Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][C:10](=[O:12])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1.CCCCCC>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10]([OH:12])[CH:9]=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OC1C=CC(c2ccccc2)(c2ccccc2)C1
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a solution of 4,4-diphenyl-2-cyclopenten-1-one (0.30 g) in toluene (3 ml) was added a 1M solution of diisobutylaluminum hydride in n-hexane (2.0 ml) at -5° C. to 4° C. After being stirred for 20 minutes, ethyl acetate (3 ml) and 10% hydrochloric acid (2 ml) was added to the solution successively, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent to give 4,4-diphenyl-2-cyclopenten-1-ol (0.29 g).
Reaction SMILES: [C:1]([O:12][C:13]1[CH:43]=[CH:42][C:16]([C:17]([O:19]C2C=CC(C(OC(CCCCCCCC)C(F)(F)F)=O)=CC=2)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O[C:45]1C=CC(C(OC(CCCCCCCC)C(F)(F)F)=O)=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>O1CCCC1>[C:1]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:42][CH:43]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:45]
Reactant: CCCCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F
Reactant: CCCCCCCCCC(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)OC(CCCCCCCC)C(F)(F)F)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the 4-undecanoyloxybenzoic acid )0.3 g) obtained in (1) above and the 1,1,1-trifluoro-2-decyl-4-hydroxybenzoate (0.3 g) obtained in Example 12, (2) in tetrahydrofuran (about 30 ml) were added dicyclohexylcarbodiimide (0.25 g) and dimethylaminopyridine (0.01 g). The mixture was stirred at room temperature for about 20 hours. The solution was distilled to remove the solvent and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and was distilled to remove the solvent. The residue was purified by silica-gel column chromatography (developer : hexane/ethyl acetate=20/1) to obtain the titled compound (0.21 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:10]1[N:14]2[CH:15]=[CH:16][N:17]=[C:18]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:13]2=[C:12]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[N:11]=1)[C:6]([O:8]C)=O)#[N:2].CO>CCO.[Ni]>[CH3:30][O:29][C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][C:18]1[C:13]2[N:14]([C:10]([CH:5]3[CH2:4][CH2:3][CH2:1][NH:2][C:6]3=[O:8])=[N:11][C:12]=2[C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)[CH:15]=[CH:16][N:17]=1
Reactant: COC(=O)c1ccc(-c2nc(C(CCC#N)C(=O)OC)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Agent: [Ni]
Solvent: CCO
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(C3CCCNC3=O)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Temperature: 75 °C
Reaction time: 7 h
Yield: 40.4 %

Procedure:
To a solution of methyl 4-(3-(4-cyano-1-methoxy-1-oxobutan-2-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzoate (12 g, 22.1 mmol) in EtOH (350 mL) was added Ra—Ni (24 g) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 75° C. for 7 hours. The reaction was complete detected by LCMS. The suspension was filtered through a pad of Celite and the pad was washed with EtOH (20 mL×3). The combined filtrates were concentrated. The residue was purified by column chromatography on silica gel eluted with DCM:MeOH=30:1 to give methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-oxopiperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)benzoate (4.6 g, yield 40%).
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:31]([S:38][C:39](=[O:42])[CH2:40][NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.CN(C=O)C>[CH2:31]([S:38][C:39](=[O:42])[CH2:40][NH:41][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH:16]2[NH:15][C:13](=[O:14])[NH:12][CH:11]2[CH2:10][S:9]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCC(=O)SCc1ccccc1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCC(=O)SCc1ccccc1
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
Biotin 19 (0.156 g, 0.64 mmol) was dissolved in 40 mL of dry THF. To this solution was added EDC (0.123 g, 0.64 mmol) and HOBt (0.098 g, 0.64 mmol) under ice-cold conditions. The reaction was allowed to stir for 30 minutes, followed by addition of 8 (0.139 g, 0.64 mmol) dissolved in minimal amount of DMF. The resulting solution was allowed to stir overnight at RT. Upon removal of the solvent in vacuo, the residue was taken into ethyl acetate and washed with 1 N HCl (2×30 ml), water (2×30 ml) and brine (2×30 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 5 (0.110 g, 42%). 1H-NMR (300 MHz, DMSO) δ 7.31-7.28 (m, 5H), 6.40-6.35 (broad, 2H), 4.37-4.32 (m, 2H), 4.22 (d, J=5.61 Hz, 2H), 4.09 (s, 2H), 3.1-3.0 (m, 1H), 2.88-2.78 (m, 2H), 2.19-2.14 (m, 2H), 1.60-1.48 (m, 6H). MS (ESI): m/z 408.0 [(M+1)]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:15][O-:16].[Na+]>>[CH3:15][O:16][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Product: COc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reaction time: 15 h

Procedure:
A mixture of 5-chloro-2-nitrobenzotrifluoride (5 g, 22.2 mmol) and 0.5M NaOMe (in MeOH) is stirred for 15 h at reflux. After removal of the solvent, the residue is diluted with H2O (40 mL) and extracted with CH2Cl2 (3×150 mL). The organic phase is washed with H2O (30 mL), and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound: ES-MS: 221.0 [M]−; single peak at tR=4.72 min (System 2).
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1(O)[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH:12]=1
Reactant: OC1(c2cnccn2)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C1=C(c2cnccn2)C2CCN1CC2
Temperature: 25 °C
Yield: 73.3 %

Procedure:
Thionyl chloride (0.24 g. 1.55 mmol) was added dropwise to a rapidly stirred solution of 3-(2-pyrazinyl)-1-azabicyclo[2.2.2]octan-3-ol (0.21 g, 1.02 mmol) in dichloromethane (10 ml) at -5° C. The reaction mixture was warmed to room temperature and then refluxed for 3 h. Water (5 ml) was added to the solution, basified to pH >10 with potassium carbonate and extracted with dichloromethane (3×50 ml). The combined extracts were dried (Na2SO4), the solvent removed under vacuum and the residue chromatographed through alumina (Grade II-III) using dichloromethane/methanol (98:2) as eluant to give 3-(2-pyrazinyl)-1-azabicyclo[2.2.2]oct-2-ene as a pale yellow solid (0.14 g), δ (360 MHz, CDCl3) 1.54-1.61 (2H, m, CH2); 1.77-1.95 (2H, m, CH2); 2.63-2.71 (2H, m, CH2 --N); 3.02-3.09 (2H, m, CH2 --N); 3.53-3.56 (1H, m, CH-bridgehead); 7.30 (1H, d, J=1.5 Hz vinyl-H); 8.41 (1H, d, J=2 Hz, pyrazine-H); 8.52 (1H, dd, J=1 and 2 Hz, pyrazine-H) 8.78 (1H, d, J=1 Hz, pyrazine-H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.C([NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(OC(C)(C)C)=O.C(N(CC)C(C)C)(C)C.CCCP(=O)=O>C(Cl)Cl>[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])[CH2:18][CH2:17]1
Reactant: COCCC(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CCCP(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCC(=O)N1CCC(N)CC1
Reaction time: 4.5 h
Yield: 36.2 %

Procedure:
3-Methoxypropanoic acid (225 μL, 2.40 mmol) was added to a solution of 4-(N-Boc-amino)-piperidine (400 mg, 2.00 mmol) in methylene chloride (25 mL) at room temperature. N,N-diisopropylethylamine (1.30 mL, 7.49 mmol) and propylphosphonic anhydride (1.78 mL, 50 wt. % in ethyl acetate, 3.00 mmol) was added, and the solution was stirred for 4.5 h. The reaction mixture was concentrated and partitioned between ethyl acetate (5 mL) and water (5 mL). The organic portion was washed with 0.2M HCl (2 mL), sat. Sodium bicarbonate (5 mL) and brine (5 mL). The solution was then dried over sodium sulfate and concentrated to a white solid. This solid was taken up in methylene chloride (6 mL), and trifluoroacetic acid (3 mL) was added at room temperature. After 1 h the solution was concentrated. The resulting solid was dissolved in methylene chloride (2 mL) and 1M sodium hydroxide (1 mL). This mixture was extracted with methylene chloride (4×2 mL) and ethyl acetate (4×2 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give 135 mg of the title compound, 1-(4-aminopiperidin-1-yl)-3-methoxypropan-1-one (36% over two steps). 1H NMR (300 MHz, CD3OD) δ 4.51-4.41 (m, 1H), 4.03-3.93 (m, 1H), 3.64 (d, J=6.3 Hz, 2H), 3.32 (s, 3H), 3.17-3.05 (m, 1H), 2.96-2.83 (m, 1H), 2.75-2.55 (m, 3H), 1.99-1.80 (m, 2H), 1.40-1.14 (m, 2H).
Reaction SMILES: C(O)(=O)C.[CH3:5][NH:6][C:7]1[N:11]=[C:10]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)OCC[O:21]3)[CH:15]=2)[CH3:13])[O:9][N:8]=1>O>[CH3:5][NH:6][C:7]1[N:11]=[C:10]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:21])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:15]=2)[CH3:13])[O:9][N:8]=1
Reactant: CNc1noc(C(C)c2cccc(C3(c4ccccc4)OCCO3)c2)n1
Solvent: CC(=O)O
Solvent: O
Product: CNc1noc(C(C)c2cccc(C(=O)c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To the mixture of acetic acid (16 ml) and water (4 ml) was added 3-methylamino-5-(1-(3-(2-phenyl-1,3-dioxolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole (0.643 g, 2.44 mmol). After the mixture was stirred at room temperature overnight, the mixture was evaporated under reduced pressure to a residue, which was extracted with dichloromethane after saturated NaHCO3 aq. was added. The extracts were washed with water, dried with anhydrous magnesium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed and recrystallized with ethyl acetate and n-hexane to afford 3-methylamino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (0.446 g, 59% yield) as crystalline material: mp 100°-101° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:10]=2[CH3:26])[CH:7]=1.C[Sn](C)(C)[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[N:36]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:11]1[C:10]([CH3:26])=[C:9]([NH:8][C:6]2[CH:7]=[C:2]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[N:36]=3)[CH:3]=[CH:4][C:5]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(Br)ccc1N1CCOCC1
Reactant: CC(=O)Nc1nccc([Sn](C)(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nccc(-c2ccc(N3CCOCC3)c(Nc3c(C)c(-c4ccccc4F)nc4ccccc34)c2)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of N-(5-bromo-2-morpholinophenyl)-2-(2-fluorophenyl)-3-methylquinolin-4-amine (100 mg, 203 μmol), N-(4-(trimethylstannyl)pyrimidin-2-yl)-acetamide (91 mg, 305 μmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 20 μmol) in toluene (4.00 mL) was purged with nitrogen and heated to gentle reflux. After 3.5 h LC-MS indicated no starting bromide remained and the reaction was removed from heat and left stirring overnight at rt before concentrating under reduced pressure. The concentrate was dissolved in 3 mL DMF and purified by reversed-phase HPLC. Mass Spectrum (ESI) m/e=549.3 (M+1).
Reaction SMILES: C1(N=C=O)C=CC=CC=1.COC(=O)C1C=CC=CC=1NC(C1C2C(OC(C)(C)O2)C(N2C=NC3C2=NC=NC=3[NH:41][C:42]([NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:43])O1)=O>>[C:45]1([NH:44][C:42]([NH2:41])=[O:43])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COC(=O)c1ccccc1NC(=O)C1OC(n2cnc3c(NC(=O)Nc4ccccc4)ncnc32)C2OC(C)(C)OC12
Solvent: O=C=Nc1ccccc1
Product: NC(=O)Nc1ccccc1

Procedure:
Phenyl isocyanate was coupled with the amide product using a method similar to those described above, affording the intermediate phenylurea compound. MW calculated for C30H29N7O7 (MH+) 600, found 600 by LCMS.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:7]=2[C:16]2[C:17]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:18]=3[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH2:3][CH2:2]1.CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:13][C:9]1[C:10]([CH3:12])=[CH:11][C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[C:7]([C:16]2[C:17]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:18]=3[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc([N+](=O)[O-])c(C)cc4OCC4CC4)cn(C)c(=O)c32)cc1
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(N)c(C)cc4OCC4CC4)cn(C)c(=O)c32)cc1

Procedure:
Example 263c was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 263b for the product of Example 2b to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-])=O)[C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.[Cl-].[Na+].O.[Fe]>[NH2:17][C:11]1[C:10]([O:20][CH3:21])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: COc1c(OCc2ccccc2)ccc(C#N)c1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(OCc2ccccc2)ccc(C#N)c1N
Yield: 87.6 %

Procedure:
A degassed solution of 4-(benzyloxy)-3-methoxy-2-nitrobenzonitrile (185 g, 651 mmol) in glacial acetic acid (3500 mL) and water (10 mL) was cooled to 5° C. and treated with iron powder (182 g, 3.25 mol). After 3 days the reaction mixture was filtered through Celite, and the filtrate concentrated under reduced pressure. The oil, thus obtained, was treated with brine, neutralized with a sodium bicarbonate solution and extracted into DCM. The resulting emulsion was filtered through Celite after which the organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated under reduced pressure to afford the title compound as a solid (145 g, 88%): 1H NMR (DMSO-d6) δ: 7.32-7.44 (5H, m), 7.15 (1H, d), 6.47 (1H, d), 5.69 (2H, s), 5.15 (2H, s), 3.68 (3H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[NH:10][CH:9]=[CH:8]2.Br[CH2:16][CH2:17][CH2:18][Cl:19].O>CN(C)C=O>[Cl:19][CH2:18][CH2:17][CH2:16][O:14][C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COc1cc2cc[nH]c2cc1O
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2cc[nH]c2cc1OCCCCl
Temperature: -5 °C
Reaction time: 0.75 h
Yield: 108.6 %

Procedure:
To a stirred suspension of sodium hydride (0.94 g, 19.6 mmol of a 50% oil dispersion) in dimethylformamide (20 ml) under nitrogen and cooled to -5° C. was added, dropwise, 5-methoxy-6-hydroxyindole (3.2 g, 19.6 mmol) dissolved in dimethylformamide (60 ml) so that the temperature did not exceed -2° C. After complete addition, the reaction was stirred for 45 minutes at 0° C. While maintaining the reaction temperature between -5° C. and 0° C., a solution of 1-bromo-3-chloropropane (3.1 g, 19.6 mmol) dissolved in dimethylformamide (15 ml) was slowly added. The mixture was stirred at ambient temperature under nitrogen for 21 hours. The reaction was cooled in an ice bath, and water was added to destroy the excess sodium hydride, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4 and concentrated to yield 5.3 g of a dark, oily liquid. This was combined with an additional sample, for a total of 10.0 g, and purification by preparative HPLC (Waters Associates prep LC/System 500) provided 5.1 g of a brown solid. A 2.5 g sample was recrystallized from isopropyl alcohol to yield 1.1 g (30%) of 6-(3-chloropropoxy)o5-methoxyindole as beige crystals, m.p.=73°-75° C.
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[C:16]([O:17][CH2:18][CH2:19][CH3:20])=[CH:15][C:14]2[C:13]([CH3:22])([CH3:21])[CH2:12][CH2:11][C:10]([CH3:24])([CH3:23])[C:9]=2[CH:8]=1)\[CH3:6])/[CH:3]=O.[OH-].[Na+].[CH3:27][C:28]([CH3:30])=[O:29]>>[F:1]/[C:2](=[C:5](/[C:7]1[C:16]([O:17][CH2:18][CH2:19][CH3:20])=[CH:15][C:14]2[C:13]([CH3:22])([CH3:21])[CH2:12][CH2:11][C:10]([CH3:23])([CH3:24])[C:9]=2[CH:8]=1)\[CH3:6])/[CH:3]=[CH:27]/[C:28](=[O:29])[CH3:30]
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C)(C)CCC2(C)C
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=O)C(C)(C)CCC2(C)C
Reaction time: 0.67 h

Procedure:
To a solution of (E)-2-fluoro-3-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enal (Intermediate 8, 208 mg, 0.63 mmol) in acetone (2 mL) was added 1M NaOH (2 mL) at 0° C. The mixture was stirred for 40 min, quenched with 2M H2SO4 (2 mL), and was stirred for 10 min. The mixture was then extracted with Et2O (×3). The combined organic layer was washed successively with brine, NaHCO3, brine, was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5%→10%→20% EtOAc-hexane) to give the title compound (35 mg) and the intermediate β-hydroxy ketone (173 mg), which was converted to the title compound using catalytic para-tolunesulfonic acid (PTSA) in refluxing benzene.
Reaction SMILES: O1CCCC1.[C:6]([C:8]1([OH:26])[C:19]([CH3:24])([C:20]([F:23])([F:22])[F:21])[CH2:18][C:11]2([O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]2)[CH:10]=[C:9]1[CH3:25])#[CH:7].[CH2:27]([SnH:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:17][CH:13]1[CH:14]([CH3:16])[O:15][C:11]2([CH2:18][C:19]([CH3:24])([C:20]([F:21])([F:23])[F:22])[C:8](/[CH:6]=[CH:7]/[Sn:31]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:27][CH2:28][CH2:29][CH3:30])([OH:26])[C:9]([CH3:25])=[CH:10]2)[O:12]1
Reactant: C#CC1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2
Reactant: CCCC[SnH](CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C/C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.4 %

Procedure:
Under argon, tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.02 mmol) was initially charged in a round-bottom flask that had been dried by heating, and abs. tetrahydrofuran (5 ml) and 8-ethynyl-2,3,7,9-tetramethyl-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-ol (100 mg, 0.33 mmol) were added. Stirring at room temperature for 5 minutes was followed by the addition of tributyltin hydride (0.11 ml, 0.39 mmol). The resulting reaction mixture was stirred at 55° C. for 1 h and, after cooling to room temperature, water was added. The aqueous phase was repeatedly extracted thoroughly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), it was possible to obtain 2,3,7,9-tetramethyl-8-[(E)-2-(tributylstannyl)vinyl]-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-ol (160 mg, 82% of theory) in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.33/6.31 (d, 1H), 5.97/5.92 (d, 1H), 5.51/5.42 (s, 1H), 4.24/3.64 (m, 2H), 2.46/2.35 (d, 1H), 1.92 (br. s, 1H, OH), 1.91/1.87 (d, 1H), 1.64/1.62 (s, 3H), 1.49 (m, 6H), 1.32-1.26 (m, 9H), 1.18 (m, 3H), 0.89 (m, 18H).
Reaction SMILES: [CH:1]1([C@@H:4]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[N:11](COCC[Si](C)(C)C)[CH:10]=2)=[O:8])[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C@@H:4]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[NH:11][CH:10]=2)=[O:8])[CH3:5])[CH2:3][CH2:2]1
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CC1
Reaction time: 0.5 h

Procedure:
A solution of crude 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide (70 mg, 0.134 mmol), 2 mL of dichloromethane and 2 mL of trifluoroacetic acid was stirred 1 h, then concentrated to a yellow solid. The solid was dissolved in 2 mL of dichloromethane and 1 mL of ethylenediamine, and the yellow solution was stirred 30 min. Water (20 mL) was added. The resultant precipitate was isolated by Buchner filtration, rinsing well with water then dichloromethane, and dried by air then in vacuo to afford 33 mg (56%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide as a pale yellow solid. MS: (M+Na)+=417; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H), 8.46 (d, J=8.69 Hz, 1H), 8.42 (s, 1H), 8.14 (d, J=7.93 Hz, 1H), 8.00 (d, J=1.51 Hz, 1H), 7.27 (dd, J=8.50, 1.70 Hz, 1H), 4.17 (s, 3H), 3.55-3.70 (m, 1H), 1.34 (d, J=6.80 Hz, 3H), 1.00-1.16 (m, 1H), 0.56 (td, J=8.31, 3.40 Hz, 1H), 0.42-0.50 (m, 1H), 0.26-0.41 (m, 2H).