Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([OH:14])=[C:9]([F:15])[CH:8]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2[S:31][C:32]([CH3:38])=[C:33]([CH2:35][CH2:36]O)[N:34]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.COC(=O)CC(=O)C(Br)C.COC1C=C(C=C(OC)C=1)C(N)=S.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]([F:15])[C:10]([O:14][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:24]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[S:31][C:32]=2[CH3:38])=[C:11]([F:13])[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cc(F)c(O)c(F)c1)OCC
Reactant: COc1cc(OC)cc(-c2nc(CCO)c(C)s2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Agent: COc1cc(OC)cc(C(N)=S)c1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc(F)c(OCCc2nc(-c3cc(OC)cc(OC)c3)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-3-(3,5-difluoro-4-hydroxy-phenyl)-2-ethoxy-propionic acid ethyl ester was reacted with 2-[2-(3,5-dimethoxy-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 3,5-dimethoxy-thiobenzamide [PCT Int. Appl. (1992), WO 92/09586 A1] in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(3,5-dimethoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-difluoro-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(3,5-dimethoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-difluoro-phenyl)-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].NC1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2C=1.O[CH:48](S([O-])(=O)=O)[CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.[Na+].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH:26][CH2:48][CH2:49][N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=S(=O)([O-])C(O)CN1CCOCC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(-c2nc3cc(NCCN4CCOCC4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 24 h
Yield: 12.5 %

Procedure:
To a slurry of 4 Å molecular sieves (0.9 g), 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.187 g, 0.475 mmol), sodium 1-hydroxy-2-morpholin-4-yl-ethanesulfonate (0.122 g, 0.523 mmol) and THF (2.5 mL) was added triethylamine (0.300 mL, 2.15 mmol). The slurry was stirred at 23° C. for 24 h, and sodium triacetoxyborohydride (0.282 g, 1.33 mmol) was added. The reaction mixture was stirred for an additional 24 h. Additional sodium 1-hydroxy-2-morpholin-4-yl-ethanesulfonate (62.0 mg, 0.270 mmol) was added and the reaction was allowed to continue for another 24 h at 23° C. The reaction mixture was diluted with EtOAc, filtered, and washed with saturated aqueous NaHCO3. The aqueous layer was further extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (EtOAc/hexanes) to yield the titled compound (30 mg, 12% crude yield). This compound was used without further purification in subsequent reactions. MS (ESI/CI): mass calcd. for C23H31ClN6O5, 506.2; m/z found, 507.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([S:9][CH3:10])=[CH:7][C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([I:16])[CH:4]=1.N1C=CN=C1.[Si:22](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CN(C=O)C>[Si:22]([O:1][CH2:2][C:3]1[C:8]([S:9][CH3:10])=[CH:7][C:6]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])=[C:5]([I:16])[CH:4]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CSc1cc(NS(C)(=O)=O)c(I)cc1CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1cc(NS(C)(=O)=O)c(I)cc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(4-(hydroxymethyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide (6.4 g, 17.2 mmol) and imidazole (1.76 g, 25.8 mmol) in CH2Cl2 (100 mL) and DMF (50 mL) at 0° C. was added tert-butyldiphenylsilyl chloride (5.8 mL, 22.4 mmol). The mixture was allowed to stir at rt overnight. The mixture was diluted with CH2Cl2 (100 mL), washed with 1N HCl solution, sat. aq. NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford N-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide. It was used for next step without further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[CH2:12][C:13]([CH3:17])=[CH:14][C:15]#[N:16]>C(O)C.CN(C)C=O.[Pd]>[O:1]=[S:2]1(=[O:18])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([CH3:17])[CH2:14][C:15]#[N:16]
Reactant: CC(=CC#N)CN1C(=O)c2ccccc2S1(=O)=O
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(CC#N)CN1C(=O)c2ccccc2S1(=O)=O
Reaction time: 12 h
Yield: 47.8 %

Procedure:
10.0 g (38 millimoles) of 3-(2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-1-cyano-2-methylprop-1-ene (Example 1) were dissolved in 200 ml of ethanol and 100 ml of dimethylformamide, 1 g of palladium on active carbon (10%) was added and hydrogenation was carried out for 12 hours at room temperature and under atmospheric pressure. The mixture was filtered, the filtrate was evaporated down under reduced pressure and the resulting greenish oil was purified by column chromatography (silica gel, mobile phase 85:15 mixture of toluene and methanol) to give 4.8 g (48%) of 3-(2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-1-cyano-2-methylpropane in the form of an oil which slowly crystallized through. Mp 83°-84° C.
Reaction SMILES: O=O.C(OCC)(=O)C.[CH:9]1([CH2:14][C:15]2[C:19](=[O:20])[O:18][CH2:17][C:16]=2[CH2:21][N:22]2[C:26](=[O:27])[C:25]([CH3:29])([CH3:28])[N:24]([CH3:30])[C:23]2=[O:31])[CH2:13][CH2:12][CH2:11][CH2:10]1>C1COCC1>[CH:9]1([CH2:14][C@H:15]2[C:19](=[O:20])[O:18][CH2:17][C@H:16]2[CH2:21][N:22]2[C:26](=[O:27])[C:25]([CH3:29])([CH3:28])[N:24]([CH3:30])[C:23]2=[O:31])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN1C(=O)N(CC2=C(CC3CCCC3)C(=O)OC2)C(=O)C1(C)C
Agent: O=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1C(=O)N(C[C@@H]2COC(=O)[C@@H]2CC2CCCC2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
In the glove box (O2 content<=2 ppm) a 10 ml measuring flask was charged with 68.3 mg [Rh((R)-3,5-iPr-MeOBIPHEP)(COD)]SbF6 (0.050 mmol) and filled to the graduation mark with 10 ml ethyl acetate. The suspension was stirred with a magnetic stirring bar for 15 min at r.t. A clear orange solution formed. The Rh-catalyst was prepared through reaction of (R)-3,5-iPr-MeOBIPHEP and [Rh(COD)2]SbF6 in THF at room temperature for 2 h in a known manner (J. Am. Chem. Soc., 93, 3089-91 (1971), J. Chem. Soc. Chem. Comm., 1990, 869-71). In the glove box a 185 ml stirred stainless steel autoclave was charged with 16.02 g 3-(4-cyclopentylmethyl-5-oxo-2,5-dihydro-furan-3ylmethyl)-1,5,5-trimethyl-imidazolidine 2,4-dione, 20 ml ethyl acetate and the above catalyst solution. The measuring flask was rinsed with a total of 11.5 ml ethyl acetate. The autoclave was then sealed and connected to a hydrogenation line. The hydrogenation was carried out while stirring at 80° C. at a total pressure of 100 bar. After 71 h the brown hydrogenation mixture was rotary evaporated and dried at 50° C./10 mbar for 2 h, affording 16.80 g of crude (3R,4R)-3-(4-cyclopentylmethyl-5-oxo-tetrahydrofuran-3ylmethyl)-1,5,5-trimethyl-imidazolidine-2,4-dione as a brown oil which solidified slowly on standing at r.t. ee: 98.2% (3R,4R). GC:98.4 area %. This crude material was employed directly in the next step.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].Br[CH2:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>O.C(#N)C>[Na+:5].[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:12]2[CH:23]=[CH:24][C:9]([CH2:8][S:1]([O-:4])(=[O:3])=[O:2])=[CH:10][CH:11]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CBr)cc2)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)[O-])cc2)cc1
Yield: 124.2 %

Procedure:
A solution of sodium sulfite (0.73 g, 7 mmol) dissolved in water (10 mL) was added to a solution of 4-(4-bromomethylbenzyl)-nitrobenzene (1.41 g, 5.6 mmol) in acetonitrile (10 mL). The mixture was stirred and heated under reflux for 2 hours. Solvents were evaporated and dried to give the 4-(4-nitrobenzyl)-phenylmethanesulfonic acid sodium salt as a white powder (2.29 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:9])=[C:6]([OH:8])[CH:7]=1.CC(C)([O-])C.[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na]>CN(C)C=O>[CH2:16]([O:8][C:6]1[CH:7]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[Br:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(Br)c(O)c1
Reactant: ClCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 106.9 %

Procedure:
To a solution of 5-amino-2-bromo-phenol (35.2 g, 0.187 mol) in N,N-dimethylformamide (350 mL) was added potassium tert-butoxide (22.9 g, 0.204 mol). After 15 min, benzyl chloride (25.5 mL, 0.222 mol) was added within 2 min. The reaction was stirred during 4 h and then poured onto an aqueous solution of sodium hydrogenocarbonate and extracted with ethyl acetate. The combined organic phases were washed with brine and water then dried over sodium sulfate, filtered, and evaporated under vacuum. 55.6 g of the title compound were obtained. Black solid, ISP-MS: m/e=279.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[CH3:19])=[CH:5][CH:4]=1.[I:20]I.CO>[O-]S([O-])(=O)=O.[Ag+].[Ag+].C(OCC)(=O)C>[I:20][C:8]1[CH:7]=[C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[CH3:19])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)c(C)c1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OC)c(I)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 10000-mL 4-necked round-bottom flask was placed methyl 4-(4-methoxyphenyl)-3-methylbenzoate (470 g, 1.83 mol, 1.00 equiv), Ag2SO4 (572.8 g, 1.84 mol, 1.00 equiv), iodine (466.3 g, 1.84 mol, 1.00 equiv), methanol (4000 mL), ethyl acetate (1000 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 3000/1500 mL of EtOAc/brine. The solid was filtered out. The filtrate was extracted with 2×1000 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 630 g (crude) of methyl 4-(3-iodo-4-methoxyphenyl)-3-methylbenzoate as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH2:9][C:10]([C:19](OCC)=[O:20])([C:14](OCC)=[O:15])[O:11][CH2:12][CH:13]=1.C(OCC)(=O)C.C(O)(C)C>O1CCCC1.O>[CH3:7][C:8]1[CH2:9][C:10]([CH2:19][OH:20])([CH2:14][OH:15])[O:11][CH2:12][CH:13]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CC(C)=CCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CC1=CCOC(CO)(CO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 200 ml tetrahydrofuran at 0° C. was added 4.0 g (0.015 mol) lithium aluminum hydride portionwise. A solution of 12.5 g (0.052 mol) of (±)-diethyl 3,6-dihydro-4-methyl-2H-pyran-2,2-dicarboxylate in 60 ml tetrahydrofuran was added dropwise over 30 minutes. The reaction mixture was warmed to ambient temperature. After 2 hours, the reaction was cooled to 0° C. and successively treated with 30 ml ethyl acetate, 30 ml isopropanol, 30 ml water dropwise keeping the temperature under 10° C. The reaction mixture was filtered through celite with acetone, dried over MgSO4, filtered, and concentrated to an oil. Flash chromatography in 1:1 hexanes:ethyl acetate followed by ethyl acetate alone yielded 5.5 g oil.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[CH3:13].C(O)(=O)C>C(O)C.O.[Fe]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:14])=[C:5]([CH3:13])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1OC(F)F
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N)ccc1OC(F)F
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 1-(difluoromethoxy)-2-methyl-4-nitrobenzene (10 g, 48.28 mmol) in ethanol (150 mL) and water (150 mL) was added iron powder (12 g, 214.29 mmol). Acetic acid (cat. amount) was added dropwise with stirring and the reaction mixture was heated at reflux for 20 minutes. The mixture was cooled to room temperature and solids were removed by filtration. Volatiles were removed in vacuo and the aqueous solution was extracted with EtOAc (3×150 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide 8 g (95%) of 4-amino-1-difluoromethoxy-2-methyl-benzene.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+].Cl>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(CCOCCc1ccc2sccc2c1)N1CC(O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1CN(CCCOCCc2ccc3sccc3c2)C1
Temperature: 10 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
In 20 mL of tetrahydrofuran was dissolved 5.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-1-azetidinyl)-1-propanone, and 1.09 g of sodium borohydride was added thereto, after which 4.25 mL of a boron trifluoride-tetrahydrofuran complex was added dropwise thereto at 10° C. and the resulting mixture was stirred at the same temperature for 1 hour and then at 40° C. for 3 hours. After the reaction mixture was cooled to 10° C., 30 mL of 6 mol/L hydrochloric acid was added dropwise thereto and the resulting mixture was refluxed for 1 hour. After cooling, the solvent was concentrated under reduced pressure, and ethyl acetate was added. The pH was adjusted to 9.4 with a 20% aqueous sodium hydroxide solution and then the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; chloroform:methanol=20:1 to 10:1) and crystallized from toluene-diisopropyl ether (1:3, 14 mL) to obtain 2.31 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][O:8][C:7]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=[C:3]([O:13][CH3:14])[C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:24]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1I
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(OC)c1-c1ccccc1C
Temperature: 90 °C
Reaction time: 32 h

Procedure:
2-Iodo-1,3-dimethoxy-4-nitrobenzene (0.5 g, 1.62 mmol) was dissolved in dioxane/acetonitrile/water (10 ml/2 ml/2 ml), and 2-tolylboronic acid was added. Pd(dppf)Cl2 (0.11 mg, 0.16 mmol) and K2CO3 (0.33 g, 2.43 mmol) were added to this, and the mixture was stirred at 90° C. for 32 h. After concentration, the residue was chromatographed on silica gel using petroleum ether/ethyl acetate. This gave 2,6-dimethoxy-2′-methyl-3-nitrobiphenyl (0.2 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl.[OH-].[Na+]>C1COCC1.C(OCC)C>[F:13][C:2]([F:1])([F:14])[S:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: N#CCc1ccc(SC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
4-(Trifluoromethylthio)phenylacetonitrile (183.4 mg, 0.844 mmol), 0.3 molar in THF, was heated to reflux and then treated with Borane-methyl sulfide complex (88.09 μL, 0.929 mmol). After 1 hour of refluxing, the reaction mixture was cooled to ambient temperature and then treated dropwise with 5.0 molar hydrochloric acid (607.9 μL, 3.040 mmol). The reaction mixture was then heated to reflux for an additional 30 minutes. After 30 minutes the reaction mixture was cooled to 0° C. and then treated with 1.0 molar sodium hydroxide (4644 μL, 4.644 mmol). The reaction mixture was diluted with diethyl ether and partitioned with deionized water. The organic layer was dried with potassium carbonate 98% powder, filtered, concentrated, and dried for one minute under high vacuum to provide the title compound (170.7 mg, 0.772 mmol, 91.2% yield) as a light yellow oil.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:17]1[O:18][C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1)[CH2:13][CH2:14][CH2:15][OH:16])=O)C1C=CC=CC=1>CO.[Pd]>[OH:16][CH2:15][CH2:14][CH2:13][C@@H:12]([NH2:11])[C:17]1[O:18][C:19]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1
Reactant: O=C(N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 5 h
Yield: 69.4 %

Procedure:
A mixture of (1R)-N-benzyloxycarbonyl-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (12 g) and 10% Pd/C (2 g) in methanol (20 ml) was stirred under H2 for 5 hours. The catalyst was filtered off and filtrate was evaporated. The residue was recrystallized with ether to give (1R)-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (5.8 g). MS (m/z): 309 (M+ +1) NMR (CDCl3, δ): 1.7-2.0 (3H, m), 2.1-2.4 (1H, m), 2.6-2.8 (3H, m), 3.5-3.8 (2H, m), 4.0-4.2 (1H, m), 7.3-7.8 (10H, m)
Reaction SMILES: O1C2C=CC(C3C=C(N)C(N)=CC=3)=CC=2OC1.[CH2:18]1[O:26][C:25]2[C:24]([N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=[C:28]3[C:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[NH:38][N:37]=3)=[CH:23][CH:22]=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:26][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=[C:28]3[C:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[NH:38][N:37]=3)=[CH:25][C:20]=2[O:19]1
Reactant: c1cc2c(c(-n3c(-c4n[nH]c5ccccc45)nc4ccccc43)c1)OCO2
Agent: Nc1ccc(-c2ccc3c(c2)OCO3)cc1N
Product: c1ccc2c(c1)nc(-c1n[nH]c3ccccc13)n2-c1ccc2c(c1)OCO2

Procedure:
By proceeding in a manner similar to Example 235(i) above but using 4-benzo[1,3]dioxol-5-ylbenzene-1,2-diamine [Reference Example 30(k)] there was prepared 3-(5-(5,6-methylenedioxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole as a white solid. MS: 355.2 (M+H)+. HPLC (METHOD B1): RT=22.04 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:23]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:21][C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=4)[N:23]=3)[C:9]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1NCCC1c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(-c2noc(CCl)n2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C(c2ccc(F)cc2)CCN1Cc1nc(-c2ccc(C(F)(F)F)cc2)no1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To 3-(4-fluorophenyl)pyrrolidin-2-one (0.106 g, 0.592 mmol; Example 189B) as suspension in tetrahydrofuran (0.5 mL) was added potassium t-butoxide (1.0 Min tetrahydrofuran) (0.651 mL, 0.651 mmol) dropwise at room temperature. After stirring for 15 minutes, 5-(chloromethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (0.171 g, 0.651 mmol) was added dropwise as a solution in tetrahydrofuran (0.5 mL). The reaction was heated to 50° C. for 1 hour. The reaction was concentrated, loaded onto silica gel SF15-12 g (Analogix®) and the product eluted using a gradient of 5% to 50% ethyl acetate/hexanes over 30 minutes (Flow rate=30 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J=8.1, 2H), 7.76 (d, J=8.2, 2H), 7.39-7.23 (m, 2H), 7.17-6.97 (m, 2H), 4.96 (d, J=17.0, 1H), 4.84 (d, J=16.5, 1H), 3.78 (t, J=8.9, 1H), 3.74-3.59 (m, 2H), 2.77-2.57 (m, 1H), 2.25 (ddt, J=8.0, 12.9, 20.7, 1H); MS (ESI+) m/z 406.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23](Cl)=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:25].[Na+].[Cl-].[Na+]>C(OC)(C)(C)C.O.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23](=[O:25])[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3nc2Cl)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3[nH]c2=O)CC1

Procedure:
4-(3-Chloro-quinoxalin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (10.0 g, 28.7 mmol; from Step 1) was added to a mixture of sodium hydroxide (40 g), water (40 g) and DMSO (40 g) at 100° C. After being stirred for 1 h at this temperature, water (200 g) and methyl tert-butyl ether (1000 g) and sodium chloride (50 g) were added. The crystals formed from the organic layer were collected by filtration and dried. This furnished 4.0 g (42%) of the title compound as white crystals. 1H NMR analysis supports the stated structure.