Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[NH:15][C:14]4[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=4[N:12]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:15]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[C:14]4[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=4[N:12]=3)=[N:9][N:8]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2nc(-c3n[nH]c4ncc(Br)cc34)[nH]c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3nn(COCC[Si](C)(C)C)c4ncc(Br)cc34)n(COCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-bromo-3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine Compound 19c (HOAc salt, 50 mg, 0.145 mmol) was added to a suspension of NaH (60% in mineral oil, 23 mg, 0.581 mmol) in DMF (5 mL). The mixture was stirred at r.t. for 5 mins, then SEMCl (97 mg, 0.581 mmol) was added. The mixture was stirred at r.t. for 12 hrs, then diluted with AcOEt (60 mL) and washed with water. The solvent was evaporated to dryness and the residue was purified by chromatography to provide 5-bromo-3-[6-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 20a (60 mg, 78% yield) as a sticky oil.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9]O.[CH:18]([NH2:21])([CH3:20])[CH3:19]>[Ni]>[CH:18]([NH:21][CH2:9][CH2:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])([CH3:20])[CH3:19]
Reactant: CC(C)N
Reactant: CC(CCO)c1ccccc1-c1ccccc1
Agent: [Ni]
Product: CC(C)NCCC(C)c1ccccc1-c1ccccc1
Reaction time: 15 h

Procedure:
2.26 g of 3-p-biphenylylbutan-1-ol are dissolved in 10 ml of isopropylamine and, after adding 0.5 g of Raney nickel, the solution is shaken for 15 hours at 160° in a tube. After cooling, filtering off the catalyst and evaporating, 1-isopropylamino-3-p-biphenylyl-butane is obtained.
Reaction SMILES: O1CCCC1.[N+:6]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH3:18][N:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:34])[N:21]([CH3:35])[C:20]1=[O:36]>C(N(CC)CC)C>[CH3:18][N:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:17][CH:16]=3)[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:34])[N:21]([CH3:35])[C:20]1=[O:36]
Reactant: Cn1c(N2CCN(CCO)CC2)cc(=O)n(C)c1=O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(CCOC(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5 ml of tetrahydrofuran were added 0.5 g of 4-nitrobenzoyl chloride, 0.47 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 41) and 1.5 ml of triethylamine, and the resulting mixture was stirred at room temperature overnight. Afterward, the used solvent was distilled off under reduced pressure, and the residue was then dissolved in chloroform. The resulting chloroform solution was washed with water, then dried over anhydrous sodium sulfate, and concentrated to dryness, thereby obtaining a crude product. The latter was then purified through a silica gel column chromatograph (chloroform/methanol=40/1 in terms of volume ratio) in order to obtain 1,3-dimethyl-6-{4-[2-(4-nitrobenzoyloxy)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione. Next, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to prepare 0.84 g of 1,3-dimethyl-6-{4-[2-(4-nitrobenzoyloxy)ethyl]piperazine-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 40).
Reaction SMILES: [C@@H:1]1([C:10](O)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7](O)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[C@@H:1]1([CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][OH:8]
Reactant: O=C(O)[C@H]1CCCC[C@H]1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OC[C@@H]1CCCC[C@@H]1CO
Temperature: 0 °C
Yield: 100.4 %

Procedure:
63 g of anhydrous cis-1,2-cyclohexanedicarboxylic acid was dissolved in 200 ml of dried ether and the solution was added dropwise to an ice-cooled suspension of 29 g of lithium aluminum hydride in 1000 ml of dried ether. After completion of the dropwise addition, the solution was heated under reflux for 30 minutes, following return to room temperature, 50 ml of water was added thereto, followed by filtration. The filter cake was washed twice with tetrahydrofuran (200 ml each time). The ethereal filtrate and the tetrahydrofuran washings were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resiude was distilled under reduced pressure and fractions boiling at 122° to 125° C. (0.7 mmHg) were collected to obtain 53 g of pure cis-1,2-cyclohexanedimethanol.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.[OH-:45].[Na+].OO.O>C(O)C>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43](=[O:45])[NH2:44])=[CH:39][CH:38]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene (282 mg) obtained in Example 191-(1) was suspended in ethanol (5 ml) and added thereto was a 6N aqueous sodium hydroxide solution (0.37 ml). The mixture was stirred at room temperature for 10 minutes. To the mixture was added a 30% aqueous hydrogen peroxide solution (0.2 ml), and the mixture was stirred at room temperature for 1.5 hours and at 45° C. for 3 hours. To the mixture was added water (20 ml) and the mixture was cooled. The powder was collected by filtration and washed with diethyl ether and dried to give the desired 1-(β-D-glucopyranosyl)-3-(5-(4-carbamoylphenyl)-2-thienylmethyl)-4-chlorobenzene (176 mg) as colorless powder. APCI-Mass m/Z 507/509 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[O:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=1)[C:39]([O:41][CH3:42])=[O:40]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:35][C:36]3[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=3)[C:39]([O:41][CH3:42])=[O:40])[CH3:23])=[C:18]([CH3:24])[CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[O:11][N:10]=1
Reactant: CNc1ccc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)cc1C
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN(C)c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenyl)-N-methylamine (0.45 g, 1.1 mmol) in dimethylformamide (4 mL) was treated with potassium carbonate (0.15 g, 1.1 mmol) followed by methyl 3-(bromomethyl)benzoate (0.25 g, 1.1 mmol). After stirring at ambient temperature for 24 h, the reaction was partitioned with ethyl acetate and water. The organic layer was washed with water (2×50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered and condensed to a residue which was chromatographed on silica gel eluting with 20% ethyl acetate/hexanes. Yield=0.43 g. (70%) of methyl 3-{[(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenyl)(methyl)-amino]methyl}benzoate.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[C:24](=[O:25])[CH:23]=[CH:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH3:26][Li]>C(OCC)C>[Si:1]([O:18][CH2:19][C@H:20]1[C@@:24]([CH3:26])([OH:25])[CH:23]=[CH:22][CH2:21]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1CC=CC1=O)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(C)(C)[Si](OC[C@@H]1CC=C[C@]1(C)O)(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A solution of (5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-1-one (250. mg, 0.713 mmol) in diethyl ether (10.0 mL) tinder an atmosphere of nitrogen was cooled to −40° C. and a 1.60 M solution of methyllithium in diethyl ether (0.579 mL, 0.926 mmol) was added slowly and the mixture was stirred at −40° C. for 3 h. TLC indicated complete conversion, and the reaction was quenched via addition of saturated aqueous ammonium chloride (5.00 mL), extracted with EtOAc (3×10.0 mL), dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes afforded the title compound (190 mg, 73%). Stereochemistry of the product was confirmed using ROESY analysis. LC/MS: Rt=2.55 min, ES+ 367 (AA standard).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([N:33]3[C:45](=[O:46])[C:44]4[S:43][C:42]5[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=5[C:36]=4[CH:35]=[N:34]3)[C:28]=2[CH:47]=[O:48])=[CH:3]1.[BH4-].[Na+].O>CO.ClCCl>[OH:48][CH2:47][C:28]1[C:29]([N:33]2[C:45](=[O:46])[C:44]3[S:43][C:42]4[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=4[C:36]=3[CH:35]=[N:34]2)=[N:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:23][O:24][CH2:25]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of 4-[1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]-2-{6-oxo-8-thia-4,5-diazatricyclo-[7.4.0.02,7]-trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde 191k (118 mg, 0.18 mmol) in methanol/dichloromethane (10/10 mL) was added NaBH4 (21 mg, 0.54 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was completed. Then the mixture was poured into water (20 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (20 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by reverse-phase prep-HPLC to afford 191 (71 mg, 60%) as white solid. MS-ESI: [M+H]+ 667. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J=2.5 Hz, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.48-8.46 (m, 2H), 7.86 (d, J=3.0 Hz, 1H), 7.54 (d, J=5.5 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.37 (dd, J=3.0, 9.0 Hz, 1H), 7.25 (d, J=9.5 Hz, 1H), 4.86-4.85 (m, 1H), 4.58-4.55 (m, 2H), 4.48-4.46 (m, 2H), 4.42-4.40 (m, 2H), 3.65-3.64 (m, 1H), 3.61 (s, 3H), 3.41-3.99 (m, 1H), 3.05-3.04 (m, 1H), 2.97-2.95 (m, 3H), 2.87-2.86 (m, 2H), 2.52-2.51 (m, 1H), 2.34-2.32 (m, 2H), 2.21-2.20 (m, 1H), 1.89-1.87 (m, 4H), 0.94 (d, J=6.0 Hz, 3H).
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][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.C([O-])(O)=O.[Na+].[I-].[K+].[CH2:28]([O:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34]Cl)[CH3:29]>C(C(C)=O)C(C)C>[CH2:28]([O:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][N:18]1[CH2:19][CH2:20][CH:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:17]1)[CH3:29]
Reactant: CCOC(=O)CCCCl
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)CCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 66 %

Procedure:
To 28 mL of methyl isobutyl keton (MIBK) was added 4-(benzhydryloxy)piperidine (1.5 g), NaHCO3 (1.42 g), potassium iodide (catalyst), and ethyl-4-chlorobutyrate (1.2 mL). The resulting mixture was refluxed for 4 hrs. The resulting mixture was cooled, and concentrated under reduced pressure. The resultant solution was then extracted by using water and chloroform. An organic solution layer was dehydrated over magnesium sulfate, filtered, and concentrated under reduced pressure. The column chromatography was performed thereon, thereby obtaining crude yellowish liquid product (1.41 g, 66% yield) of the title.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][OH:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 97.9 %

Procedure:
The product of Step b (20.0 g, 102 mmol) was dissolved in anhydrous THF (500 ml), and the mixture was cooled to 0° C. To this solution, 1M LAH in THF (100 ml) was added dropwise, then the mixture was allowed to come to room temperature and stirred for three days. The reaction was quenched by the careful sequential addition of water (3.8 ml), 15% NaOH (3.8 ml), and water (11.4 ml). The resulting slurry was stirred for 1 hour, the solids were removed by filtration and rinsed with EtOAc, and the combined filtrates were stripped to yield 15.4 g of a colorless oil. This material was used as-is in the next step. NMR (300 MHz, CDCl3) δ 7.20-7.05 (m, 2H); 6.97 (t, 2H, J=7 Hz); 3.69 (q, 2H, J=7 Hz); 2.70 (t, 2H, J=7 Hz); 1.88 (t of t, 2H, J=7, 7 Hz); 1.31 (t, 1H, J=7 Hz).
Reaction SMILES: C([O-])(=O)C.[NH4+].[O:6]=[C:7]1[N:12]([CH2:13][CH:14]=O)[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[O:9][CH2:8]1.C([BH3-])#[N:21].[Na+].N>CCO>[NH2:21][CH2:14][CH2:13][N:12]1[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[O:9][CH2:8][C:7]1=[O:6]
Reactant: O=CCN1C(=O)COc2ccccc21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: N
Agent: [NH4+]
Solvent: CCO
Product: NCCN1C(=O)COc2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 113.4 %

Procedure:
Dissolve ammonium acetate (1.3 g, 16.19 mmol) in EtOH (15.69 mL); add 2-(3-oxo-1,4-benzoxazin-4-yl)acetaldehyde (150 mg, 0.78 mmol), sodium cyanoborohydride (155.7 mg, 2.35 mmol), and aqueous ammonia (32%; 5.64 g, 105.91 mmol). Charge a sealable tube with the mixture and seal the tube. Heat to 80° C. and stir overnight. Thereafter allow the mixture to cool to ambient temperature and remove the solvent under reduced pressure. Add EtOAc; wash with brine; NaHCO3 (saturated, aqueous); dry; filter; and concentrate the filtrate under reduced pressure. Purify via flash column chromatography eluting with a step gradient of 5%, 10% and 20% MeOH in DCM. Combine the desired fractions and remove the solvent under reduced pressure to provide the title compound (170 mg, 80%). MS (m/z): 193 (M+1).
Reaction SMILES: BrC1C=C([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[N:13]([CH3:19])[N:12]=2)C(=O)N(C)C=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:63]1[C:64](=[O:71])[N:65]([CH3:70])[N:66]=[C:67]([Cl:69])[CH:68]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:69][C:67]1[CH:68]=[C:63]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[N:13]([CH3:19])[N:12]=2)[C:64](=[O:71])[N:65]([CH3:70])[N:66]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: COCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COCc1cc(Nc2cc(Cl)nn(C)c2=O)nn1C
Yield: 93.5 %

Procedure:
A mixture of 5-(methoxymethyl)-1-methyl-1H-pyrazol-3-amine 176b (600 mg, 4.26 mmol), XantPhos (300 mg, 0.51 mmol), Pd2 dba3 (310 mg, 0.34 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (103e) (1.22 g, 5.53 mmol) and Cs2CO3 (4.2 g. 12.8 mmol) in 1,4-dioxane (40 mL) was heated at reflux for 2 h. After the completion of the reaction, the mixture was filtered off and washed with methanol (100 mL). The filtrate was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 187a (1.13 g, 94%). MS: [M+H]+ 284.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[S:5][CH:6]=1.[Li]CCCC.[F:21][C:22]([F:42])([F:41])[C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[N:29]=[CH:28]2)=[O:24]>CCOCC>[Si:9]([O:8][CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:29]=[CH:28]3)([OH:24])[C:22]([F:41])([F:21])[F:42])[N:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(Br)cs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1nc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 66.6 %

Procedure:
To a chilled (−78° C.) solution of 4-bromo-2-(tert-butyldimethylsilanyloxymethyl)thiazole (339 mg, 1.10 mmol) (prepared according to a procedure described by Nicolaou et al., Bioorg. Med. Chem. 1999, 7, 665-697) in dry ether (5 mL) was added n-BuLi (440 μL, 2.5 M in hexane, 1.10 mmol). After 2 minutes, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (308 mg, 1.00 mmol) in 5 mL of dry ether added. After 15 minutes, the mixture was warmed to room temperature and quenched with 20 mL of saturated aqueous ammonium chloride and extracted with three 20 mL portions of diethyl ether. The combined organic layers were washed with 20 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on SiO2 (0-30% ethyl acetate in hexanes, gradient) to afford 358 mg (67%) of 1-[2-(tert-butyldimethylsilanyloxymethyl)thiazol-4-yl]-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol. MS m/z 538.97 (MH+).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:34])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[O:32][CH3:33])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4]>[OH-].[K+].O1CCOCC1>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:34])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[O:32][CH3:33])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CNC(=O)c3cc(Cl)ccc3OC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1C(=O)NCc1ccc(-c2ccc(OC(C)(C)C(=O)O)cc2)cc1
Yield: 72 %

Procedure:
2-Methyl-2-{4-(2-methoxy-5-chloro-benzamido-methyl)-biphenyl-4'oxy}-propionic acid was prepared by alkaline hydrolysis of ethyl 2-methyl-2-{4-[2-methoxy-5-chloro-benzamido-methyl]-biphenyl-4'-oxy}-propionate in 1 N potassium hydroxide and dioxane (1:5) at room temperature. Yield: 72% of theory; m.p. 104° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:11]3[C:25]([O:27]CC)=[O:26])=[CH:4][C:3]=2[O:2]1.C1OC2C=CC(C3C4C(=CC=CC=4)C(C4C=CC=CC=4)=C3C(OCC)=O)=CC=2O1>CCO.[Pd]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:11]3[C:25]([OH:27])=[O:26])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Solvent: CCO
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 65 %

Procedure:
Ethyl (1RS,2SR,3SR)-1-(3,4-Methylenedioxyphenyl)-3-phenylindane-2-carboxylate. To a solution of ethyl (RS)-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.00 g, 2.60 mmol) in EtOH (25 ml) was added 10% palladium on activated carbon (30 mg). The resulting suspension was stirred under an atmosphere of H2 overnight. Thin layer chromatographic analysis indicated that the reaction was incomplete, so additional 10% palladium on activated carbon (30 mg) was added, and the mixture was shaken on a Parr hydrogenator at 30 psi H2 for 2 d. At this time, thin layer chromatographic analysis again indicated that the reaction was incomplete. The reaction mixture was filtered through a pad of Celite, and 10% palladium on activated carbon (250 mg) was added. The reaction mixture was shaken on a Parr hydrogenator at 60 psi H2 overnight. Filtration and repetition of the latter hydrogenation conditions led to complete consumption of starting material. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to afford the title compound (650 mg, 65%), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:9]([C:22]([OH:24])=O)=[N:10][C:11]([C:18]([F:21])([F:20])[F:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.Cl.[NH2:26][CH2:27][C:28]([CH3:34])([OH:33])[C:29]([F:32])([F:31])[F:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN1C(=O)CCC1>[F:30][C:29]([F:32])([F:31])[C:28]([OH:33])([CH3:34])[CH2:27][NH:26][C:22]([C:9]1[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])=[CH:13][C:12]([C:14]([F:15])([F:17])[F:16])=[C:11]([C:18]([F:21])([F:19])[F:20])[N:10]=1)=[O:24]
Reactant: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(C(F)(F)F)nc1C(=O)O
Reactant: CC(O)(CN)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(C(F)(F)F)nc1C(=O)NCC(C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate M) (1.16 g, 3.29 mmol) in NMP (32 ml) was added 3-Amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride (commercially available) (591 mg, 3.29 mmol) followed by HATU (1.25 g, 3.29 mmol) and NEt3 (918 ul, 6.59 mmol) and the reaction mixture was left to stir at RT. After 1 h a further 0.2 equiv. NEt3 was added. After 15 min a further 0.4 equiv. NEt3 and 0.2 equiv. amine were added. After 30 min a further 0.1 equiv HATU was added. After 30 min most of the starting material had been consumed. The reaction mixture was added to EtOAc (50 ml), washed with 0.1M NaOH and the aqueous layer was back extracted with EtOAc (2×50 ml). The combined organic extracts were washed with water (2×150 ml), brine (100 ml), dried (MgSO4) and concentrated in vacuo to give the crude product as an orange oil.