Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@:2]12[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C@H:10](N1)C[C:8]1[CH:7]=[CH:6]C=C[C:3]2=1.[Cl-].C1(N2C=[NH+]N(C3C=CC=CC=3)N2C2C=CC=CC=2)C=CC=CC=1.[OH2:42].[Cl-].[Na+].[OH2:45]>>[CH2:3]([CH:2]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:45])[O:42]1)[CH2:8][CH2:7][CH3:6]
Reactant: O
Reactant: C[C@]12N[C@H](Cc3ccccc31)c1ccccc12
Agent: C1=[NH+]N(c2ccccc2)N(c2ccccc2)N1c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: CCCCC1OC(=O)c2ccccc21

Procedure:
l-, d-, and dl-NBP were all provided by department of synthetic pharmaceutical chemistry of our institute, both optical and chemical purity of which are >99%, and the optical activity of which is −66.49°, +66.88° and 0°, respectively. They were formulated with vegetable oil. MK801 is the product of Sigma, and was formulated with physiological brine. Triphenyltetrazolium chloride (TTC), which was manufactured by Beijing Chemical Plant, was formulated with distilled water into 4% solution for use.
Reaction SMILES: FC(=C(F)F)[CH2:3][C:4]([OH:6])=[O:5].[Cl:10][C:11]([F:17])(Br)[C:12]([F:15])([F:14])[Br:13]>[Zn]>[Br:13][C:12]([F:15])([F:14])[C:11]([Cl:10])([F:17])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: FC(F)(Br)C(F)(Cl)Br
Reactant: O=C(O)CC(F)=C(F)F
Agent: [Zn]
Product: O=C(O)CC(F)(Cl)C(F)(F)Br

Procedure:
A mixture of 1,1,2-trichlorotrifluoroethane (X) (9.37 g, 50 mmol), vinylidene chloride (4.85 g, 50 mmol), ammonium persulfate (11.41 g, 50 mmol), sodium formate (3.4 g, 50 mmol) and water (1.8 g, 0.1 mol) in DMF (80 mL.) was stirred (dry-ice/acetone condensor) at room temperature with air bubbling. After 30 min, an aliquot of the reaction mixture was acidified with dilute HCl, extracted with ether and analyzed by GC, which indicated the formation of two products. These products were identified by GC/MS (EI) as 4-chloro-3,4,4-trifluoro-2-butenoic acid and novel compound 3,4-dichloro-3,4,4-trifluorobutanoic acid (XI). The compound XI gives 3,4,4-trifluoro-3-butenoic add (IV) upon reaction with zinc. Under the above reaction conditions, 1-chloro-1,2-dibromotrifluoroethane (VI) gave 3-chloro-4-bromo-3,4,4-trifluorobutanoic acid (VIII) as one of the products.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.CCOC(C)=O>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][O:7][Si:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]([CH3:26])([CH3:24])[CH3:25])[CH2:4][OH:5]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCC(CO)(CO)CO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
2,2-bis(hydroxymethyl)propane-1,3-diol (10.55 g, 77 mmole) was taken up in dry pyridine (100 mL). Tert-butyldiphenylsilyl chloride (4.26 g, 15 mmole, 0.2 eq) was then added dropwise over 10 minutes to the pyridine solution at ambient temperature. The reaction mixture was stirred at ambient temperature for 24 hours. TLC (EtOAc) indicated that the reaction was complete. The reaction was diluted with EtOAc (250 mL), washed with 10% HCl (3×200 mL). The organic layer was dried over sodium sulfate and then concentrated in vacuo to afford a thick pale yellow oil. Column chromatography on silica gel (200 g), eluted with EtOAC followed by concentration of the appropriate fractions gave 5.01 g of the title compound as a clear colorless oil which solidified very slowly upon standing (86%). 1H NMR (300 MHz, CDCl3) δ 7.65 (m, 4H), 7.42 (m, 6H), 3.74 (s, 6H), 3.66 (s, 2H), 1.08 (s, 9H); MS (70 eV, EI) 392 (M+NH4)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C:9]1([C@@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[C:9]1([C@@H:15]([NH:17][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: C[C@H](N)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccc[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a solution of 1H-pyrrole-2-carbonyl chloride (1.3 g, 10 mmol) (from Example 30) in DCM (20 mL) was added (S)-1-phenyl-ethylamine (1.4 g, 11.55 mmol) (Aldrich, Milwaukee, Wis.), followed by triethylamine (1.5 mL). The reaction was stirred at room temperature for overnight. The reaction was washed with 1N NaOH, water, brine, dried and concentrated to give 867 mg (40%) of 1H-pyrrole-2-carboxylic acid ((S)-1-phenyl-ethyl)-amide.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:18]Cl)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:18][S:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2c(-c3ccccc3)cc(CCl)cc2c1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2c(-c3ccccc3)cc(CSc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the halide from Step 2 (600 mg, 0.22 mmoL) in dry DMF (5 mL) was added at r.t. NaH (90 mg, 2.2 mmoL), followed by thiophenol (114 mL, 1.1 mmoL). The reaction mixture was stirred at r.t. for 18 hr., then transferred to H2O and extracted with EtOAc. The combined organic phases were washed with brine, and dried over MgSO4. After evaporation of the solvent and purification by flash chromatography on silica gel (hexanes:EtOAc; 7:3) the title compound was obtained.
Reaction SMILES: Br[CH:2]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[SH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCC#CC(Br)CCCCC(=O)OC
Reactant: COC(=O)CCCCCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC#CC(CCCCC(=O)OC)SCCCCCC(=O)OC

Procedure:
A mixture of methyl 6-bromo-7-eicosynoate, methyl 6-mercaptohexanoate (1.21 g) in 70 ml DMF was treated with Cs2CO3 (2.44 g) as in Example 45 to give 1.02 g of methyl-6-[(6-methoxy-6-oxohexyl)thio]-7-eicosynoate.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].Cl[CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][NH:4][C:3]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: ClCC1OCCO1
Reactant: Cc1ccc(Cl)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1NCC1OCCO1
Reaction time: 26 h

Procedure:
2-Methyl-5-chloroaniline (75 grams), 2-chloromethyl- 1,3-dioxolane (25 grams), potassium carbonate (22 grams) and dimethylformamide (50 ml) were charged with a glass reaction vessel equipped with a mechanical stirrer, thermometer, and reflux condenser. The reaction mixture was heated, with stirring, for a period of about 26 hours. After this time the reaction mixture was filtered and then distilled to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-2-methyl-5-chloroaniline having a boiling point of 116° to 118°C at 0.1 mm of Hg pressure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[CH:11]=1.[CH2:12]([Mg]Br)[CH2:13][CH3:14].Cl>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:12][CH2:13][CH3:14])=[N:6][N:5]2[CH:11]=1
Reactant: Clc1cn2nc(Cl)ccc2n1
Reactant: CCC[Mg]Br
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1ccc2nc(Cl)cn2n1
Temperature: 5 °C

Procedure:
Under a nitrogen stream, 2,6-dichloroimidazo[1,2-b]pyridazine (0.50 g, 2.66 mmol) and iron(III) acetylacetonate (0.094 g, 0.27 mmol) were added to tetrahydrofuran (5.0 ml), and a solution of n-propylmagnesium bromide in tetrahydrofuran (2 M, 1.99 ml, 3.99 mmol) was added dropwise over 13 minutes to the mixture with stirring at 0 to 10° C. After stirring for 10 minutes under ice-cooling, the reaction mixture was warmed to room temperature and stirred for 6 hours at room temperature. The reaction mixture was poured onto ice-cold water, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated saline. The resulting organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7) to give the title compound as pale yellow crystals. The yield was 0.28 g (53.8%).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:15][O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.C(N(CC)CC)C>S(Cl)(Cl)=O>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[C:17]([O:16][CH3:15])=[O:23])=[O:6]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A mixture of 18.51 g (0.10 mol; 1.0 eq) of 2-fluoro-3-nitrobenzoic acid and 100 ml of thionyl chloride was refluxed for 3 hours. The excess thionyl chloride was then concentrated and the residue was co-evaporated twice with toluene. The resulting acid chloride was taken up in 250 ml of dichloromethane. To this mixture, cooled to 0° C., were added 16.56 g (0.10 mol; 1.0 eq) of L-proline methyl ester hydrochloride and then 30.50 ml (0.22 mol; 2.2 eq) of triethylamine. After 30 minutes at 0° C. and one hour at ambient temperature, the reaction medium was diluted and washed with 250 ml of a 1 M aqueous hydrochloric acid solution and then with 250 ml of a saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated. 25.64 g of methyl (S)-1-(2-fluoro-3-nitrobenzoyl)pyrrolidine-2-carboxylate were obtained. Yield=87%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.C1COCC1.C[O:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:33](=[O:32])[C:34]([CH3:39])([CH3:38])[CH2:35][OH:36])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: COCC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(CO)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 9.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-107 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.100 g, 0.271 mmol), THF:DMF (5 mL:1 mL), 3-methoxy-2,2-dimethylpropanoic acid (0.053 g, 0.407 mmol), TBTU (0.261 g, 0.813 mmol), TEA (2.0 mL). The obtained crude was purified by column chromatography using basic alumina as stationary phase and eluting with the solution of 2% ammonia in 10.0% MeOH:DCM to afford 0.012 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.05 (s, 6H), 3.30 (s, 211), 4.30 (d, J=4.5 Hz, 1H), 4.36 (s, 1H), 7.53 (d, J=6.3 Hz, 1H), 7.75 (s, 1H), 8.08 (t, J=4.5 Hz, 1H), 8.21 (d, J=6.3 Hz, 2H); MS (m/z): 469.04 (M+H)+.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].[C:11]1([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N+]=[N-])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH:17]([O:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1cc(CO)occ1O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: O=c1cc(CO)occ1OC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 56.8 %

Procedure:
14.2 g (0.1 mol) of kojic acid was added to ethanol (400 ml), and heated to 60° C. and dissolved. After cooling the solution to room temperature, 29.1 g (0.15 mol) of diphenyldiazomethane was added thereto, and the mixture was reacted at room temperature for 18 hours under stirring. The reaction solution was concentrated to dryness, and benzene (300 ml) was added thereto. Then, insolubles were removed by filtration. To the filtrate, water (300 ml) was added, and the precipitates thereby formed were collected by filtration, and washed with benzene to obtain 17.5 g (yield: 56.8%) of the above identified compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.[NH2:11][CH2:12][CH2:13][OH:14].C(N(C(C)C)CC)(C)C>CC(O)C>[NH2:1][C:2]1[C:7]([NH:11][CH2:12][CH2:13][OH:14])=[N:6][C:5]([CH3:9])=[N:4][C:3]=1[Cl:10]
Reactant: NCCO
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(Cl)c(N)c(NCCO)n1
Temperature: 150 °C
Reaction time: 27 h
Yield: 61.5 %

Procedure:
Charge a 1 L auto-clave with 5-amino-4,6-dichloro-2-methylpyrimidine (50.0 g, 0.281 mol), 2-amino ethanol (18.8 g, 0.309 mol), diisopropylethylamine (54.5 g, 0.421 mol), and IPA (500 mL). Heat the mixture to 145-155° C., with stirring for 24 to 30 h. Cool the reaction to 25-30° C. Concentrate the reaction mixture, removing the solvent under vacuum below 50° C. Charge DCM (500 mL) into the mixture and stir at 10-25° C. for 2 h. Filter the mixture and dry the cake in the oven at 45-50° C. to give the product as a pale yellow solid (35.0 g). 1H NMR (dmso-d6): δ 6.76 (s, 1H); 4.79 (s, 3H); 3.53-3.37 (m, 4H); 2.09 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[CH3:13][N:14]([CH2:16][CH2:17][NH2:18])[CH3:15]>>[CH3:13][N:14]([CH3:15])[CH2:16][CH2:17][NH:18][C:9]([C:5]1[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])=[O:11]
Reactant: CN(C)CCN
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Yield: 52 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (0.5 g, 2.99 mmol) was reacted with dimethylaminoethylamine (0.32 mL) to give 0.37 g (52% yield) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)-amide by using General Amidation Procedure 1, 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.84 (br s, 1H, NH), 9.52 (s, 1H, CHO), 7.47 (m, 1H, NH), 3.3 (m, 2H, CH2), 2.55 (m, 2H, CH2), 2.35 (s, 3H, CH3), 2.29 (s, 6H, 2×CH3), 2.30 (s, 3H, CH3). MS m/z 266 [M+1].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[Cl:21][CH2:22][CH2:23][CH2:24]I>CN(C=O)C>[Cl:21][CH2:22][CH2:23][CH2:24][S:11]([C:8]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: O=C(O)c1cc(S(=O)O)ccc1O
Reactant: ClCCCI
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(S(=O)(=O)CCCCl)ccc1O
Temperature: 40 °C

Procedure:
To 16.7 mmol 2-hydroxy-5-sulfino-benzoic acid and 41.7 mmol triethylamine in 40 ml DMF was added 18.3 mmol 1-chloro-3-iodopropane, and the mixture heated at 40° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: dichloromethane/methanol/acetic acid gradient) to afford the title compound. MS (m/e): 279.1 ([{37Cl}M−H]−, 33%), 277.0 ([{35Cl}M−H]−, 100%)
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)c1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2cccc([N+](=O)[O-])c2)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(O)C.[OH-].[Na+:29]>O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+:29]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
8.5 g. of behenic acid were dissolved in 150 ml. of ethanol at 60° C. with stirring, and a solution of 1 g. of sodium hydroxide in 100 ml. of water was dropwise added at 60° C. with stirring to form sodium behenate. 200 ml. of hot water of about 70° C. were then added and sodium behenate was completely dissolved at about 70° C. with continuation of stirring. Subsequently, an about 1/100 N aqueous nitric acid solution containing an equimolar amount, to that of the charged behenic acid, of silver nitrate was dropwise added at 70° C. with stirring. The dissolved sodium behenate was converted to insoluble silver behenate. The obtained silver behenate was recovered by filtration and repeatedly washed with hot water of about 80° C. and hot ethanol of about 70° C., followed by drying.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:16])([C:10]#[C:11][Si](C)(C)C)[CH3:9])=[N:6][CH:7]=1.[F-].[K+]>CO.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:16])([C:10]#[CH:11])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(O)(C#C[Si](C)(C)C)c1ccc(F)cn1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CC(C)(O)c1ccc(F)cn1
Yield: 86.3 %

Procedure:
A solution of 2-(5-fluoropyridin-2-yl)-4-(trimethylsilyl)but-3-yn-2-ol (1 g, 4.21 mmol) and potassium fluoride (987 mg, 16.99 mmol) in methanol (10 mL) was stirred for 2 hr at 50° C. The resulting solution was diluted with ethyl acetate (20 mL) and the solid material was removed by filtration. The filtrate was concentrated in vacuo to give 600 mg (86%) of the title compound as yellow oil: LC-MS: m/z=+166 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH2:9](Br)[CH3:10].O.N.C(O)(=O)C>O>[CH2:9]([S:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[NH2:2])[CH3:10]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCBr
Agent: Cl
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: CCSC[C@H](N)C(=O)O
Temperature: 25 °C

Procedure:
SEC is synthesized from L-cysteine hydrochloride (1.58 g, 0.01 mol) and ethyl bromide (1.09 g, 0.01 mol) with the following steps. The reaction mixture is diluted with water in a titration manner until a clear solution is formed. No more than necessary amount of water should be added to further dilute the mixture. Ammonia water was added to PH 9.5-10 with stirring at room temperature. After 2 hours reaction, the mixture is acidified with acetic acid to PH 5-5.5. The desired product was cooled in the refrigerator, filtered and washed successively with water and ethyl ether. The chemical structure of SEC is determined by Proton Nuclear Magnetic Resonance Spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([CH:11]=[O:12])[CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[C:4]([CH:3]=1)[CH:11]=[O:12]
Reactant: c1cn[nH]c1
Reactant: O=Cc1cc(Cl)ccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=Cc1cc(Cl)ccc1-n1cccn1
Reaction time: 48 h
Yield: 22.2 %

Procedure:
To a solution of 4-chloro-2-formylphenylboronic acid (200 mg, 1.09 mmol) in DMF (10 mL) are added pyrazole (88 mg, 1.3 mmol), Cu(OAc)2 (295 mg, 1.6 mmol), pyridine (171 mg, 2.2 mmol) and molecular sieve (200 mg) at room temperature. The mixture is stirred for 48 hours with open cap. The mixture is filtered through a short pad of diatomaceous earth (2 g) rinsing with MeOH (10 mL). The combined filtrate is extracted with H2O (15 mL) and EtOAc (3×10 mL). The combined organic layer is dried with MgSO4 and filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography eluting with 10% EtOAc in heptane to afford 5-chloro-2-pyrazol-1-yl-benzaldehyde (50 mg, 22%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([O:21]CC)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([OH:21])=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Temperature: 50 °C
Yield: 83.6 %

Procedure:
A solution of Intermediate 16 (0.21 g) in ethanol:water (95:5, 10 ml) was treated with sodium hydroxide (0.12 g). The mixture was heated at 50° C. for 8 h, then concentrated in vacuo, dissolved in water and acidified to pH 4 with acetic acid. The resultant white solid was removed by filtration and dried under vacuum to afford Intermediate 17 as an off-white solid (0.16 g). LCMS showed MH+=291; TRET=2.11 min.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[C:3]=1[CH3:12]
Reactant: CO
Reactant: Cc1c(C(=O)O)ccc(O)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(O)c1C
Temperature: 25 °C
Yield: 83 %

Procedure:
To a round bottom flask equipped with magnetic stirring and a reflux condenser was added 3,4-dihydroxy-2-methylbenzoic acid (23.3 g, 139 mmol), methanol (139 mL), and concentrated sulfuric acid (0.77 mL, 13.9 mmol). This mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature and the methanol evaporated. The residue was taken up in ether and washed once with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to give a brown solid, methyl-3,4-dihydroxy-2-methylbenzoate, (20.9 g, 114 mmol) in 83% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.47 (s, 3H), 3.79 (s, 3H), 6.78 (d, 1H), 7.46 (d, 1H); TLC: Rf=0.54 (1:1 ethyl acetate/hexane).