Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([O:17][CH3:18])[C:14](O)=[O:15].[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([O:17][CH3:18])[C:14]([NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([C:22]#[N:21])=[CH:24][CH:25]=1)=[O:15]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
(RS)-(2,4-Bis-trifluoromethyl-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-(2,4-bis-trifluoromethyl-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Colorless gum.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:19][C:17](=[O:18])[C@H:16]([CH3:20])[C@@H:15]([O:21][C@@H:22]2[O:27][C@@H:26]([CH3:28])[C@H:25]([OH:29])[C@@:24]([O:31][CH3:32])([CH3:30])[CH2:23]2)[C@H:14]([CH3:33])[C@@H:13]([O:34][C@@H:35]2[O:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([N:42]([CH3:44])[CH3:43])[C@H:36]2[OH:45])[C@@:12]([O:47][CH3:48])([CH3:46])[CH2:11][C@@H:10]([CH3:49])/[C:7](=N\O)/[C@H:6]([CH3:50])[C@@H:5]([OH:51])[C@@:4]1([OH:53])[CH3:52].C(O)C.[OH-:57].[Na+]>O>[CH3:1][CH2:2][C@H:3]1[O:19][C:17](=[O:18])[C@H:16]([CH3:20])[C@@H:15]([O:21][C@@H:22]2[O:27][C@@H:26]([CH3:28])[C@H:25]([OH:29])[C@@:24]([O:31][CH3:32])([CH3:30])[CH2:23]2)[C@H:14]([CH3:33])[C@@H:13]([O:34][C@@H:35]2[O:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([N:42]([CH3:43])[CH3:44])[C@H:36]2[OH:45])[C@@:12]([O:47][CH3:48])([CH3:46])[CH2:11][C@@H:10]([CH3:49])[C:7](=[O:57])[C@H:6]([CH3:50])[C@@H:5]([OH:51])[C@@:4]1([OH:53])[CH3:52]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)/C(=N\O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 80 °C

Procedure:
In the present method, acid is added to the mixture of protected silylated clarithromycin oxime, ethanol, water and deoximating agent and the mixture is heated at reflux (about 80° C.) Heating is then continued and the suspension is stirred for an amount of time sufficient to finish the reaction. The mixture is then cooled to about 20° C. and sodium hydroxide solution having a concentration of from about 20% to about 47%, preferably 47%, is added at this temperature until the pH of the reaction mixture reaches about 10 to about 11, preferably about 10.2 to about 10.5. Crystalline clarithromycin is then isolated, preferably by filtration, with no further water addition. The obtained clarithromycin may subsequently be further purified and/or isolated and the crystalline form of clarithromycin may be altered to the desired form (such as crystal form 0, I, II, or IV) for use.
Reaction SMILES: C(OC1C(OCC)=CC=C([N+]([O-])=O)C=1C=C[N+]([O-])=O)C1C=CC=CC=1.[CH2:26]([O:33][C:34]1[CH:44]=[CH:43][C:37]([CH:38]=[CH:39][N+]([O-])=O)=[C:36]([N+:45]([O-])=O)[C:35]=1[O:48][CH3:49])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34]1[C:35]([O:48][CH3:49])=[C:36]2[C:37]([CH:38]=[CH:39][NH:45]2)=[CH:43][CH:44]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1c(OCc2ccccc2)ccc(C=C[N+](=O)[O-])c1[N+](=O)[O-]
Agent: CCOc1ccc([N+](=O)[O-])c(C=C[N+](=O)[O-])c1OCc1ccccc1
Product: COc1c(OCc2ccccc2)ccc2cc[nH]c12
Yield: 75 %

Procedure:
This compound is obtained according to the operating method described in Example 1c, in which the 2-benzyloxy-3-ethoxy-6,β-dinitrostyrene is replaced with 4-benzyloxy-3-methoxy-2,β-dinitrostyrene. White crystals (yield=75%, m.p.=66°-67° C.) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1>C(O)C.[Pt]=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCC#Cc1cccc(Br)c1
Agent: O=[Pt]
Solvent: CCO
Product: OCCCCc1cccc(Br)c1
Yield: 84.2 %

Procedure:
A solution of 4-(3-bromophenyl)but-3-yn-1-ol (21 g) in ethanol (1000 ml) was hydrogenated over platinum oxide (500 mg) for 4 h. The catalyst was removed by filtration and the filtrate was evaporated to give the title compound (18 g) tlc (SiO2) diethyl ether Rf=0.38.
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH2:23])[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
2-[2-(4-benzhydryloxy-piperidin-1-yl)-ethyl]-isoindole-1,3-dione (0.548 g, 1.24 mmol) was dissolved in ethanol (2 ml), followed by the addition of hydrazine hydrate (large excess, 2-3 ml). The solution was refluxed for 2 hours. The white solid was precipitated. After cooling to the room temperature, the white solid was filtered off and washed with small amount of ethanol. The filtrates were combined and concentrated. The resulted residue was dissolved in toluene (100 ml). The solution was washed with water (3×20 ml) and dried over anhydrous Na2SO4. After evaporated the solvent, the crude product, 2-(4-benzhydryloxy-piperidin-1-yl)-ethylamine was obtained (0.326 g, 84.4% yield). 1H-NMR (CD3OD, ppm): 7.15-7.40 (m, 10H), 5.58 (s, 1H), 3.46 (m, 1H), 2.77 (m, 2H), 2.72 (t, 2H), 2.40 (t, 2H), 2.18 (m, 2H), 1.89 (m, 2H), 1.70 (m, 2H). ESMS 311.2 (M+1), 333.2 (M+23).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:2]1.Br[CH2:25][CH2:26][CH2:27][S:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:22][C:17]([F:23])([C:8]1[N:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:25][CH2:26][CH2:27][S:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:2][CH2:3]2)[C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[N:9]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: Fc1ccc(SCCCBr)cc1
Reactant: Fc1ccc2c(c1)nc(C(F)(F)C(F)(F)F)n2C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(SCCCN2CCC(n3c(C(F)(F)C(F)(F)F)nc4cc(F)ccc43)CC2)cc1
Yield: 8.6 %

Procedure:
3.9 g 1-(Piperidin-4-yl)-5-fluoro-2-pentafluoroethyl-1H-benzoimidazole, 4.4 g 1-(3-bromo-propylsulfanyl)-4-fluoro-benzene and 2 g K2CO3 were stirred in 50 ml DMF at 100° C. for 2 h. After cooling the mixture was poured into water and was extracted 2× with ethyl acetate. The organic layer was tracted 3× with water, dried and evaporated. The resulting oil was purified by flash chromatography with dichloromethane, the purified fractions were dissolved in acetone after evaporation of the solvent, and the solution was acidified with etherical HCl. After evaporation of the solvent the resulting crystals were filtered with diisopropyl ether. The crystals were dissolved in acetone again and evaporated to a volume of 2 ml. The product crystallized as hydrochloride to give 0.5 g product (mp. 208–209° C.).
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][S:26]([CH2:29][C:30]([OH:32])=O)(=[O:28])=[O:27])=[CH:16][CH:15]=1.Br.[NH2:34][CH2:35][CH2:36][C:37]1[C:45]2[S:44][C:43](=[O:46])[NH:42][C:41]=2[C:40]([OH:47])=[CH:39][CH:38]=1.Cl>CN(C=O)C.CCOCC.C(N(CC)CC)C>[OH:47][C:40]1[C:41]2[NH:42][C:43](=[O:46])[S:44][C:45]=2[C:37]([CH2:36][CH2:35][NH:34][C:30](=[O:32])[CH2:29][S:26]([CH2:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)(=[O:27])=[O:28])=[CH:38][CH:39]=1
Reactant: O=C(O)CS(=O)(=O)CCCOCCc1ccc(F)cc1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Agent: Br
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(CS(=O)(=O)CCCOCCc1ccc(F)cc1)NCCc1ccc(O)c2[nH]c(=O)sc12
Reaction time: 0.67 h

Procedure:
Carbonyl diimidazole (1.94 g) was added to a stirred solution of the acid from step c) (3.64 g) in DMF (15 ml). Stirring was continued for 40 min at room temperature. To this solution was added 7-[2-aminoethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-one hydrobromide (3.48 g) followed by triethylamine (1.7 ml). The whole was left overnight. The reaction mixture was then added slowly to a rapidly stirred mixture of 10% aqueous hydrochloric acid and ether (100 ml each). A pale yellow solid gradually settled out and was filtered off, washed with pentane and dried in vacuo. This provided the subtitled compound as a buff coloured material which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][CH:14]2[CH2:16][CH2:15]2)[N:8]=[C:7]([NH:17][CH:18]([CH3:20])[CH3:19])[N:6]=1>CO>[CH:14]1([NH:13][C:9]2[N:8]=[C:7]([NH:17][CH:18]([CH3:20])[CH3:19])[N:6]=[C:5]([O:2][CH3:1])[C:10]=2[C:11]#[N:12])[CH2:16][CH2:15]1
Reactant: CC(C)Nc1nc(Cl)c(C#N)c(NC2CC2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(NC(C)C)nc(NC2CC2)c1C#N
Yield: 89.1 %

Procedure:
To a stirred solution of 0.9 gram of sodium methoxide in 100 ml of methanol was added, in one portion, 4.0 grams of 4-chloro-6-cyclopropylamino-2-isopropylamino-5-pyrimidinecarbonitrile. The reaction mixture was then heated under reflux for 3 hours. The methanol was removed by evaporation under reduced pressure to give a residue. The residue was washed with water, and the solid was collected by filtration to yield 3.5 grams of 6-cyclopropylamino-2-isopropylamino-4-methoxy-5-pyrimidinecarbonitrile; mp, 142°-147°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH:6]=[C:7]([O:12]C)[C:8]=1[CH:9]([CH3:11])[CH3:10].Cl.N1C=CC=CC=1.CCOCC>C(OCC)(=O)C>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:15]=[CH:14][C:5]1[CH:6]=[C:7]([OH:12])[C:8]([CH:9]([CH3:10])[CH3:11])=[C:3]([OH:2])[CH:4]=1
Reactant: COc1cc(C=Cc2ccccc2F)cc(OC)c1C(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)c1c(O)cc(C=Cc2ccccc2F)cc1O
Temperature: 200 °C
Yield: 95.9 %

Procedure:
A mixture of 2-(3,5-dimethoxy-4-i-propylphenyl)-1-(2-fluorophenyl)ethene (27B) (0.308 g, 1.03 mmol) and pyridine hydrochloride (0.72 g, 6.2 mmol) was heated at 200° C. for 4 h under a stream of argon. The reaction mixture was cooled to room temperature. 2NHCl (10 mL) and ether (15 mL) was added. The organic layer was separated and the aqueous layer was extracted with ether (3×10 mL). The extract was dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using 15% ethyl acetate in hexane afforded pure 5-[2-(2-fluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol (37B) (0.269 g, 95% yield) as an off-white solid. 1HNMR (CDCl3, ppm): δ 1.41 (d, J=7.2 Hz, 6H), 3.51 (qint., J=7.2 Hz, 1H), 5.01 (b, 2H), 6.56 (s, 2H), 6.98 (d, J=17.6 Hz, 1H), 7.0-7.3 (m, 4H), 7.60 (ddd, J=7.5, 7.5, 2.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:8]O)[N:5]=[N:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:52]=[N+]=[N-].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.[C].[Pd].C1C=CC=CC=1>[CH3:1][C:2]1[N:6]([CH:7]([CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:8][NH2:52])[N:5]=[N:4][N:3]=1
Reactant: [N-]=[N+]=N
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)n1nnnc1C
Agent: [Pd]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)n1nnnc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred solution of 1.02 g (2.25 mM) of 2-(5-methyl-1H-tetrazol-1-yl)-3-octadecylcarbamoyloxypropanol V i2, 885 mg (3.38 mM) of triphenylphosphine, and 1.9 ml (3.38 mM) of 1.8 mM benzene solution of hydrazoic acid in 50 ml of tetrahydrofurane at -50° C. is added 0.53 ml (3.38 mM) of diethyl azodicarboxylate dropwise and the mixture is raised to room temperature during 2 hr. Subsequently, 150 mg of 10% palladium carbon is added to the mixture which is stirred under hydrogen gas for 30 minutes. After 10% palladium carbon filtered off, the solvent is evaporated. The residue obtained is purified by column silica gel chromatography using ethyl acetate-chloroform/methanol (9/1) mixture as an eluent and 0.82 g (81% yield) of the title compound is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]=[C:4]([CH2:7][OH:8])[CH2:5][OH:6].[C:9]([Si:13]([CH3:16])([CH3:15])Cl)([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+]>O1CCCC1>[Si:13]([O:6][CH2:5][C:4](=[CH2:3])[CH2:7][OH:8])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:16])[CH3:15]
Reactant: C=C(CO)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(CO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, to a suspension of sodium hydride (490 mg, 60 wt. % oil dispersion) in tetrahydrofuran (10 ml) were sequentially added 2-methylene-1,3-propanediol (1 ml) and tert-butyldimethylchlorosilane (2.22 g) at 0° C., and then the mixture was stirred at room temperature for 1 hour. To this reaction mixture was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to give the titled compound (1.62 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([NH2:15])=[O:14].C([O:20]O)(C)(C)C.[Se](=O)=O>ClCCl.CC(C)(CC(C)C)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([OH:20])/[C:6]/2=[CH:12]\[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)/C=C1\CCc2c(F)cc(F)cc21
Reactant: CC(C)(C)OO
Agent: O=[Se]=O
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Product: NC(=O)/C=C1/c2cc(F)cc(F)c2CC1O
Temperature: 25 °C

Procedure:
A suspension of (E)-2-(4,6-difluoro-1-indanylidene)acetamide (10.0 g, 0.05 mol, prepared as in Example 5 g in dichloromethane (250 mL) was added portionwise over a 10 min. period to a mixture of 70% aqueous t-butylhydroperoxide (19.8 mL, 0.15 mol, Aldrich) and selenium dioxide (3.7 g, 0.03 mol, Aldrich) in dichloromethane (500 mL) at ambient temperature. After 18h, additional t-butylhydroperoxide (10 mL of a 5.0M solution in 2,2,4-trimethylpentane, 0.05 mol, Aldrich) and selenium dioxide (1.8 g, 0.02 mol) were added and the mixture was stirred at ambient temperature. After 18h, additional t-butylhydroperoxide (10 mL of 70% aqueous solution, 0.08 mol) and selenium dioxide (3.7 g, 0.05 mol) were added and the mixture was stirred at ambient temperature for 8 days. The resulting solid was filtered off and washed with dichloromethane to give 5.85 g of crude (Z)-2-(4,6-difluoro-2-hydroxy-1-indanylidene)acetamide. After 7 days at ambient temperature a second crop of crude (Z)-2-(4,6-difluoro-2-hydroxy-1-indanylidene)acetamide was obtained from the filtrate. Column chromatography on silica gel using ethyl acetate as the eluent followed by a second column chromatography on silica gel using ethyl acetate:hexanes (3:2) as eluent and trituration of the resulting solid with pentane gave 2.38 g of (Z)-2-(4,6-difluoro-2-hydroxy-1-indanylidene)acetamide as a pink solid: m.p. 235-237° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23](=[O:25])[CH3:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(CC)CC>ClCCl>[C:23]([N:22]([S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:14][CH:15]=1)(=[O:20])=[O:21])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:25])[CH3:24]
Reactant: CC(=O)NS(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2C)cc1
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C(C)=O)S(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2C)cc1
Reaction time: 168 h
Yield: 31.9 %

Procedure:
To a stirred solution of N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide (Example 39) (0.612 g, 1.72 mmol) in dichloromethane was treated with ethyl bromoacetate (0.20 mL, 0.29 g, 1.72 mmol) and Et3N (0.26 mL, 0.19 g, 1.89 mmol). After 7 days the reaction was still incomplete by TLC. Additional ethyl bromoacetate (0.20 mL, 0.29 g, 1.72 mmol) and Et3N (0.26 mL, 0.19 g, 1.89 mmol) were added and the reaction was stirred for an additional 6 days. The reaction was diluted with dichloromethane and washed with KHSO4 solution, NaHCO3 solution, and brine, dried over MgSO4, filtered and concentrated in vacuo yielding a clear oil. This oil was purified by flash chromatography yielding N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine, ethyl ester (0.243 g, 32%) as a clear colorless oil of suitable purity for use in the next step: 1H NMR (CDCl3/300 MHz) 8.03 (d, 2H, J=8.7 Hz), 7.47-7.27 (m, 9H), 4.61 (s, 2H), 4.21 (q, 2H, J=7.1 Hz), 2.51 (s, 3H), 2.33 (s, 3H), 1.28 (t, 3H, J=7.1 Hz). FABLRMS m/z 443 (M+H). FABHRMS m/z 442.1201 (M+, C22H22N2O6S Calc'd 442.1199).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([CH3:14])=[C:4]([CH3:15])[N:3]=1.[NH3:16].C(O)C>>[NH2:16][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([CH3:14])=[C:4]([CH3:15])[N:3]=1
Reactant: CCCCCNc1nc(Cl)nc(C)c1C
Reactant: N
Solvent: CCO
Product: CCCCCNc1nc(N)nc(C)c1C
Reaction time: 10 h
Yield: 3.5 %

Procedure:
A mixture of N-(2-chloro-5,6-dimethylpyrimidine-4-yl)-N-pentylamine (131 mg, 0.575 mmol) and 5M ammonia-ethanol (40 ml) was kept at 170° C. for 10 hours. The reaction mixture was concentrated in vacuo, purified by preparative TLC (20% MeOH/CHCl3) to give the object compound (4.2 mg, 3.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[CH2:4][NH:5][CH:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]>CC(O)=O>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:6]([NH:5][CH2:4][C:3]2[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:2]=2[Cl:1])[C:7]([O:9][CH3:10])=[O:8])=[CH:13][CH:14]=1
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NCc1c(Cl)cccc1Cl
Solvent: CC(=O)O
Product: COC(=O)C(Cc1ccc(N)cc1)NCc1c(Cl)cccc1Cl
Reaction time: 0.08 h

Procedure:
To methyl 2-[(2,6-dichlorobenzyl)amino]-3-(4-nitrophenyl)propanoate 7a (8.2 g) solubilized in CH3COOH in an ultrasonic bath is added PtO2 hydrate (typical Pt content 79-84%) (0.02 g). A H2 pressure of 15 psi is then applied at RT and consumed after 5 min. An other H2 pressure of 10 psis is then applied at RT and consumed after 5-10 min. A H2 pressure of 10 psis is again applied at RT and a stabilization is observed after 5 min. The catalyst is filtered over celite under nitrogen and washed with CH3COOH. The solvent is evaporated. AcOEt (200 ml) is added to the residue and this organic phase is washed three times with saturated NaHCO3 (200 ml), dried over MgSO4 and evaporated. The residue is purified by silica gel chromatography using CH2Cl2/CH3OH/NH4OH cc (99.75/0.25/0.025) as eluent.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:19][O:20][CH3:21])=[C:8]([C:22](OCC)=[O:23])[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:19][O:20][CH3:21])=[C:8]([CH2:22][OH:23])[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cnc(C(=O)OCC)c1-c1ccc(OC)cc1OCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCn1cnc(CO)c1-c1ccc(OC)cc1OCOC
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of ethyl 1-n-butyl-5-(2-methoxymethoxy-4-methoxyphenyl)-1H-imidazole-4-carboxylate (0.06 g, 0.17 mmol) in THF (5 mL) was added LAH (0.20 mL) at room temperature. The mixture was stirred for 2 h. After an aqueous work up, extracting with ethyl acetate (3×20 mL), the combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ethyl acetate/hexane) of the residue afforded the title compound as an oil (0.05 g, 96%). 1H NMR (400 MHz, CDCl3)δ 7.53 (s, 1H), 7.19 (d, 1H), 6.85 (d, 1H), 6.65 (dd, 1H), 5.05 (d, 2H), 4.41 (dd, 2H), 3.85 (s, 3H) 3.80 (t, 2H), 3.45 (s, 3H) 3.23 (b, 1H), 1.55 (quintet, 2H), 1.25 (quintet, 2H), 0.83 (t, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:13]=[C:14]([S:22][CH3:23])[NH:15][C:16](=[O:21])[C:17]=2[C:18]([NH2:20])=[O:19])[CH:8]=[CH:9][CH:10]=1)=[O:4].ClCCl.CO.[OH:29]OS([O-])=O.[K+]>O.C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:13]=[C:14]([S:22]([CH3:23])=[O:29])[NH:15][C:16](=[O:21])[C:17]=2[C:18]([NH2:20])=[O:19])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)c1cccc(Nc2nc(SC)[nH]c(=O)c2C(N)=O)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1cccc(Nc2nc(S(C)=O)[nH]c(=O)c2C(N)=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 306) (500 mg), dichloromethane (40 mL) and methanol (40 mL), a mixture of Oxone® (922 mg) and water (10 mL) was added and stirred at room temperature for 18 hours. To the reaction liquid, chloroform and water were added, and the precipitated solid was collected by filtration and washed with water to give 4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfinyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (234 mg) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[H-].[Na+].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](Br)([F:39])[F:38])=[CH:33][CH:32]=1>CN(C=O)C>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:38])[O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:33][CH:32]=1
Reactant: FC(F)(Br)c1ccc(Br)cc1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OC(F)(F)c3ccc(Br)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a cooled (0° C.) solution of the title compound from Example 1 Step B (515 mg, 1.37 mmol) in DMF (5 mL) was added NaH (35.0 mg, 1.46 mmol). The reaction vessel was then allowed to warm to ambient temperature for 25 min, followed by addition of 1-bromo-4-[bromo(difluoro)methyl]benzene (445 mg, 1.56 mmol, synthesized according to U.S. Pat. No. 6,939,990) and heated at 60° C. After 24 h, the reaction mixture was cooled, quenched by addition of 2 N HCl and extracted with hexane-EtOAc. Purification by silica gel flash chromatography (5% EtOAc in hexanes to 10% EtOAc in hexanes) yielded the title compound: LCMS m/z 564.1 [M−F]+; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.88-7.82 (m, 2H), 7.78 (d, J=7.1 Hz, 1H), 7.57 (dd, J=7.8, 0.7 Hz, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.46-7.41 (m, 2H), 7.39-7.32 (m, 3H), 4.37 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H).