Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH:10](N2C(C)=CC=C2C)[CH3:11])[C:5]=1[F:19])[CH3:2].Cl.[NH2:21]O.[OH-].[K+].C(O)C>O>[NH2:21][CH2:11][CH2:10][C:6]1[C:5]([F:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=1
Reactant: CCOc1ccnc(C(C)n2c(C)ccc2C)c1F
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccnc(CCN)c1F
Temperature: 25 °C

Procedure:
A mixture of 825 mg (3.15 mmole) of N-[(4-Ethoxy-3-fluoropyrid-2-yl)eth-2-yl]-2,5-dimethylpyrrole, 1.4 g (20.1 mmole) of hydroxylamine hydrochloride, 700 mg (12.5 mmole) of potassium hydroxide, 20 ml of ethanol, and 8 ml of water was refluxed for 3 days under nitrogen. The solution was cooled to room temperature, concentrated, and partitioned between 50 ml of 2N hydrochloric acid and ethyl acetate (3×). The aqueous layer was basified with 5N sodium hydroxide, extracted with ethyl acetate (3×), dried over sodium sulfate, and concentrated. The resulting red oil was found to be the titled compound with a small amount of 2,5-hexanedione dioxime also present. The oil was used as such for reaction without further purification: IR (KBr, cm-1) 2989, 1609, 1495, 1306, 1075; 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, 1H), 7.05 (t, 1H), 4.20 (q, 2H), 2.60-3.00 (m, 6H), 1.38 (t, 3H); MS (FD) m/e 185 (Mt).
Reaction SMILES: SC([OH:4])C.C1C(CN2C(=O)C=CC2=O)CCC(C(ON2C(=O)CCC2=O)=O)C1.C([O-])(=O)CCCCC.C1C(SSC2C=CC([N+]([O-])=O)=C(C(O)=O)C=2)=CC(C(O)=O)=C([N+]([O-])=O)C=1.[C:63]([CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][NH:71][C:72]([CH:74]1[CH2:79][CH2:78][CH:77]([CH2:80][N:81]2[C:85](=[O:86])[CH2:84][CH:83]([CH2:87][CH2:88]C(O)=O)[C:82]2=[S:92])[CH2:76][CH2:75]1)=[O:73])([OH:65])=[O:64]>>[C:63]([CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][NH:71][C:72]([CH:74]1[CH2:79][CH2:78][CH:77]([CH2:80][N:81]2[C:85](=[O:86])[CH2:84][CH:83]([CH2:87][CH2:88][OH:4])[C:82]2=[S:92])[CH2:76][CH2:75]1)=[O:73])([OH:65])=[O:64]
Reactant: CC(O)S
Reactant: O=C(O)CCCCCNC(=O)C1CCC(CN2C(=O)CC(CCC(=O)O)C2=S)CC1
Agent: CCCCCC(=O)[O-]
Agent: O=C(O)c1cc(SSc2ccc([N+](=O)[O-])c(C(=O)O)c2)ccc1[N+](=O)[O-]
Agent: O=C(ON1C(=O)CCC1=O)C1CCC(CN2C(=O)C=CC2=O)CC1
Product: O=C(O)CCCCCNC(=O)C1CCC(CN2C(=O)CC(CCO)C2=S)CC1
Reaction time: 12 h

Procedure:
Mercaptoethanol (0.0045 ml of 1.43M solution in dimethylformamide, 6.4×10-6 mol) was added to SMCC-caproate (0.016 ml, 6.4×10-6 mol) in pyridine (see Example 6). The solution was gassed with argon and the tube sealed. After 12 hr at room temperature, no thiol remained (as determined by reaction with DTNB) and the solvents were removed in vacuo. The residue was dissolved in 0.03 ml of 0.2M potassium phosphate, pH 7, to make a 213 mM solution of the desired compound (see FIG. 1D).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[OH:15].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(Br)cc(Br)c1O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Br)cc(Br)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a stirred mixture of sodium hydride (0.6 g) in DMF (50 mL) was slowly added 14 (7.1 g). After the addition was complete, the mixture was stirred at room temperature for 15 minutes, then benzyl chloride (3.05 g) was added all at once. The mixture was then heated at 90° C. for six hours, cooled, poured into water (500 mL) and extracted with ether (2×200 mL). The ether extracts were combined, washed with 2N NaOH (50 mL), dried (MgSO4) and the solvent was evaporated to give 15 as a light yellow solid (8.3 g). Recrystallization from a small volume of methanol gave an analytical sample, m.p. 75-76° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=[O:16])[CH:3]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]([OH:17])=[O:16])[C:3]=1[Cl:18]
Reactant: Nc1cc(C(=O)O)nc(-c2ccc(Cl)cc2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(Cl)cc2)nc(C(=O)O)c1Cl
Temperature: 65 °C

Procedure:
To a solution of 6-amino-2-(4-chlorophenyl)-4-pyrimidinecarboxylic acid (i.e. the product of Step B) (75 g, 300 mmol) in N,N-dimethylformamide (300 mL) at 50° C. was added portionwise N-chlorosuccinimide (44.1 g, 330 mmol). The temperature of the reaction mixture increased exothermically to 65° C. Then the reaction mixture was heated at 55° C. for 3 h. Additional N-chlorosuccinimide (14 g, 90 mmol) was added portionwise, and the reaction mixture was maintained at 55° C. for 30 minutes. After the reaction mixture was cooled water was added. The resulting solid was isolated by filtration, washed with water, dissolved in ethyl acetate, washed with water and dried. The solvent was removed using a rotary evaporator to afford the title product, a compound of the present invention, as a tan solid (73.68 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][N:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH:48]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH2:28][C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)[CH2:48][C:44]3[N:43]([CH3:42])[CH:47]=[CH:46][N:45]=3)=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccnc1C=O
Reactant: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cn1ccnc1CN(Cc1ccc(CNc2ccc(CN(C(=O)OCc3ccccc3)C3CCCCC3)cc2)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
The compound (236 mg) obtained in Example 87-4 and 1-methyl-2-imidazole carboxaldehyde (46.5 mg) were dissolved in anhydrous methanol (7.1 ml). The solution was added with sodium cyanoborohydride (54.0 mg) and then adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. After the reaction, the solvent was distilled-off. A 1 mol/l sodium hydroxide aqueous solution was added to the residue, and chloroform extraction was then carried out. The extract was washed with saturated saline solution and then dried with magnesium sulfate, followed by distilling the solvent off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (212 mg) as a white solid.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.S([N:29]=[N+:30]=[N-])(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>C(#N)C>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([C:10]([S:11]([C:14]([F:16])([F:17])[F:15])(=[O:13])=[O:12])=[N+:29]=[N-:30])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: Cc1ccc(S(=O)(=O)CS(=O)(=O)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Crude p-toluenesulfonyl-trifluoromethanesulfonyl-methane (5 g, 0.017 mole) is dissolved in acetonitrile (200 ml) under nitrogen and the solution is cooled to 0° C. using an ice bath. Tosyl azide (16.3 g, 0.083 mole) and then triethylamine (4.6 ml, 0.063 mole) are added in one portion and the reaction mixture is stirred at that temperature for 24 h. After adding water (11), the mixture is extracted twice with dichloromethane (300 ml) and the combined organic phases are washed with 1 N HCl, saturated sodium bicarbonate and water. After drying over MgSO4 and removal of the solvent, the resulting yellow orange oil was chromatographed on silica gel using ethyl acetate/cyclohexane 1:5 as eluent, yielding p-toluenesulfonyl-trifluoromethanesulfonyl-diazomethane as a yellowish solid. The structure was confirmed by 1H/13C NMR and IR spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH:7]=[O:8])[CH3:2].[N+](C1C=CC=CC=1C(O)=O)([O-])=O.N1CCCC1.[OH:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:29]=1[CH:30]=O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:5]1[C:6]([CH:7]=[O:8])=[CH:30][C:29]2[C:28](=[CH:35][CH:34]=[CH:33][C:32]=2[O:36][CH3:37])[O:27]1)=[O:9])[CH3:2]
Reactant: COc1cccc(O)c1C=O
Reactant: CCOC(=O)/C=C/C=O
Agent: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: C1CCNC1
Solvent: CS(C)=O
Product: CCOC(=O)C1Oc2cccc(OC)c2C=C1C=O
Temperature: 25 °C
Reaction time: 78 h
Yield: 13.1 %

Procedure:
(E)-4-oxo-but-2-enoic acid ethyl ester (7.63 mL, 63.09 mmol), 2-nitro benzoic acid (1.77 g, 10.52 mmol), and pyrrolidine (0.87 mL, 10.52 mmol) were added simultaneously to a solution of commercially available 2-hydroxy-6-methoxy-benzaldehyde (8.0 g, 52.58 mmol) in dimethysulfoxide (50 mL) at 25° C. and the solution was stirred for 78 hours at 25° C. The reaction was quenched by the addition of water. The reaction mixture was then partitioned between water and ethyl acetate. The combined organics were washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The residue obtained was purified on a silica gel flash column chromatography using ethyl acetate-hexanes as eluants, yielding 5-methoxy-3-formyl-2H-chromene-2-carboxylic acid ethyl ester as a solid (1.80 g, 51.9%).
Reaction SMILES: [F:1][CH:2]([CH3:12])[CH2:3][O:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:13][O:14][C:15]([C:17]1[S:26][C:20]2[N:21]=[CH:22][N:23]=[C:24](Cl)[C:19]=2[C:18]=1[CH3:27])=[O:16].Cl.CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1>O1CCOCC1>[CH3:13][O:14][C:15]([C:17]1[S:26][C:20]2[N:21]=[CH:22][N:23]=[C:24]([NH:11][C:10]3[C:5]([O:4][CH2:3][CH:2]([F:1])[CH3:12])=[N:6][CH:7]=[CH:8][CH:9]=3)[C:19]=2[C:18]=1[CH3:27])=[O:16]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(F)COc1ncccc1N
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OCC(C)F)c2c1C

Procedure:
2-(2-Fluoropropoxy)pyridin-3-amine (153 mg) was dissolved in dioxane (30 ml), 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (174.54 mg) and HCl in dioxane (4M; 25 μl) was added. The reactin was stirred at 60° C. for three days. The reaction was concentrated in vacuo.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+].Br[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].O>C(O)C>[CH2:1]([NH:4][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[CH:2]=[CH2:3]
Reactant: COC(=O)C(C)Br
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCNC(C)C(=O)OC
Yield: 60.1 %

Procedure:
To a mixture of 10 g (0.18 mole) of allylamine, 10.8 g (0.2 mole) of sodium bicarbonate in 50 ml of ethanol is added 30 g (0.18 mole) of methyl 2-bromopropionate dropwise. The resulting mixture is heated under reflux for 5 hours. The reaction mixture is cooled, poured into water, and extracted with ether. The combined ether extracts are washed with water and dried over magnesium sulfate. The drying agent is filtered and the filtrate is concentrated under reduced pressure to give 15.5 g of a light yellow oil. This material is further purified by distillation to give 10.5 g of pure product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]1([CH3:15])[CH2:14][CH2:13]1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28](O)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[C:3]([C:12]4([CH3:15])[CH2:13][CH2:14]4)=[CH:4]5)=[O:29])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cn1c(C2(C)CC2)cc2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(C2(C)CC2)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21
Temperature: 80 °C
Reaction time: 6 h

Procedure:
1-Methyl-2-(1-methylcyclopropyl)-1H-indol-5-amine (20.0 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (42.1 μL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 6 h at 80° C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(1-methyl-2-(1-methylcyclopropyl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 388.2, found 389.2 (M+1)+. Retention time of 3.05 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:9]2=[O:14])=[CH:20][CH:19]=1
Reactant: O=C1NCCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To the product from Example 90B (0.43 g, 1.50 mmol) as a solution in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran) (1.80 mL, 1.80 mmol) via syringe under nitrogen followed by the addition of ethyl 2-bromoacetate (0.18 mL, 1.65 mmol). The reaction mixture heated at 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated, diluted with ethyl acetate, washed with water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:4) gave the title compound. MS (DCI) m/z 374 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:13][CH2:21][CH3:22])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: CCI
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1Br
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Into a round bottom flask was placed 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (6.0 g, 23 mmol) in anhydrous DMF (22.8 mL). Potassium carbonate (6.3 g, 46 mmol) was then added followed by iodoethane (2.73 mL, 34.2 mmol). The resulting suspension was stirred at 60° C. for 2 h. The mixture was poured into 100 mL water and extracted with 200 mL of ethyl ether. The organic layers were separated, combined and washed with water and saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated to 6.0 g of tan oil. LCMS calculated for C11H13BrClO2 (M+H)+: m/z=293.0; Found: 293.0
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=[O:7].[CH2:17]([NH2:20])[C:18]#[CH:19].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(#N)C>[CH3:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[NH:8][C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:20][CH2:17][C:18]#[CH:19])=[O:7].[CH3:31][C:21]1[CH:22]=[CH:23][C:24]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: Cc1cccc(C)c1NC(=O)NCCCCl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C#CCN
Solvent: CC#N
Product: C#CCNCCCNC(=O)Nc1c(C)cccc1C
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
A mixture of 65 grams of N-(3-chloropropyl)-N'-(2,6-dimethylphenyl)urea, 350 ml. of acetonitrile, and 50 grams of propargylamine was refluxed for 19 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in chloroform and extracted with 250 ml. of 20% hydrochloric acid. The acid extract was cooled and made basic with 50% sodium hydroxide solution. The mixture was extracted with dichloromethane. After drying over magnesium sulfate, the dichloromethane was removed in vacuo to obtain a solid residue, m.p. 139°-143° C. The solid was treated with p-toluenesulfonic acid to obtain the salt. Recrystallization from ethanol-ether afforded N-(2,6-dimethylphenyl)-N'-[3-(2-propynylamino)propyl]urea, 4-methylbenzenesulfonate, m.p. 143°-144.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CCOC(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: CC1=CC(=O)C=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc(C)c1O
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A mixture of 2,6-dimethyl-[1,4]benzoquinone (5 g) and sodium hydrosulfite (10 g) in EtOAc (50 mL) and water (20 mL) was stirred for 30 min. After separation with EtOAc, the organic phase was dried and evaporated to dryness to give a off-white solid 5 g of 2,6-dimethyl-benzene-1,4-diol. The solid was dissolved in dry ether, cooled in an ice-water bath, followed by dropwise addition of sulfuryl chloride (5 g). After stirring the solution at RT for 3 h, workup and purification on silica gel column chromatography (30% EtOAc in hexane) gave 2.2 g 2-chloro-3,5-dimethyl-benzene-1,4-diol.
Reaction SMILES: [Br: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:5].IC.[C:16](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Br
Yield: 95.9 %

Procedure:
A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM), and potassium carbonate (19.0 g, 137.4 mM) in 100 mL dimethylformamide was stirred at room temperature for 72 hours. The mixture was poured into 1.5 liters of water. The resultant precipitate was collected by filtration and dried in vacuo to afford 28.79 g (96%) of methyl 2-bromo-3-nitrobenzoate as a white solid. 1H NMR (DMSO-d6) δ8.3 (dd, 1H, J=1 and 8 Hz), 7.9 (dd, 1H, J=1 and 8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm−1) 2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e 259, 261.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[CH2:11][C@@H:10]([CH3:12])[N:9](C(=O)C(F)(F)F)[C@@H:8]([CH3:19])[C:7]1=[O:20].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.O>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[CH2:11][C@@H:10]([CH3:12])[NH:9][C@@H:8]([CH3:19])[C:7]1=[O:20]
Reactant: COc1ccc(CN2C[C@@H](C)N(C(=O)C(F)(F)F)[C@@H](C)C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CN2C[C@@H](C)N[C@@H](C)C2=O)c(OC)c1
Yield: 90.3 %

Procedure:
(3S, 5R)-1-(2,4-Dimethoxy-benzyl)-3,5-dimethyl-4-trifluoroacetyl-piperazin-2-one (575 mg, 1.54 mmol) is dissolved in 30 mL of methanol and 3 mL of H2O. Potassium carbonate (883 mg, 6.4 mmol) is added to the solution, and the reaction is refluxed for one and half hours before concentration. Ethyl acetate (3×50 mL) is used to extract the aqueous layer. Removal of Ethyl acetate afforded the crude amine (387 mg, 91% yield) as a clear oil. C15H22N2O3 MS m/z: 279.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:17]=2)=[C:10]([CH3:33])[CH:9]=1)=[O:6].[OH-].[K+]>CO.O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[OH:22])[O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:34])=[O:2])=[CH:9][C:10]=2[CH3:33])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(NC(=O)CC(=O)O)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid methyl ester (7.14 g, 14.6 mmol) in 50% aqueous methanol (56 mL) was added a 5 M solution of potassium hydroxide (8.8 mL, 44 mmol) to give a reddish-brown solution. The solution was stirred at RT for 45 min then diluted with water (200 mL). The solution was washed with EtOAc (3×50 ml) and the combined washings were extracted with 0.1 M KOH (50 mL). The combined basic aqueous solutions were acidified with concentrated HCl and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to a dark amber oil. The oil was dissolved in EtOAc (20 mL) and cyclohexane (100 mL) was added to give an oil, which slowly solidified on stirring at RT. The suspension was stirred 64 h at RT, then filtered. The solid was washed with cyclohexane (3×50 mL) and dried to give the title compound of Step F and Example 4-2 (6.26 g) as a solid. MS (APCl+) Calc.: 473.1. Found: 474.3 (M+1).
Reaction SMILES: C(O)=[O:2].[Cl:4][C:5]1[CH:6]=[C:7]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][C:10]=1[S:11][CH3:12].OO.C(OCC)(=O)C.CCCCCC.[OH2:33]>>[Cl:4][C:5]1[CH:6]=[C:7]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:12])(=[O:2])=[O:33]
Reactant: O
Reactant: O=CO
Reactant: COC(=O)C(C)c1ccc(SC)c(Cl)c1
Agent: OO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(C)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Formic acid (20.8 mL, 1 eq) was added to methyl 2-(3-chloro-4-(methylthio)phenyl)propanoate (3.2 g, crude) and cooled to 0° C. Hydrogen peroxide (4.48 mL, 3 eq) was added drop wise at 0° C. and the reaction mass was stirred for overnight at room temperature. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane, Rf˜0.3). On completion of the reaction, the contents were cooled to 0° C., water was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined extract was washed with NaHCO3 solution, dried over sodium sulfate and concentrated under reduced pressure to obtain methyl 2-(3-chloro-4-(methylsulfonyl)phenyl)propanoate as a colorless thick liquid (3.2 g, crude). Crude product obtained was directly used for the next step.
Reaction SMILES: [OH-:1].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl>C(O)CCC>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:1][C:7]2[CH:8]=[CH:9][C:4]([I:3])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(I)cc1
Reactant: [OH-]
Reactant: ClCCOCCCl
Agent: [Na+]
Solvent: CCCCO
Product: Ic1ccc(OCCOCCOc2ccc(I)cc2)cc1

Procedure:
A mixture prepared by adding 3.08 g of sodium hydroxide and 40 ml of n-butanol to 15.4 g of 4-iodophenol was refluxed. 2 ml of n-butanol solution of 5.01 g of 1,5-dichloro-3-oxapentane was added dropwise to the above prepared mixture over a period of 5 minutes.