Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].F[C:4]1[CH:9]=[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])[CH:7]=[CH:6][C:5]=1[C:20]1[N:24]([C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[N:23]=[CH:22][C:21]=1[C:30]([NH2:32])=[O:31].O.C(O)(=O)C>CS(C)=O>[CH3:18][O:17][C:12]1[C:11]([CH3:19])=[C:10]([C:8]2[CH:9]=[CH:4][C:5]3[C:20]4[N:24]([C@H:25]5[CH2:29][CH2:28][O:27][CH2:26]5)[N:23]=[CH:22][C:21]=4[C:30](=[O:31])[NH:32][C:6]=3[CH:7]=2)[C:15]([CH3:16])=[CH:14][N:13]=1
Reactant: COc1ncc(C)c(-c2ccc(-c3c(C(N)=O)cnn3[C@H]3CCOC3)c(F)c2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: COc1ncc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn([C@H]4CCOC4)c23)c1C
Reaction time: 0.83 h
Yield: 96.1 %

Procedure:
Sodium hydroxide powder (9.43 g) was added at one time to a solution of 5-[2-fluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxamide (37.2 g) in DMSO (186 mL) at room temperature. The reaction mixture was stirred at the same temperature for 50 minutes and then at 70° C. for 45 minutes. Under water-cooling, water (600 mL) was added dropwise to the reaction mixture, and then acetic acid (13.5 mL) was added dropwise. The precipitated powder was collected by filtration. The collected subject was washed with water and MTBE and then dried under reduced pressure to give the title compound (34.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20]CC)=[O:19])=[C:16]([CH3:23])[N:15]=[C:14]3[S:24][C:25]([NH:35]C(OC(C)(C)C)=O)=[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].C(O)=O>CS(C)=O.O>[NH2:35][C:25]1[S:24][C:14]2=[N:15][C:16]([CH3:23])=[C:17]([C:18]([OH:20])=[O:19])[C:12]([NH:11][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:9])=[O:10])=[C:13]2[C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1
Reactant: CCOC(=O)c1c(C)nc2sc(NC(=O)OC(C)(C)C)c(-c3cccc(OC)c3)c2c1NS(=O)(=O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: O=CO
Product: COc1cccc(-c2c(N)sc3nc(C)c(C(=O)O)c(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 150 °C
Yield: 81.1 %

Procedure:
A mixture of ethyl 4-{[(3-chlorophenyl)sulfonyl]amino}-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridine-5-carboxylate (Description 83) (600 mg, 0.949 mmol) and aqueous NaOH (2M) (2.373 mL, 4.75 mmol) in DMSO (10 mL) was heated at 150° C. for 40 min. After cooling to RT, the mixture was diluted with water (20 mL) and acidified with formic acid to pH 6. The mixture was then extracted with ethyl acetate (30 mL×5) and the combined organics concentrated. The residue was passed through a phase separator (C18 cartridge) eluting with water (20 mL×3) and MeOH (20 mL×5) and the combined methanolic fractions concentrated and dried, to give the title compound (388 mg). LCMS (A) m/z: 504 [M+1]+, Rt 1.17 min (acidic).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][Br:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:24][N:25]([CH2:27][CH2:28][OH:29])[CH3:26].CN(C=O)C>CCOCC>[Br-:21].[CH2:1]([S:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][N+:25]([CH3:26])([CH3:24])[CH2:27][CH2:28][OH:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(CBr)OC
Reactant: CN(C)CCO
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCSCC(C[N+](C)(C)CCO)OC
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 32 %

Procedure:
Into a two neck 25 ml round bottom flask equipped with an air condenser, thermometer and stir bar, was placed 2.0 g (0.005 mol) of (+)-1-hexadecylthio-2-methoxy-3-bromopropane, 0.5 ml (0.006 mol) of N,N-dimethylaminoethanol and 15 ml of DMF. The solution was maintained at 45°-50° C. for 72 hours with continuous stirring. The reaction mixture was then cooled to room temperature, 125 ml of ether was added and the solution was kept at 0° C. for 24 hours. The resulting precipitate (800 mg) was filtered and swirled with five 50 ml portions ofetherto give (±)-3-hexadecylthio-2-methoxy-N,N-dimethyl-N-β-hydroxyethyl-1 -propyl ammonium bromide (32%), (mp 107°-109° C.). 1 H-NMR (CDCl3): delta, 0.87 (t, 3 H, terminal methyl), 1.2-1.6[m, 28 H, (CH2)14 ],2.45-3.0(m, 4 H, S-C2, CH2 -S), 3.48[s, 9 H, CH3 -O, N(CH3)2 ], 3.9-4.3(m, 7 H, CH, CH2N, N-CH2 -CH2 -OH). Anal. (C24H52NO2SBr) C,H,N.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:43])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=2)=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)[C:45](N)(CO)[CH2:46][OH:47].[O:52]1CCC[CH2:53]1>O>[N:30]([CH2:27][CH2:26][OH:41])([CH2:31][CH2:53][OH:52])[CH2:45][CH2:46][OH:47].[C:1]([NH:9][C@@H:10]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:43])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=2)=[CH:19][CH:20]=1)[CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: NC(CO)(CO)CO
Agent: COc1cc(CC(=O)Nc2ccc([C@@H](CC(=O)O)NC(=O)c3ccccc3)cc2)ccc1NC(=O)Nc1ccccc1C
Solvent: O
Product: OCCN(CCO)CCO
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A mixture of (R)-3-benzoylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetyl-amino}phenyl)-propanoic acid [1.0 g, Example 5(a)], tris(hydroxymethyl)aminomethane (0.208 g), tetrahydrofuran (80 ml) and water (15 ml) was stirred at 50° C. for 1.5 hours, then cooled to room temperature and then evaporated. The residue was recrystallised from ethanol to give the title compound as a white crystalline solid (1.1 g), m.p 135-140° C. (with decomposition). [Elemental analysis:—C, 61.6; H, 6.1; N, 9.5%. Calculated for C33H32N4O6.C4H11NO3.H2O:—C, 61.75; H, 6.3; N, 9.7%].
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5](=[O:22])[CH2:4]1.[C:23]1(C)[C:24]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.N1C=CC=C[CH:35]=1>>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH:7]2[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5](=[O:22])[CH2:4][CH:3]2[CH2:2][O:1][S:29]([C:24]2[CH:23]=[CH:28][C:27]([CH3:35])=[CH:26][CH:25]=2)(=[O:30])=[O:31])[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(C2C(CO)CC(=O)N2c2ccccc2)c1
Reactant: c1ccncc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: COc1cccc(C2C(COS(=O)(=O)c3ccc(C)cc3)CC(=O)N2c2ccccc2)c1

Procedure:
To 17.2 gm. of 4-hydroxymethyl-5-(3-methoxyphenyl)-1-phenylpyrrolidin-2-one in 35 ml. of dry pyridine was added at 5°-10° 12.2 gm of p toluenesulfonyl chloride over one hour. Workup of the reaction following the procedure given in example 1E provided 17.6 gm of product as a crude oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12](/[C:15](=[C:20](\[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)/[C:21]([O:23][CH3:24])=[O:22])/[C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([O:44][C:43]([NH:42][CH2:41][CH2:40][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25]/[C:20](=[C:15](\[C@H:12]2[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11]2)/[C:16]([O:18][CH3:19])=[O:17])/[C:21]([O:23][CH3:24])=[O:22])=[CH:31][CH:30]=1)=[O:49])([CH3:48])([CH3:47])[CH3:46]
Reactant: COC(=O)/C(Cc1ccc(O)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
A suspension of dimethyl 2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-3-(4-hydroxybenzyl)maleate (35 mg, 0.075 mmol) and cesium carbonate (27 mg, 0.083 mmol) in DMF (1.2 ml) was cooled to 0° C., a solution of tert-butyl (2-bromoethyl)carbamate (20 mg, 0.091 mmol) in DMF (0.5 ml) was added dropwise, and the mixture was stirred at room temperature for 19 hr. The reaction mixture was diluted with water and was extracted with ethyl acetate, the organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the filtrate was removed by distillation under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=8:2) to give the title compound as an oil (20 mg, yield 43%).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>O.CO>[N:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 81.2 %

Procedure:
A solution of sodium dithionite (2.5 g) in water (10 ml) was added to a warmed solution of 1-(4-pyridyl)-4-(4-nitrophenyl)piperazine (0.551 g) in methanol (50 ml) and the mixture was allowed to reflux for 2 hours. The methanol was removed by evaporation and the resulting concentrated solution was basified with solid Na2SO4. The organic material was extracted into ethyl acetate, washed with water, brine, dried (Na2SO4) and evaporated to give 1-(4-pyridyl)-4-(4-aminophenyl)piperazine (0.4 g) as an oil. NMR: (CDCl3) 3.14(t,4H), 3.48(t, 4H), 6.68(m,4H), 6.85(d,2H), 8.31(bd,2H): MS: m z 255 (MH)−.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1C=O.[CH3:13][O:14]S([O-])(=O)=O.[CH3:19][S+](C)C.[OH-].[Na+]>ClCCl>[O:14]1[CH2:13][CH:19]1[C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=1
Reactant: COS(=O)(=O)[O-]
Reactant: O=CC1COc2ccccc2O1
Reactant: C[S+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: c1cc2c(cc1C1CO1)OCCO2
Reaction time: 70 h
Yield: 100.7 %

Procedure:
A mixture of 1,4-benzodioxanecarboxaldehyde [RN 29668-44-8](1.5 g, 9.14 mmol), trimethylsulfonium methyl sulfate (2.24 g, 11.9 mmol), dichloromethane (35 ml) and 50% aqueous sodium hydroxide (5 ml) were vigorously stirred for 70 hours. The mixture was partitioned between water and diethyl ether and the layers separated. The aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water, brine, then dried over magnesium sulfate and evaporated to give crude 6-oxiranyl-2,3-dihydro-benzo[1,4]dioxine (1.64 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[N:10]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:11]=[CH:12][CH:13]=1)=[O:8].CN.O.C(OCC)(=O)C>CN(C=O)C>[NH2:14][N:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:8]
Reactant: Cc1ccsc1C(=O)c1cccn1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccsc1C(=O)c1cccn1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 79.4 %

Procedure:
To a solution consisting of 2-[2-[(3-methyl-2-thienyl)carbonyl]-1H-pyrrol-1-yl]-1H-isoindole-1,3(2H)dione (11.5 g) in DMF (30 ml) was added 40% methylamine (aq., 34.0 ml) solution at room temperature. The reaction mixture was stirred at ambient temperature for 3.5 hours, then poured into water and ethyl acetate. The layers were separated and the aqueous phase was extracted thrice with EtOAc. The combined organics were washed with water, brine, and dried (MgSO4). Filtration and concentration gave the crude product. Purification via preparative HPLC (silica gel, 2:1 heptane/EtOAc), followed by crystallization from ether/pentane afforded 5.6 g of the product as a solid, m.p. 42°-44° C.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][C:18]=1[CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH:5]([CH2:6][CH3:7])[C:4]([OH:30])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(CC)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Temperature: 55 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Under N2, a solution of 2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}butyric acid ethyl ester (216 mg, 0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a white solid (155 mg, 77%): 1H NMR (400 MHz, CDCl3) δ 1.05 (t, 3H, J=7.57 Hz), 1.92-1.96 (m, 2H), 2.35 (s, 3H), 2.94 (t, 2H, J=6.35 Hz), 4.16 (t, 21H, J=6.60 Hz), 4.41 (t, 1H, J=6.11 Hz), 6.76-6.83 (m, 4H), 7.39-7.41 (m, 3H), 7.97-7.99 (m, 2H); MS (ES) m/e 382.0 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].[NH3:15]>CO>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][CH2:4][C:3]([NH2:15])=[O:2]
Reactant: COC(=O)CNc1c(C)cccc1C
Reactant: N
Solvent: CO
Product: Cc1cccc(C)c1NCC(N)=O
Reaction time: 8 h

Procedure:
22.3 g of 2,6-dimethylanilinoacetic acid methyl ester are dissolved in 150 ml of absolute methanol and dry ammonia is passed in with stirring until the solution is saturated. In the course thereof the temperature rises to 37° C. The reaction mixture is left to stand overnight. It is then concentrated in vacuo to leave as residue a yellow oil which crystallises on scratching. Recrystallisation from toluene yields 15.3 g of 2,6-dimethylanilino acetic acid amide which melts at 89°-92° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([Mg]Br)C.C(OCC)C.IC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a solution of 5-benzyloxyindole (19.8 g, 88.68•mmol) in THF (200 mL) pre-cooled with an ice bath, was added a 3.0 M solution of ethyl magnesium bromide in diethyl ether (44.3 mL, 133.02 mmol). The ice bath was removed and the resulting mixture was gradually warmed to rt over 5 h. The reaction mixture was cooled to 0° C. and iodomethane (37.8 g, 266.04 mmol) was added. The mixture was warmed to rt and stirred for 12 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (50 mL). The reaction mixture was diluted with diethyl ether (150 mL), and then washed with water and a brine solution consecutively. The combined organic layers were dried over magnesium sulfate, filtered, and then concentrated via rotary evaporation to give a dark brownish solid. The crude mixture was purified on silica gel (95:5 hexane:dichloromethane) to give the title compound (12.6 g, 60%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (br s, 1H), 7.50 (d, 2H), 7.45 (m, 3H), 7.32 (s, 1H), 7.11 (d, 1H), 6.95 (m, 2H), 5.13 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:12]([OH:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:9]=1)=[O:7])[CH3:4].[CH2:28](Br)[CH:29]=[CH2:30].C(OCC)(=O)C>CS(C)=O>[CH2:3]([O:5][C:6]([C:8]1[C:12]([O:13][CH2:30][CH:29]=[CH2:28])=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:9]=1)=[O:7])[CH3:4]
Reactant: C=CCBr
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C=CCOc1c(C(=O)OCC)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 0.75 h

Procedure:
To a slurry of sodium hydride (39 mg of 60% in oil) in DMSO (2.4 ml) was added 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester I-1d (300 mg, 0.8 mmol) and the mixture was agitated for 45 minutes. Allyl bromide (0.1 ml, 1.2 mmol) was added and stirring was continued for 4.5 hours. The reaction solution was diluted into ethyl acetate, washed with water (2×), brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (I-1e) as an orange oil, 340 mg. This material was taken onto the next step without further purification.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[C@:6]([NH:12]C(=O)C)([CH2:7][CH2:8]1)[CH2:5][O:4][CH2:3]2.N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.C(O)C(O)C>C1COCC1>[CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[C@:6]([NH2:12])([CH2:7][CH2:8]1)[CH2:5][O:4][CH2:3]2
Reactant: CC(=O)N[C@@]12CC[C@@](C)(COC1)C2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC(O)CO
Product: CC1(C)[C@@]2(C)CC[C@]1(N)COC2
Temperature: 25 °C

Procedure:
To a solution of step 3 intermediate (0.165 g, 0.78 mmol) in 3 mL of dry THF and pyridine (0.37 mL, 47 mmol) maintained at 0° C., oxalyl chloride was added with stirring. After 30 minutes propylene glycol (0.46 mL, 63 mmol) was added to the above reaction mixture and reaction warmed to room temperature. Reaction mixture was concentrated after adding ethyl alcohol. The residue was partitioned between 1N HCl and tert-butyl ether. Aqueous layer was separated and basified with 4N NaOH and extracted with ethyl acetate. Ethyl acetate layer was separated, dried and concentrated. Crude material was carried to next step without further purification. m/z (M+1): 170.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[CH3:22][NH2:23]>O.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10]([NH:23][CH3:22])=[O:11])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Solvent: CCO
Solvent: O
Product: CNC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Yield: 79 %

Procedure:
19.4 g (0.05 mole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propanoate, 200 ml of 40% solution of methylamine in water and 30 ml of absolute ethanol was stirred for 24 hours at room temperature. The precipitate was filtered off and recrystallized from isopropyl alcohol, which gave 13.2 g (79%) of the amide. M.p. 188°-191° C. The formula C15H15BrN2O2 was verified through elemental analysis. (The elemental analyses throughout this application were carried out for all elements of the compounds prepared, and are within±0.4 percent of the theoretical values if not otherwise stated.) ##STR27##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:36](=[O:37])[C:30]2[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=2)[C:39]1=[O:38]
Reactant: COc1ccc(-c2nc3cc(-c4ccc(F)c(F)c4)ccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3cc(-c4ccc(F)c(F)c4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-(3,4-difluorophenyl)benzoxazole (63 mg, 0.18 mmol) and 1,2,4-benzenetricarboxylic anhydride (35 mg, 0.18 mmol) the title compound was obtained (25 mg, 27%). 1H NMR (DMSO) δ 8.53(dd, 1H), 8.42(m, 3H), 8.18(m, 2H), 7.94(m, 2H), 7.79(dd, 1H), 7.60(m, 3H), 3.95(s, 3H). MS 527 m/z (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[NH:19]([C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[C:20]([NH2:22])=[NH:21].[OH-].[Na+]>CO.O>[N:27]1[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][C:23]=1[N:19]=[C:20]1[NH:22][C:8]2([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[NH:22][C:20](=[N:19][C:23]3[NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[NH:21][C:10]2([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[NH:21]1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccc(F)cc2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1

Procedure:
Following the procedure of Example 1, 4,4'-difluorobenzil (1.0 g, 4.06 mmol) and 2-guanidinobenzimidazole (0.6 g, 3.4 mmol) in methanol (40 mL) was treated with a solution of sodium hydroxide (200 mg, 5 mmol) in 5 mL of water. The title compound was isolated as pale yellow crystals (750 mg, 79% yield). MS (ESI) m/z 561 [M+H]+.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:18][Mg]Br.O1CCCC1.Cl>CCOCC>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([CH:14]([OH:15])[CH3:18])=[CH:16][CH:17]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C[Mg]Br
Reactant: CCCC(c1ccc(CO)cc1)n1ccnc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(c1ccc(C(C)O)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
460 mg of the aldehyde of example 5 in 8 ml of ether is mixed with 1.5 ml of a 3M methyl magnesium bromide solution in ether with ice cooling and is stirred for 20 hours at room temperature; 10 ml of tetrahydrofuran is added and heated to 60° C. in 6 hours. It is added to 1M of hydrochloric acid, extracted with ether, then the water phase is alkalized with potassium carbonate and extracted with ether. After drying and concentration by evaporation of this ether phase, the residue is chromatographed on silica gel (methylene chloride/methanol (95:5)). 300 mg of the title compound is obtained.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])[NH2:11].N1C=CC=CC=1.Cl>ClCCl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to a stirred solution of 3-bromo-4-(2,4-difluorophenoxy)aniline (328 mg, 1.1 mmol) and pyridine (178 μL, 2.2 mmol) in dichloromethane (2 ml) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir overnight, it was treated with 1N HCl (10 ml) and extracted with dichloromethane (3×10 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (430 mg, 99%) as a tan solid which was carried forward without purification. LCMS (M−H)−=391.