Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[O:4][C:3]=1[C@H:13]([OH:16])[CH2:14][OH:15].N1C=CN=C1.[C:22]([Si:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)Cl)([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5](=[O:12])[O:4][C:3]=1[C@H:13]([OH:16])[CH2:14][O:15][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1oc([C@H](O)CO)c(Br)c2ccccc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H](O)c1oc(=O)c2ccccc2c1Br)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 63.5 %

Procedure:
A solution of 4-bromo-3-[(1R)-1,2-dihydroxyethyl]-1H-2-benzopyran-1-one (145 mg, 0.509 mmol) and imidazole (51.9 mg, 0.763 mmol) in N,N-Dimethylformamide (DMF) (2.4 mL) was treated with tert-butyldiphenylchlorosilane (159 μl, 0.610 mmol). After 20 min, the reaction mixture was poured into water and extracted with EtOAc. The organic phase was dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate-hexanes 0-50%) to afford the title compound (169 mg, 0.323 mmol, 64% yield) as a white foam: Rt=1.24 min, ES+ MS: 546 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:4][CH:3]=1.[OH:25]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[O:25])=[CH:4][CH:3]=1
Reactant: O=c1ccc2cc(OCCCCSc3ccc(Cl)cc3)ccc2[nH]1
Reactant: OO
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc(Cl)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-chlorophenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:26])[CH:3]=1.[O:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[CH2:30][CH2:31][O:27][C:28]5=[O:32])=[CH:3][C:4]=4[CH3:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Product: Cc1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 88.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (347 mg) described in Preparation Example 130 and oxazolidin-2-one (109 mg), the title compound (313 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=2)=[CH:13][C:12]=1[CH3:18])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)ccc1NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A suspension of benzyl(4-bromo-2-methylphenyl)carbamate (I51) (1.00 g, 3.12 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (37) (1.16 g, 3.74 mmol), PdCl2(dppf)-DCM complex (310 mg, 0.374 mmol) and potassium carbonate (1.29 g, 9.36 mmol) in DMF (30 mL) was stirred under nitrogen at 80° C. for 16 hours. The volatiles were evaporated under reduced pressure and the residue adsorbed onto silica gel. Chromatography on silica gel (0-30% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I52) (949 mg, 72%) as a yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.83-7.70 (m, 1H), 7.41-7.34 (m, 5H), 7.21 (dd, J=8.5, 1.9 Hz, 1H), 7.16 (d, J=1.8 Hz, 1H), 6.56 (s, 1H), 5.97 (s, 1H), 5.20 (s, 2H), 4.05 (d, J=2.9 Hz, 2H), 3.61 (t, J=5.7 Hz, 2H), 2.48 (d, J=1.5 Hz, 2H), 2.23 (s, 3H), 1.50 (d, J=2.6 Hz, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:42]1[C:47]([O:48][CH3:49])=[C:46]([O:50][CH3:51])[CH:45]=[CH:44][C:43]=1[C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[C:57](=[O:61])[O:56][CH2:55]2>O1CCCC1.C(OCC)(=O)C>[CH3:49][O:48][C:47]1[C:46]([O:50][CH3:51])=[CH:45][CH:44]=[C:43]([C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[C:57](=[O:61])[O:56][CH2:55]3)[C:42]=1[O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(C)CO
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC
Temperature: 70 °C
Yield: 28.6 %

Procedure:
To a stirring solution of methyl 3-hydroxy-2,2-dimethylpropanoate (2.76 g, 20.94 mmol, in portions) in tetrahydrofuran (25 mL) was added diethylazodicarboxylate (2.43 g, 13.96 mmol), triphenylphosphine (3.59 g, 13.96 mmol) and 5-(2-hydroxy-3,4-dimethoxyphenyl)isobenzofuran-1(3H)-one (2 g, 6.98 mmol) and the resultant reaction mixture was heated to 70° C. for 6 h. The reaction mixture was diluted with ethyl acetate layer, washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by flash, column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford Methyl 3-(2,3-dimethoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)-2,2-dimethylpropanoate as a solid (800 mg, 28.6%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([NH:48][NH2:49])=[O:47])=[CH:44][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH:48]([C:46]([C:45]1[CH:50]=[CH:51][C:42]([NH:41][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:43][CH:44]=1)=[O:47])[NH2:49]
Reactant: NNC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)NN)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 67.3 %

Procedure:
To a solution of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (52.7 mg, 0.113 mmol) in dichloromethane (3 mL) were added DIPEA (71.2 mg, 0.55 mmol), 4-aminobenzhydrazide (33.1 mg, 0.22 mmol, Aldrich) and HATU (72.3 mg, 0.19 mmol). (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 minutes the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by HPLC with acetonitrile and water (with TFA 0.1% VAT) to give chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydrazinocarbonyl-phenyl)-amide (45.7 mg., 67.5%) as a white solid. HRMS (ES+) m/z Calcd C30H29Cl2F2N5O2+H [(M+H): 600.1739. Found: 600.1737.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([C:15]([F:18])([F:17])[F:16])[C:8]=1[F:19].[C:20](=[O:22])=[O:21].C(O)(C(F)(F)F)=O>CCOCC>[F:19][C:8]1[C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=1[C:20]([OH:22])=[O:21]
Reactant: Fc1cc(Br)c(F)c(C(F)(F)F)c1F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)c1cc(F)c(F)c(C(F)(F)F)c1F
Temperature: -78 °C
Yield: 69 %

Procedure:
A solution of n-butyl lithium (2.6M in hexanes, 9.6 ml, 25 mmol) was added dropwise through an addition funnel over 15 minutes to a solution of 1-bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene (7.00 g, 25 mmol) in ether (100 ml) stirred under N2 at -78° C. After 5 minutes the mixture was rapidly blown by catheter onto a suspension of dry ice (100 g) in ether (100 ml). After 5 minutes TFA (2 ml) was added to this. When the solution had warmed up to 20° C., it was washed with diluted HCl (0.5M, 20 ml), and extracted with dilute base (0.5N, 2×50 ml). The combined basic extracts were washed with ether (25 ml), made acidic with concentrated HCl (~4 ml), and extracted with ether (3×50 ml). The combined ethereal extracts were washed with water (50 ml), saturated brine (50 ml), and dried (MgSO 4). The solvent was removed under reduced pressure to give 2,4,5-trifluoro-3-(trifluoromethyl)benzoic acid (4.21 g, 69%) as white microscopic needles; mp 87°-90° C. Nmr (CDC3) δ 11.80 (1H, br s, OH), 8.05 (1H, d of t, Jd =6 Hz, aromatic).
Reaction SMILES: O/[C:2](=[CH:8]\[C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH:26]1([NH:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CCO.CCOC(C)=O>[CH:26]1([N:32]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][CH:11]=3)=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:33]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NNC1CCCCC1
Reactant: CCOC(=O)/C(O)=C/C(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Yield: 98.6 %

Procedure:
The butenoate 1.2 (5.00 g, 15.3 mmol) and cyclohexylhydrazine hydrochloride (2.77 g, 18.4 mmol) were heated at refluxed in EtOH (60 ml) for 2 h. Concentration in vacuo resulted in formation of a solid which was suspended in EtOAc and filtered through a 1″ pad of SiO2, elution with ethyl acetate. The filtrate was concentrated to afford 6.10 g (98%) of the desired pyrazole ester 1.3. MS (ESI) 405.4 (M+H+).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)O)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:21])[F:1])[CH:4]=1
Reactant: OC(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cccc(C(Cl)c2cccc(C(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of bis(3-(trifluoromethyl)phenyl)methanol (1.1 g, 3.4 mmol) in CH2Cl2 (10 mL) was added dropwise thionyl chloride (0.50 ml, 6.9 mmol) at rt. The reaction was stirred at 50° C. for 4 h, concentrated under vacuum, azeotroped with toluene, and dried under vacuum to give crude chlorobis(3-(trifluoromethyl)phenyl)methane. The crude chlorobis(3-(trifluoromethyl)-phenyl)methane was added to a solution of piperazine (0.81 ml, 10 mmol) in acetonitrile (10 mL), heated to 100° C. for 18 h and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3, filtered, and concentrated to give 1-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazine. The crude 1-(bis(3-(trifluoromethyl)phenyl)-methyl)piperazine was dissolved in acetonitrile (10 mL) and tert-butyl bromoacetate (0.55 mL, 3.4 mmol) and triethylamine (0.96 ml, 6.9 mmol) was added. The solution was stirred for 4 h, diluted with water, and extracted with CH2Cl2. The organic layer was washed with saturated NaCl solution, then dried over Na2SO4, and concentrated. The crude product was purified by ISCO using 0-50% EtOAc in haxanes to give tert-butyl 2-(4-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazin-1-yl)acetate (0.86 g, 50% yield). MS (ESI, pos. ion) m/z: 503.1 (M+1), which was then converted to the title compound by proceeding as described in Example 4 above.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:16]([F:15])[CH:17]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)c(F)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)c(F)c1
Yield: 65.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-fluoro-4-(3-fluorobenzyl)benzamide was prepared according to Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.075 g; 0.318 mmol), 3-fluoro-4-(3-fluorobenzyl)benzoic acid (0.087 g; 349 mmol), HATU (0.121 g: 0.318 mmol) and N,N-diisopropylethylamine (0.139 mL; 0.795 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent: 0 to 10% of ethyl acetate in dichloromethane) followed by recrystallization from a mixture of dichloromethane/heptane, furnished 0.088 g (65%) of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][N:6]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH:21]=2)=[C:14]([Cl:36])[CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[OH-].[Na+]>CO.O>[Cl:18][C:16]1[CH:17]=[C:12]([N:6]([CH2:5][C:4]([OH:37])=[O:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:13]=[C:14]([Cl:36])[C:15]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27](=[O:35])[C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[CH:21]=1
Reactant: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(O)c(C(=O)c3ccc(Cl)cc3)c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(=O)N(CC(=O)O)c1cc(Cl)c(Oc2ccc(O)c(C(=O)c3ccc(Cl)cc3)c2)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
The ester (2.27 g, 4.0 mmol) was dissolved in MeOH (14 mL) and to that solution of NaOH (0.48 g, 12 mmol) in H2O (7 mL) was added and it was stirred at 60° C. for 1 hr. Methanol was evaporated from the reaction mixture and H2O was added, washed with diethyl ether. The aqueous layer was acidified to pH 4 using 10% HCl solution and extracted with ethyl acetate The organic layer was washed with water, brine, dried over sodium sulphate, filtered and concentrated to give pure product ({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-ethoxycarbonyl-amino)-acetic acid. (1.7 g, 79% yield)
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24](OC)=[O:25])=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[NH3:40]>CO>[OH:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:40])=[O:25])=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:38])([F:37])[F:39])[CH:20]=3)[C:12]=2[CH:11]=1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OCc1ccccc1C(F)(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnc(CO)cc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 3.15 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B2b) and 218 ml of a saturated solution of ammonia in methanol was stirred in an autoclave at 120° C. for 3 h. The mixture was allowed to cool down to room temperature and concentrated to dryness to give the crude corresponding acid amide that was immediately used for the next step without further purification. The residue was dissolved in 180 ml tetrahydrofuran and to this solution is added 2.0 ml of tetra-n-butylammonium fluoride solution (˜75% in H2O) at 0° C. The reaction mixture was stirred at 0° C. for 12 h. The solvent was evaporated and the residue was treated with 250 ml dichloromethane and 60 ml saturated aqueous NaHCO3 solution. The resulting precipitate was dissolved by addition of propan-2-ol, the organic layer was separated, washed with 60 ml saturated aqueous NaHCO3 solution, dried with MgSO4 and concentrated under vacuum. The residue was suspended in 40 ml dichloromethane and stirred for one hour. The suspension was filtered, the filter cake washed with 20 ml dichloromethane and dried under vacuum to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:25])([F:24])[C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15]>>[CH2:7]([N:6]1[C:2]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:17]([NH:16][C:14](=[O:15])[C:13]([F:24])([F:12])[F:25])[CH2:18][CH2:19]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=[N:5]1)[CH3:8]
Reactant: CCn1ncc([N+](=O)[O-])c1Cl
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Product: CCn1ncc([N+](=O)[O-])c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 60 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-ethyl-4-nitro-1H-pyrazole and (R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide (0.1 g, 0.476 mmol) gave (R)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.1 g, 60%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 6.39-6.36 (m, 1H), 4.23-4.19 (m, 1H), 4.12 (q, J=7 Hz, 2H), 3.42-3.35 (m, 1H), 3.27-3.18 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H), 1.47 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.CCN(C(C)C)C(C)C.[Cl:33][C:34]1[S:35][C:36]2[C:37](=[C:39]([C:43](Cl)=[O:44])[CH:40]=[CH:41][CH:42]=2)[N:38]=1>CC#N>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:43]([C:39]2[CH:40]=[CH:41][CH:42]=[C:36]3[S:35][C:34]([Cl:33])=[N:38][C:37]=23)=[O:44])=[O:10])[N:12]=1
Reactant: O=C(Cl)c1cccc2sc(Cl)nc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3sc(Cl)nc23)c1
Reaction time: 0.5 h

Procedure:
A solution of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone (0.24 mmol) in MeCN (1.0 mL) is treated successively with DIPEA (0.49 mmol) and 2-Chloro-benzothiazole-4-carbonyl chloride (0.24 mmol; U.S. Pat. No. 3,654,296). The mixture is stirred for 30 min and purified by prep. HPLC to give the desired amide. LC-MS: tR=1.03 min; [M+H]+=523.0.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=C)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:34])=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:28])([F:27])[F:29])([CH3:3])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C(F)(F)F)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 33 %

Procedure:
To 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 14B, 0.18 g, 0.451 mmol) in THF (2 mL) was added N-methylmorpholine-N-oxide (50% in water) (0.093 mL, 0.451 mmol) followed by osmium tetroxide (0.071 mL, 9.01 μmol) in one portion at room temperature. The contents were stirred at room temperature for 14 h. LCMS indicated formation of a major peak corresponding to the diol intermediate. Sodium periodate (0.145 g, 0.676 mmol) dissolved in 2 mL of water was added in one portion at room temperature. The milky heterogeneous solution was stirred at room temperature for 45 min. The reaction mixture was concentrated and partitioned between ethyl acetate (15 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated and purified by silica gel column chromatography (hexane/ethyl acetate) to yield 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.06 g, 0.149 mmol, 33.2% yield) as a white solid. LC/MS M+1=402.1.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1.C[Si](C)(C)[C:14]([F:17])([F:16])[F:15].Cl.CCOC(C)=O>C1(C)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Br:10][C:6]1[CH:5]=[C:4]([C:3](=[O:11])[C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1cccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(c1cccc(Br)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 20 h
Yield: 63.7 %

Procedure:
In a dry round bottom flask, 3-bromo-benzoic acid methyl ester (2 g, 9.3 mmol, Aldrich Chemical Company) and trimethyl(trifluoromethyl)silane (1.72 mL, 11.6 mmol, Aldrich Chemical Company) were dissolved in dry toluene (50 mL). Upon cooling the solution to −78° C., TBAF (232 μL, 0.23 mmol) was added and the reaction was allowed to warm up slowly to rt overnight. After stirring for 20 hr, 2N HCl (50 mL) and EtOAc (100 mL) were added, the layers were separated, and the aqueous layer was extracted with another portion of EtOAc. The combined organic fractions were dried (MgSO4), concentrated in vacuo, and resulting crude oil was purified using SiO2 flash chromatography (elution: 5–20% EtOAc in hexanes) to give 1.5 g (65%) the title compound as a light yellow oil. 1H-NMR (CDCl3; 400 MHz) δ 8.18 (br s, 1H), 7.98–8.00 (m, 1H), 7.82–7.85 (m, 1H), 7.42–7.46 (m, 1H). 19F-NMR (CDCl3; 400 MHz) δ −72.06 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH2:26]([O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1)[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:26]([O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: CCOC(=O)Cc1ccc(CN)cc1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC(=O)Cc1ccc(CNC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid, Example 26, step 3, was reacted with 4-(aminomethyl)phenylacetic acid ethylester (CAS 17841-69-9) and HBTU at 80° C. 4 h to give the title compound as a white foam. MS (m/e)=569.0 [M+H+].