Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]([C:19]#[CH:20])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(OCC)(=O)C.[Cu](I)I>[CH3:16][C:15]([CH3:18])([CH3:17])[C:19]#[C:20][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1C#CC(C)(C)C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
Methyl 2-bromo-4-nitrobenzoate (2.0 g, 7.7 mmol) and t-butylacetylene (0.70 g, 8.5 mmol) were dissolved into 50 mLs. of dry triethylamine to which 2 mole % of copper iodide (0.029 g, 0.15 mmol) and 5 mole. % of tetrakis(triphenylphosine)palladium(0) (0.45 g, 0.38 mmol) were added. The reaction was stirred at 400° C. for 16 hours before an additional ½ equivalent of t-butylacetylene was added. The reaction continued for an additional 24 hours at which time the reaction was completed as determined by TLC. The reaction mixture was taken up in ethyl acetate, washed with distilled water and the organic layer dried over magnesium sulfate. After concentrating, the residue was purified by chromatography (1:9 ethyl acetate/hexanes ) to give the title compound (1.7 g, 85%) as a white solid. m.p. 88-89° C.; 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J=2.2 Hz, 1H, Aromatic), 8.10 (dd, J=2.3, 8.6 Hz, 1H, Aromatic), 7.99 (d, J=8.7 Hz, 1H, Aromatic), 3.99 (s, 3H, OCH3), 1.35 (s, 9H, t-Butyl); 13C NMR (75 MHz, CDCl3) δ 165.9, 149.4, 137.7, 131.4, 128.7, 126.2, 121.8, 107.1, 76.5, 52.8, 30.8, 28.6; MS m/e calc'd 261.1001, found 261.1007.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][NH2:10])=[O:8].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][NH:10][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([C:12]([F:11])([F:22])[F:23])=[CH:14][CH:15]=1)=[O:8]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NNC(=O)c1sccc1Cl
Product: O=C(NNC(=O)c1sccc1Cl)c1ccc(C(F)(F)F)cc1

Procedure:
Compounds of this invention with Formula VI may be prepared as illustrated by the exemplary reaction in Scheme 6. Reaction of 3-chloro-thiophene-2-carboxylic acid hydrazide with 4-trifluoromethylbenzoyl chloride produces N-(3-chloro-thiophene-2-carbonyl)-N′-(4-trifluoromethylbenzoyl)-hydrazine, followed by treating with thionyl chloride produces 5-(3-chloro-2-thienyl)-3-(4-trifluoromethylbenzoyl)-[1,3,4]-oxadiazole.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[N:18][O:19][CH3:20])[C:14]([NH:16][CH3:17])=[O:15]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:3][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[C:13](=[N:18]\[O:19][CH3:20])/[C:14]([NH:16][CH3:17])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CNC(=O)/C(=N/OC)c1ccccc1CCl
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Thionyl chloride (3.0 ml) was added to a mixture of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (3.0 g), tetrabutylammonium chloride (380 mg) and toluene (30 ml) at room temperature. The mixture was stirred for 10 minutes, and then stirred at 60° C. for 1.5 hours. After the mixture was cooled by allowing it to stand, the solvent was evaporated under reduced pressure. The residue was dissolved in diethyl ether, and washed successively with water and saturated brine. The ether layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in a small amount of diethyl ether. Hexane was added to the solution to obtain the title compound as crystals (2.6 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10](SC)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=O)C=1.S(=O)(O)[O-].[Na+].[NH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10]([N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cccc(Cl)c2)n1
Reactant: C1CCNCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(N2CCCCC2)nc(-c2cccc(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
44.0 mg (0.107 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of dichloromethane. 36.9 mg (0.213 mmol) of mCPBA (m-chloroperbenzoic acid) was added thereto at 0° C. and stirred at the same temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite solution was added thereto at the same temperature and stirred for 30 minutes heating to room temperature. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of toluene and 91.1 mg (1.07 mmol) of piperidine was added at room temperature and stirred at 80° C. for 6 hours. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: O.[Cl-].[NH4+].[CH2:4]([N:6]1[CH:10]=[C:9]([CH2:11][N:12]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:13]([CH:15]2[C:24]3[C:19](=[C:20]([N+:25]([O-])=O)[CH:21]=[CH:22][CH:23]=3)[O:18][CH2:17][CH2:16]2)=[O:14])[CH:8]=[N:7]1)[CH3:5]>C(O)C.[Fe]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[O:18][CH2:17][CH2:16][CH:15]2[C:13]([N:12]([CH2:11][C:9]1[CH:8]=[N:7][N:6]([CH2:4][CH3:5])[CH:10]=1)[C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)=[O:14]
Reactant: CCn1cc(CN(C(=O)C2CCOc3c2cccc3[N+](=O)[O-])c2ccc(C(C)C)cc2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCn1cc(CN(C(=O)C2CCOc3c(N)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 78.6 %

Procedure:
To a mixed solvent of ethanol (43 mL) and water (18 mL) were added iron (0.43 g) and ammonium chloride (0.06 g), and a solution of N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (0.9 g) in ethanol (10 mL) was added dropwise with heating and stirring at 50° C.-70° C. After stirring at 50° C.-70° C. for 3 hr, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 8-amino-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.66 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[Cl:16][S:17](O)(=[O:19])=[O:18].C(Cl)(=O)C(Cl)=O>ClCCl>[C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC#CCOc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)OCC#CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: -7.5 °C
Reaction time: 1 h

Procedure:
A 22-L reactor was equipped with a thermometer, a water condenser, a cooling bath/heating mantle, and an addition funnel, and dichloromethane (11 L) was charged. A solution of 4-phenoxy-2-butynyl acetate in dichloromethane (2.04 kg, 10 mol) was charged to the reactor, followed by 2 L of dichloromethane and the solution was cooled −5 to −10° C. Chlorosulfonic acid (0.73 L, 1.28 kg, 11 mol) was added slowly via an addition funnel maintaining temperature between −5 and 0° C. After the addition was complete, the cooling bath was removed and the reaction mixture was stirred for 1–2 h at 18–22° C. The progress of the reaction was monitored by TLC or HPLC (disappearance of starting material). DMF (155 mL, 146 g) was added portion wise. The reaction mixture was heated to reflux (38–40° C.). Oxalyl chloride (1.13 L, 1.65 kg, 13 mol) was added through an addition funnel into the boiling solution over a period of 2–3 h maintaining gentle reflux. After all the oxalyl chloride was added, reflux was continued for 1 h. The completion of reaction was checked by HPLC (less than 3% of intermediate sulfonic acid remaining). After completion, the heating was stopped and the reaction mixture was cooled to 18–22° C. and stirred for 16 h. The reaction mixture was quenched into a 50-L reactor with 5 L of cold (5 to 10° C.) water and stirred for 10–20 min while maintaining the temperature below 20° C. The organic layer was separated and the aqueous layer was extracted with (2 L) of fresh dichloromethane. The combined organic layers were washed with 4 L of sodium bicarbonate solution until pH=7–8. The dichloromethane layer was separated and concentrated in vacuo at 35–40° C. to a volume of 5 to 7 L. This solution was mixed with 3 kg of silica gel and concentrated in vacuo until a free-flowing powder was obtained. The silica gel powder was transferred to a filter funnel with a Celite bed and eluted with 22 L of isopropyl ether. The ether solution was concentrated in vacuo to yield about 3 L of a slightly viscous liquid. This residue was transferred to a 5-L reaction flask with overhead stirrer, seeded and stirred for 16–18 h at 18–22° C. Crystallization began after several hours. Stirring continued at low temperature (0 to −10° C.). The solid was filtered on Buchner funnel lined with polypropylene and washed with 2 L of cold (5° C.) IPE, then dried under vacuum (30 mm) at 18–20° C. to yield 1.1 kg (55%, HPLC strength 94.8%) of product.
Reaction SMILES: [C:1]([N:9]([CH3:11])[OH:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]([S:14](Cl)(=[O:16])=[O:15])=[CH2:13].C(N(CC)CC)C>O1CCCC1>[CH:12]([S:14]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([N:9]([CH3:11])[OH:10])=[O:8])(=[O:16])=[O:15])=[CH2:13]
Reactant: CN(O)C(=O)c1ccccc1
Reactant: C=CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)c1ccccc1C(=O)N(C)O
Reaction time: 2 h
Yield: 76.6 %

Procedure:
130 ml of tetrahydrofuran was added to a mixture of 7.6 g of N-benzoyl-N-methylhydroxylamine and 6.3 g of vinylsulfonyl chloride and a solution of 5.1 g of triethylamine in 20 ml of tetrahydrofuran was dropwise added to the mixture over 2 hours with stirring while cooling the mixture so that the temperature was maintained at 25 ° C. or less. The reaction was continued for additional 2 hours at a temperature ranging from 15° to 25 ° C. and then the same procedures used in Preparation Example 4 were repeated to give 9.2 g of o-vinylsulfonyl-N-benzoyl-N-methylhydroxylamine.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=O)[C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([Cl:22])[C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C

Procedure:
Part B. A solution of the pyridone from Part A (6.72 g, 25.9 mmol) in phosphorus oxychloride (52 mL, 25.5 mmol) was stirred at ambient temperature for 3 d. The reaction mixture was poured into a mixture of ice (150 g) and dichloromethane (200 mL). After the ice had melted, 100 mL more dichloromethane was added, and the pH of the mixture was adjusted to 7 with solid NaHCO3. The mixture was separated, and the aqueous phase was extracted with dichloromethane. The extracts were combined, dried over sodium sulfate, filtered and evaporated to afford the product (4-benzylamino-2-chloro-6-methyl-3-nitropyridine) as a bright yellow crystalline solid (6.45 g, 23.2 mmol, 90%). TLC RF 0.76 (ethyl acetate). 1H NMR (300 MHz, CDCl3): d 7.43-7.26 (5H, m), 7.04 (1H, br), 6.47 (1H, s), 4.48 (2H, d, J=5.5 Hz), 2.40 (3H, s). MS(NH3 -CI): m/e 281 (5), 280 (35), 279 (17), 278 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-fluorobenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.73 min.; [M+H]+: 344.22 g/mol.
Reaction SMILES: [Si:1]([CH3:5])([CH3:4])(Cl)[Cl:2].N(CC)(CC)CC.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>CCCCC>[Cl:2][Si:1]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:5])[CH3:4]
Reactant: CC(C)(C)N
Reactant: C[Si](C)(Cl)Cl
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)N[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Me2SiCl2 (151.50 g, 1.17 moles) was stirred in pentane (2 L) as N(C2H5)3 (119.62 g, 1.18 moles) was added slowly. t-Butylamine (85.85 g, 1.17 moles) in pentane (100 mL) was then added dropwise and the reaction allowed to stir at room temperature for 16 hours. After the reaction period the mixture was filtered and concentrated to 600 mL at which time more salts began to precipitate. The mixture was then refiltered and concentrated to 250 mL and then transferred to a 250 mL roundbottom flask equipped with a microdistillation apparatus and a thermometer. Distillation was performed until the reflux temperature reached 50° C. The clear, colorless liquid remaining was then determined to be pure by NMR and the yield to be essentially quantitative.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:25].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(O)C.[OH-].[Na+].O>[CH3:25][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:1][CH2:26][CH:28]1[CH2:29][O:30]1
Reactant: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.3 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (300 mg, 0.86 mmol) in 2-propanol (7.5 mL) and 3 N aq. NaOH (2.5 mL) is treated with epichlorohydrine (158 mg, 1.72 mmol) and the mixture is stirred at rt for 24 h, then diluted with water and extracted with EA. The solvent of the organic extract is evaporated and the residue is purified by CC on silica gel eluting with hepaten:EA 5:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (92 mg) as an oil; LC-MS: tR=1.13 min, [M+1]+=407.24.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:60][C:61]([F:65])([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][C:61]([F:65])([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)(F)F)C4CC4)c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
To a solution of [9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (120 mg, 0.26 mmol), 1,1′-(azodicarbonyl)dipiperdine (131 mg, 0.52 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.130 mL, 0.52 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2,2-trifluoroethanol (0.189 mL, 2.58 mmol) was added to the reaction mixture. The mixture was stirred at 60° C. for 5 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (77.4 mg, 0.155 mmol, 60%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([Cl:19])[N:13]=1.Cl>C(OCCO)C>[ClH:19].[NH2:11][C:12]1[N:13]=[C:14]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:15]=[C:16]([CH3:18])[N:17]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCOCCO
Product: Cc1cc(Nc2ccc(C(=O)O)cc2)nc(N)n1
Temperature: 20 °C
Yield: 95.3 %

Procedure:
p-Aminobenzoic acid (D1) (1.48 g, 10.8 mmol) and 4-chloro-6-methyl-2-pyrimidinamine (A8) (1.60 g, 11.9 mmol) was dissolved in warm 2-ethoxyethanol (20 mL),then two drops of c.HCl was added and refluxed for 1 h. The reaction mixture was cooled to 20° C. and the resulting precipitate was filtered washed with more 2-ethoxyethanol and EtOAc. The solid was boiled in MeOH, cooled and filtered washed with more MeOH and dried to give D2 (2.89 g, 95%); m.p. (MeOH)>300° C.; 1H NMR [(CD3)2SO] δ12.93 (br, 1 H, N+H or COOH), 12.80 (br, 1 H, N+H or COOH), 10.87 (s, 1 H, NH), 7.92 (s, 6 H, ArH &NH2)), 6.27 (s, 1 H, ArH), 2.32 (s, 3 H, CH3); mass APCI+ 245.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:18]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: C=CCOc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 91.3 %

Procedure:
A solution prepared by adding 20 g of 4-cyano-4′-hydroxybiphenyl, 20 g of allyl bromide and 25 g of potassium carbonate to 250 ml of 2-butanone was refluxed for 7 hours. Water was added to the reaction solution for liquid-liquid separation, and the organic layer was washed with water and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through silica gel column chromatography using toluene as an eluent solvent and then further recrystallized from ethanol to obtain 22 g of 4-allyloxy-4′-cyanobiphenyl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].F[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)Nc1ccc(O)cc1C(=O)OC
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)Nc1ccc(Oc2ccccc2[N+](=O)[O-])cc1C(=O)OC
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A mixture of 5-hydroxy-2-propionylamino-benzoic acid methyl ester (1.0 g, 4.5 mmol) and potassium carbonate (0.62 g, 4.5 mmol) was stirred in DMF (5 mL) for 10 minutes. 2-fluoronitrobenzene (0.63 g, 4.5 mmol) was then added and stirring was continued at room temperature overnight. Water (10 mL) was added and the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give pure 2-propionylamino-5-(2-nitro-phenoxy)-benzoic methyl ester (1.16 g, 3.4 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:28]=[CH:27][C:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[CH2:31]([O:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:28]=[CH:27][C:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(S(=O)(=O)c3cccc(O)c3)cc2CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(S(=O)(=O)c3cccc(OCc4ccccc4)c3)cc2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A solution of D3 (270 mg, 0.67 mmol) in dimethylformamide (5 mL) was treated with 60% sodium hydride (40 mg) at 0° C., then allowed to warm to room temperature. Benzyl bromide (137 mg, 0.8 mmol) in dimethylformamide (2 mL) was added, and the solution stirred overnight. The mixture was then poured onto water and extracted with ethyl acetate. The combined organic layers were washed with brine dried and evaporated. Chromatography on silica, eluting with 40% ethyl acetate in hexane afforded the product (200 mg). MH+ 494.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([OH:26])[C@@H:15]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C@H:10]1[S:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.[Br:45][CH2:46][C:47](Br)=[O:48]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@@:16]([C:47](=[O:48])[CH2:46][Br:45])([OH:26])[C@@H:15]([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:14][C@H:10]1[S:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCS[C@@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C(Br)CBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCS[C@@H]1O[C@H](COCc2ccccc2)[C@@](O)(C(=O)CBr)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 305.9 %

Procedure:
A mixture of ethyl 2,3,6-tri-O-benzyl-1-thio-β-D-galactopyranoside (4.14 g, 8.38 mmol), sym. collidine (3.65 g, 30.16 mmol), and 4-dimethylaminopyridine in dry CH2Cl2 (60 ml) was stirred at 0° C. and bromoacetyl bromide (2.53, 2.57 mmol) in CH2Cl2 added dropwise in 15 minutes. The reaction mixture was diluted with CH2Cl2 (100 ml) and washed with 5% HCl solution (3×30 ml) and saturated NaHCO3 solution (30 ml). The solution was dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane/EtOAc 2:1 as the mobile phase to give ethyl 2,3,6-tri-O-benzyl-4-bromoacetyl-1-thio-β-D-galacto-pyranoside (4.84 g, 94%)