Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].CC(C)([O-])C.[K+].F[C:14]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[S:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([C:46]([F:49])([F:48])[F:47])[CH2:42][CH2:41]2)[C:19]([F:50])=[CH:18][C:15]=1[C:16]#[N:17].O>O1CCCC1.C(O)(C)(C)C>[F:50][C:19]1[C:20]([O:22][CH2:23][C:24]2[S:28][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[N:26][C:25]=2[CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([C:46]([F:49])([F:47])[F:48])[CH2:42][CH2:41]2)=[CH:21][C:14]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc(F)c(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)c(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1OCC(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
To a solution of 190 mg of trifluoroethanol in 1.16 mL of tetrahydrofuran at 5° C. was slowly added 2.2 mL of a molar solution of potassium tert-butoxide in tert-butanol. After stirring at 5° C. for 30 minutes, the resulting solution was slowly added to a solution of 890 mg of 2,5-difluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile in 3.1 mL of tetrahydrofuran at −60° C. The resulting mixture was stirred overnight allowing the temperature to warm up to room temperature. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with diisopropyl ether and filtered to give 410 mg of 5-fluoro-2-(2,2,2-trifluoro-ethoxy)-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(S(C)(=O)=O)nc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Nc3ccc(S(C)(=O)=O)nc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
N-tert-Butyl-2-(6-(methylsulfonyl)pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (97 mg, 187 μmol) was dissolved in dichloromethane (2.88 mL) and treated with trifluoroacetic acid (426 mg, 288 μL, 3.74 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.5 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-2-(6-(methylsulfonyl)pyridin-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (71 mg, 183 μmol, 98%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.51 (s, 1H), 10.26 (s, 1H), 8.99 (d, J=2.5, 1 H), 8.37 (dd, J=8.4, 2.7, 1 H), 8.14 (s, 1H), 8.11 (s, 1H), 7.92 (d, J=8.7, 1 H), 7.62 (s, 1H), 3.21 (s, 3H), 1.45 (s, 9H); MS (EI/CI) m/z: 389.2 [M+H].
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH2:13][CH3:14])[CH:5]([CH3:12])[CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10].[OH:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][O:23]2)=[CH:18][CH:17]=1>>[CH2:13]([C:4]([CH:5]([CH3:12])[CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH2:2][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][O:23]2)=[CH:18][CH:17]=1)[CH3:14]
Reactant: Oc1ccc2c(c1)OCCC2
Reactant: CCC(C)=CCC(C)C(=CCBr)CC
Product: CCC(C)=CCC(C)C(=CCOc1ccc2c(c1)OCCC2)CC

Procedure:
Following the procedure of Example 1, 1-bromo-3-ethyl-4,7-dimethyl-2,6-nonadiene and 7-hydroxy-chromane are reacted to form 7-(3-ethyl-4,7-dimethyl-2,6-nonadienyloxy)-chromane, nD20 = 1.5226.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]2=[O:16])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1.I[CH3:18]>>[F:1][C:2]1[C:3]([N:9]2[CH2:13][C:12]([CH3:14])([CH3:15])[N:11]([CH3:18])[C:10]2=[O:16])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1
Reactant: CI
Reactant: CC1(C)CN(c2ncc(I)cc2F)C(=O)N1
Product: CN1C(=O)N(c2ncc(I)cc2F)CC1(C)C

Procedure:
The title compound, a yellow oil, MS: m/e=350.0 (M+H+), was prepared in accordance with the general method of Example 16 from 1-(3-fluoro-5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 110, step 1) and iodomethane.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][N:16]=1)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]2)(=O)=O.[CH:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+].CCO>O.Cl[Pd]Cl.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.[Fe+2].C1(C)C=CC=CC=1>[CH:26]1([C:29]2[N:30]=[CH:31][C:32]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][N:16]=3)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]4)=[CH:33][CH:34]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ncc2C1
Reactant: CC1(C)OB(c2ccc(C3CC3)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3ccc(C4CC4)nc3)ncc2C1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
tert-Butyl 6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (0.34 g, 0.90 mmol), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.20 g, 0.82 mmol), PdCl2×dppf (0.050 g), saturated sodium carbonate (2 mL), EtOH (4 mL) and toluene (4 mL) were stirred at 80° C. for 2 h. The solution was cooled to RT, taken up in water (15 mL) and extracted three times with EtOAc-Et2O. The combined organic phases were dried, filtered and concentrated. Purification by column chromatography with EtOAc-heptanes (1:1 through 3:1) and EtOAc-MeOH (9:1) as eluents gave 0.22 g (70%) of tert-butyl 6-(6-cyclopropylpyridin-3-yl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]2=[O:22])=[CH:24][CH:25]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCCCCN2C(=O)c3ccccc3C2=O)cc1

Procedure:
A suspension of 6.8 g of 2-[4-(4-nitro-phenoxy)butyl]-1H-isoindole-1,3(2H)-dione (Example 33) in 200 ml of ethanol is treated with 500 mg of 10% Pd on carbon, and reduced in a Parr hydrogenator. After filtration, concentration of the filtrate gives the desired product, m.p. 119°-121° C.; yield 4.3 g.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8].[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O.CCOC(C)=O>[N+:15]([C:10]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8])([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(OC(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-trifluoromethoxybenzoic acid (49.0 g, 0.24 mol) in sulfuric acid (500 mL) at less than 0° C. (ice-MeOH bath) was added a solution of potassium nitrate (31.3 g, 0.31 mol) in sulfuric acid (200 mL) over 20 minutes. The resulting solution was stirred at 0° C. for 2 hours, then warmed to room temperature and stirred for 18 hours. The reaction was poured into ice and the resulting acidic solution was extracted with EtOAc (5×). The combined organics were washed with H2O (1×), brine (2×), H2O (1×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo to give the crude sub-title compound (65.7 g) as a solid contaminated with HOAc. The crude sub-title compound was dissolved in EtOAc and toluene and concentrated in vacuo to give a HOAc free solid (58.4 g, 97%) that was used in the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:31])[N:13]([CH:16]([CH3:30])[CH2:17][C:18]1[CH:29]=[CH:28][C:21]2[O:22][CH:23]([C:25](=O)[NH2:26])[O:24][C:20]=2[CH:19]=1)[CH2:14][CH3:15])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12](=[O:31])[N:13]([CH:16]([CH3:30])[CH2:17][C:18]1[CH:29]=[CH:28][C:21]2[O:22][CH:23]([CH2:25][NH2:26])[O:24][C:20]=2[CH:19]=1)[CH2:14][CH3:15])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc2c(c1)OC(C(N)=O)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc2c(c1)OC(CN)O2
Temperature: -60 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
A flask containing 20 mL of freshly distilled THF was cooled to −60° C., and 615 mg (16.2 mmol) of lithium aluminum hydride (LAH) was added To the reaction mixture, a solution of 1.8 g (5.13 mmol) 2E in 20 mL of freshly distilled THF was added dropwise under argon atmosphere. The reaction mixture was allowed to stir at −60° C. for 20 minutes, 45 minutes at 0° C. and 2 hours at room temperature. The reaction was quenched with 430 μL of 15% NaOH and 3 mL of water and allowed to stir at room temperature for 10 minutes. The resulting solution was filtered through CELITE and the residue was washed with 100 mL of THF. The filtrate was concentrated to dryness under reduced pressure and purified by silica gel column chromatography using ethyl acetate as eluent to give 1.3 g (3.86 mmol, 75%) of 2F as a colorless gum (M+Na, 359).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.O=[C:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=3)[CH:3]=[C:2]2[NH:1][CH:27]2[CH2:28][CH2:23][CH2:24][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]2)=[CH:7][CH:8]=1
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Product: CNc1nccc(-c2cc(NC3CCCN(C(=O)OC(C)(C)C)C3)c3cc(OC)ccc3c2)n1

Procedure:
tert-butyl 3-((7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)amino)piperidine-1-carboxylate 151 was synthesized according to General Procedure E except compound 33 was used a starting material and replacing tert-butyl 4-oxopiperidine-1-carboxylate with tert-butyl 3-oxopiperidine-1-carboxylate. LCMS: 464 [M+H].
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([NH2:14])=O)=[CH:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CS(OS(C)(=O)=O)(=O)=O>ClCCl>[C:1]1([N:7]2[C:11]([C:12]#[N:14])=[CH:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cnnn1-c1ccccc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cnnn1-c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 9B (crude product) and DIPEA (1.5 mL, 8.4 mmol) in dichloromethane (10 mL), methanesulfonic anhydride (1.17, 6.7 mmol) was added to the mixture. Then it was stirred for overnight. The organic layer was washed with brine twice. The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was purified by flash column (Rf: 0.6, 15% EtOAc/Hexanes) to provide the desired product. MS (m/z) 171 [M+H]+.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[CH3:16][CH:17]([CH2:20][CH3:21])[CH2:18][OH:19]>CCCCCC>[CH3:1][Si:2]([CH3:9])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[O:19][CH2:18][CH:17]([CH3:16])[CH2:20][CH3:21]
Reactant: CCC(C)CO
Reactant: C[Si](C)(Cl)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: CCC(C)CO[Si](C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 ml, three-necked flask was fitted with a large magnetic, egg-shaped stir bar, a small, pressure-equalizing addition funnel, a thermocouple connected to a THERM-O-WATCH®, a reflux condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 28.74 grams (0.168 mole, 1.01 equivalents) of dimethylphenylsilyl chloride, 11.69 grams (0.172 mole, 1.03 equivalents) of imidazole, and 100 mls of hexane. 2-Methyl-1-butanol, 14.69 grams (0.167 mole, 1.00 equivalent), was then added dropwise to the resultant slurry. A very mild exotherm was detected. The total feed time was twelve minutes. A fine white precipitate formed almost immediately. The reaction mixture was heated to 40° C. with a heating mantle, controlled by the THERM-O-WATCH®. A more vigorous exotherm was noted as the heat was applied. The heating mantle was removed. After the exotherm had subsided, the reaction mixture was again heated to 40° C. with the heating mantle. The reaction mixture was stirred overnight at 40° C. The progress of the reaction was monitored by gas chromatography (GC). An aliquot of the clear supernatant was injected into the GC. The sample at 15 hours indicated all the starting material had been consumed, with the formation of a single, higher boiling component. The reaction mixture was allowed to cool to room temperature, then it was transferred to a small, dry, Chemglass pressure filter. The filtrate was collected in a dry, 500 ml flask. The filter cake was rinsed with additional hexane (2×100 ml). The solvent was removed on the rotary evaporator, with the bath temperature set at 40° C.
Reaction SMILES: [C:1]1([NH:7][CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.CC(C)([O-])C.[K+].O1CCCC1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2)CC1
Reactant: FC(F)(F)c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(N(c2ccccc2)C2CCNCC2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A mixture of tert-butyl 4-(phenylamino)piperidine-1-carboxylate (2.30 g, 8 mmol), 1-iodo-3-(trifluoromethyl)benzene (1 ml, 8 mmol), palladium(ii) acetate (0.07 g, 0.3 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.2 g, 0.3 mmol), and potassium tert-butoxide, 1.0M solution in tetrahydrofuran (1 ml, 10 mmol) in toluene (20 mL) was heated at 110° C. for 18 h. The reaction mixture was diluted with EtOAc, filtered, washed with 1N NaOH and brine, and the organic layer was concentrated under vacuum. Conc HCl (20 mL) was added to the residue and the solution was concentrated under vacuum. Conc HCl (20 mL) was added to the residue and the solution was stirred at RT for 8 h and concentrated. The pH was adjusted to 11 with the addition of 1N NaOH solution and the product was extracted with DCM. The DCM layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified with ISCO using 0-15% MeOH in DCM to give product N-phenyl-N-(3-(trifluoromethyl)phenyl)piperidin-4-amine (1.5 g, 56% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([Cl:29])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([N:19]3[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]3)[C:15]2=[O:26])=[C:11]([Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:37]([Si:40](OS(C(F)(F)F)(=O)=O)([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:30])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([N:19]3[CH2:20][CH2:21][CH:22]([O:25][Si:40]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:37]([CH3:39])[CH3:38])[CH2:23][CH2:24]3)[C:15]2=[O:26])=[C:27]([Cl:29])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1N1CCC(O)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Yield: 72 %

Procedure:
Stir a mixture of (R)-3-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-one (1.23 g, 2.75 mmol) and 15 mL of dichloromethane in an ice bath. Add pyridine (0.52 g, 6.6 mmol) followed by triisopropylsilyltrifluoromethane sulfonate (0.924 g, 3.02 mmol). Remove the cold bath and stir the reaction 12 hours at room temperature. Dilute the reaction with dichloromethane and wash with water. Dry the organic phase over sodium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography by eluting with 4:1 hexanes:ethyl acetate to give 1.2 g (72%) of the title compound. MS (m/z): 605 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([F:9])[CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Br)c(F)c1)OCc1ccccc1

Procedure:
To a solution of 10 g of 4-bromo-3-fluoroaniline (52 mmol) in 300 ml acetone were added successively 150 ml of a saturated sodium bicarbonate solution and at 0° C. 9 ml of benzyl chloroformate (63 mmol). The reaction was monitored by TLC. The acetone was evaporated, the residue extracted twice with ethyl acetate, washed with water and brine, dried and evaporated. The residue was crystallized from an ethyl acetate/hexane mixture.
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]([CH:13]=O)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.[CH3:15][N:16]1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:15][NH:16][CH2:13][C:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[N:4]2[CH2:3][CH2:2][CH2:1][C:5]=12
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: O=Cc1c2n(c3ccccc13)CCC2
Product: CNCc1c2n(c3ccccc13)CCC2
Yield: 54 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 2,3-dihydro-1H-3a-azacyclopenta[a]indene-8-carboxaldehyde (0.17 g, 0.92 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.1 g, 54%) was prepared as a yellow oil: MS (ES) m/e 201 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[N:15]=[C:14]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[NH:13][C:12]=3[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[N:15]=[C:14]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[N:13]([CH3:26])[C:12]=3[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c2nc(CC(C)(C)O)[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2nc(CC(C)(C)O)n(C)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30.7 %

Procedure:
To a solution of methyl 4-(4-fluorophenyl)-2-(2-hydroxy-2-methylpropyl)-1H-benzimidazole-6-carboxylate (125 mg, 0.365 mmol) and cesium carbonate (297 mg, 0.913 mmol) in N,N-dimethylformamide (0.730 mL) was added methyl iodide (0.025 mL, 0.402 mmol). Stirred at ambient temperature for 2.5 h. Filtered and purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TFA) gave the title compound (40 mg): LC-MS [M+1]=357.2.
Reaction SMILES: [N:1]1([C:5](=[O:21])[CH2:6][C:7]2[CH:12]=[CH:11][C:10](B3OCC(C)(C)CO3)=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[Cl:32])[NH:28][CH:27]=[C:26]2[CH:33]=[O:34].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>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].CCO>[N:1]1([C:5](=[O:21])[CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][C:31]=3[Cl:32])[NH:28][CH:27]=[C:26]4[CH:33]=[O:34])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: CC1(C)COB(c2ccc(CC(=O)N3CCC3)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(CC(=O)N4CCC4)cc3)cc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a degassed mixture of 1-(azetidin-1-yl)-2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]ethanone (0.78 g, 2.7 mmol), 5-bromo-6-chloro-1H-indole-3-carbaldehyde (700 mg, 2.7 mmol) and 2 M aqueous K2CO3 (5.4 mL, 10.8 mmol) in a solvent mixture of toluene and EtOH (v/v=3/1, 14 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (197.6 mg, 0.27 mmol). The reaction mixture was stirred under microwave irradiation at 120° C. for 30 min. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc (50 mL/50 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (first EtOAc in Petroleum 25%, then MeOH in DCM 10%) to give 5-{4-[2-(azetidin-1-yl)-2-oxoethyl]phenyl}-6-chloro-1H-indole-3-carbaldehyde (0.4 g, 42%) as a brown solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[C:33]([C:42]([OH:44])=O)=[CH:32]1)([CH3:30])[CH3:29].[NH2:45][C:46]1[S:47][CH:48]=[CH:49][N:50]=1>C(Cl)Cl>[S:47]1[CH:48]=[CH:49][N:50]=[C:46]1[NH:45][C:42]([C:33]1[C:34]2[C:39](=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:31]([CH:28]([CH3:29])[CH3:30])[CH:32]=1)=[O:44]
Reactant: Nc1nccs1
Reactant: COc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(C(=O)Nc3nccs3)cn(C(C)C)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A solution of triphenylphosphine (219 mg, 0.84 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (149 mg, 0.84 mmol). The reaction was stirred at 0° C. for 15 min. At this time, the reaction was treated with 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (150 mg, 0.64 mmol). The reaction was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-aminothiazole (148 mg, 1.48 mmol) and stirred at 25° C. for 24 h. At this time, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid thiazol-2-ylamide (101 mg, 50%) as a tan solid: mp 182-185° C.; EI-HRMS m/e calcd for C16H17N3O2S (M+) 315.1041, found 315.1039.