Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:8][C:9]([C:11]2[C:12]([O:29][CH3:30])=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:10])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1.CO.O>[F:28][C:25]1[CH:24]=[CH:23][C:22](/[CH:21]=[CH:20]/[C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:9]([NH:8][C:5]4([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]4)=[O:10])[C:12]=3[O:29][CH3:30])[NH:16][N:15]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)C1(NC(=O)c2ccc3[nH]nc(/C=C/c4ccc(F)cc4)c3c2OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1c(C(=O)NC2(C(=O)O)CC2)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a mixed solution of 200 mg of 1-({3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazol-5-carbonyl}-amino)-cyclopropane carboxylic acid methyl ester obtained in Example 1317 in 5 ml of tetrahydrofuran and 2 ml of methanol was added 2 ml of a 1N sodium hydroxide aqueous solution, followed by stirring at room temperature overnight. The reaction mixture was diluted with water and the aqueous layer was washed with diethyl ether. The aqueous layer was adjusted to pH 2 by adding 1N hydrochloric acid, and the precipitated solid was collected by filtration with glass filter. The solid was washed with water and was dried under reduced pressure, to give 151 mg of the title compound as a brown solid.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.CO[C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][N:33](C=O)C>>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([O:25][C:21]3[CH:22]=[CH:23][C:24]([C:32]#[N:33])=[CH:19][CH:20]=3)=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: O=c1[nH]c2ncccc2c2cc(F)ccc12
Reactant: COc1cccc(O)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(Oc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
9-Fluoro-5H-benzo[c][1,8]naphthyridin-6-one (40 mg, 0.19 mmol), 3-methoxyphenol (70 mg, 0.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were suspended in DMF (1.5 mL), and stirred for 20 minutes at 180° C. in the microwave. The reaction mixture was quenched with H2O. The resulting precipitate was filtered and washed with H2O. The precipitate was triturated with MeOH, filtered, washed with MeOH, and dried under vacuum to provide 76 (22 mg, 37% yield) as a brown solid. LC-MS (M+H=319, obsd.=319). 1H NMR (400 MHz, d6-DMSO): δ 11.99 (s, 1H), 8.73 (dd, 1H), 8.50 (dd, 1H), 8.32 (d, 1H), 8.14 (d, 1H), 7.38 (t, 1H), 7.30 (dd, 1H), 7.22 (dd, 1H), 6.83 (dd, 1H), 6.77 (t, 1H), 6.71 (dd, 1H), 3.77 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH2:20][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:22][OH:23])=[CH:18][N:17]([C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].CCN(CC)CC.[CH:43]([N:46]=[C:47]=[O:48])([CH3:45])[CH3:44]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH2:20][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:22][O:23][C:47](=[O:48])[NH:46][CH:43]([CH3:45])[CH3:44])=[CH:18][N:17]([C:27]3[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=3)[C:14]2=[CH:15][N:16]=1)[CH3:10]
Reactant: CC(C)N=C=O
Reactant: CCCC(CO)Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(COC(=O)NC(C)C)Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-pentan-1-ol (100 mg, 0.20 mmol) in DCM (3 mL), DMAP (1 mg), Et3N (60 μL, 0.42 mmol), and isopropyl isocyanate (30 μL, 0.3 mmol) are added, and the mixture is stirred for 18 h at room temperature. All volatiles are removed under reduced pressure, and the product is purified by chromatography on silica gel (EtOAc-hexane, 2:1) to afford isopropyl-carbamic acid 2-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-pentyl ester as colorless oil: LCMS m/z 554.18 (2.71 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([NH:27][C:28](=[O:37])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([C:18](=[O:23])C(Cl)(Cl)Cl)[C:10]=12.[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>CN(C=O)C>[N:42]1[CH:43]=[CH:44][CH:45]=[C:40]([CH2:39][NH:38][C:18]([C:17]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25]([NH:27][C:28](=[O:37])[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[O:26])=[CH:3][C:2]=3[F:1])[NH:15][CH:16]=2)=[O:23])[CH:41]=1
Reactant: NCc1cccnc1
Reactant: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc3[nH]cc(C(=O)C(Cl)(Cl)Cl)c23)c(F)c1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc3[nH]cc(C(=O)NCc4cccnc4)c23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 1-(3-fluoro-4-(3-(2,2,2-trichloroacetyl)-1H-pyrrolo[2,3-b]pyridine 4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea (7.0 mg, 0.012 mmol, Example 270) in 0.5 mL of DMF was added 3-(aminomethyl)pyridine (10 mg, 0.092 mmol, Aldrich). The reaction mixture was stirred at rt for 1 h, and quenched by the addition of 1 mL of cold water. The precipitate that formed was collected by filtration, washed with cold water (1 mL) and cold acetonitrile(1 mL) and dried under vacuum to afford the desired product (4.3 mg, 64%) as a white solid. 1H NMR (DMSO-d6) δ 12.38 (s, 1H), 11.03 (s, 1H), 10.57 (s, 1H), 8.48 (s, 1H), 8.40 (t, 1H, J=5.5 Hz), 8.34 (d, 1H, J=3.3 Hz), 8.11 (d, 1H, J=5.5 Hz), 8.00 (s, 1H), 7.73 (d, 1H, J 13.2 Hz), 7.65 (d, 1H, J=7.7 Hz), 7.37–7.29 (m, 4H), 7.16 (t, 3H, J=8.8 Hz), 6.34 (d, 1H, J=5.5 Hz), 4.48 (d, 2H, J=5.5 Hz), 3.74 (s, 2H); MS(ESI+) m/z 567.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[O:9][C:8]([CH2:10][CH2:11][NH2:12])=[CH:7][C:6]=2[CH:13]=1.C(O)=O.C(O[C:22](=O)[CH3:23])(=O)C.F[C:26](F)(F)C(O)=O>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[O:9][C:8]3[CH2:10][CH2:11][NH:12][C:22]([CH3:23])([CH3:26])[C:7]=3[C:6]=2[CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NCCc1cc2cc(Br)cc(Cl)c2o1
Reactant: CC(=O)OC(C)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(C)=O
Solvent: O=CO
Product: CC1(C)NCCc2oc3c(Cl)cc(Br)cc3c21
Temperature: 90 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
A mixture of the product of step E (75 mg, 0.27 mmol), acetone (3 mL) and titanium tetra-isopropoxide (93 mg, 0.32 mmol), was heated at 90° C. under an argon atmosphere. After 3 h, the reaction mixture was cooled to 0° C. and a solution of formic acid (1.03 mL, 27.3 mmol) and acetic anhydride (4.21 mL, 54.6 mmol) was added. After heating the reaction mixture to 90° C. for 2 h, trifluoroacetic acid was added and the reaction was maintained at 90° C. for 16 h. The reaction mixture was cooled to ambient temperature, quenched with methanol (10 mL) and diluted with 20% methanol/dichloromethane (120 mL). The mixture was passed through a short silica gel column and the filtrate concentrated in vacuo. The residue was dissolved in ethanol (6 mL) and 20% aqueous sodium hydroxide (6 mL) was added. After refluxing for 15 h, the reaction mixture was cooled, diluted with water (30 mL), and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 95:5 dichloromethane/methanol) providing 8-bromo-6-chloro-1,1-dimethyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (45 mg, 52%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.49 (d, J=2.0 Hz, 1H), 7.36 (d, J=1.6 Hz, 1H), 3.24 (t, J=5.6 Hz, 2H), 2.77 (t, J=5.6 Hz, 2H), 1.49 (s, 6H).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[N:11]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=2)C=CC=CC=1.[NH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([N:38]2[C:46]3[CH:45]=[CH:44][N:43]=[CH:42][C:41]=3[CH:40]=[CH:39]2)=[CH:30][CH:29]=1.CO>CS(C)=O.ClCCl>[C:15]([C:13]1[CH:14]=[C:10]([NH:9][C:8]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([N:38]3[C:46]4[CH:45]=[CH:44][N:43]=[CH:42][C:41]=4[CH:40]=[CH:39]3)=[CH:30][CH:29]=2)=[O:26])[N:11]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[N:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: Nc1ccc(-n2ccc3cnccc32)c2ccccc12
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(-n3ccc4cnccc43)c3ccccc23)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester (144 mg, 0.411 mmol, 1.1 equiv.) and 1-(4-aminonaphthalen-1-yl)pyrrolo[3,2-c]pyridine (Example 1) (97 mg, 0.374 mmol, 1 equiv.) were combined in 2 mL anhydrous DMSO. The mixture was stirred under inert atmosphere for 1.5 h, then heated to 60° C. for 0.5 h. The reaction was allowed to cool, quenched with 5% aqueous NaOH and extracted with EtOAc three times. The combined organic extracts were washed with water, then brine. They were then dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was purified by column chromatography using 3-4% MeOH in dichloromethane providing 161 mg title compound (0.313 mmol, 84%) as a glassy solid.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20]COS(C)(=O)=O)[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH3:34].O1CCOC[CH2:36]1>>[CH3:27][O:28][CH2:29][CH2:30][N:31]([CH2:32][CH2:33][CH3:34])[CH2:36][CH2:20][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[O:12]1
Reactant: C1COCCO1
Reactant: CCCNCCOC
Reactant: CS(=O)(=O)OCCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Product: CCCN(CCOC)CCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21

Procedure:
A solution of methanesulfonic acid 2-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-ethyl ester (50 mg, 0.135 mmol) and N-(2-methoxyethyl)-N-propylamine (191 μl, 1.35 mmol) in dioxane (0.8 ml) was heated at 75° C. for 19 hours. The reaction was partitioned between EtOAc and water. The EtOAc layer was washed with water, brine, dried with anhydrous Na2SO4 and rotary evaporated to give brown oil. The brown oil was chromatographed with CHCl3 to give 3-(3-{2-[(2-methoxy-ethyl)-propyl-amino]-ethyl}-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one as a yellow-brown film (11 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH:20]1([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH2:13][CH:26]3[CH2:27][CH2:28][N:23]([CH:20]4[CH2:22][CH2:21]4)[CH2:24][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CCN(C2CC2)CC1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CNCC3CCN(C4CC4)CC3)cc2n1
Yield: 57 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylamine was reacted with 1-cyclopropyltetrahydro-4(1H)-pyridinone using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-cyclopropylpiperidin-4-yl)methyl-amine as a solid (57% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was purified by mass directed chromatography (18% yield) to give 339. NMR (CDCl3, 400 MHz), 0.39-0.47 (4H, m), 1.58-1.66 (3H, m), 1.83 (2H, d, J=12.1), 2.19 (2H, t, J=9.9), 2.36 (3H, s), 2.54-2.58 (1H, m), 3.13 (2H, d, J=11.5), 3.88-3.92 (6H, m), 4.03-4.06 (4H, m), 5.22 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=481
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=O)[CH:9]([S:14]([CH3:16])=O)[CH2:8]2.C[OH:18]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH:10]=[C:9]([S:14][CH3:16])[C:8]2=[O:18]
Reactant: COc1cccc2c1OC(=O)C(S(C)=O)C2
Reactant: CO
Agent: Cl
Product: COc1cccc2c(=O)c(SC)coc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
A mixture of 8-methoxy-3-(methylsulfinyl)chromanone (20 g), methanol (100 ml) and 1N hydrochloric acid (100 ml) is stirred at room temperature for 20 hrs. The methanol is removed at reduced pressure and the aqueous residue is extracted with chloroform. The chloroform extracts are combined, extracted with 1N sodium hydroxide solution, washed with water, dried over MgSO4 and evaporated to give an oil. The oil is heated at 100° C. in 5N hydrochloric acid (100 ml) for 5 hrs. The solution is cooled and the product which precipitated is filtered off. Recrystallization from ethanol gives 8-methoxy-3-(methylthio)chromone (2) as white crystals (12.1 g, 65%), mp 113°-115° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[C:13]([CH:17]=2)=[N:14][O:15][N:16]=3)[C:5]([OH:8])=[CH:6][CH:7]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[C:13]([CH:17]=2)=[N:14][O:15][N:16]=3)[C:5]([O:8][CH3:18])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)cc1-c1ccc2nonc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(Br)cc1-c1ccc2nonc2c1
Temperature: 18 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 5-(3-bromo-6-hydroxyphenyl)benzofurazan (8.70 g, 30 mmol), potassium carbonate (14.42 g, 90 mmol) and methyl iodide (2.83 mL, 45 mmol) in dimethylformamide (100 mL) is stirred at 18° C. for 16 h. The mixture is then treated with water (600 mL) and extracted with ethyl acetate (3×150 mL). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from t-butylmethyl ether-hexane to give 5-(3-bromo-6-methoxyphenyl)benzofurazan as a beige crystalline solid. m.p. 135-137° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N(CC)CC)C.Cl[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH2:7]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])[S:27]([CH:26]=[CH2:25])(=[O:29])=[O:28])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCOC(CNCc1ccccc1)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N(Cc1ccccc1)CC(OCC)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzylamino-acetaldehyde diethyl acetal (14.6 ml, 61.3 mmol) and triethylamine (19.0 ml, 122.0 mmol) in dichloromethane (200 ml) at 0° C. under argon was added 2-chloro-1-ethanesulfonyl chloride (10.0 g, 61.3 mmol). After stirring at rt for 3 h, the reaction mixture was quenched with water (300 ml), extracted with dichloromethane (200 ml×2), washed with brine (150 ml), dried over MgSO4, filtered, and concentrated in vacuo to give the title compound which was used in next step without further purification; 1H NMR (CDCl3): 1.23 (t, 6H), 3.22(d, 2H), 353 (m, 2H), 3.72 (m, 2H), 4.52 (s, 12H), 4.63 (t, 1H), 5.88 (d, 1H), 6.23 (d, 1H), 6.50–6.43 (m, 1H), 7.35 (m, 5H); LCMS: 268 (MH+−46).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:28]=1[N:36]=[C:37]=[O:38])([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:34])[CH3:35])[C:28]=1[NH:36][C:37](=[O:38])[N:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:14][CH:13]=1)([CH3:25])[CH3:26]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1ccc(NCc2ccc(OCC(F)(F)F)cc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(N(Cc2ccc(OCC(F)(F)F)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-isopropylphenyl){(4-(2,2,2-trifluoroethoxy)phenyl)methyl}amine (1.12 g) in toluene (15 mL) was added 2,6-diisopropylphenyl isocyanate (1.1 mL), and the mixture was stirred at overnight room temperature. The reaction mixture was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The obtained crystals were subjected to recrystallization from diisopropyl ether to give N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-{(4-(2,2,2-trifluoroethoxy)phenyl)methyl}urea (0.54 g). melting point: 138° C.
Reaction SMILES: [O:1]1[C:11]2C=CC=[C:7](C(O)=O)[C:6]=2[CH:5]=[CH:4][C:2]1=[O:3].[NH2:15][C:16]1([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.C(OCC)(=[O:34])C>CN(C)C=O>[O:3]=[C:2]1[CH:4]=[CH:5][C:6]([C:7]([NH:15][C:16]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:34])=[CH:11][O:1]1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C(O)c1cccc2oc(=O)ccc12
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccc(=O)oc1
Yield: 60 %

Procedure:
2.37 g (10 mmol) of 5-coumarincarboxylic acid N-hydroxysuccineimide ester and a solution of 1.43 g (10 mmol) of 1-aminocyclohexanecarboxylic acid and 3.04 g (30 mmol) of triethylamine in 20 ml of dimethylformamide were stirred overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with a 10% aqueous potassium hydrogensulfate solution and then saturated brine. After it was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.42 g (60%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.BrC1N=C(O[C@@H]([C@H]2CNC(=O)C2)C)C2N(C3CC3)C=NC=2C=1.[CH3:45][N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52](B3OC(C)(C)C(C)(C)O3)[CH:53]=2)[C:48]2([CH2:66][N:65]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:64]2)[C:47]1=[O:74].C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@@H:11]4[CH2:12][C:13](=[O:16])[NH:14][CH2:15]4)[CH3:10])=[N:7][C:2]([C:52]4[CH:53]=[C:54]5[C:49]([C:48]6([CH2:64][N:65]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:66]6)[C:47](=[O:74])[N:46]5[CH3:45])=[CH:50][CH:51]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: CN1C(=O)C2(CN(C(=O)OC(C)(C)C)C2)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)N(C)C(=O)C32CN(C(=O)OC(C)(C)C)C2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C

Procedure:
In a 5 mL microwave vial, a mixture of (R)-4-((R)-1-((6-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one and (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 2.71 (50 mg, 0.14 mmol), tert-butyl 1′-methyl-2′-oxo-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indoline]-1-carboxylate 7.59 (68 mg, 0.16 mmol), cesium carbonate (140 mg, 0.43 mmol), and PEPPSI-IPr catalyst (8.2 mg, 0.01 mmol) were taken up in dimethoxyethane (1.8 mL) and water (0.9 mL). After evacuating and backfilling with argon, mixture was heated at 100° C. for 90 minutes in a microwave reactor. After cooling to rt, reaction mixture was poured into water and extracted with ethyl acetate. Combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel column chromatography (0-10% methanol/dichloromethane) to yield tert-butyl 6′-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-methyl-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 3.84 (53 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H37N6O5: 573.27; found: 573.27.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=2)[N:4]([CH3:15])[N:3]=1.Br[C:17]1[N:22]=[C:21]2[C:23]([C:34]([O:36][CH3:37])=[O:35])=[CH:24][N:25]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]2=[N:19][CH:18]=1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC>CN(C=O)C.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>[CH3:37][O:36][C:34]([C:23]1[C:21]2=[N:22][C:17]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=4)[N:4]([CH3:15])[N:3]=3)=[CH:18][N:19]=[C:20]2[N:25]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])[CH:24]=1)=[O:35]
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Reactant: Cn1nc(I)c2cc(S(C)(=O)=O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4ccc(S(C)(=O)=O)cc34)nc12
Temperature: 100 °C
Yield: 70.7 %

Procedure:
To a solution of 3-iodo-1-methyl-5-(methylsulfonyl)-1H-indazole (127 mg, 0.37 mmol), methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (128 mg, 0.34 mmol) and Pd(PPh3)4 (20 mg, 0.017 mmol) in DMF (8 mL) was added hexa-N-butylditin (299 mg, 0.51 mmol). The reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 100° C. for 15 hours under nitrogen. After cooling to room temperature, water (40 mL) was added and product extracted with EtOAc (3×30 mL), organics combined dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with EtOAc/petroleum ether=2:1) to give methyl2-(1-methyl-5-(methylsulfonyl)-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (120 mg, 69.7%) as an off-white solid. LCMS: (M+H)+=500; 1H NMR (300 MHz, DMSO): δ 9.43 (d, 1H, J=1.2 Hz), 9.21 (s, 1H), 8.95 (d, 1H, J=1.2 Hz), 8.77 (s, 1H), 8.01 (s, 1H), 6.33 (s, 2H), 4.24 (s, 3H), 4.04 (s, 3H), 3.28 (s, 3H), 1.09 (s, 9H).
Reaction SMILES: [C:1]([O:9][CH:10]([O:14][C:15]([NH:17][CH2:18][C:19]1([CH2:25][C:26]([OH:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[CH:11]([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[C:1]([O:9][CH:10]([O:14][C:15]([NH:17][CH2:18][C:19]1([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[CH:11]([CH3:12])[CH3:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccccc1
Reactant: CC(C)C(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)C(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 1-{[(α-benzoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid (84) (150 mg, 0.38 mmol), benzene (18 mL), and methanol (2 mL) was cooled to 0° C. Trimethylsilyldiazomethane was added slowly at 0° C. until the yellow color persisted. The mixture was stirred at 0° C. for 30 min until the reaction was complete (monitored by TLC). After removing the solvent under reduced pressure, chromatography of the residue on silica gel, eluting with 5% ethyl acetate/hexane gave 98 mg (64%) of the title compound.