Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([NH:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:32])[CH3:31]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC1=C2C=C[C@H]3[C@@H]4CC[C@H](C(=O)NC(C)(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A solution of 4-amino-N-(1,1-dimethylethyl)-3-oxoandrosta-4,6-diene-17β-carboxamide (0.9 g, 2.34 mmole) in acetic anhydride (3 mL) and pyridine (6 mL) was stirred overnight at room temperature. Water was added and the mixture was stirred for 3 hours. The solids were collected by filtration to give a brown solid which was purified by flash chromatography (hexane-50% ethyl acetate, ethyl acetate) to give 4-acetamido-N-(1,1-dimethylethyl)-3-oxoandrosta-4,6-diene-17β-carboxamide (0.29 g, 30.4%, diethyl ether-hexane). IR 3442, 3382, 1664, 1616 cm-1 ; MS (CI) m/z 427 (100%, M+ +1); (EI) m/z 426 (65%, M+), 57 (100%); 1H NMR (CDCl3) δ 0.78 (3H, s, C18 -Me), 1.13 (3H, s, C19 -Me), 1.35 (s, 3× tBu-Me's), 2.14 (s, Ac-Me), 5.13 (1H, s, NHCOBu), 6.16 (2H, s, C6 -H+C7 -H), 7.12 (1H, NHAc); 13C NMR (CDCl3) δ 124.65, 124.89, 139.95, 153.20, 168.74, 171.44, 194.93. This compound has the following structure: ##STR4##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[C:11](I)[C:10]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[N:9]2)=[CH:5][CH:4]=1.[CH3:22][C:23]1[N:28]=[C:27]([O:29][C:30]2[S:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[N:34]=2)[CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.O.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]>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:33]3[N:34]=[C:30]([O:29][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:22])[N:28]=4)[S:31][CH:32]=3)[C:10]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(I)c(C(=O)N(C)OC)n2)cc1
Reactant: Cc1cccc(Oc2nc(B3OC(C)(C)C(C)(C)O3)cs2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2cc(-c3csc(Oc4cccc(C)n4)n3)c(C(=O)N(C)OC)n2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
According to Scheme 5, Step 4: A mixture of 1-(4-methoxybenzyl)-4-iodo-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide (0.59 mmol, 238 mg), 2-(6-methylpyridin-2-yloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (0.49 mmol, 157 mg), PdCl2(dppf) (49 μmol, 40 mg) and N-ethyl-N-isopropylpropan-2-amine (0.99 mmol, 0.17 mL) in dioxane/water (1:1, 3.3 mL) was stirred at 120° C. for 30 minutes under microwave conditions. The reaction mixture was filtered through a pad of celite and was washed with DCM. The organic phase was washed with water, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude mixture was purified by flash chromatography over silica gel using cyclohexane/EtOAc (90:10 to 70:30) as eluent to yield 1-(4-methoxybenzyl)-N-methoxy-N-methyl-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazole-3-carboxamide (99 μmol, 46 mg, 15%) as an oil.
Reaction SMILES: CC([O-])(C)C.[Na+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH2:15][CH3:16]>C1COCC1.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]1([C:14](=[O:17])[CH:15]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(=O)c1ccccc1
Reactant: Clc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C(=O)c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 97 %

Procedure:
Pd(OAc)2 (4.5 mg, 0.020 mmol), Tri-cyclohexyphosphine (5.6 mg, 0.020 mmol) and NaOtBu (144 mg, 1.50 mmol) were suspended in 1 mL of THF in a screw-capped vial. The vial was sealed with a cap containing a PTFE septum and removed from the dry box. Chlorobenzene (113 mg, 1.00 mmol) and propiophenone (144 mg, 1.10 mmol) were added to the reaction mixture by syringe. The reaction mixture was stirred at 50° C. and monitored by GC analysis. The crude reaction was diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc=95/5) to give 204 mg (97%) of 1,2-Diphenyl-1-propanone.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:21]1[C:22]([F:28])=[N:23][CH:24]=[CH:25][C:26]=1[F:27])=[CH:11][CH:10]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1>O1CCOCC1.O.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[F:28][C:22]1[C:21]([C:12]2[CH:13]=[C:14]3[C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]4[CH:3]=[C:2]([C:40]5[CH2:41][CH2:42][O:37][CH2:38][CH:39]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[C:26]([F:27])[CH:25]=[CH:24][N:23]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3c(F)ccnc3F)ccc1Oc1cnc(Cl)cc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CO1)c1cc(-c3c(F)ccnc3F)ccc1Oc1cnc(C3=CCOCC3)cc12
Temperature: 110 °C

Procedure:
A glass microwave reaction vessel was charged with (S)-3-chloro-7-(2,4-difluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.190 g, 0.474 mmol), potassium phosphate (0.302 g, 1.422 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.169 g, 0.806 mmol) and bis(di-tert-butylphenylphosphine)dichloropalladium (II) (0.029 g, 0.047 mmol) in dioxane (4 mL) and water (1.2 mL). The reaction mixture was heated in microwave at 110° C. for 30 min. The mixture was diluted with EtOAc and saturated Na2CO3. The organic layer was washed twice with saturated Na2CO3, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (2-10% MeOH—CH2Cl2) to provide a residue that was purified by HPLC to provide the titled compound as a white solid. MS m/z=449.2 [M+H]+. Calculated for C24H18F2N4O3: 448.13.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4].O.C(OCC1C=CC=CC=1)[C@@H]1OC1>CC(O)=O.C1COCC1>[C:1]([O:6][CH2:7][C@H:8]1[O:10][CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC1CO1
Agent: c1ccc(COC[C@H]2CO2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)OC[C@@H]1CO1
Yield: 44 %

Procedure:
Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (+/−)-glycidyl butyrate (4.32 g, 30.0 mmol), AcOH (32 mL, 0.6 mmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-glycidyl butyrate 5d (1.90 g, 13.2 mmol, 44%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 torr). The product was determined to be >99% ee by conversion to and analysis of the 2-napthylsulfide (obtained by ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C.; Chiralcel OD, 97:3 hexanes:EtOH, 1 mL/min, 260 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]2[CH2:13][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C:10](=[O:20])[O:9]2)=[CH:4][CH:3]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>O1CCOCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]([OH:9])[CH2:13][N:12]([CH2:11][C:10]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccccc2)CC(COc2ccc(Cl)cc2)O1
Reactant: CC(C)N
Solvent: C1COCCO1
Product: CC(C)NC(=O)CN(CC(O)COc1ccc(Cl)cc1)c1ccccc1
Reaction time: 8 h
Yield: 10.5 %

Procedure:
After 7.0 g (0.22 moles) of 6-(p-chlorophenoxymethyl)-4-phenyl-2-morpholinone and 20 g of isopropylamine were dissolved in 50 ml of dioxane and the resulting Solution was left to stand overnight at room temperature, the reaction mixture was concentrated in vacuo. The residue was solidified by addition of a small amount of ether. The solid was filtered, washed with ether and dried to give 8.7 g of the product. Recrystallization from ethanol afforded 5.5 g (66.3%) of crystals, with a melting point of 140.5° to 142.5°.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([O:22]CC)=O)([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.[CH2:25]([Mg]Cl)[CH2:26][CH3:27].[Cl-].[NH4+]>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Si:1]([O:18][CH2:19][C:20]1([OH:22])[CH2:25][CH:26]1[CH3:27])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCC[Mg]Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC1CC1(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
According to the description in a reference (see: Syn. Lett. 07, 1053-1054, 1999), the title compound was prepared as follows. 50 g (146 mmole) of ethyl 2-{[t-butyl(diphenyl)silyl]oxy}acetate was dissolved in 700 ml of tetrahydrofuran (THF) and 30.0 ml of titaniumtetraisopropoxide was added thereto. To the mixture was slowly added 290 ml of propylmagnesiumchloride (2.0M in THF) at −10° C., and the reaction solution was stirred for 12 hours at room temperature. 200 ml of saturated ammonium chloride was added to stop the reaction. The tetrahydrofuran (THF) used as a solvent was removed by distillation under reduced pressure, and the reaction mixture was extracted twice with 2000 ml of n-hexane. The n-hexane extract was distilled under reduced pressure and purified by silica gel column to give 42 g of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[N+:14]([C:10]1[C:8]2[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: COC(=O)c1cc2cccc([N+](=O)[O-])c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cccc([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a suspension of 7-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester (1.0 g) in THF/MeOH (40 mL/40 mL) was added 8.4 mL (2.0 eq) of 1N NaOH. The reaction was stirred at room temperature for 2 h. The solvent was removed in vacuo. The residue was diluted with H2O/EtOAc, acidified with 3N HCl and extracted with EtOAc. The organics were dried over MgSO4, filtered and concentrated to give 7-nitro-benzo[b]thiophene-2-carboxylic acid as a light yellow solid (928 mg, 98% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.N1C=CN=C1.[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To a stirring solution of 4-bromo-2,6-dimethylphenol (6 g, 29.85 mmol) in CH2Cl2 (80 mL) at 0° C. was added imidazole (4.1 g, 59.70 mmol) and triisopropylsilyl chloride (7.1 mL, 32.84 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:9) to afford (4-bromo-2,6-dimethylphenoxy)triisopropylsilane as a colorless oil (1.6 g, 15%): 1H NMR (300 MHz, DMSO-d6): δ 7.19 (s, 2 H), 2.20 (s, 6 H), 1.29 (m, 3 H), 1.10 (d, J=7.2 Hz, 18 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (5:95); Rf=0.70.
Reaction SMILES: [CH2:1]([CH:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16]C)[C:13]([CH2:18][CH2:19][CH:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][C:11]=1[O:35]C)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].B(Br)(Br)Br.CO.Cl>ClCCl.O>[CH2:29]([CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][CH2:18][C:13]1[CH:12]=[C:11]([OH:35])[C:10]([CH2:9][CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:15][C:14]=1[OH:16])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCC(CCCCCC)CCc1cc(OC)c(CCC(CCCCCC)CCCCCCCC)cc1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCCCCCCCC(CCCCCC)CCc1cc(O)c(CCC(CCCCCC)CCCCCCCC)cc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
1,4-Bis-(3-hexyl-undecyl)-2,5-dimethoxy-benzene (7.000 g; 11.38 mmol) is dissolved in anhydrous dichloromethane (115 cm3) before cooling down the solution to −78° C. Neat boron tribromide (2.69 ml; 28.5 mmol) is added dropwise over 15 minutes. The resulting mixture is stirred at −78° C. for 1 hour before being warmed to 23° C. for 18 hours. Methanol (25 cm3) and then diluted HCl (75 cm3) is added before pouring the reaction mixture into water. The organic layer is separated and the aqueous layer extracted tow times with diethyl ether (2×250 cm3). The organic fractions are combined, dried over magnesium sulfate and the solvents removed under vacuum. The crude product is used, as it, without further purification (6.51 g, Yield: 97%). NMR (1H, 300 MHz, CDCl3): δ 6.54 (s, 2H); 4.24 (br, 2H); 2.47 (m, 4H); 1.51 (m, 4H); 1.26 (m; 50H); 0.88 (t, J=6.7 Hz, 12H).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:8][C:9]1([C:32]([O:34]CC)=O)[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][C:27]([CH3:29])=[N:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:16][N:17]=[C:10]12.[Cl-].[NH4+].O>C1COCC1>[F:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:8][C:9]1([C:32](=[O:34])[CH3:1])[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][C:27]([CH3:29])=[N:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:16][N:17]=[C:10]12
Reactant: C[Mg]Br
Reactant: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(C)=O)ccc1-c1cnc(C)o1

Procedure:
Methylmagnesium bromide (12% THF solution, 13 mL) was added to a mixture of ethyl 8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1.60 g) in THF (16 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, and methylmagnesium bromide (12% THF solution, 13 mL) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and further recrystallized from ethyl acetate/hexane to give the title compound (121 mg).
Reaction SMILES: [CH3:1][C:2]1[N:40]=[C:5]2[N:6]([CH2:33][CH:34]([OH:39])[C:35]([F:38])([F:37])[F:36])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C>[CH3:1][C:2]1[N:40]=[C:5]2[N:6]([CH2:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(O)C(F)(F)F)c2nc(C)nn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C(F)(F)F)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(3,3,3-trifluoro-2-hydroxypropyl) [1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.41 g), Dess-Martin reagent (0.47 g) and acetonitrile (10 mL) was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate and sodium thiosulfate-pentahydrate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.18 g, 43%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.C[CH2:23][O:24]C(C)=O>CN(C=O)C.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]>[F:8][C:5]1[CH:4]=[C:3]2[C:2]([C:23](=[O:24])[NH:12][C:9]32[CH2:11][CH2:10]3)=[CH:7][CH:6]=1
Reactant: NC1(c2cc(F)ccc2Br)CC1
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1NC2(CC2)c2cc(F)ccc21
Temperature: 25 °C
Yield: 65.2 %

Procedure:
A solution of 1-(2-bromo-5-fluoro-phenyl)-cyclopropylamine (4.2 g, 18.3 mmol), Pd(dppf)Cl2 (0.42 g), DIPEA (7 g, 54.8 mmol) in 40 mL of DMF was heated at 130° C. under 2 MPa of CO for 12 hours. After it was cooled to room temperature, EtOAc was added it was washed with brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography to give title compound (0.3 g, yield 65.2%) as a solid; meanwhile, 3.3 g of starting material was recovered.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:16]=[C:15]3[C:17]([C:20](O)=[O:21])=[CH:18][NH:19][C:14]3=[N:13][CH:12]=2)=[N:3]1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:23]([NH:27][C:20]([C:17]1[C:15]2[C:14](=[N:13][CH:12]=[C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[N:3]=3)[N:16]=2)[NH:19][CH:18]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2ccccc21
Yield: 32.9 %

Procedure:
2-(1-Methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (120 mg, 0.41 mmol), tert-butylamine (0.1 mL, 0.9 mmol) and HATU (233 mg, 0.61 mmol) in 20 mL of dry THF was stirred for 4 hours. The reaction mixture was evaporated to dryness, 20 mL of 0.5N HCl were added to the residue, product extracted with ethyl acetate (3×50 mL), combined organics dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with ethyl acetate/petroleum ether=2:1) to give N-tert-butyl-2-(1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (47 mg, 33.7%). LCMS: (M+H)+=349; 1H NMR (300 MHz, DMSO): δ 12.75 (s, 1H), 9.07 (s, 1H), 8.48 (d, 1H, J=7.8 Hz), 8.35 (s, 1H), 7.96 (s, 1H), 7.5 (d, 1H, J=7.8 Hz), 7.49 (t, 1H, J=7.5 Hz), 7.27-7.22 (m, 1H), 4.17 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:2]=1.C=O.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:21][C:1]1[CH:6]=[CH:5][C:4]2[S:7][CH2:8][CH2:9][N:10]([C:11]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:20])[CH2:24][C:3]=2[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(SCCNC(=O)OCc2ccccc2)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CCS2
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of compound 25(120 mg), paraformaldehyde (120 mg, excess), p-toluenesulfonic acid (40 mg) in toluene (10 mL) was stirred at 70° C. for 24 h. The reaction mixture was filtered and washed with sat. NaHCO3 (2×5 mL). Removal of the solvent gave product 26 as a pure product by TLC and NMR. Yield: 110 mg, 89%.
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[CH:6]([O:7]2)[CH2:5][N:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[N-:14]=[N+:15]=[N-:16].[Na+].[NH4+].[Cl-]>COCCO>[N:14]([CH:8]1[CH:2]([OH:1])[CH2:3][N:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH:6]1[OH:7])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)N1CC(O)C2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: COCCO
Product: CCOC(=O)N1CC(O)C(N=[N+]=[N-])C(O)C1
Temperature: 125 °C
Yield: 26 %

Procedure:
To a solution of Compound 239G (2.0 g, 10.7 mmol) in 2-methoxyethanol (40 mL) was added NaN3 (3.5 g, 53.4 mmol) and NH4Cl (2.3 g, 42.72 mmol). The reaction mixture was heated at 125° C. overnight. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was taken into EtOAc (50 mL), washed with water (10 mL×2) and dried over anhydrous Na2SO4. Concentration in vacuo followed by flash chromatography (hexane-EtOAc: 1:1 to 1:2) on silica gel afforded 0.64 g of 239I (higher Rf) as a crystalline material. The stereochemistry was confirmed by a single x-ray crystallographic determination.