(Cl)c2c(=O)c(-c3ccccc3O)coc2c1
Yield: 63.6 %

Procedure:
In 100 ml of dried dichloromethane was dissolved 1.7 g of ethyl {[5-chloro-3-(2-hydroxyphenyl)-4-oxo-4H-1-benzopyran-7-yl]oxy}acetate, and the solution was cooled with dry ice-acetone. Three milliliters of boron tribromide were added to the cooled solution in small portions, and the resulting mixture was refluxed for 3 hours. After cooling, the solvent was removed by distillation under reduced pressure, and to the residue was added dilute hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, air-dried, and recrystallized from ethanol to obtain 1.0 g of the entitled compound having a melting point of 188°-189° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1(=[O:18])[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12]1>O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:16]2[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12][C:11]=2[OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: O=S(O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccc(F)cc1)c1cc(O)ccc1O
Reaction time: 4 h

Procedure:
A solution of the title A compound, 4-fluorobenzenesulfinic acid (3 g, 18.75 mmol) in 10 mL of water is added to a solution of 1,4 benzoquinone (1.93 g, 17.86 mmol) in 30 mL of CH2Cl2 at RT. After 4 h, the precipitated product is collected by vacuum filtration and washed with cold CH2Cl2 and dried under vacuum to afford 2-(4-fluorobenzenesulfonyl)-benzene-1,4-diol: NMR (DMSO-d6) 6.73 (d, 1H, J=9), 6.92 (dd, 1H, J=9, 3), 7.31 (d, 1H, J=3),7.41 (app t, 2H, J=9), 7.96 (dd, 2H, J=9, 5), 9.41 (s, 1H), 10.05 (s, 1H); ESI-MS 267 [M-1]−.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[F:16][C:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH:18]=1>CCO>[F:16][C:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:19][CH:18]=1
Reactant: NCC1CC=C(F)CC1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CC=C(F)CC2)c([N+](=O)[O-])c1

Procedure:
N-(4-Fluoro-3-nitrophenyl)acetamide (460 mg, 2.32 mmol) and [(4-fluorocyclohex-3-en-1-yl)methyl]amine hydrochloride (350 mg, 2.11 mmol) were stirred in 20 mL of EtOH containing TEA (0.735 mL, 5.28 mmol) at 75° C. for 48 h. The solvent was concentrated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 2:1/hexanes:acetone as eluent. Yield: 553 mg (85%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.51-1.61 (m, 1 H), 1.84-1.93 (m, 1 H), 1.96-2.03 (m, 2 H), 2.16-2.18 (m, 3 H), 2.22-2.32 (m, 3 H), 3.26 (m, 2 H), 5.19 (m, 1 H), 6.84 (d, J=9.37 Hz, 1 H), 7.21 (s, 1 H), 7.79 (dd, J=9.18, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 2 H).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CCO>[CH2:1]([C:5]1[C:6]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)OCC)cc2)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccc(OC)cc1
Yield: 89.2 %

Procedure:
Ethyl ester (162) (0.25 g, 0.52 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.21 g (88%) of compound 163 as a white solid. mp 186-187° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.78 (t, J=7.3 Hz, 3H), 1.15-1.29 (m, 2H), 1.40-1.50 (m, 2H), 2.62 (t, J=7.3 Hz, 2H), 3.75 (s, 3H), 6.26 (d, J=15.9 Hz, 1H), 6.56 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.6 Hz, 2H), 7.30-7.40 (m, 3H), 7.47 (t, J=7.5 Hz, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.50-7.56 (m, 2H), 7.89 (d, J=8.2 Hz, 1H). LCMS (ESI): m/z 453 (M+H)+, m/z 451 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([CH:6]=[C:7]([CH3:21])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([Cl:20])=[CH:12][CH:11]=1)[NH2:5].[Cl:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([N:28]=[C:29]=[O:30])=[O:27]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:5][C:29]([NH:28][C:26](=[O:27])[C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=2[Cl:23])=[O:30])[CH:6]=[C:7]([CH3:21])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([Cl:20])=[CH:12][CH:11]=1
Reactant: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2Cl)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
Into a solution containing 3.0 grams (9.0 mmol) of 3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylaniline prepared in Part B in 25 milliliters of toluene which solution was warmed to a temperature of 50° C. and placed under a nitrogen atmosphere was slowly added a solution containing 2.5 grams (13.8 mmol) of 2-chlorobenzoyl isocyanate in 5 milliliters of toluene. After stirring for 1 hour at a temperature of 50° C., the reaction mixture was cooled to room temperature, placed in an ice bath, and filtered through a Buchner funnel. The collected solid was dried under vacuum at a temperature of 50° C. to afford 3.15 grams of 1-[3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylphenyl]-3-(2-chlorobenzoyl)urea as a white solid having a melting point of 187° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH:15]([C:23]([O:25][C:26]([C:29]1[CH:38]=[C:35]([O:36][CH3:37])[CH:34]=[C:31]([O:32][CH3:33])[CH:30]=1)([CH3:28])[CH3:27])=[O:24])[C@H:16]([C:20](O)=[O:21])[CH:17]([CH3:19])[CH3:18].C1C=C2C(N(O)N=NC2=CC=1)=O>CN(C=O)C>[NH:15]([C:23]([O:25][C:26]([C:29]1[CH:30]=[C:31]([O:32][CH3:33])[CH:34]=[C:35]([O:36][CH3:37])[CH:38]=1)([CH3:28])[CH3:27])=[O:24])[C@@H:16]([C:20]([NH:1][C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:21])[CH:17]([CH3:18])[CH3:19]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: COc1cc(OC)cc(C(C)(C)OC(=O)N[C@H](C(=O)O)C(C)C)c1
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](NC(=O)OC(C)(C)c1cc(OC)cc(OC)c1)C(C)C

Procedure:
Solution Phase Couplings with Ddz-Xxx-Pfp and Ddz-Xxx-ODhbt. The efficiency of acylation of ODhbt esters, in terms of both coupling and racemization, was examined through the acylation of a simple amino acid alkyl ester, i.e., the acylation of H-Tyr-OMe with Ddz-L-Val-Dhbt and Ddz-D-Val-ODhbt in DMF at 0.1M. The dipeptides Ddz-L-Val-Tyr-OMe and Ddz-D-Val-Tyr-OMe were obtained in high yield (>90%) after a simple extractive workup and the Ddz-L-Val-Tyr-OMe gave a clean, single peak HPLC trace. Ddz-D-Val-ODhbt was not obtained as a solid, as it was contaminated with 5% of the azidobenzoate impurity, as mentioned by Atherton, et al.,54 which showed up in the HPLC trace. Both dipeptides gave clean 1H-NMR spectra. The attempted separation of the diastereomeric dipeptides by HPLC was unsuccessful over a wide range of isocratic gradients. In the 1H-NMR spectra, however, there is a slight difference in shift of the Val α-CH between the two dipeptides, hence there is no evidence in either spectra of any measurable amount of racemization.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][CH:12]2[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)[CH3:23])=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][CH:12]([OH:13])[CH2:14][O:36][C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH2:26][CH2:25][CH:24]([N:22]([C:19]4[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=4)[CH3:23])[CH2:29][CH2:28]3)=[CH:35][CH:34]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1cn(CCC2CO2)c(Cl)n1
Reactant: CN(c1ccc(Cl)cc1)C1CCN(c2ccc(O)cc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(c1ccc(Cl)cc1)C1CCN(c2ccc(OCC(O)CCn3cc([N+](=O)[O-])nc3Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
2-Chloro-4-nitro-1-(2-oxiranylethyl)-1H-imidazole (810 mg) was suspended in ethanol (20 ml) and 4-{4-[N-(4-chlorophenyl)-N-methylamino]piperidin-1-yl}phenol (982 mg) and tripotassium phosphate (200 mg) were added thereto, followed by stirring at 70° C. overnight. Thereafter the reaction solution was cooled to room temperature, and filtered through Celite to remove insoluble matter and, then the residue was washed with ethyl acetate. The filtrate and liquid were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:1) and recrystallized from methylene chloride-ethyl acetate to afford the title compound as a yellow solid (486 mg).