Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][C@@H:4]([OH:8])[C:5]#[C:6][CH3:7].[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21](O)=[O:22])([O-:17])=[O:16].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([O:8][C@H:4]([CH2:3][C@H:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]#[C:6][CH3:7])=[O:22])([O-:17])=[O:16]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC#C[C@H](O)C[C@H](C)CCCC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC#C[C@@H](C[C@H](C)CCCC(C)C)OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
This compound was prepared similar to the method described in Example 44 from 4.22 g (21.6 mmol) of 6(R),10-dimethyl-undecan-2-yn-4(R)-ol,4.58 g (21.6 mmol) of 3,5-dinitrobenzoic acid and 8.25 g (43.2 mmol) of p-toluenesulfonyl chloride in dry pyridine (total 55 ml) at 4° C. for 31/2 hr. It was worked up as described in Example 44 to give recrystallization once from methanol 6.73 g (84.2%) of pure 6(R),10-dimethyl-undecan-2-yn-4(R)-ol 3,5-dinitrobenzoate, m.p. 90°-91°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH2:11]C)[C:7]=1[C:13]([OH:15])=O)=[O:5])[CH3:2].S(Cl)([Cl:18])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:13]([Cl:18])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(CC)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1cnn(C)c1C(=O)Cl

Procedure:
A mixture of 2-ethyl-2H-pyrazole-3,4-dicarboxylic acid 4-ethyl ester (Example 10, steps 1-3, 3 g, 15 mmol) and thionyl chloride (40 ml) was heated to reflux (4 h). The thionyl chloride was evaporated, and the residue (3.38 g, 64%) was used in the next step without further purification.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:35])([CH3:17])[C:15](=[O:36])[CH2:14][CH2:13]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(OCC)(=O)C>[F:35][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:36])[C@H:11]2[C@H:20]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[CH:25][C:26]=1[CH2:27][C@H:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(OC5CCCCO5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
7.4 g of 7α-(5-acetoxypentyl)-11β-fluoro-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-17-one in 370 ml of methanol and 37 ml of water is stirred at room temperature with 1.8 g of potassium carbonate. After 3 hours, the reaction mixture is added to ice water. The precipitated product is suctioned off, dissolved in ethyl acetate, washed neutral with water, dried and concentrated by evaporation in a vacuum. 7.0 g of 11β-fluoro-7α-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-17-one is obtained as foam.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=O)[CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[CH2:16]([NH:23][CH:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reaction time: 5 h

Procedure:
Under nitrogen, to a solution of 3-nitro-5,7,8,9-tetrahydrobenzocyclohepten-6-one (300 mg) in 1,2-dichloroethane (10 ml) were added benzylamine (0.24 ml), sodium triacetoxyborohydride (460 mg) and acetic acid (0.17 ml) at room temperature, and the mixture was stirred at the same temperature for 5 hours. The resulting mixture was poured into aqueous 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 1:5) to give N-benzyl-(3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (342 mg).
Reaction SMILES: Br[C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[Cl:21]Cl>ClC1C=CC=CC=1>[Cl:21][C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: ClCl
Reactant: Cn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Solvent: Clc1ccccc1
Product: Cn1c(-c2ccc(Cl)cc2)c(C#N)c(Cl)c1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 4-bromo-2-(p-chlorophenyl)-1-methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (20.0 g, 0.055 mol) in chlorobenzene at 60° C. is treated with chlorine gas at 60° C. over a 1/2 hour period, cooled to room temperature, washed sequentially with water, aqueous sodium metabisulfite and water, dried over sodium sulfate and concentrated in vacuo to give a residue. The residue is crystallized in heptane to give the title product as a pale yellow solid, 17.6 g (quantitative yield), mp 109.5°-110.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27](B(O)O)[CH:28]=1.[CH2:34]([SH:37])[CH:35]=[CH2:36]>>[CH2:34]([S:37][CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]3[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=3[O:32][CH3:33])[CH:8]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=1)[CH:35]=[CH2:36]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: C=CCS
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: C=CCSCC1=CC(C)(C)Nc2ccc(-c3cc(F)ccc3OC)cc21

Procedure:
(Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 5-fluoro-2-methoxyphenylboronic acid. Bromination and coupling reaction with allyl mercaptan gave 17 mg of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].C(C1C=CC2OC(C)(C)[C@@H](O)[C@H]([N:31]([C:35]3[CH:36]=[C:37]4[C:41](=[CH:42][CH:43]=3)[CH2:40]C[CH2:38]4)[C:32](=[O:34])N)C=2C=1)#N.[CH3:45][N:46](C=O)C>>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:32]([NH:31][C:35]3[CH:36]=[C:37]4[C:41](=[CH:42][CH:43]=3)[CH2:40][N:46]([CH3:45])[CH2:38]4)=[O:34])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N(C(N)=O)c2ccc3c(c2)CCC3)[C@@H]1O
Reactant: CN(C)C=O
Product: CN1Cc2ccc(NC(=O)N[C@@H]3c4cc(C#N)ccc4OC(C)(C)[C@H]3O)cc2C1

Procedure:
The title compound was prepared from (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H- 1-benzopyran-6-carbonitrile (0.42 g, 1.3 mmol, compound of example 1, part B) and title A compound by the procedure described in Example 8 to give a colorless solid, m.p. 220°-222° C. (foaming, started @ 155°). [αD ]=-12.8° (c=0.525, DMF).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:12].[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C=CC=C2C=1C(C#N)=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: N#Cc1c[nH]c2ccc(Br)cc12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Yield: 85 %

Procedure:
3-(3-Cyano-1H-Indol-5-yl)-3-phenyl-acrylic acid ethyl ester LXIII (1.82 g, 85% yield) was prepared from 5-bromo-1H-indole-3-carbonitrile using the procedure described for 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][CH2:13][C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[CH:19][NH:20]3)=[CH:16][CH:15]=2)=[O:11])=[CH:6][C:5]=1[Cl:23].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:23][C:5]1[CH:6]=[C:7]([C:10]([NH:12][CH2:13][C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[CH:19][NH:20]3)=[CH:16][CH:15]=2)=[O:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:24])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)NCc2ccc3cc[nH]c3c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccc2cc[nH]c2c1)c1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
A solution of 2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid methyl ester (Example 80; 2.00 g, 5.9 mmol) in tetrahydrofuran/methanol (1:1; 10 mL) was added to a solution of lithium hydroxide monohydrate (491 mg, 11.7 mmol) in water (5 mL). The solution was allowed to stir at room temperature for 72 h and then concentrated under reduced pressure to remove tetrahydrofuran and methanol. The remaining solution was diluted with water and acidified with 1N hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to afford 2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid (1.90 g, 99% yield) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15](O)[CH2:14][C@H:13]2[CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:20])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:64]([OH:67])(=[S:66])[CH3:65]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:66][C:64](=[O:67])[CH3:65])[CH2:14][C@H:13]2[CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:20])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(O)=S
Reactant: COc1ccc(COC(=O)C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)C[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.5 h

Procedure:
(2S,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-p-methoxybenzyloxycarbonylmethyl-4-hydroxypyrrolidine (1.40 g) and triphenylphosphine (1.18 g) were dissolved in 7 ml of dry tetrahydrofuran under nitrogen stream. To the resulting solution was added 783 mg of diethyl azodicarboxylate at 0° C., followed by stirring at the same temperature for 30 minutes. Thereafter, 342 mg of thioacetic acid was added thereto, and the mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography to give (2R,4S)-1-(p-nitrobenzyl-oxycarbonyl)-2-p-methoxybenzyloxycarbonylmethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:30](=[O:32])[CH3:31])[CH2:14][CH2:13]1
Reactant: CC(=O)Cl
Reactant: Clc1ccc(Oc2ccccc2NC2CCNCC2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To an ice cooled solution of [2-(2,4-dichlorophenoxy)phenyl]piperidin-4-ylamine (AMR01040, 132 mg, 0.39 mmol) in dry DCM (5 mL) were added triethylamine (0.137 mL, 0.98 mmol) and acetyl chloride (0.031 mL, 0.43 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1 h), and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane to EtOAc gradient as eluent gave 1-{4-[2-(2,4-dichlorophenoxy)phenylamino]piperidin-1-yl}ethanone (95.3 mg, 64%) as a white solid after, mp 145-146° C. Rf: 0.22 (EtOAc) LC/MS (APCI) tr=1.44 min, m/z 381.29 (63), 379.34 (M++H, 100) HPLC tr=3.10 min (99.31%) 1H NMR (270 MHz, CDCl3) δ 1.36 (2H, m, CH2), 2.06 (2H, m, CH2), 2.08 (3H, s, CH3), 2.89 (1H, m), 3.20 (1H, m), 3.53 (1H, m), 3.74 (1H, m), 4.05 (1H, m), 4.37 (1H, m), 6.63 (1H, m, ArH), 6.74 (1H, dd, J=7.9, 1.5 Hz, ArH), 6.75 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.80 (1H, d, J=8.9 Hz, ArH), 7.03 (1H, m, ArH), 7.12 (1H, dd, J=8.9, 2.5 Hz, ArH) and 7.43 (1H, d, J=2.5 Hz, ArH). Anal. Calcd. for C19H20Cl2N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 59.90; H, 5.47; N, 7.13%.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:16]=1[CH:17]=[CH:18][C:19](O)=O>>[CH3:13][O:14][C:15]1[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:16]=1/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1C
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c(OC)c1C
Yield: 27.7 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 1.0 g (5.88 mmol) of 5,6-diamino-1,3dimethyluracil and 1.44 g (6.45 mmol) of 2,4 -dimethoxy-3methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 581 mg (yield 28%) of Compound 94 as pale yellow needles.
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[CH3:18][C@H:19]1[S:23][C:22](=[O:24])[NH:21][C@@H:20]1[C:25]([OH:27])=O.[N+]([O-])(O)=O.[N+:32]([O:35][CH2:36][CH2:37][NH2:38])([O-:34])=[O:33]>O1CCCC1>[N+:32]([O:35][CH2:36][CH2:37][NH:38][C:25]([C@@H:20]1[C@@H:19]([CH3:18])[S:23][C:22](=[O:24])[NH:21]1)=[O:27])([O-:34])=[O:33]
Reactant: NCCO[N+](=O)[O-]
Reactant: C[C@H]1SC(=O)N[C@@H]1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=[N+]([O-])O
Product: C[C@H]1SC(=O)N[C@@H]1C(=O)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 65.1 %

Procedure:
1.33 ml of triethylamine and 0.36 ml of diethyl cyanophosphonate were added, whilst ice-cooling and stirring, to a suspension of 322 mg of (4R,5R)-5-methyl-2-oxothiazolidine-4-carboxylic acid and 406 mg of N-(2-nitrooxyethyl)amine nitrate in 40 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 1 hour and 25 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with ethyl acetate. The resulting mixture was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residual yellow oil thus obtained was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 324 mg of the title compound as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:30]2[CH2:32][CH2:31]2)=[C:11]([F:29])[CH:12](O)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)=[CH:6][CH:5]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:30]2[CH2:32][CH2:31]2)=[C:11]([F:29])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)=[CH:6][CH:5]=1
Reactant: OC(Cc1ccc(F)c(Oc2ccccc2)c1)C(F)=C(c1ccc(Cl)cc1)C1CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
A suspension of sodium hydride (6.3 mg, 0.26 mmol) in tetrahydrofuran (1 ml) is treated with a solution of 1-(p-chlorophenyl)-1-cyclopropyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-1-buten-3-ol (106.7 mg, 0.25 mmol) in tetrahydrofuran (1.5 ml), stirred at 50° C. for 10 minutes, cooled to room temperature, treated with a solution of p-toluenesulfonyl chloride (49.6 mg, 0.26 mmol) in tetrahydrofuran (1 ml), stirred at 60° C. for 1 hour, quenched with water, and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product (62 mg, 61% yield) which is identified by 1H, 19F and 13C NMR spectral analyses.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)[NH2:3].C([O-])(=O)C.[Na+].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>O.C(O)C>[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[N:3][NH:2][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)NCc1ccc(NN)cc1
Reactant: C1=COCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)NCc1ccc(NN=CCCCCO)cc1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a solution of 23.9 g of crude N-[(4-hydrazinylphenyl)methyl]methanesulfonamide hydrochloride in 175 mL of water and 300 mL of ethanol was added sufficient sodium acetate to bring the pH to 4. To the resulting suspension was added 10.4 mL (114 mmol, 1.3 equiv.) of 3,4- dihydro-2H-pyran. The mixture was then stirred for twenty hours at room temperature. The ethanol was removed in vacuo. The pH was raised to 10 by adding solid potassium carbonate and the mixture was extracted three times with 50 mL portions of methylene chloride. The combined organic layers were washed with 25 mL of saturated aqueous sodium chloride, dried over magnesium sulfate and filtered to give an oil. The oil was purified by chromatography on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide to yield 11.1 g (39%, two steps) of pure N-[[4-[2-(5-hydroxypentylidene)hydrazinyl]phenyl]methyl]methanesulfonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([S:29]([OH:32])(=[O:31])=[O:30])[CH:14]=[C:15]3[C:20]=2[C:19]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:18][C:17]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:16]3)=[O:9])=[C:6]([S:35]([OH:38])(=[O:37])=[O:36])[CH:5]=1)([O-])=O.C1C(C(N)=O)=CN(C2OC(COP(OP(OCC3OC(N4C5N=CN=C(N)C=5N=C4)C(OP([O-])([O-])=O)C3O)([O-])=O)([O-])=O)C(O)C2O)C=C1.[Na+].[Na+].[Na+].[Na+]>O.[Pd]>[NH2:1][C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([S:29]([OH:32])(=[O:30])=[O:31])[CH:14]=[C:15]3[C:20]=2[C:19]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:18][C:17]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:16]3)=[O:9])=[C:6]([S:35]([OH:38])(=[O:37])=[O:36])[CH:5]=1
Reactant: O=C(Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: [Pd]
Agent: NC(=O)C1=CN(C2OC(COP(=O)([O-])OP(=O)([O-])OCC3OC(n4cnc5c(N)ncnc54)C(OP(=O)([O-])[O-])C3O)C(O)C2O)C=CC1
Agent: [Na+]
Solvent: O
Product: Nc1ccc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c(S(=O)(=O)O)c1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A mixture of 42.4 g of 8-(4-nitro-2-sulfobenzamido)-1,3,6-naphthalenetrisulfonic acid, tetrasodium salt, and 1.5 g of 10% palladium-on-carbon in 150 ml of water was hydrogenated in a Parr shaker for one hour. The mixture was filtered through diatomaceous earth. The filtrate was concentrated to about 130 ml and poured with vigorous stirring into 500 ml of absolute ethanol. The resulting gum was collected by filtration through diatomaceous earth and then dissolved from the diatomaceous earth with water. The aqueous solution was concentrated to 15 ml and then diluted with 85 ml of ethanol giving a gum which was stirred with absolute ethanol giving a solid which was dried overnight in a pistol at 110° C. giving 36.15 g of 8-(4-amino-2-sulfobenzamido)-1,3,6-naphthalenetrisulfonic acid, tetrasodium salt.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.O.O=[CH:11][C:12]([OH:14])=[O:13].[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH:11]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:12]([OH:14])=[O:13])=[CH:19][CH:18]=1
Reactant: O=CC(=O)O
Reactant: COc1ccc(N)cc1
Reactant: OB(O)c1ccsc1
Solvent: O
Product: COc1ccc(NC(C(=O)O)c2ccsc2)cc1
Temperature: 100 °C
Yield: 77.4 %

Procedure:
A mixture of thiophen-3-ylboronic acid (339 mg, 2.65 mmol), 2-oxoacetic acid hydrate (244 mg, 2.65 mmol), and 4-methoxyaniline (326 mg, 2.65 mmol) was heated under microwave irradiation at 100° C. for 1 hour. The precipitate was recovered and washed sequentially with acetonitrile, DCM and Et2O. The compound was dried under vacuum at 40° C. to obtain 2-(4-methoxyphenylamino)-2-(thiophen-3-yl)acetic acid (540 mg, 77% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:14][CH2:15]O>Cl>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: COc1ccc(CC(=O)O)cc1Br
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-4-methoxyphenylacetic acid (4.1 g, 16.7 mmol) and concentrated hydrogen chloride (2 drops) in EtOH (100 mL) were stirred at 80° C. for 3 days. After cooling to room temperature, the mixture was concentrated to dryness to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:17]=[CH:16][C:13](C=O)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]([O-])(=O)C.[Na+].[C:25]([CH2:28][CH2:29][N:30]1[C:34](=[O:35])[CH2:33][S:32][C:31]1=[S:36])([OH:27])=[O:26]>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:17]=[C:16]([CH:20]=[C:33]3[S:32][C:31](=[S:36])[N:30]([CH2:29][CH2:28][C:25]([OH:27])=[O:26])[C:34]3=[O:35])[CH:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(O)CCN1C(=O)CSC1=S
Reactant: CC(C)(C)c1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(Oc2cccc(C=C3SC(=S)N(CCC(=O)O)C3=O)c2)cc1

Procedure:
Under nitrogen atmosphere in a round bottom flask 4-[4-(t-butyl)phenoxy]benzaldehyde (2.0 g, 7.8 mmol) was dissolved in 40 ml of acetic acid with stirring. To this solution was added sodium acetate (2.56 g, 31.2 mmol) followed by the addition of N-(2-carboxyethyl)rhodanine (1.79 g, 8.7 mmol). The reaction mixture was heated to reflux. The progress of the reaction was monitored by thin layer chromatography. The reaction was allowed to reflux overnight.