Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[K+]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)C)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(N)c([N+](=O)[O-])c1
Reaction time: 5 h
Yield: 65 %

Procedure:
To a solution of N-(4-isopropyl-2-nitrophenyl)acetamide obtained in step II above (1.0 eq) in MeOH and water was added KOH (1.5 eq) at room temperature and stirred for 5 hrs. Water was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired 4-isopropyl-2-nitroaniline. (Yield=65%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4](=[O:21])[C:3]=1[C:22]#[N:23].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=3)[C:2]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[C:3]([C:22]#[N:23])[C:4]2=[O:21])=[CH:15][CH:16]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2Cc1ccc(F)cc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2Cc1ccc(F)cc1
Yield: 70.5 %

Procedure:
A solution of Compound 22 (1.6 g, 4.9 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (2.2 g, 24.5 mmol) in CH2Cl2 at room temperature and further stirred overnight. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 1.30 g (72%) of yellow solids. M.P. 121° C. 1H NMR (DMSO-d6): δ 2.35 (s, 3H), 2.96 (m, 4H), 3.54 (m, 4H), 5.42 (s, 2H), 7.11-7.17 (m, 2H), 7.23-7.26 (m, 2H), 7.44 (dd, J=1.2, 8.6 Hz, 1H), 7.64 (s, 1H). EIMS m/z 377 (M+1).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:43]=[C:42]2[C:37]([CH2:38][CH2:39][CH2:40][C:41]2=[O:44])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[CH:35]=[CH:36][C:37]5[CH2:38][CH2:39][CH2:40][C:41](=[O:44])[C:42]=5[CH:43]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)C(=O)CCC5)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added 7-bromo-3,4-dihydro-1(2H)-naphthalenone (292 mg, 1.30 mmol), and potassium carbonate (360 mg, 2.60 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before the addition of tetrakis (triphenylphosphosphine) palladium (0) (50 mg, 0.043 mmol). The reaction was then heated in the microwave for 30 min at 160° C. The reaction was then filtered and the solid was dissolved in EtOAc and H2O. The organic layer was separated and concentrated. The crude residue was purified by Gilson Preparatory HPLC to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(8-oxo-5,6,7,8-tetrahydro-2-naphthalenyl)-1H-indole-7-carboxamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:6][C@@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C.O>ClCCl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][C@H:4]1[CH2:6][C@@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2ccc([C@H]3C[C@@H]3CCO)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCC[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Example 28F (4′-[(1S,2R)-2-(2-hydroxyethyl)cycloprop-1-yl]biphenyl-4-carbonitrile) and methanesulfonyl chloride (1.2 equivalents) in dichloromethane under N2 was added triethylamine (1.4 equivalents) at 0° C. The mixture was stirred at room temperature overnight, and then the mixture was treated with H2O. The separated organic layer was washed with brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluted with 4:1 hexanes/ethyl acetate to provide the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[C:8]([OH:16])[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[C:17]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(O)cccc1CC=C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCOC(=O)c1c(CC=C)cccc1OC
Temperature: 25 °C
Reaction time: 40 h
Yield: 98 %

Procedure:
To a solution of allyl 6-allyl-2-hydroxybenzoate (v) (1.2 g, 5.5 mmol) in acetone (12 mL) was added K2CO3 (0.84 g, 6.05 mmol) and MeI (1.04 mL, 16.5 mmol) and the mixture was stirred for 40 h at rt. After filtration of the mixture through a short plug of silicagel, the filtrate was concentrated in vacuo and the residue purified by 1FC (3% Et2O/pentane) to give 1.25 of allyl 6-allyl-2-methoxybenzoate (via) (98%) as a colorless oil. via: IR 2918, 2850, 1733, 1715, 1585, 1363, 1244, 1223, 914, 733 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.29 (1H, app.t, J=8.0 Hz), 6.83 (1H, d, J=7.6 Hz), 6.79 (1H, d, J=8.4 Hz), 5.97-6.06 (1H, m), 5.86-5.96 (1H, m), 5.42 (1H, br d, J=17.2 Hz), 5.28 (1H, br d, J=10.4 Hz), 5.0 (1H, br d, J=16.8 Hz), 5.04 (1H, br d, J=10.0 Hz), 4.82 (2H, br d, J=6.0 Hz), 3.82 (3H, s), 3.36 (2H, d, J=6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 167.8, 156.6, 138.7, 136.4, 132.1, 130.6, 123.6, 121.8, 118.8, 116.5, 109.2, 66.0, 56.1, 37.9; MS (EI) 232 (M+, 18), 191 (28), 175 (34), (147 (50), 132 (100), 115 (58). Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.10; (MOM): IR 2956, 2928, 2853, 1732, 1636, 1589, 1466, 1256, 1153, 1031, 919 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.26 (1H, dd, J=7.6, 8.4 Hz), 7.01 (1H, d, J=7.6 Hz), 6.88 (1H, d, J=Hz), 6.01 (1H, ddt, J=5.6, 10.0, 17.2 Hz), 5.90 (1H, ddt, J=6.8, 10.4, 16.8 Hz), 5.42 (1H, br d, J=17.2 Hz), 5.28 (1H, br d, J=10.0 Hz), 5.17 (2H, s), 5.06 (1H, br d, J=16.8 Hz), 5.05 (1H, br d, J=10.4 Hz), 4.81 (2H, d, J=5.6 Hz), 3.46 (3H, s), 3.37 (2H, d, J=6.8 Hz), 13C NMR (75 MHz, CDCl3) 8167.8, 154.2, 138.8, 136.5, 132.2, 130.7, 124.7, 123.0, 118.9, 116.6, 112.9, 94.9, 66.0, 56.4, 37.8. HRMS Calcd for C15H804Li (MLi+): 269.1365. Found: 269.1371.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.C[O:9][C:10](=[O:36])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([C:20]1[C:21]([CH3:35])=[N:22][O:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)=[O:19]>>[CH3:35][C:21]1[C:20]([C:18]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([OH:36])=[O:9])=[O:19])=[C:24]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=2)[O:23][N:22]=1
Reactant: COC(=O)c1ccccc1NC(=O)c1c(C)noc1-c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Product: Cc1noc(-c2ccc(C(F)(F)F)cc2)c1C(=O)Nc1ccccc1C(=O)O
Yield: 60 %

Procedure:
To a heterogeneous mixture of the above carboxylic acid (1.00 g, 4.34 mmol) and anhydrous DMF (2 drops) in anhydrous CH2Cl2 (5 mL) at 0° C. was added dropwise oxalyl chloride (760 μL, 8.69 mmol). The resultant mixture was warmed to RT and stirred for 2.5 h, whereupon it was concentrated to a heterogeneous yellow mixture and purged of excess oxalyl chloride in vacuo. The acid chloride was then added to a homogeneous solution of anthranilic acid (1.19 g, 8.69 mmol) in 2.5 N aqueous NaOH (6.95 mL, 17.4 mmol) at 5° C., resulting in the instantaneous formation of a white precipitate. The reaction mixture was then warmed to RT, whereupon it was diluted with a minimal amount of water to facilitate stirring, which was continued for an additional 1.5 h. The mixture was acidified to pH 2 by addition of concentrated HCl (1.63 mL), diluted with 2.0 N HCl, and stirred for 1.5 h. Filtration of the suspension followed by washing with water, air drying and subsequent recrystallization from MeOH. The title compound which was separated from unreacted starting material by exhaustive methylation of the acid groups with (trimethylsilyl)diazomethane. The isolated 2-{[3-Methyl-5-(4-trifluoromethyl-phenyl)isoxazole-4-carbonyl]-amino}-benzoic acid methyl ester was saponified in a manner similar to Step 2 of this Example to give the title compound (60%): mp (trimethylsilyl)diazomethane. The isolated 2-{[3-Methyl-5-(4-trifluoromethyl-phenyl)-isoxazole-4-carbonyl]-amino}-benzoic acid methyl ester was saponified in a manner similar to Step 2 of this Example to give the title compound (60%): mp 204.6-205.5° C.; 1H NMR (DMSO-d6) δ 13.52 (br s, 1 H), 11.47 (s, 1 H), 8.42 (d, 1 H), 7.97 (ABq, 4 H), 7.93 (dd, 1 H), 7.64 (ddd, 1 H), 7.23 (ddd, 1 H) 2.47 (s, 3 H); IR (KBr) 3374, 3118, 2987, 2656, 1681, 1659, 1604, 1585, 1532, 1441, 1263, 1166, 1075, 1014, 905, 847, 762, 719, 701 cm-1 ; MS (m/z) 380 [M+ ].
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:13]C)=[CH:8][CH:9]=2)[CH2:4]1.C(OCC)C.[BrH:20]>C(O)(C)C>[BrH:20].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[CH2:4]1
Reactant: COc1ccc2c(c1)CC(N)CC2
Agent: Br
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: NC1CCc2ccc(O)cc2C1

Procedure:
A suspension of the compound obtained in step (b) (6.6 g) in 48% hydrobromic acid (80 ml) is refluxed for 2 hours. The obtained solution is evaporated to dryness and the residue is twice taken up in absolute ethanol and concentrated to dryness. An oily product is thus obtained which is dissolved in hot isopropanol (20 ml). Ethyl ether (30 ml) is added thereto and a crystalline precipitate of 2-amino-7-hydroxytetralin hydrobromide (6.8 g) is obtained. M.p. 171°-173° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][C@:14]2([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[Si](C)(C)C>C(#N)C>[S:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C@:14]12[CH2:16][NH:17][CH2:18][C@H:13]1[CH2:12][S:11][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N:15]2
Reactant: O=C(NC1=N[C@@]2(c3cccs3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: O=C(NC1=N[C@@]2(c3cccs3)CNC[C@H]2CS1)c1ccccc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A solution of benzyl(4aR,7aR)-2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (14 g, 29.3 mmol) in acetonitrile (210 mL) is treated with iodotrimethylsilane (7.53 mL, 52.7 mmol) at room temperature. The solution is stirred for 1 hour and the solvent is evaporated. The residue is quenched with 1 M hydrochloric acid and ethyl acetate and the resulting mixture is filtered through diatomaceous earth. The aqueous layer is separated, neutralized with 50% w/w aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic extracts are dried over sodium sulfate and concentrated to give the title compound (7.9 g, 78%). ES/MS (m/e): 344 (M+H).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][C:24]1([CH3:32])[CH3:31].C(OCC)(=O)C>CN(C)C=O.O>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([S:1][CH2:21][CH2:22][N:23]3[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][C:24]3([CH3:31])[CH3:32])[NH:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: CC1(C)CCCC(C)(C)N1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2nc(SCCN3C(C)(C)CCCC3(C)C)[nH]c2c1
Reaction time: 4.5 h
Yield: 80 %

Procedure:
In 15 ml of N,N-dimethylformamide was dissolved 810 mg of 2-mercapto-5-methoxybenzimidazole, and 933 mg of potassium carbonate and 1.62 g of 1-(2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride were added to the solution, followed by stirring at 65° to 70° C. for 4.5 hours. After completion of the reaction, 200 ml of ethyl acetate and 70 ml of water were added to the reaction mixture, and the thus extracted ethyl acetate layer was washed successively with a diluted sodium hydrogencarbonate aqueous solution and a diluted sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The extracting solution was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 25:1 by volume) to obtain 1.25 g (80%) of the titled compound.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH3:14].Cl.C(OCC)(=O)C>C(O)C>[C:2]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:14]
Reactant: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Reactant: N
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.2 Grams of a 2-(trichloromethyl)benzimidazole compound [compound (101)] of the formula (XI) in which X is H and Z is OCF2CFHO was dissolved in 30 ml of ethanol. The resulting solution was added by drops to 4 ml of a 25% aqueous ammonia at 5° C. After stirring for 1 hour at 5° to 15° C., the reaction solution was poured into an ice/conc. hydrochloric acid mixture and extrac.ted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the dried layer by distillation gave 2.83 g of a 2-cyanobenzimidazole compound [compound (i)] of the formula (II) in which X is H and Z is OCF2CFHO.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=4[CH3:25])[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)c(C#N)c2)C1=O
Yield: 60.9 %

Procedure:
Using 5-bromo-2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]benzonitrile (996 mg) described in Preparation Example 188 and 1-acetylimidazolidin-2-one (384 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (679 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][C:62]1[C:66]([NH2:67])=[CH:65][O:64][N:63]=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:67][C:66]1[C:62]([CH3:61])=[N:63][O:64][CH:65]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Reactant: Cc1nocc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nocc1NC(=O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-4-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 65; 90 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.46 mmol), HATU (156 mg, 0.41 mmol) and 3-methyl-4-isoxazolamine (26.8 mg, 0.27 mmol). The solution was stirred for 18 hours. The solvent removed in vacuo and purified by MDAP to give the title compound as a white solid. 65 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([OH:22])[CH:14]=2)=[CH:8][CH:7]=1.[K+].[Br-]>>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:23]=[CH:24][C:25]([NH2:26])=[C:2]([OH:1])[CH:3]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[OH:22]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Oc3ccc([N+](=O)[O-])c(O)c3)cc2)cc1O
Agent: [Br-]
Agent: [K+]
Product: Nc1ccc(Oc2ccc(Oc3ccc(N)c(O)c3)cc2)cc1O
Yield: 83 %

Procedure:
1,4-Bis(4-amino-3-hydroxyphenoxy)benzene was synthesized in a manner analogous to Example 2 from 1,4-bis(3-hydroxy-4-nitrophenoxy)benzene. Yield: 83%; mp>220° C. (decompose); IR (KBr): 3360, 3288, 3040, 1603, 1514 cm−1; MS (EI) m/z 324 (M+, 100); Elemental Anal. Calcd. for C18H16N2O4: C, 66.67; H, 4.94; N, 8.64. Found: C, 66.52; H, 5.01; N, 8.56.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9](C(OC(C)(C)C)=O)[CH:10]([CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][C:18]([NH2:22])=[C:19]([CH3:21])[CH:20]=1)[CH3:11]>C1(OC)C=CC=CC=1>[CH3:8][NH:9][CH:10]([CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][C:18]([NH2:22])=[C:19]([CH3:21])[CH:20]=1)[CH3:11]
Reactant: Cc1cc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cnc1N
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C/C=C/c1cnc(N)c(C)c1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 12.2 %

Procedure:
Under a nitrogen atmosphere, trifluoroacetic acid (17.76 g, 155.76 mmol) was added dropwise, via addition funnel, over 30 min to a cold (0-5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine (1.11 g, 3.47 mmol) in anisole (15 mL). The resulting solution was stirred for 45 min at 0-5° C. and was then concentrated by rotary evaporation. The viscous, brown oil was further dried under high vacuum for 18 h. The crude product was cooled (0-5° C.), basified with 10% NaOH solution (10 mL), treated with saturated NaCl solution (10 mL), and extracted with CHCl3 (5×10 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, followed by further drying under high vacuum yielding a dark-brown oil. The crude product was purified by column chromatography on silica gel (50 g), eluting with CHCl3—CH3OH—Et3N (4:1:1, v/v/v). Selected fractions containing the product (Rf 0.13) were combined and concentrated by rotary evaporation, and the residue was re-chromatographed on silica gel (50 g) eluting with CHCl3—CH3OH (7:3, v/v). Fractions containing the product (Rf 0.12) were combined and concentrated by rotary evaporation. The residue was dissolved in CHCl3, and the CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried affording a yellow oil (0.087 g) which tended to crystallize. The semi-crystalline material was dissolved in a warm solution of hexane containing a small amount of ethyl acetate. The warm solution was decanted from an insoluble gum. The solution was allowed to cool to ambient temperature and was further cooled at 5° C. for 18 h. The resulting crystalline solids were collected, washed with hexane, and vacuum dried at 40° C. for 16 h. The yield was 30.8 mg (4.3%) of a light-yellow powder, mp 78-81° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:28](Cl)(=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:28]([N:2]([CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:1])(=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCC(=O)Cl
Reactant: CCOC(=O)CC(=Cc1ccc(-c2cccc(CNC)c2)cc1)C(=O)OC
Product: CCCCCCC(=O)N(C)Cc1cccc(-c2ccc(C=C(CC(=O)OCC)C(=O)OC)cc2)c1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1.5 g (4.2 mmol) of methyl ethyl 2-(3′-methylaminomethylbiphenyl-4-ylmethylene)succinate with 740 μl (4.8 mmol) of heptanoyl chloride, and after purification, 1.8 g (89%) of the expected product are obtained.
Reaction SMILES: OC[C:3]1[S:4][S:5][C:6]([CH2:9][O:10][Si](C(C)(C)C)(C)C)=[CH:7][CH:8]=1.O[C:19]1[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:25]([C:21]1[CH:20]=[C:19]([O:10][CH2:9][C:6]2[S:5][S:4][CH:3]=[CH:8][CH:7]=2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Reactant: C#Cc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#Cc1cccc(OCC2=CC=CSS2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a stirred solution of 3-(hydroxymethyl)-6-[(tert-butyldimethylsilyloxy)methyl]-1,2-dithiin (U.S. Ser. No. 08/212,096) (235 mg, 0.802 mmol) in 1 mL of dry THF was added a solution of 3-hydroxyphenylacetylene (142 mg, 1.20 mmol) in 1 mL THF, followed by the addition of triphenylphosphine (315 mg, 0.977 mmol). The resulting solution was cooled to 0° C., then 190 μL (210 mg, 1.037 mmol) of diethylazodicarboxylate was added, and the reaction mixture was kept at 0°-5° C. for 1.5 h until TLC analysis showed the reaction to be complete. For 5 isolation of the products, the reaction mixture was chromatographed directly on a silica gel column, using ethyl acetate-hexane, 1:20, to yield 3-[tert-butyldimethylsilyloxy)methyl]-6-[(3-ethynylphenyloxy)methyl]-1,2-dithiin (175 mg, 56.0%); 1H-NMR (CDCl3) δ7.23 (t, J=8.0, 1 H), 7.12 (d, J=8.0, 1 H), 7.05 (s, 1 H), 6.93 (dd, J=6.0, 2.4, 1 H), 6.44 (d, J=6.0, 1 H), 6.37 (d, J=6.0, 1 H), 4.66 (s, 2 H), 4.30 (s, 2 H), 3.07 (bs, 1 H), 0.92 (s, 9 H), 0.10 (s, 6 H); 13C--NMR (CDCl3) δ157.79, 136.21, 132.54, 129.46, 128.74, 127.03, 125.43, 123.45, 118.29, 116.22, 83.28, 77.21, 69.73, 64.79, 25.76, 18.31, -5.41. MS (EI) 390.1 (M+).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH2:8])=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: Clc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: NN(c1ccccc1)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 38 %

Procedure:
Phenylhydrazine (1.2 equiv., 0.6 mmol, 0.06 mL), 4-chlorobromobenzene (1.0 equiv., 0.5 mmol, 96 mg), Pd(OAc)2 (0.05 equiv., 0.025 mmol, 6 mg), BINAP (0.05 equiv., 0.025 mmol, 16 mg), NaOtBu (1.4 equiv., 0.7 mmol, 67 mug) and dilsopropylamine (2 mL) were added to an oven dried test tube which was capped with a septum and purged briefly with argon (˜1 min.), and then heated to 80° C. under argon for 2.5 hours. The reaction was then cooled to room temperature, diluted with Et2O (2 mL), filtered through Celite and concentrated under vacuum. The crude mixture was purified by flash column chromatography (10% EtOAc/Hex) to give the title product as a yellow oil (42 mg, 0.19 mmol, 39% yield).