Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:34][CH3:35])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:33])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[S:26][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.Cl[C:46](=[O:51])[C:47]([O:49][CH3:50])=[O:48]>ClCCl.C(OCC)(=O)C>[CH3:35][O:34][CH:3]([O:2][CH3:1])[CH2:4][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:33])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[S:26][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:24][CH:23]=2)[CH2:17][CH2:16]1)[C:46](=[O:51])[C:47]([O:49][CH3:50])=[O:48]
Reactant: COC(=O)C(=O)Cl
Reactant: COC(CNc1ccccc1C(=O)CCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1)OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)N(CC(OC)OC)c1ccccc1C(=O)CCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound prepared in Example 323 (555 mg) in dichloromethane (7.0 mL) at 0° C. was added diisopropylethylamine (0.59 mL) followed by methyl 2-chloro-2-oxoacetate (0.16 mL). The reaction was allowed to warm to room temperature and then stirred for 2 hours. The solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 80% ethyl acetate/hexane with 3% (9:1 methanol/concentrated ammonium hydroxide)) to furnish the title compound (392 mg) with the following physical properties.
Reaction SMILES: Cl.[CH2:2]1[C:5]2([CH2:9][CH2:8][O:7][CH2:6]2)[CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30]([N:32]3[CH2:35][CH:34]([O:36][C:37]4[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=4)[CH2:33]3)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:2]1[C:5]2([CH2:9][CH2:8][O:7][CH2:6]2)[CH2:4][N:3]1[CH2:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][CH:34]2[CH2:35][N:32]([C:30]([C:28]3[O:29][C:25]([C:22]4[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=4)=[N:26][N:27]=3)=[O:31])[CH2:33]2)=[CH:44][CH:43]=1
Reactant: C1CC2(CNC2)CO1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CC6(CCOC6)C5)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Oxa-2-azaspiro[3.4]octane HCl salt (0.052 g, 0.35 mmol) was dissolved in dichloromethane (2 ml). Triethylamine (0.052 ml, 0.38 mmol) was added, followed by 4-(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.11 g, 0.29 mmol) and then sodium triacetoxyhydroborate (0.123 g, 0.58 mmol). The reaction was stirred at ambient temperature overnight. The reaction mixture was then diluted with dichloromethane (10 ml), after which it was shaken with NaHCO3 (sat. 2 ml).
Reaction SMILES: [Si:1]([O:18][C@@H:19]([CH3:23])[C:20](O)=[O:21])([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.[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[C:32]1[S:36][C:35]([CH2:43][O:44][CH2:45][O:46][CH3:47])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:34][N:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:1]([O:18][C@@H:19]([CH3:23])[C:20]([N:34]1[N:33]=[C:32]([C:26]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=2[F:24])[S:36][C@@:35]1([CH2:43][O:44][CH2:45][O:46][CH3:47])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:21])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: COCOCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCOC[C@@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.6 %

Procedure:
To a solution of (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid (0.70 g, 2.14 mmol) in DMF (20 mL) was added 5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (0.50 g, 1.43 mmol) followed by PyBOP (1.11 g, 2.14 mmol) and DIEA (497 μL, 2.85 mmol). After stirring at room temperature for 16 hours, the mixture was treated with saturated NaHCO3 (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with water (6×30 mL) and brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The yellow residue was chromatographed (19:1 to 9:1 hexanes/ethyl acetate) to afford the less polar diastereomer (S)-2-(tert-butyldiphenylsilyloxy)-1-((R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one (110 mg, 12%), and the more polar diastereomer (S)-2-(tert-butyldiphenylsilyloxy)-1-((S)-5-(2,5-difluorophenyl)-2-((methoxy-methoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one (146 mg of a 1:1 mixture with starting material) as yellow oils. Absolute stereochemistry was assigned by inference from (S)-1-((R)-5-(2,5-difluorophenyl)-2-(hydroxymethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH:4]=[CH2:5].[CH2:17]([Zn]CC)C.ICI>C1(C)C=CC=CC=1>[CH:4]1([CH2:3][CH:2]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=2[CH3:16])[C:9]([O:11][CH3:12])=[O:10])[OH:1])[CH2:17][CH2:5]1
Reactant: CC[Zn]CC
Reactant: C=CCC(O)c1cc(C(=O)OC)ccc1C
Solvent: ICI
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(C(O)CC2CC2)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
Into a 100-mL 3-necked round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(1-hydroxybut-3-en-1-yl)-4-methylbenzoate (compound 4.3, 50 mg, 0.23 mmol). Diethylzinc (1 M in toluene) (3.45 mL, 3.45 mmol) in toluene (10 mL) was added and the mixture was cooled to 0-5° C., then diiodomethane (924 mg, 3.45 mmol) was added drop-wise. The resulting mixture was stirred for 2 h at room temperature, then carefully quenched with 1 M aqueous HCl (50 mL) and diluted with MTBE (50 mL). The aqueous phase was extracted with MTBE (3×20 mL) and the combined organics was washed with saturated sodium bicarbonate (2×20 mL), brine (2×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) as the eluent to yield the title compound as a yellow oil (40 mg, 74%).
Reaction SMILES: [BH4-].[Na+].[N:3]1([CH2:8][C:9]([C:11]2[CH:23]=[CH:22][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][N:5]=[CH:4]1>C(O)C>[CH:12]1[C:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][C:11]=1[CH:9]([OH:10])[CH2:8][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C(Cn1ccnc1)c1ccc2c(c1)Cc1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(Cn1ccnc1)c1ccc2c(c1)Cc1ccccc1-2
Reaction time: 1 h

Procedure:
Two grams of sodium borohydride were added in portions to a stirred suspension of ten grams of 2-(1H-imidazol-1-yl)-1-(9H-fluoren-2-yl)ethanone in 100 ml. of ethanol at room temperature. After one hour, the reaction mixture was poured into 700 ml. of water and the resulting precipitate was recovered by filtration. Crystallization of the solid from tetrahydrofuran/hexane provided 9.7 g. of the desired title product, m.p. 196°-199° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]1([CH2:41][OH:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.[H-].[Na+]>CN(C=O)C.O>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28]([O:42][CH2:41][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: OCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(OCc3cccc4ccccc34)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
To a solution of 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (0.200 g, 0.423 mmol) and 1-naphthalenemethanol (0.140 g, 0.888 mmol) in DMF (1 mL) was added sodium hydride (0.0355 g, 0.888 mmol) and stirred for 3 h. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0 to 20% EtOAc/hexanes) to afford the title compound (0.139 g, 55%).
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[OH:5][CH2:4][C:3]1[C:2]([CH3:1])=[N:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cccnc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ncccc1CO
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of ethyl 2-methylnicotinate (1.50 g, 9.09 mmol) in freshly distilled THF (100 mL) at 0° C. was added diisobutylaluminum hydride (11.2 mL of a 1.5M solution in toluene, 16.9 mmol). The solution was stirred for 6 h at 0° C. and then warmed to ambient temperature. After 1 h, the solution was cooled in an ice bath and 1N HCl (75 mL) was added to quench the reaction. The mixture was made alkaline with aqueous NaOH (pH=8.5), filtered, and the solvents were concentrated under reduced pressure. The resulting aqueous solution was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was separated, and the aqueous layer was washed with additional CHCl3 (5×40 mL). The organic layers were combined, dried (MgSO4), and evaporated under reduced pressure. 3-Hydroxymethyl-2-methylpyridine was obtained as a slightly amber oil and was used in the next step without purification (TLC: Rf =0.40 (5% MeOH:CH2Cl2)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([CH2:19][OH:20])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>CS(C)=O.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][CH:10]=[C:11]([CH:19]=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: OCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CS(C)=O
Product: O=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
118.00 g (440 mmol) of manganese dioxide were added to a solution of 10.73 g (40 mmol) of 2-(4-fluorophenyl)-4-hydroxymethyl-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in step (ii) above] in 120 ml of dimethyl sulfoxide, after which the resulting mixture was stirred at 50° C. overnight. At the end of this time, the reaction mixture was filtered, water was added to the filtrate, and this was then extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to afford a solid which was washed with diethyl ether to give 7.35 g (yield 69%) of the title compound as a brown powder.
Reaction SMILES: CCOC(C)=O.CO.C([O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:24]2)=[CH:19][C:18]=1[C:39]1[N:40]=[N:41][C:42]([N:45]([CH3:56])[CH:46]2[CH2:51][C:50]([CH3:53])([CH3:52])[NH:49][C:48]([CH3:55])([CH3:54])[CH2:47]2)=[CH:43][CH:44]=1)C1C=CC=CC=1>C(Cl)Cl.CCOCC.[Pd]>[OH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:24]2)=[CH:19][C:18]=1[C:39]1[N:40]=[N:41][C:42]([N:45]([CH3:56])[CH:46]2[CH2:51][C:50]([CH3:53])([CH3:52])[NH:49][C:48]([CH3:55])([CH3:54])[CH2:47]2)=[CH:43][CH:44]=1
Reactant: CN(c1ccc(-c2cc3ccc(OCCCNC(=O)OC(C)(C)C)cc3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(c1ccc(-c2cc3ccc(OCCCNC(=O)OC(C)(C)C)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
Pd/C (10% wt 80 mg, 0.075 mmol) was added to a EtOAc (5 mL)/MeOH (5 mL) solution of tert-butyl (3-((7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yl)oxy)propyl)carbamate (492 mg, 0.752 mmol) at RT. The reaction mixture was evacuated and filled with H2 (2×) then stirred at RT under H2 (1 atm) for 16 h. The reaction mixture was filtered through celite washing with MeOH, wash then concentrated in vacuo to dryness affording a tan solid. The solid was dissolved in DCM then adsorbed onto a silica bound amine column (Si—NH2 column 10 g, Varian brand, Bond Elut NH2). The column was then washed with MeOH (150 mL) then the solvent was concentrated in vacuo affording a yellow oil. The oil was dissolved in Et2O then concentrated in vacuo affording the title compound as a beige solid (386 mg, 91% yield). MS (M+1)=564.3; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.29 (br. s, 1H), 8.34 (s, 1H), 8.28 (d, J=10.10 Hz, 1H), 7.76 (d, J=9.09 Hz, 1H), 7.34 (d, J=10.11 Hz, 1H), 7.15 (s, 1H), 7.08 (d, J=2.53 Hz, 1H), 6.94 (dd, J=9.09, 2.53 Hz, 1H), 4.89-5.06 (m, 1H), 4.56 (s, 1H), 4.09 (t, J=6.32 Hz, 2H), 3.09-3.16 (m, 2H), 2.98 (s, 3H), 1.80-1.95 (m, 2H), 1.50-1.61 (m, 2H), 1.44 (t, J=12.38 Hz, 2H), 1.38 (s, 9H), 1.27 (s, 6H), 1.10 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[F:21][C:22]1[N:23]=[CH:24][C:25]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Brc1ccc(CCNc2ncnc3nccnc23)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2ccc(CCNc3ncnc4nccnc34)cc2)cn1
Yield: 9.5 %

Procedure:
To a round bottom flask was added [2-(4-bromophenyl)-ethyl]-pteridin-4-yl-amine (200 mg, 0.61 mmol), 2-fluoro-5-pyridineboronic acid (102 mg, 0.73 mmol), NaHCO3 (102 mg, 1.21 mmol), PdCl2(PPh3)2 (213 mg) and 50% aqueous ethylene glycol dimethyl ether (DME; 3.0 mL). The reaction was heated to reflux for 4.5 h, after which the reaction was cooled and the resulting orange precipitate filtered. The filtered material was washed with EtOAc and the filtrate washed with H2O. The organic fractions were pooled and concentrated in vacuo. The residue (229 mg) was purified by preparative RP-HPLC to afford {2-[4-(6-fluoropyridin-3-yl)-phenyl]-ethyl}-pteridin-4-yl-amine (20 mg) as an orange solid: mp 184-186° C.; EIMS m/z 346 ([M]+).
Reaction SMILES: [CH:1]([C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([OH:13])[O:5]1)([CH3:3])[CH3:2].[CH2:14]([Mg]Cl)[CH:15]([CH3:17])[CH3:16].C(Cl)C(C)C.[Mg]>C1COCC1>[OH:5][C@H:4]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@@H:6]([OH:13])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1OC(O)c2ccccc21
Reactant: CC(C)C[Mg]Cl
Agent: [Mg]
Solvent: CC(C)CCl
Solvent: C1CCOC1
Product: CC(C)C[C@H](O)c1ccccc1[C@@H](O)C(C)C

Procedure:
To a solution of (3S)-3-isopropyl-1,3-dihydro-isobenzofuran-1-ol (14.11 g, 0.129 mol) in THF (250 ml) was added at reflux temperature through a Teflon tube, which ended under the surface in the reaction mixture, a solution of isobutyl magnesium chloride (freshly prepared from 0.387 mol isobutyl chloride and 0.58 mol magnesium in 250 ml of THF) slowly within 20 minutes under efficient stirring. The mixture was then quenched with a solution of ammonium chloride (10%). The organic layer was separated, and the solvent was removed on the rotavapor. The residue was re-dissolved in ethyl acetate (200 ml), and this solution was washed with water (150 ml) and brine (150 ml). After drying and removal of the solvent the product was obtained as a yellow oil (31.5 g). 1H/13C-NMR (300 MHz, CDCl3, HSQC/HMBC) δ/δ 0.78 (d, J=6.9 Hz)/19.00, 1.04 (d, J=6.5 Hz)/20.22 (2 i-Pr CH3); 0.95 (d, J=6.5 Hz)/23.87, 0.96 (d, J=6.5 Hz)/22.32 (2 i-Bu CH3); 1.80 (m)/25.33 (i-Bu CHMe2); 2.02 (m)/35.13 ((i-Pr CHMe2); 1.47/1.72 (m)/48.03 (CH2); 3.09 (br s, 2 OH); 4.53 (d, J=8.1 Hz)/77.55 (CH(OH)i-Pr); 5.08 (dd, J=4.7 Hz, J=9.5 Hz)/68.87 (CH(OH)i-Bu); 7.40 (m)/126.44 (Ar i-Bu ortho-CH); 7.21 (m)/127.37 (Ar meta-CH); 7.28 (m)/127.55 (Ar i-Pr ortho-CH); 7.23 (m)/127.71 (Ar meta-CH); 140.56 (Ar i-Pr ipso-C); 142.66 (Ar i-Bu ipso-CH).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH3:27])[C:13]2[CH:14]=[CH:15][C:16]([F:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([N:12]([CH3:27])[C:13]1[CH:14]=[CH:15][C:16]([F:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:22])[F:23])[CH:18]=1)[N:10]=2
Reactant: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc(N)cn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
Potassium thiocyanate (2.96 g, 30.5 mmol) was suspended in acetic acid (20 mL), and the suspension was stirred at room temperature for 10 min. To the obtained solution was added N-{5-[(5-aminopyridin-2-yl)(methyl)amino]-2-fluorophenyl}-2,2,2-trifluoroacetamide (2.0 g, 6.96 mmol), and the mixture was further stirred at room temperature for 10 min. The obtained solution was slowly added dropwise to a solution of bromine (1.17 g, 7.30 mmol) in acetic acid (10 mL). After the completion of the dropwise addition, the mixture was stirred at room temperature for 20 hr. The resultant black insoluble material was filtered off, and washed with acetic acid. The combined filtrate and washing were concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (100 mL), washed with saturated aqueous sodium hydrogen carbonate solution (70 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (1.00 g, 43%) as a colorless powder.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:27]=[CH:26][C:7]([O:8][C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:19]=[CH:20][CH:21]=3)[CH:10]=2)=[CH:6][CH:5]=1.[F:30][C:31]([F:38])([F:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH2:14]([N:13]1[C:9]([O:8][C:7]2[CH:26]=[CH:27][C:4]([CH:3]=[O:2])=[CH:5][CH:6]=2)=[CH:10][C:11]([C:16]2[CH:17]=[C:18]([C:22]([NH:25][S:33]([CH2:32][C:31]([F:38])([F:37])[F:30])(=[O:35])=[O:34])([CH3:24])[CH3:23])[CH:19]=[CH:20][CH:21]=2)=[N:12]1)[CH3:15]
Reactant: CCn1nc(-c2cccc(C(C)(C)N)c2)cc1Oc1ccc(C(OC)OC)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
2-(3-{5-[4-(dimethoxymethyl)phenoxy]-1-ethyl-1H-pyrazol-3-yl}phenyl)propan-2-amine (8.84 g, 22.35 mmol, 1 equiv) was stirred at −78° C. in anhydrous DCM (224 mL). 2,2,2-trifluoroethanesulfonyl chloride (4.90 g, 26.80 mmol, 1.2 equiv) was added, followed by triethylamine (4.67 mL, 33.50 mmol, 1.5 equiv). After stirring at −78° C. for 10 minutes the cooling bath was removed and the mixture was allowed to slowly warm to 22° C. Upon reaching 22° C. 7:1 Water:TFA (4.5 equiv) was added to the vigorously stirring reaction mixture. After stirring for 1 hour the mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the N-(2-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}propan-2-yl)-2,2,2-trifluoroethanesulfonamide (98% Yield). Calcd (M+1)+: 496.1. Found: 496.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[Li][CH3:13].CI.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: [Li]C
Reactant: COc1ccc(CC#N)cc1
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COc1ccc(C(C)C#N)cc1
Reaction time: 3 h
Yield: 112.8 %

Procedure:
To a mixture of 4-methoxyphenylacetonitrile (17 g, 0.11 mol) and MeLi (1M; 100 ml, 0.11 mol) in THF (200 ml) was added MeI (32 g, 0.22 mol) at -78° C. After the mixture was stirred for 3 hours, the mixture was poured into H2O (100 ml), and extracted with AcOEt. The combined extracts were dried (Na2SO4), and concentrated to give a yellow oil (20 g), which was purified by a column chromatography on silica gel to give Compound 13 as a colorless oil (11 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 2,5-dimethyl-4-nitrobenzoic acid (480 mg, 2.4 mmol) in dry methanol (8.2 mL) at 0° C. under dry nitrogen was added thionyl chloride (0.538 mL, 7.38 mmol). The resulting mixture as allowed to warm to room temperature and stirred for about 7 hours. Additional thionyl chloride (0.300 mL) was added and stirring was continued at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide methyl 2,5-dimethyl-4-nitrobenzoate (578 mg) as a pale yellow solid. HPLC (10-70) Rt=4.61; 1H NMR (300 MHz, CDCl3) δ 2.57 (s, 3H), 2.61 (s, 3H), 3.94 (s, 3H), 7.82 (s, 1H), 7.87 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[CH:8][C:9]=2[F:10])[CH2:3][CH2:2]1.Cl[C:21]1[CH:22]=[C:23]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[N:24]=[N:25][CH:26]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:21]3[CH:22]=[C:23]([CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH3:33])[N:24]=[N:25][CH:26]=3)[CH:7]=[CH:8][C:9]=2[F:10])[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2ccc(F)c(C3CC3)c2)OC1(C)C
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc(F)c(C3CC3)c2)cnn1

Procedure:
The title compound, MS: m/e=309.4 (M+H30), was prepared from 2-(3-cyclopropyl-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.