Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:14].[F:16][C:17]([F:29])([F:28])[CH:18](OS(C(F)(F)F)(=O)=O)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][C@@H:18]([CH3:19])[C:17]([F:29])([F:28])[F:16])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:15])(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O
Reactant: CC(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 21.7 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid methyl ester [68029-77-6], 32.5 mmol trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester [212556-43-9], 43.4 mmol potassium carbonate in 87 ml DMF was stirred at 80° C. for 48 hour After cooling to RT, the mixture was concentrated in vacuo, taken in water and stirred for 1 hour. Filtration yielded the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8](/[CH:9]=[N:10]/[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[Li+].C(N(CC)CC)C.[CH:28]([S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])=[CH2:29].C(OC(C)=O)(C)C>C1COCC1>[CH2:15]([O:14][C:12]([CH:11]1[CH2:29][CH:28]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:31])=[O:32])[CH:9]([C:8]2[CH:17]=[CH:18][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[NH:10]1)=[O:13])[CH3:16]
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C/N=C/c1ccc(C(C)(C)C)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CC(=O)OC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2)C(c2ccc(C(C)(C)C)cc2)N1
Temperature: 0 °C
Yield: 8 %

Procedure:
To a stirred solution of (E)-ethyl 2-(4-tert-butylbenzylideneamino)acetate (226 mg, 914 umol; example 441a) in THF (5 ml) under an argon atmosphere were added lithium bromide (119 mg, 1.37 mmol), triethylamine (191 ul, 1.37 mmol) and phenyl vinyl sulfone (154 mg, 914 umol; CAS Reg. No. 5535-48-8). The mixture was stirred at ambient temperature for 20 h. iPrOAc (50 ml) and ice water (40 ml) were added and the layers were separated. The organic layer was washed with brine (40 ml), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, iPrOAc/n-heptane) to obtain the title compound (56 mg, 73 umol; 8%) as colorless solid. MS (ESI): m/z=416.2 [M+H]
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][C:14](Cl)=[C:13]([CH:17]=[O:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[H][H]>[Pd].O.C(O)C.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc(C=O)c(Cl)s1
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1cc(C=O)cs1

Procedure:
A slurry of palladium on carbon (10%, 0.28 g) in water (0.5 mL) was added cautiously to a solution of 5-(2-(tert-butyldimethylsilyloxy)ethyl)-2-chlorothiophene-3-carbaldehyde [Aromatic Intermediate 17, step 1)] (0.80 g) and triethylamine (0.91 mL) in ethanol (50 mL) and the resulting mixture stirred overnight under 4 bar pressure of hydrogen. The mixture was filtered through Celite and the filter pad washed with ethanol (10 mL). The combined filtrate and washings were evaporated and azeotroped with toluene (20 mL) to give a yellow oil. The residue was dissolved in DCM (100 mL), manganese dioxide (2.28 g) was added and the resulting suspension heated at reflux overnight. The mixture was filtered through Celite and the filter pad washed with DCM (50 mL). The combined filtrate and washings were evaporated to give the titled compound as a yellow oil. Yield 0.60 g.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH2:25])(=[O:24])=[O:23])[CH:13]=[CH2:14]>C(Cl)Cl>[O:9]1[CH2:14][CH:13]1[CH2:12][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH2:25])(=[O:23])=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1ccccc1S(N)(=O)=O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1OCC1CO1
Yield: 78 %

Procedure:
To a mixture of 15.3 g of 3-chloroperbenzoic acid in 270 ml of absolute methylene chloride are added 14.2 g of 2-allyloxyphenylsulfonamide over 2 minutes. The solution is then heated to reflux for 3 hours, cooled, and then washed three times with saturated sodium carbonate solution and once with water. The organic phase is dried and concentrated, affording 11.9 g of 2-oxiranylmethoxyphenylsulfonamide with a melting point of 132°-133° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[OH:10][CH2:11][C:12]([N+:17]([O-])=O)([CH2:15]O)[CH2:13][OH:14]>>[NH2:17][C:12]1([CH2:13][OH:14])[CH2:11][O:10][CH:4]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH3:2])[O:5][CH2:15]1
Reactant: O=[N+]([O-])C(CO)(CO)CO
Reactant: CCCCC(C=O)CC
Product: CCCCC(CC)C1OCC(N)(CO)CO1
Yield: 95.1 %

Procedure:
Procedure of Example 2 was repeated with 6.41 g of 2-ethylhexanal and 7.56 g of 2-(hydroxymethyl)-2-nitro-1,3-propanediol to give 11 g of 5-nitro-5-hydroxymethyl-1,3-dioxane derivative, which was reduced and distilled at 175°-178° C. to give 8.7 g of the product.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])[CH:10]=[CH:11][CH:12]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][C:5]([OH:44])=[O:4])[CH:8]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:33])([F:32])[F:34])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cccc(CC(=O)OC)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cccc(CC(=O)O)c2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.065 mL, 0.065 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2′-methyl-biphenyl-3-yl)acetic acid methyl ester (Example 71-(1); 12.8 mg, 0.022 mmol) in methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred at 60° C. for one hour. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=8:3, saturated with water) to give the target compound as a colorless oil (12.1 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([I:12])=[C:4](C)[C:3]=1[C:14](=[O:16])C.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([I:12])=[CH:4][C:3]=1[CH2:14][OH:16]
Reactant: CC(=O)c1c(C)c(I)c2ccccc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1cc(I)c2ccccc2c1Br
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 29 (50 mg) in methanol (5 ml) was added 1 ml solution of K2CO3 and the mixture was stirred for 2 hr. at room temperature. The methanol was removed in vacuo and the residue was extracted with methylene chloride (2×50 ml). The methylene chloride fraction was washed with 1N HCl, H2O, brine, dried with anhydrous MgSO4 and evaporated in vacuo to give 40 mg of 30 (90%) as white crystalline solid which upon TLC analysis (silica, hexane/ethyl acetate, 90:10) showed a single component Rf, 0.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]1([CH2:36][CH2:37]O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>>[ClH:1].[CH2:37]([O:24][C:23]([C:18]1([C:20]([O:22][CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCCc1ccccc1
Agent: Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCc1ccccc1)(C(=O)OCCc1ccccc1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-phenylethanol accord-ing to the procedure of Example 1 as a colorless oil; 1H NMR (300 MHz, CDCl3): d 1.30-1.45 (brs, 3H), 2.80-2.90 (brm, 1H), 2.89 (t, J=6.9 Hz, 4H), 3.10-3.30 (brm, 2H), 3.39-3.69 (brm, H), 4.40 (t, J=6.8 Hz, 4H), 5.45-5.61 (brs, 2H), 6.70-6.91 (brm, 3H), 7.10-7.35 (complex m, 13H), 7.40-7.51 (brs, 1H), 8.60-8.85 (brs, 1H), 9.91-10.20 (brs, 1H); MS (ES) m/z (relative intensity): 630 (M+ -HCl, 40), 144 (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](F)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(C(Cl)=O)=C([F:32])C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(F)c2)C1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2F)C1

Procedure:
In analogy to (RS)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (Example 1, steps a-g) using 4-bromo-2-fluorobenzoyl chloride (CAS 151982-51-3) instead of 4-bromo-3-fluorobenzoyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccc(Cl)c1
Reaction time: 2 h

Procedure:
To a suspension of creatinine (5.66 g, 0.05 mole) in 150 ml. of dry dimethylformamide (DMF) is added 7.68 g (0.05 mole) of m-chlorophenylisocyanate. The mixture is stirred for 2 hours and heated on a steam bath for 30 minutes. During this time the solution becomes clear (yellow). The solution is filtered and the filtrate cooled. Ice and ice-water are added to the filtrate. A light yellow solid precipitates and is filtered off. After recrystallizations from acetone-methanol and tetrahydrofuran-ether, the pure product, 1-m-chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea, is obtained, mp 180°-180.5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.F.C(F)([F:18])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([F:18])=[O:10])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1C(F)(F)F
Reactant: O=C(F)F
Agent: F
Product: O=C(F)Nc1ccc(Cl)cc1C(F)(F)F
Temperature: 24 °C

Procedure:
4-Chloro-2-(trifluoromethyl)phenyl carbamic fluoride was prepared in situ by the reaction of 221 parts of 4-chloro-2-(trifluoromethyl)-isocyanatobenzene and 380 parts of hydrogen fluoride added over a period of about 15 minutes at about 4° C. The reaction mixture was then sealed in a polytetrafluoroethylene reactor, heated to about 24° C. and maintained at about that temperature, with agitation, for about 96 hours. The reactor was then opened to atmospheric pressure and most of the hydrogen fluoride and carbonyl fluoride gases removed. Analysis of the remaining organic product by gas chromatographic techniques, using n-pentadecane as an internal standard, indicated as yield of 55 parts of 4-chloro-2-(trifluoromethyl)benzenamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[O:11])[C:6]=2[CH:20]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:23].C(Cl)(Cl)Cl.CO>CS(C)=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:7]2[C:6]3[C:20](=[O:23])[C:2](=[O:1])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)c2coc3ccc(O)cc23)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)C=C3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of compound 9 (100 mg, 0.371 mmol) in DMSO (1.5 mL) was added Dess-Martin periodinane (315 mg, 0.743 mmol) at 0° C. The resulting mixture was stirred at room temperature for 20 min and poured into ice water (2 mL). The resulting precipitate was filtered, washed with water, and dried under high vacuum to obtain compound SKC-BF-02 (50 mg, 50%) as a red solid. Rf=0.6 (CHCl3-MeOH, 9:1); 1H NMR (CDCl3) δ 7.85 (d, J=9.0 Hz, 2H), 7.81 (s, 1H), 7.40 (d, J=10.3 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.32 (d, J=10.3 Hz, 1H), 3.88 (s, 3H); MS (ES) m/z 317 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[C:7]([N:10]=O)[CH:6]=[N:5]1.[S:12](=[O:16])(=[O:15])([OH:14])[OH:13]>O.CO.[Pd]>[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].[F:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[C:7]([NH2:10])[CH:6]=[N:5]1
Reactant: Nc1c(N=O)cnn1CCF
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: Nc1cnn(CCF)c1N
Reaction time: 7.5 h
Yield: 95.2 %

Procedure:
To a solution of 1-(2-fluoroethyl)-4-nitroso-1H-pyrazol-5-amine (4.8 g) in water (30 ml) and methanol (30 ml) were added sulfuric acid (2.98 g) and 10% palladium on carbon (2.5 g), and the mixture was hydrogenated under balloon pressure for 7.5 hours. The reaction mixture was filtered through a bed of Celite, and the filtrate was concentrated in vacuo. 2-Propanol was added to the residue, and the precipitate was collected by filtration to give 1-(2-fluoroethyl)-1H-pyrazole-4,5-diamine sulfate (7 g).
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:9][C:10]1[C:11]([O:13][C:14](=O)[C:15]=1[CH3:16])=[O:12]>O>[OH:4][CH2:3][C:2]([N:1]1[C:11](=[O:12])[C:10]([CH3:9])=[C:15]([CH3:16])[C:14]1=[O:13])([CH2:5][OH:6])[CH2:7][CH3:8]
Reactant: CCC(N)(CO)CO
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: O
Product: CCC(CO)(CO)N1C(=O)C(C)=C(C)C1=O
Temperature: 70 °C

Procedure:
2-amino-2-ethyl-1,3-propanediol (I-a) (297.9 grams, 2.50 moles) is charged to a reactor and heated to 70° C. under nitrogen. Then, 315.0 grams (2.50 moles) of 2,3-dimethylmaleic anhydride (DMMA) (II-a) is added portionwise with stirring to the reactor. The material is heated to a sufficient temperature (110°-130° C.) to drive off the water of condensation which is collected in a Dean-Stark trap. Once the theoretical amount of water is collected the product is isolated by vacuum distillation (167°-176° C. at 3 mm Hg). This product is used as an intermediate for the formation of polyurethanes and polyesters as will be described in succeeding examples.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[OH:36])[CH2:5][NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12]([O:26]C(=O)C(C)(C)C)[C:13]([C:19]([O:21]CCCC)=[O:20])=[CH:14][CH:15]=2)[N:10]=1)=[O:8].[OH-].[Na+].S(=O)(=O)(O)O>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[OH:36])[CH2:5][NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12]([OH:26])[C:13]([C:19]([OH:21])=[O:20])=[CH:14][CH:15]=2)[N:10]=1)=[O:8]
Reactant: CCCCOC(=O)c1ccc2ccc(C(=O)NCc3ccc(O)c(O)c3)nc2c1OC(=O)C(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1ccc(O)c(O)c1)c1ccc2ccc(C(=O)O)c(O)c2n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
A mixture of the preceding amide 7 (step 6) (0.5 g, 1.0 mmol) and 6.5 ml of a 3 N sodium hydroxide solution in 10 ml of methanol is stirred at 20° C. for 3 hours. The pH is adjusted to 4 with 1 N sulfuric acid solution. The reaction mixture is concentrated under reduced pressure, and then dried under vacuum over phosphoric anhydride. The residue is taken up in 10 ml of anhydrous ethanol in the hot state and the insoluble sodium sulfate is filtered. The filtrate is concentrated under reduced pressure and then taken up in 2 ml of anhydrous ethanol. The medium is cooled: a yellowish solid crystallizes. The latter is washed with dichloromethane, and then dried under vacuum over phosphoric anhydride so as to give 250 mg of acid 8 in the form of a brown solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:4]1.Cl.O[N:32]=[C:33]([NH2:36])[CH2:34][CH3:35]>>[CH2:34]([C:33]1[N:36]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:5]3[CH2:6][CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4]3)=[O:10])[CH2:12]2)[O:29][N:32]=1)[CH3:35]
Reactant: COC1CCCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)C1
Reactant: CCC(N)=NO
Agent: Cl
Product: CCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCCC(OC)C3)C2)n1

Procedure:
250 mg (0.434 mmol, 72% pure) of 1-[(3-methoxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 207A) and 59.5 mg (0.712 mmol) of N′-hydroxypropanimidamide hydrochloride were reacted according to the General Method 1. Yield: 93.9 mg (46% of theory).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:7])=[CH:4][N:3]=1.C[C@H]1CNC[C@@H](C)N1>>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:26]=[CH:27][CH:2]=[N:3][CH:4]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(Cl)nc1
Agent: C[C@@H]1CNC[C@H](C)N1
Product: NC(=O)c1cccnc1

Procedure:
6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.16 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.83 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-(3S,5R)-3-5-dimethylpiperazine-1-yl)-nicotinamide. MS (Q1) 498.0 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]#[N:22]>CC(C)=O>[C:21]([CH2:20][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])#[N:22]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1OCC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A stirred solution of 2-methoxy-5-nitrophenol (2 g, 0.012 mole) and potassium carbonate (1.64 g, 0.012 mole) in acetone (10 ml) was treated with bromoacetonitrile (0.19 ml, 0.013 mole) in acetone (10 ml) and stirred for 3 hours at room temperature. The mixture was concentrated in vacuo and the residue treated with 10% NaOH solution, then extracted with ethyl acetate. The organic extract was dried (Na2SO4) and evaporated in vacuo to give the title compound (2.35 g, 96%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]#[N:30].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:27][CH2:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)CC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CC(=O)c1c(-c2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 6, of Example 1, the title compound was prepared from 2-({1-bromo-6-[3-(3-methylbutanoyl)-1-benzofuran-2-yl]-2-naphthyl}oxy) acetonitrile (0.207 g, 0.448 mmol), sodium azide (0.147 g, 2.26 mmol) and ammonium chloride (0.125 g, 2.34 mmol) in DMF (10 mL). The compound was purified by HPLC using 75% acetonitrile/0.1% TFA in water. Drying for 14 hours at 90° C. yielded a cream-colored solid (0.0966 g), mp 176-177° C. Mass spectrum (−ESI, [M−H]−) m/z 503. 1HNMR (500 MHz, DMSO-d6): δ16.8-17.1 (br s, 1H), 8.5 (d, 1H, J=1.7 Hz), 8.25 (q, 2H, J=8.2 Hz), 8.0-8.05 (m, 2H), 7.75 (q, 2H, J=8.3 Hz), 7.4-7.5 (m, 3H), 5.8 (s, 2H), 2.7 (d, 2H, J=6.9 Hz), 2.05-2.15 (m, 1H), and 0.75 ppm (d, 6H, J=6.6 Hz). Elemental Analysis for C25H21BrN4O3.0.10 H2O: Calculated: C, 59.20; H, 4.21; N, 11.05. Found: C, 58.84; H, 3.80; N, 10.83.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]([C:8]([O-:10])=[O:9])[CH2:6][CH2:5][C:4]1=[O:11].[Na+]>O>[C:8]([CH2:7][NH:3][C:4](=[O:11])[CH:5]=[CH2:6])([OH:10])=[O:9]
Reactant: O=C1CCC(C(=O)[O-])N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)NCC(=O)O
Yield: 234.1 %

Procedure:
100 g of 25 wt % polyacrylic acid aqueous solution (viscosity 8000-12000 cps, 30 ° C.) and 3 g of N-carboxy methyl acrylamide were polymerized at 70° C. for 3 hours for partial crosslinking. Sodium hydroxide was added to neutralize the pH value to 7.0 and 20 g of poly(ether alcohol)(GEP-2800, Dow Chemical Co., U.S.A.) and 1.5 g of sodium 2-pyrrolidone-5-carboxylate were added. Deionized water was then added to the resulting product to adjust the solid content thereof to 35 wt %. The viscosity of the resultant solution was measured as 6000 to 6500 cps(30° C.). The resulting product was tested according to the procedures as set forth in Example 1 and the test results are listed in Table 1.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([O:13][C:12]([NH:11][C@H:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:12]([O:13][CH3:14])=[O:18])[CH:10]=2)[CH2:6][CH2:7]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Temperature: 75 °C
Yield: 76 %

Procedure:
A solution of (R)-tert-butyl 6-bromo-2,3-dihydro-1H-inden-1-ylcarbamate (15.0 g, 48.07 mmol, 1.0 eq.) in a mixture of MeOH (200 ml) and DMSO (30 ml) was degassed with argon for 30 min followed by addition of palladium acetate (0.53 g, 2.40 mmol, 0.05 eq.), 1,3-bis(diphenylphosphino)propane (0.99 g, 2.40 mmol, 0.05 eq.) and TEA (20 ml, 144.21 mmol, 3.0 eq.). The reaction mixture was then sealed in an autoclave using CO pressure (80 psi) and heated at 75° C. for 16 h. The mixture was evaporated to dryness, diluted with water (150 ml) and extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na2SO4 and evaporated to give the crude product which was purified by column chromatography (silica gel; 5% ethyl acetate/hexanes) to yield the desired product as a white solid. Yield: 76% (10.6 g, 36.43 mmol).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][S:14][CH3:15])[CH:7]=1)[C:3]([OH:5])=[O:4].I([O-])(=O)(=O)=[O:17].[Na+]>>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][S:14]([CH3:15])=[O:17])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCc1cc(C(N)C(=O)O)ccc1O
Agent: [Na+]
Product: CS(=O)Cc1cc(C(N)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an aqueous solution (500 ml) of α-amino-4-hydroxy-3-[(methylthio)methyl]benzeneacetic acid (1 mole) is added sodium metaperiodate (1 mole). The mixture is stirred at room temperature for 5 hours, it is filtered and the filtrate is lyophilyzed to give a quantitative yield of the title compound.