Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:20])[CH2:11][CH:10]2[CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:7][CH:8]=1.[CH3:33][NH:34][CH3:35]>CN(C)C=O>[CH3:33][N:34]([CH2:21][CH:10]1[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:20])[CH2:11]1)[CH3:35]
Reactant: COc1cccc(C2C(COS(=O)(=O)c3ccc(C)cc3)CC(=O)N2c2ccccc2)c1
Reactant: CNC
Solvent: CN(C)C=O
Product: COc1cccc(C2C(CN(C)C)CC(=O)N2c2ccccc2)c1
Reaction time: 3 h

Procedure:
To 22.0 gm. of 5-(3-methoxyphenyl)-1-phenyl-4-(p-toluenesulfonyloxymethyl)pyrrolidin-2-one in 150 ml. of dimethylformamide was added 21 ml. of 40% aqueous dimethylamine, the solution refluxed for 3 hours and then 21 ml. more of 40% aqueous dimethylamine added and reflux continued for an additional 3 hours. After cooling the reaction was decanted into ice water and acidified. Extraction with ether followed by basification of the aqueous phase with potassium carbonate yielded a semi-solid which was extracted with chloroform, dried (Na2SO4), filtered and concentrated in vacuo to a solid. Recrystallization from acetonitrile provided 7.0 gm. of beige crystals, m.p. 88°-92°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[S:5][CH:6]=1.[H-].[Na+].[CH:14](I)([CH3:16])[CH3:15].O>CN(C)C=O.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][N:9]([CH:14]([CH3:16])[CH3:15])[N:8]=2)[S:5][CH:6]=1
Reactant: Brc1csc(-c2cc[nH]n2)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ccc(-c2cc(Br)cs2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
3-(4-bromo-2-thienyl)-1H-pyrazole (8.7 mmol) was dissolved in 20 mL dry N,N-dimethylformamide under argon atmosphere. Sodium hydride (10.5 mmol, 60% dispersion in mineral oil) was added in portions at room temperature. The reaction mixture was stirred at room temperature for 15 min. Isopropyl iodide (13.1 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 14 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:ethyl acetate 100:0 to 0:100) to afford 1.90 g 3-(4-bromo-2-thienyl)-1-isopropyl-1H-pyrazole (71% yield). Traces of the minor regioisomer 5-(4-bromo-2-thienyl)-1-isopropyl-1H-pyrazole were collected and analyzed as well.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl>C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[C:28]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=1)=[O:34])[CH3:33]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCCCCCCCCCCCOc1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOc1ccc(NC(=O)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
In a 1 L jacketed flask under a nitrogen atmosphere is added 60 g (0.2425 mols) of p-dodecyloxyaniline, 650 mL of CH2Cl2 and 56.6 g of pyridine (0.716 mols) and the resulting solution is cooled to 0° C. Maintaining an internal temperature below 5° C., 46.3 g (0.339 mols) of ethyl chlorooxoacetate is then added dropwise over a period of one hour. After the addition is complete, the internal temperature is maintained at 10° C. overnight. To the resultant reaction mixture is added rapidly 400 mL of 1N HCl and the resultant mixture is allowed to warm to RT. The reaction mixture is stirred for one hour than the organic phase separated. The organic phase is dried over anhydrous sodium sulphate and isolubles removed by filtration. The volatiles are removed in vacuo and the residue is recrystallized from ethanol (250 mL). The solid is washed twice with ethanol (50 mL) at 0° C. to give 64.1 g of a white solid, mp. 70.5–72° C. The NMR, MS and IR spectra are consistent with the product.
Reaction SMILES: [C:1]1([CH:7]([C:9]([OH:11])=[O:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1(C)[CH:17]=CC(S(O)(=O)=O)=[CH:14][CH:13]=1.COC1CCC(OC)O1.O>CN(C)C=O>[N:8]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]([OH:11])=[O:10])[CH:14]=[CH:13][CH:12]=[CH:17]1
Reactant: NC(C(=O)O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC1CCC(OC)O1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C(c1ccccc1)n1cccc1
Reaction time: 1 h

Procedure:
15.1 g (0.1 mole) of alpha-phenylglycine were resuspended in 450 ml of dimethylformamide, followed by the addition of 15 g of p-toluene sulphonic acid and 13.2 g (0.1 mole) of 2,5-dimethoxytetrahydrofuran. The mixture was heated to boiling, and at about 95° C. all the solid product was dissolved, the boiling temperature being held for about 60 minutes. After this time, the mixture was cooled, 400 ml of cold water were added and the total mixture was cooled to between 0°-5° C. The mixture was extracted twice with 200 ml of ethyl ether each time, the ether phases being discarded. The aqueous phase was extracted with 500 ml chloroform at pH 1.5. The chloroform extract was treated with 600 ml water and the pH was adjusted to 11. After separating the phases, 500 ml of chloroform were added to the aqueous extract, the pH being adjusted to 1.5 with 2N HCl. The chloroform phase was concentrated to obtain an oil which was crystallised from methanol-water. After drying, the alpha-(N-pyrrolyl)-phenylacetic acid obtained weighed 5.8 g.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>S(=O)(=O)(O)O.O>[C:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([CH3:3])=[CH2:2])=[CH:5][CH:6]=1)(=[O:13])[CH3:12]
Reactant: C=C(C)c1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(C)c1ccc(OC(C)=O)cc1
Yield: 85 %

Procedure:
A mixture of 12 g. (0.09 mole) of p-isopropenylphenol (prepared as described in Preparation 1) and 12 g. (0.118 mole) of acetic anhydride was stirred at ambient temperature (circa 20° C.) while two drops of concentrated sulfuric acid were added. Stirring was continued until the exothermic reaction subsided and the reaction product was then poured into an excess of water. The organic material was extracted with a mixture of ether and n-hexane and the extract was dried over anhydrous sodium sulfate and evaporated to dryness. There was thus obtained 16.5 g. of acetylated product which was found by nuclear magnetic resonance spectral analysis to be a mixture of 20% w/w of p-isopropenyl-phenol acetate and 80% w/w of the dimer diacetate. The product was subjected to pyrolysis by adding 0.1 g. of p-toluenesulfonic acid and heating to a temperature of 200°-240° C. under reduced pressure (circa 18 mm. mercury) to yield a distillate which was found to be 13.44 g. (85% yield) of monomeric p-isopropenylphenol acetate. The latter was mixed with a small amount of chloroform and hydrogen chloride gas was bubbled into the mixture until saturated. There was thus obtained a solution of p-(2-chloroisopropyl)phenol acetate.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:7]1[C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1Br
Temperature: 100 °C
Yield: 8588.6 %

Procedure:
4,5-Dichloro-2-nitroaniline (41.0 g, 1.98 mmol), N-bromosuccinimide (42.86 g, 2.41 mmol) and N,N-dimethylformamide were combined and heated to 100° C. for 1 h. The mixture was allowed to cool to room temperature and was poured into a flask containing ice water (1 L). The yellow solid was collected and was dissolved in dichloromethane (2 L), resulting in two phases. The organic layer was collected and was dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure using a rotary evaporator to leave 48.62 g (86%) of a brown solid. Anal. Calcd. for C6H3BrCI2N2O2: C, 25.21; H, 1.06; N, 9.80. Found: C, 25.32; H, 1.13; N, 9.68.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:13][CH:14]([O:16][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:15]2)[S:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
To a solution of 1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (2.91 g, 11.1 mmol) (obtained as described in Reference Example 41(2)) in methylene chloride (146 ml) were added methanesulfonyl chloride (2.58 ml, 33.3 mmol) and triethylamine (4.67 ml, 33.3 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue were added ethyl acetate and diisopropyl ether, and then the mixture was filtered and the resulting residue was washed with diisopropyl ether to give 1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (2.71 g, yield 77%) as pale brown crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:17])[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[NH:5][C:4]1=[O:16].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>N1C=CC=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>[CH3:18][N:19]([CH3:23])[C:20]([O:16][C:4]1[C:3]([CH2:2][O:1][C:20](=[O:21])[N:19]([CH3:23])[CH3:18])([CH3:17])[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=1)=[O:21]
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc(N2CC(C)(CO)C(=O)N2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1ccc(N2CC(C)(COC(=O)N(C)C)C(OC(=O)N(C)C)=N2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
4-hydroxymethyl-4-methyl-1-(4-methoxyphenyl)pyrazolidinone [1.2 g] and dimethylcarbamoyl chloride [0.8 mL] were combined in 10 mL pyridine and 3 mL triethylamine. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride solution (30 mL), dried over MgSO4, and evaporated. The resulting crude material was taken up in 20 mL anhydrous methanol and sodium methoxide [0.4 g] was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with methylene chloride (50 mL), washed with saturated ammonium chloride solution (30 mL), dried over MgSO4, and evaporated. This crude oil was dissolved in 10 mL pyridine and 3 mL triethylamine. Dimethylcarbamoyl chloride [0.45 mL] was added and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride solution (30 mL), dried over MgSO4, and evaporated. Chromatography on silica gel gave 0.86 g (45%) of pure 3-(N,N-dimethylcarbamoyloxy)-4-(N,N-dimethylcarbamoyloxymethyl)-4-methyl-1-(4-methoxyphenyl)-2-pyrazoline as a light yellow oil. 1H NMR: 7.1 (4H, dd, j=7,2), 3.8 (4H, m), 3.2 (6H, s), 3.1 (6H, s), 2.0 (3H, s), 1.4 (3H, s).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:25]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:26])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2)on1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2C(=O)N2CCOCC2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)-amide; hydrochloride (0.2 g; 0.731 mmol) in N,N-dimethylformamide (2 mL) is added morpholine carbonylchloride (0.084 mL; 0.731 mmol) and N,N-diisopropylethylamine (0.267 mL; 1.535 mmol) and the reaction mixture stirred overnight at room temperature. After this time, the mixture is diluted with water and extracted with ethyl acetate. The combined organics are washed with 1N hydrochloric acid and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material is purified by preparative HPLC to afford title compound. ESI m/z 351 [M+H]+/349 [M−H]−
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH:4]([C:12](Cl)=[O:13])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC.C(Cl)Cl>[N+:1](=[CH:3][C:12]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13])=[N-:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)C=Cc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of diazomethane (9.66g, 0.23 mole) in dry ether (1250 ml.) maintained at 0° to -5°, was added a suspension of the styrene-carbonyl chloride polymer (10.0g) from example 7(c) in methylene chloride (50 ml.) over 15 minutes. Stirring was maintained for 5 hours at 0° to -5° and then for 16 hours at room temperature. The reaction mixture was filtered and the polymer washed with ether (2 × 100 ml.) and chloroform (2 × 100 ml.) and dried in vacuo at room temperature to constant weight. The title polymer (10.76g) was deep yellow in colour and the IR spectrum exhibited absorptions at 2100 (diazo) and 1610 (carbonyl) cm-1. The composition of the polymer was confirmed by microanalysis.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[CH:7][C:8](=[S:19](=[O:21])=[O:20])[CH:9]([CH3:18])[C:10]=1[C:11]1[CH2:15][CH:14]([CH2:16][Cl:17])[O:13][N:12]=1)[C:4](Cl)=[O:5].[CH:22]12[CH2:29][CH:26]([CH2:27][CH2:28]1)[C:25](=[O:30])[CH2:24][C:23]2=[O:31].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C[Si](C#N)(C)C>[CH3:1][C:2]1[C:3](=[CH:7][C:8](=[S:19](=[O:21])=[O:20])[CH:9]([CH3:18])[C:10]=1[C:11]1[CH2:15][CH:14]([CH2:16][Cl:17])[O:13][N:12]=1)[C:4]([CH:24]1[C:25](=[O:30])[CH:26]2[CH2:29][CH:22]([CH2:28][CH2:27]2)[C:23]1=[O:31])=[O:5]
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: CC1=C(C2=NOC(CCl)C2)C(C)C(=S(=O)=O)C=C1C(=O)Cl
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1=C(C2=NOC(CCl)C2)C(C)C(=S(=O)=O)C=C1C(=O)C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen and at 0-5° C., 0.7 g (2 mmol) of 2-methyl-3-(5-chloromethyl-4,5-dihydroisoxazol-3-yl)-4-methyl-sulfonylbenzoyl chloride in 40 ml of acetonitrile was added dropwise to 0.28 g (2 mmol) of bicyclo[3.2.1]octane-2,4-dione and 0.4 g (4 mmol) of triethylamine in 40 ml of acetonitrile, and the mixture was stirred at room temperature for 4 hours. 1 drop of trimethylsilyl cyanide and 0.05 g of potassium carbonate were then added, and the mixture was stirred at 40° C. for 2 hours and then at room temperature for 12 hours. Following this, the solvent was removed, the residue was taken up in ethyl acetate and the solution was extracted repeatedly with 5% strength potassium carbonate solution. The combined extracts were then adjusted to pH 2-3 using 10% strength hydrochloric acid and extracted repeatedly with methylene chloride. These combined organic extracts were then washed with water and dried, and the solvent was removed. The oily yellow residue was chromatographed over silica gel (mobile phase: methylene chloride/methanol=99/1 to 97/3). This gave 0.4 g (44% of theory) of the title compound of melting point 98-103° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Solvent: C1CCOC1
Product: Fc1ccc(Br)c2[nH]ccc12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
1.12 g (5 mmol) of 2-bromo-5-fluoro-nitrobenzene were dissolved in 50 ml THF. At a temperature of −45° C. 15 ml of a 1M vinyl magnesium bromide solution in THF were added under nitrogen in such a way that the temperature did not exceed −40° C. After complete addition the dark solution was stirred for 30 min at −40° C. The reaction mixture was quenched with 10 ml aqueous saturated ammonium chloride solution and extracted twice with diethyl ether. The combined organic layers were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was dissolved in DCM and purified by column chromatography (100 g silica gel; heptane/EtOAc 9:1) to yield 501 mg (47%) 7-bromo-4-fluoro-1H-indole as an orange oil. MS (EI) 213.0 (100), 215.0 (100) (M)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([O:12][C:13](=[O:36])[NH:14][CH2:15][CH:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:33]=[CH:32][C:31](=[O:34])[CH2:30][CH2:29]3)=[C:24]([F:35])[CH:23]=2)[CH2:17]1)(C)(C)C.ClC(OC)=O>ClC(Cl)C.CC#N>[CH3:8][O:12][C:13](=[O:36])[NH:14][CH2:15][CH:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:29]=[CH:30][C:31](=[O:34])[CH2:32][CH2:33]3)=[C:24]([F:35])[CH:23]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Agent: COC(=O)Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 1.5 h

Procedure:
TFA (1.5 mL) is added to a solution of {3-[3-fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (300 mg, 0.74 mmol) in dichloroethane (6.0 mL). This solution is stirred for 1.5 h. Removed solvent under vacuum, and the residue is dissolved in MeCN (3.0 mL). TEA (0.41 mL, 3 mmol) is added followed by methyl chloroformate (98 mg, 1 mmol). The mixture is stirred at r.t. for 16 h. Solvent is removed under vacuum, and the residue is purified by silica gel column chromatography (eluent: EtOAc) to afford the product as a yellow solid. Yield 100 mg (37%). MS (m/z): 364 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ7.62–7.30 (m, 4H), 4.98 (dd, J=7.7 Hz, 3.0 Hz, 1H), 4.80–4.65 (m, 1H), 4.11 (dd, J=6.86 Hz, 2H), 3.79–3.74 (m, 1H), 3.53 (s, 3H), 3.40–3.30 (m, 2H), 2.49–2.44 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:26])([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>C(O)C>[CH:11]1([C:9]2[N:10]=[C:6]3[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:23])([F:24])([F:25])[F:26])=[CH:18][CH:17]=4)[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: Cc1cc(Cl)n2nc(C3CC3)nc2n1
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: CCO
Product: Cc1cc(Nc2ccc(S(F)(F)(F)(F)F)cc2)n2nc(C3CC3)nc2n1

Procedure:
To a suspension of Intermediate 20 (0.04 g, 0.192 mmol) in ethanol (2.5 mL), 4-aminophenylsulfur pentafluoride (MANCHESTER, 0.042 g, 0.192 mmol) was added and the mixture was stirred under reflux overnight. Solvent was removed in vacuo and the crude mixture was purified by preparative HPLC (SunFire 19×150 mm, H2O 0.1% TFA-ACN 0.1% TFA gradient from 10 to 100%) to yield the title compound as a beige solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.O1CCOCC1.[C].[Pd]>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cccc(Nc2ncccc2N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A mixture of 3-nitro-2-[(m-tolyl)amino]pyridine (825 mg) and 10% palladium carbon (0.3 g) in ethanol (15 ml) and 1,4-dioxane (15 ml) was stirred under hydrogen (3 atm) at room temperature for 30 minutes. The catalyst was removed and the solvent was evaporated. The solids were collected and washed with isopropyl ether to give 3-amino-2-[(m-tolyl)amino]pyridine (660 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH2:17][CH:18]=[CH2:19])[C:11]2=[O:20])=[N:7][N:6]=1)(=[O:4])=[O:3].[C:21]1(C)[C:22](S(O)(=O)=O)=CC=[CH:25][CH:26]=1>C(O)CCC>[CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][CH2:22][CH2:21][CH2:26][CH3:25])[CH2:14][CH2:13][N:12]([CH2:17][CH:18]=[CH2:19])[C:11]2=[O:20])=[N:7][N:6]=1)(=[O:4])=[O:3]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: C=CCN1CCC(O)N(c2nnc(S(C)(=O)=O)s2)C1=O
Solvent: CCCCO
Product: C=CCN1CCC(OCCCC)N(c2nnc(S(C)(=O)=O)s2)C1=O

Procedure:
Tetrahydro-1-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-3-allyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), butyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-3-allyl-6-butoxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH2:1]([C:3]1[C:4](N)=[N:5][C:6]([O:22][CH3:23])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[O:20][CH3:21])[N:8]=1)[CH3:2].N([O-])=O.[Na+].[BrH:29]>O.[Cu](Br)Br>[Br:29][C:4]1[N:5]=[C:6]([O:22][CH3:23])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[O:20][CH3:21])=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: Br
Reactant: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1N
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1Br
Temperature: 70 °C

Procedure:
To a stirred solution of 3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-ylamine (86 mg, 0.25 mmol) in 48% hydrogen bromide (0.3 mL) at 0° C. is added a solution of sodium nitrite (21 mg, 0.3 mmol) in water (1 mL). After 1.5 h copper bromide (43 mg, 0.3 mmol) is added and the mixture heated to 70° C. for 1 h. The mixture is cooled to room temperature and extracted with ether. The extracts are dried (sodium sulfate), filtered and concentrated to give [4-(5-bromo-6-ethyl-3-methoxypyrazin-2-yl)-3-methoxyphenoxy]trifluoromethane (76 mg).