Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=1)(=O)=O.[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(O)(C)C>[CH3:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][CH2:6][O:5][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: Oc1ccccc1
Reactant: Cc1cccc(CCOS(C)(=O)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cccc(CCOc2ccccc2)n1
Temperature: 90 °C
Yield: 26 %

Procedure:
MsCl (6.7 mmol, 0.52 mL) was added to a solution of 6-methyl-2-pyridineethanol (6.7 mmol, 0.92 g) and triethyl amine (13.4 mmol, 1.88 mL) in toluene (6 mL) at 0° C. dropwise. The resulting mixture was stirred at 0° C. for 30 min. The precipitate generated from reaction was filtered off. The filtrate was concentrated in vacuo to give crude 2-(6-methylpyridin-2-yl)ethyl methanesulfonate which was used for next step without further purification. A mixture of above described 2-(6-methylpyridin-2-yl)ethyl methanesulfonate, PhOH (13.4 mmol, 1.26 g) and NaOH (13.4 mmol, 0.54 g) in isopropanol (20 mL) was refluxed at 90° C. for 3 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc which was washed with water. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography to give desired 2-methyl-6-(2-phenoxyethyl)pyridine as a colorless oil in 26% yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[CH:22]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:31])[C:8]=2[CH:22]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc2c(c1)C(c1ncccc1C)CC(C)(C)O2
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(c1c(C)ccc[n+]1[O-])CC(C)(C)O2
Yield: 26.3 %

Procedure:
101 mg of 6-acetyl-3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1-benzopyran were dissolved in 5 ml of dichloromethane at room temperature and 91 mg of m-chloroperbenzoic acid were added. After 1 hour the mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water. The organic extract was dried over sodium sulphate and evaporated to give an oil. This oil was triturated with t-butyl methyl ether to give a solid which, after recrystallization from ethyl acetate/t-butyl methyl ether, gave 28 mg of 2-(6-acetyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-methylpyridine N-oxide of melting point 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:15])[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:18][N:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccncc1)c1ccc(Cl)s1
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccc(Cl)s1)c1ccncc1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
To a suspension of 1-(5-chloro-2-thienyl)-2-(pyridin-4-yl)ethanone (21 mmol) in 13 mL N,N-dimethylformamide, was added N,N-dimethylformamide dimethyl acetal (71.5 mmol). The mixture was refluxed for 3 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried over MgSO4 filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol 100:1 to 20:1) to afford 3.3 g (51% yield) of 1-(5-chloro-2-thienyl)-3-(dimethylamino)-2-(pyridin-4-yl)prop-2-en-1-one.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH3:29])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Cl:39][C:40]([Cl:45])([Cl:44])[C:41](Cl)=[O:42]>ClCCl>[Cl:39][C:40]([Cl:45])([Cl:44])[C:41]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15](=[O:16])[C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH3:29])=[CH:21][CH:22]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:42]
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)CCCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)C(Cl)(Cl)Cl)n4Cc4ccccc43)cc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.7 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(2-methyl-cyclohex-1-en-1-yl)-phenyl]-methanone of Step D (1 g, 2.21 mmol) and N,N-diisopropylethylamine (0.770 mL, 4.42 mmol) were combined in anhydrous dichloromethane (11.1 mL) and trichloroacetyl chloride (0.740 mL, 6.63 mmol) was added dropwise. After stirring at room temperature for four hours, the solvent was removed and the residue dissolved in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue purified by flash column chromatography. Recrystallization from petroleum ether afforded 1.21 g of the title compound as white crystals, m.p. 171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].CC(C)=O.O.[Cl:15][C:16]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([C:28]([F:31])([F:30])[F:29])=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:16]=2[Cl:15])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a solution of 3,4-dichloroaniline (2.6 g; 2 eq.) in a 1/1 acetone/water mixture (30 ml) is added dropwise at 0° C. a solution of 2-chloro-3-nitro-5-trifluoromethylbenzoyl chloride (2.3 g; 1 eq.) in acetone (10 ml). After 18 hours at room temperature, 20 ml of water are added. The resulting solid is filtered off by suction, washed with water and dried. 3.1 g of N-(3,4-dichlorophenyl)-2-chloro-3-nitro-5-trifluoromethylbenzamide are obtained (m.p.=202° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[N:8]=2)=[O:4].C1C(=O)N([Br:34])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH2:15][Br:34])=[CH:11][CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[N:8]=2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(CBr)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Yield: 98.1 %

Procedure:
In a 50 mL pear-shaped flask, 3-methyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (0.45 g, 1.24 mmol), NBS (221 mg, 1.24 mmol) and benzoyl peroxide (60.2 mg, 0.248 mmol) were combined with carbon tetrachloride (12 mL) to give a light yellow suspension. The reaction mixture was refluxed for 2 hr. The reaction mixture was cooled, diluted with methylene chloride (50 mL), washed with saturated aqueous NaHCO3 (1×20 mL), and brine (1×20 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give crude 3-bromomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (536.6 mg, 97.9%) as a pale yellow solid. The material was not further purified. 1H NMR (DMSO-d6) δ ppm 8.89 (d, J=8.2 Hz, 1H) 7.99 (d, J=8.2 Hz, 1H) 7.44-7.62 (m, 5H) 4.53 (s, 2H) 3.55 (s, 3H). MS calcd. for C18H12BrF3N2O3 [(M+H)+] 442.0, obsd. 443.0.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:15])[C:12]([OH:14])=[O:13].[OH-].[Na+:22].O>C(O)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:15])[C:12]([O-:14])=[O:13].[Na+:22]
Reactant: O=C(O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6.24 g of 2-(2,6-dichloroanilino)phenylglycolic acid in 30 ml of ethanol were added 10 ml of a 5 N aqueous sodium hydroxide solution and the mixture was stirred at room temperature for 1 hour. Then, 20 ml of water were added, and the mixture was concentrated to have a volume of 30 ml. The concentrate was cooled and the solid thus deposited was recovered by filtration. Recrystallization from water gave sodium 2-(2,6-dichloroanilino)phenylglycolate. m.p. 101°-104° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][NH:4][C:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:7])[CH3:6].[CH3:15]CN(CC)CC.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.O>ClCCl>[CH3:15][CH2:1][CH2:2][CH2:3][NH:4][C:5]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:7])[CH3:6]
Reactant: CCN(CC)CC
Reactant: CCCNC(C)(C)CC1CCCCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCCCNC(C)(C)Cc1ccccc1
Temperature: 25 °C
Yield: 134.6 %

Procedure:
To a solution of compound D-3-7 (100 g, 380 mmol) and Et3N (76.8 g, 760 mmol) in dichloromethane (1.5 L), cooled to 0° C., is added triflic anhydride (Tf2O) (107.0 g, 380 mmol) via an addition funnel. Upon complete addition of Tf2O the solution is then warmed to room temperature for 5 h. The reaction mixture is then treated with H2O and dichloromethane and the organic phase is separated. The organic phase is washed with brine and dried over anhydrous Na2SO4. The mixture is then filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (using 20:1 petroleum ether:EtOAc) to provide compound D-3-8 (105 g, 70% yield).
Reaction SMILES: [Na].[CH2:2]([N:9]1[C:19]2[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:10]1=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21]([OH:26])[CH:22]([OH:25])[CH2:23]Cl>CO>[CH2:2]([N:9]1[C:19]2[C:14](=[C:15]([O:20][CH2:23][CH:22]([OH:25])[CH2:21][OH:26])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:10]1=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCc2c(O)cccc2N1Cc1ccccc1
Reactant: OCC(O)CCl
Agent: [Na]
Solvent: CO
Product: O=C1CCc2c(OCC(O)CO)cccc2N1Cc1ccccc1
Yield: 36.7 %

Procedure:
0.23 g of sodium metal was dissolved in 40 ml of methanol, and 2.53 g of 1-benzyl-5-hydroxy-3,4-dihydrocarbostyril and 1.3 g of glycerol α-monochlorohydrin were added to the resulting solution followed by refluxing the mixture for 6 hours. After allowing the mixture to cool, the precipitated crystals were filtered, and the filtrate was concentrated to dryness. The residue thus obtained was extracted with 50 ml of chloroform, and the extract was washed with a 5% aqueous sodium hydroxide solution and then water and then dried over anhydrous sodium sulfate. The chloroform was then removed by distillation and the resulting residue was recrystallized from ethanol to give 1.2 g of 1-benzyl-5-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 153° - 155° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17](=O)[NH2:18])=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:20])[CH3:7]>N1C=CC=CC=1>[CH2:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:20])[CH3:7]
Reactant: CCn1c(C)nc2cc(C(N)=O)ccc21
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1c(C)nc2cc(C#N)ccc21
Temperature: 60 °C
Yield: 61 %

Procedure:
42.4 ml (0.44 mole) of phosphorus oxychloride were added to a stirred and ice-cooled solution of 81.2 g (0.4 mole) of compound IV in 160 ml of pyridine. The temperature reached 45° C. Thereupon the mixture was heated to 60° C. The reddish-brown oil obtained was poored immediately in 1 kg of an ice-water mixture with stirring. The precipitate was filtered, washed with ice-cold water and dried. The crude product obtained was crystallized from pyridine (1.5 ml/g) and water (9 mg/g). Melting point: 162° C. Yield: 61% (452 g).
Reaction SMILES: [CH3:1][Mg]Br.[I-].[CH3:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N+:7]=1[CH3:16]>C1COCC1>[CH3:5][C:6]1([CH3:1])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]1[CH3:16]
Reactant: CC1=[N+](C)CCc2ccccc21
Reactant: C[Mg]Br
Agent: [I-]
Solvent: C1CCOC1
Product: CN1CCc2ccccc2C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl magnesium bromide (4.5 ml, 3M in Et2O) was added to a stirred suspension of 1,2-dimethyl-3,4-dihydroisoquinolinium iodide (1.3 g) in dry THF (20 ml) at −70° C. under argon. After 1 h, the mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was quenched by cautious addition of water and extracted with ethyl acetate. The extract was washed with water, brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a pink oil (730 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[C:4]=2[CH:3]=C1.C([OH:25])C>>[CH:3]([C:4]1[C:5]([OH:1])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)=[O:25]
Reactant: CCO
Reactant: CCOC(=O)c1ccc(COc2cccc3occc23)cc1
Product: CCOC(=O)c1ccc(COc2cccc(O)c2C=O)cc1
Temperature: -65 °C

Procedure:
Ethyl 4-(4-benzofuranyloxymethyl)benzoate (1.84 g, 0.004 M) was dissolved in absolute ethanol (180 ml) and cooled to -65° C. with stirring and exclusion of moisture. Ozonised air was bubbled through the solution at a rate of 20 liters/hr for 1 hr. Nitrogen was then bubbled through the solution (5 mins) to remove excess ozone before the addition of dimethyl sulphide (1.2 ml). The mixture was allowed to warm to room temperature overnight (16 hr.). The solvent was removed in vacuo and the residue recrystallised from ethyl acetate-petrol to give ethyl 4-(2-formyl-3-hydroxyphenoxymethyl)benzoate, m.p. 105°-107° C. (Found: C, 67.59; H, 5.21. C17H16O5 requires C, 67.99; H, 5.37%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[F:13][C:14]1[C:15]([F:20])=[C:16]([Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH:18][C:19]=1[Si:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)Cl
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1ccc([Si](C)(C)C)c(F)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
step 1—To a solution of di-iso-propylamine (150 mL, 108.3 g, 1.07 mol) in THF (500 mL) cooled to −78° C. and maintained under a N2 atmosphere was added over 1 15 min period, n-BuLi (100 mL, 1.00 mol, 10M in hexanes). The resulting mixture was stirred for 30 min at −78° C. A mixture of 54a (45 mL, 52.110 g, 0.457 mol) and chlorotrimethylsilane (130.0 mL, 111.28 g, 1.024 mol) was added at a rate which maintained the internal reaction temperature below −50° C. The solution was stirred at −78° C. for 1 h. The reaction was quenched at −78° C. by addition of 1M H2SO4, diluted with MTBE and the mixture was saturated with solid NaCl. The phases were separated and the aqueous phase was extracted with MTBE (300 mL). The combined organic extracts were dried (MgSO4), filtered and the solvents evaporated to afford 118 g (100%) of 54b as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:12]([OH:14])[CH:13]=1.C(=O)([O-])[O-].[Ca+2]>O1CCOCC1>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:12]([OH:14])[CH:13]=1)=[O:3])[CH3:6]
Reactant: Nc1ccc(NC(=O)OCc2ccccc2)c(O)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: CCOC(=O)Nc1ccc(NC(=O)OCc2ccccc2)c(O)c1

Procedure:
0.14 mole (15.7 g) of ethyl chloroformate is slowly added dropwise to 0.13 mole (33 g) of 5-amino -2-(benzyloxycarbonylamino)phenol (prepared in Example 1, 2nd stage) and 7.1 g of calcium carbonate in 100 ml of dioxane brought to 80° C. The mixture is heated for a further 20 minutes after the addition is complete. The reaction mixture is filtered while hot in order to remove the inorganic salts. The expected product is precipitated by diluting the cooled filtrate with ice-cold water. When recrystallized from ethyl acetate, it melts at 190° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]#[N:12])=[N:8][CH:9]=1.Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Br.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]#[N:12])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:8][CH:9]=1
Reactant: N#CCc1ccc(Br)cn1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(Br)cn2)CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (55% in mineral oil, 0.23 g) was added to a solution of (5-bromo-pyridin-2-yl)-acetonitrile (0.50 g) in N,N-dimethylformamide (5 mL) chilled in an ice bath. The resulting mixture was stirred for 10 min in the cooling bath prior to the dropwise addition of bis(2-bromoethyl)ether (0.35 mL) dissolved in N,N-dimethylformamide (2 mL). The mixture was stirred with cooling for 2 h and at room temperature for 1 h. Water was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) to give the title compound as a colorless oil. Yield: 0.62 g (91% of theory); LC (method 1): tR=1.70 min; Mass spectrum (ESI+): m/z=267/269 (Br) [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[S:15](Cl)(=[O:18])(=[O:17])[OH:16].CCN(C(C)C)C(C)C>ClCCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH:11]([S:15]([OH:18])(=[O:17])=[O:16])[C:12]([OH:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)CCCSSc1ccccn1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C(CCSSc1ccccn1)S(=O)(=O)O
Yield: 48.7 %

Procedure:
4-(pyridin-2-yldisulfanyl)butanoic acid (102 mg, 0.445 mmol) was coevaporated with 1,2-dichloroethane, (2×6 ml) (to remove moisture) and re-dissolved in 6 ml of 1,2-dichloroethane. The resulting solution was then placed in a preheated oil bath (75-80° C.). To this solution, sulfurochloridic acid (100 μL, ˜3 eq) was added and the resulting mixture was stirred for 5˜8 min. DIPEA (117 μL, 1.5 eq) was then added (to precipitate the product) and the resulting mixture was stirred for 5 min. Another portion of sulfurochloridic acid (40 ul, 1.33 eq) was added and the mixture was stirred for ˜15 min, followed by addition of DIPEA (63 μL, 0.81 eq) and stirred for 5 min. A third portion of sulfurochloridic acid (40 ul, 1.33 eq) was added and the mixture was stirred for 15˜20 min. The resulting mixture was removed from the oil bath and cooled (on ice bath). Aqueous NaOH (0.5 M) or concentrated Na2CO3 was added to raise the pH ˜12 and the reaction mixture was stirred for 10 min. The organic phase was separated, washed with water (2×10 ml), and neutralized with H3PO4 to pH 7. The organic phase was then concentrated to ˜5 ml and acidified with HCl to pH ˜4. The crude product was purified by passing through a C-18 column using eluting with a gradient of 100% water (containing 0.5% HAc) to 75% of water (containing 0.5% HAc)/25% of MeOH. Fractions containing the desired product (eluted out at 5˜10% of MeOH) were pooled, evaporated to afford 4-(pyridin-2-yldisulfanyl)-2-sulfobutanoic acid (67 mg, 0.217 mmol, 48.7% yield). 1H NMR (D2O) 8.41 (dd, 1H, J=1.5, 4.9 Hz), 7.89 (m, 2H), 7.31 (m, 1H), 3.75 (dd, 1H, J=5.1, 9.6), 2.97 (m, 1H), 2.82 (m, 1H), 2.28 (m, 2H); 13C NMR 176.60, 160.28, 150.60, 140.27, 123.39, 122.92, 69.07, 37.56, 29.45; ESI MS m/z-307.8 (M-H).
Reaction SMILES: [CH2:1]([N:3]1C([N+]([O-])=O)=CN=C1C=CC1C=CC=CC=1)C.NN1[NH:24][CH:23]=[C:22]([C:25]2[N:26]([CH2:33][CH2:34][CH3:35])[C:27]([N+:30]([O-:32])=[O:31])=[CH:28][N:29]=2)[S:21]1>>[NH2:3][C:1]1[S:21][C:22]([C:25]2[N:26]([CH2:33][CH2:34][CH3:35])[C:27]([N+:30]([O-:32])=[O:31])=[CH:28][N:29]=2)=[CH:23][N:24]=1
Reactant: CCn1c([N+](=O)[O-])cnc1C=Cc1ccccc1
Reactant: CCCn1c([N+](=O)[O-])cnc1C1=CNN(N)S1
Product: CCCn1c([N+](=O)[O-])cnc1-c1cnc(N)s1

Procedure:
The procedure of Example 23, with the substitution of β-(1-propyl-5-nitro-2-imidazolyl)styrene for β-(1-ethyl-5-nitro-2-imidazolyl)styrene in the first step is utilized to prepare 2-(2-amino-5-thiadiazolyl)-1-propyl-5-nitroimidazole, melting at 234.5°-236° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH:25]=O)[CH:7]=1)[CH3:2].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:16]=2[CH2:25][NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=1)[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2C=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CNCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and benzylamine.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].CN(P(N(C)C)(N(C)C)=O)C>CCOC(C)=O>[CH2:3]=[C:2]([CH2:3][CH2:2][C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: C=CC(=O)OCc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 140 °C

Procedure:
Benzyl acrylate (500 g, 3 mol) was heated to 100° C. under an atmosphere of nitrogen. The heating was stopped and HMPT (10 g, 61 mmol) was added dropwise while maintaining an internal temperature of 135-145° C. Once addition was complete the mixture was cooled to room temperature and a slurry of silica with 5:1 Hex/EtOAc was added. The slurry was then transferred to a column containing a plug of dry silica. The column was then washed with 1:1 Hex/EtOAc and the solvent was collected and evaporated. The clear yellow liquid was distilled under high vacuum (200 μHg) to give an initial fraction of 8 g distilling at 45° C. and then the desired product at 180-185° C. (212 g, 42%) as a clear and colorless liquid. 1H NMR (CDCl3) 7.3 ppm (3, 10H); 6.2 ppm (s, 1H); 5.5 ppm (s, 1H); 5.2 ppm (s, 2H); 5.1 ppm (s,2H); 2.6 ppm (m, 4H).