Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]2[C:19]([C:20]([O:22]CC3C=CC=CC=3)=[O:21])=[C:18]([CH3:30])[NH:17][C:16](=[O:31])[N:15]2[C:32](=[O:49])[NH:33][CH2:34][CH2:35][CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:11]=[CH:12][CH:13]=1>[H][H].[Pd]>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]2[C:19]([C:20]([OH:22])=[O:21])=[C:18]([CH3:30])[NH:17][C:16](=[O:31])[N:15]2[C:32](=[O:49])[NH:33][CH2:34][CH2:35][CH:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2cccc(Cl)c2)N(C(=O)NCCC(c2ccccc2)c2ccccc2)C(=O)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)N(C(=O)NCCC(c2ccccc2)c2ccccc2)C(=O)N1

Procedure:
10 ml of ethyl acetate was added to a mixture of 141 mg (0.237 mmol) of benzyl 4-(3-chlorophenyl)-3-(3,3-diphenylpropylcarbamoyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and a catalytic amount of 10% palladium/carbon, and they were stirred at room temperature in hydrogen atmosphere under normal pressure overnight. The catalyst was filtered out, and the obtained filtrate was concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (1/1) and then dried under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5](N(OC)C)=[O:6].[CH2:15]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:16]#[CH:17].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[C:17]#[C:16][CH2:15][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: C#CCOC1CCCCO1
Reactant: CON(C)C(=O)c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(C#CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a mixture of 3,4-dichloro-N-methoxy-N-methyl-benzamide from Example 511 (0.68 g, 2.9 mmol) and tetrahydro-2-(2-propynyloxy)-2H-pyran (0.40 mL, 2.9 mmol) in 3.5 mL of dry THF at −25° C. was added lithium bis(trimethylsilyl)amide (LHMDS, 1 M in THF) between −25° C. and −18° C. The reaction mass was stirred at that temperature range for 1 h. The reaction was quenched with 10 mL of 1 M citric acid and was allowed to warm to 10° C. EtOAc (5 mL) was added and the mass was stirred for 15 min. The pH of the aqueous layer was 5. The layers were separated and the organic layer was concentrated to give a light yellow oil (110%, including residual solvent). HPLC (Method U): Rt=15.42 min. MS (ES+): mass calculated for C15H14Cl2O3, 312.03; m/z found, 325.1 [M+Na]+. 1H NMR (400 MHz, CDCl3): 8.19 (d, J=2 Hz, 1H), 7.95 (dd, J=8.4, 2.1 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 4.94-4.81 (m, 1H), 4.56 (s, 2H), 3.97-3.82 (m, 1H), 3.71-3.55 (m, 1H), 1.91-1.54 (m, 6H). 13C NMR (100 MHz, CDCl3): 175.0, 139.0, 136.0, 133.4, 131.4, 131.2, 130.8, 128.3, 97.7, 92, 82.9, 62.2, 54.2, 30.1, 25.2, 18.9.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=1)[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>CO.O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCCCCN(C)Cc1cc(C)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCN(C)Cc1cc(C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-methyl-5-{[methyl(pentyl)amino]methyl}benzoate (120 mg, 0.46 mmol) in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) is added lithium hydroxide (191 mg, 4.6 mmol), and the reaction mixture stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in methylene chloride, filtered, and the filtrate concentrated under reduced pressure to provide the title compound. ESI MS m/z 250 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].C(O)C.C(=O)(O)[O-].[Na+].[F:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:38][C:37]=1[C:51]1([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:54][CH2:53][CH2:52]1>C1(C)C=CC=CC=1>[F:35][C:36]1[CH:41]=[C:40]([C:2]2[N:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:5]3=[N:4][C:3]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:39]=[CH:38][C:37]=1[C:51]1([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:59])[CH3:60])[CH2:54][CH2:53][CH2:52]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CCC1
Reactant: Cc1ccccc1-c1nc2n(c1Br)-c1cccnc1Nc1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1nc2n(c1-c1ccc(C3(NC(=O)OC(C)(C)C)CCC3)c(F)c1)-c1cccnc1Nc1ccccc1-2
Temperature: 100 °C
Reaction time: 8 h
Yield: 152.1 %

Procedure:
To a suspension of 3-bromo-2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.06 g, 1 eq.) in a mixture of toluene (0.5 mL), ethanol (0.5 mL), and saturated sodium bicarbonate (0.1 mL) was added tert-butyl (1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (0.088 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.017 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (30 mL). The aqueous phase was extracted with dichloromethane (2×30 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (5% ethyl acetate in dichloromethane) gave tert-butyl (1-(2-fluoro-4-(2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.133 g, 40%). M.p.: 138-140° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.63 (s, 1H), 8.13 (d, J=4.4 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.37-7.26 (m, 2H), 7.25-7.13 (m, 5H), 7.08 (t, J=7.4 Hz, 1H), 6.95 (bs. S, 1H), 6.74 (br. S, 1H), 6.69-6.63 (m, 2H), 2.42-2.28 (m, 4H), 2.08 (s, 3H), 2.04-1.94 (m, 1H), 1.76-1.64 (m, 1H), 1.34-1.10 (m, 9H, rotamers from BOC group); LCMS: 588 [M+H].
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16](I)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Br:1][C:2]1[S:3][C:4]([C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:31]#[C:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccccc3)c([N+](=O)[O-])c2)sc1Br

Procedure:
A solution of 2 (150 mg, 0.29 mmol), phenylacetylene (32 μL, 0.29 mmol), Pd(PPh3)2Cl2 (21 mg, 0.03 mmol), K2CO3 (42 mg, 0.29 mmol), and Et3N (40 μL, 0.29 mmol) in DMF (3 mL) was stirred for 24 hours at room temperature. Water (5 mL) was added to the mixture and then extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 3 as a solid foam (101 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=1.6 Hz, 1H), 8.06 (dd, J=1.6, 8.0 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.64 (m, 2H), 7.52 (s, 1H), 7.42 (m, 3H), 3.75 (s, 3H), and 3.70 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 183.9, 170.1, 149.5, 142.2, 137.0, 136.3, 135.7, 135.3, 132.9, 132.5, 130.1, 128.8, 125.6, 124.3, 122.8, 122.1, 101.1, 84.7, 52.7, and 35.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH2:16][NH2:17])[CH:13]=[CH:14][CH:15]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Br:8][C:4]1[N:3]=[C:2]([NH:17][CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: NCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Fc1cccc(CNc2cccc(Br)n2)c1
Temperature: 117.5 °C
Reaction time: 168 h
Yield: 84.3 %

Procedure:
A solution of 2,6-dibromopyridine (7.1 g, 30.0 mmol) in NMP (16 mL) was mixed with a mixture of (3-fluorophenyl)methanamine (4.13 g, 33.0 mmol) and Huenig's Base (5.76 mL, 33.0 mmol). The resulting mixture was stirred under argon at 115-120° C. for about 168 hr. The mixture was then cooled to ambient temperature and diluted with EtOAc (250 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (2×), water (2×), brine (1×), dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude material. The crude material was purified by column chromatography [SiO2, 120 g, EtOAc/hexane=0/100 to 20/80] providing 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (7.11 g) as an off-white solid. LCMS (m/z): 281.1/283.1[M+H]+; Retention time=1.03 min.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Nc1nnc(-c2ccc(Cl)cc2)c(-c2ccccc2)n1
Yield: 55.3 %

Procedure:
6-(4-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (125 mg, 56%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 4-chlorophenylboronic acid (0.12 g, 0.80 mmol) according to the general procedure of Example 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=4)[CH:21]=[C:20]([C:33]([O:35][CH3:36])=[O:34])[C:7]=3[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9]=2[CH:10]=1.[CH3:37][N:38]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:32][C:26]1[CH:25]=[C:24]([C:22]2[CH:21]=[C:20]([C:33]([O:35][CH3:36])=[O:34])[C:7]3[N:8]([CH2:11][C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)[C:9]4[CH:10]=[C:2]([N:41]5[CH2:42][CH2:43][CH2:44][N:38]([CH3:37])[CH2:39][CH2:40]5)[CH:3]=[CH:4][C:5]=4[C:6]=3[N:23]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH3:31]
Reactant: CN1CCCNCC1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nc2c3ccc(Cl)cc3n(Cc3ccc(OC)cc3)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nc2c3ccc(N4CCCN(C)CC4)cc3n(Cc3ccc(OC)cc3)c12
Temperature: 110 °C
Yield: 67.2 %

Procedure:
A microwave vial containing a mixture of methyl 7-chloro-2-(3-fluoro-4-methoxyphenyl)-5-(4-methoxybenzyl)-5H-pyrido[3,2-b]indole-4-carboxylate (60 mg, 0.12 mmol), 1-methyl-1,4-diazepane (41 mg, 0.36 mmol), biphenyl-2-yldi-tert-butylphosphine (14 mg, 0.048 mmol), and Pd(OAc)2 (5.3 mg, 0.024 mmol) was flushed with nitrogen. Toluene (0.5 mL) was added and the vial was sealed and heated at 110° C. for 20 hr. The reaction was partitioned between EtOAc and water, the organic phase was washed with brine and the product was captured on an SCX column, washed with MeOH and then removed with 2 N NH3 in MeOH. The solvent was removed to leave crude methyl 2-(3-fluoro-4-methoxyphenyl)-5-(4-methoxybenzyl)-7-(4-methyl-1,4-diazepan-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (47 mg). This was placed in a microwave vial, TFA (3 mL) and anisole (0.088 mL, 0.81 mmol) were added. The vial sealed and heated at 70° C. for 3 hr. The solvents were removed and the residue was dissolved in MeOH and applied onto an SCX column. This was washed with MeOH and product was released with 2 N NH3 in MeOH to leave crude methyl 2-(3-fluoro-4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (37 mg). This was suspended in 7 N NH3 in MeOH (5 mL) and heated at 80° C. for 15 hr. Preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=100:0 to A:B=40:60 [A=95% H2O:5% MeOH:0.1% TFA; B=5% H2O:95% MeOH:0.1% TFA] over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 2-(3-fluoro-4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-5H-pyrido[3,2-b]indole-4-carboxamide (3.2 mg, 6.8 μmol, 7% yield overall) as an orange solid. MS (ESI) m/z 448.29 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.24 (1H, d, J=8.85 Hz), 8.06 (1H, s), 7.82- 7.94 (2H, m), 7.24 (1H, t, J=8.55 Hz), 6.97 (1H, d, J=2.14 Hz), 6.91 (1H, dd, J=8.85, 2.44 Hz), 3.97 (5H, br. s.), 3.73 (2H, t, J=5.95 Hz), 3.38-3.66 (4H, m), 3.00 (3H, s), 2.28-2.43 (2H, m).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:21])=[C:18]([SH:20])[CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[N:21]=[C:7]([C:6]3[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=3)[S:20][C:18]=2[CH:19]=1
Reactant: COc1ccc(N)c(S)c1
Reactant: CNc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNc1ccc(-c2nc3ccc(OC)cc3s2)cc1
Temperature: 170 °C
Yield: 22.3 %

Procedure:
A mixture of 4-methylaminobenzoic acid (11.5 g, 76.2 mmol) and 5-methoxy-2-aminothiophenol (12.5, g, 80 mmol) was heated in PPA (˜30 g) to 170° C. under N2 atmosphere for 1.5 hr. The reaction mixture was then cooled to room temperature and poured into 10% K2CO3 solution. The precipitate was filtered under reduced pressure. The crude product was re-crystallized twice from acetone/water and THF/water followed by the treatment with active with carbon to give 4.6 g (21%) of 6-Methoxy-2-(4-methylaminophenyl)benzothiazole as a yellow solid. 1HNMR (300 MHz, acetone-d6) δ: 7.84(d, J=8.7 Hz, 2H, H-2′6′), 7.78(dd, J1=8.8 Hz, J2=1.3 Hz, 1H, H-4), 7.52(d, J=2.4 Hz, 1H, H-7), 7.05(dd, J1=8.8 Hz, J2=2.4 Hz, H-5), 6.70(d, J=7.6 Hz, 2H, H-3′5′), 5.62(s, 1H, NH), 3.88(s, 3H, OCH3), 2.85(d, J=6.2 Hz, 3H, NCH3)
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[C:6]3[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]=3[S:13][C:4]=2[CH2:3]1.[C:16]([O:19][CH2:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=1Br)(=[O:18])[CH3:17].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]([O:19][CH2:20][C:21]1[C:22]([N:9]2[CH2:10][CH2:11][C:6]3[C:5]4[CH2:14][C:2]([CH3:15])([CH3:1])[CH2:3][C:4]=4[S:13][C:7]=3[C:8]2=[O:12])=[CH:23][C:24]([F:28])=[CH:25][C:26]=1[Br:27])(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Reactant: CC1(C)Cc2sc3c(c2C1)CCNC3=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 71.1 %

Procedure:
A mixture of 4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-9-one (105h) (2 g, 9.05 mmol), 2,6-dibromo-4-fluorobenzyl acetate (197c) (8.8 g, 27.15 mmol), XantPhos (524 mg, 0.9 mmol), Pd2(dba)3 (828 mg, 0.9 mmol) and Cs2CO3 (5.9 g, 18 mmol) in dioxane (200 mL) was heated at 100° C. for 15 h under nitrogen. The reaction mixture was filtered and the filtrated was evaporated in vacuo. The residue was purified by silical-gel column eluting with 1:1 ethyl acetate/petroleum ether to give 247a as a yellow solid (3 g, 71%). MS: (M+H)+ 466.
Reaction SMILES: C(=[C:3]([C:21](=[O:23])[CH3:22])[C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:5])=O>C(O)(C(F)(F)F)=O.ClCCl>[O:23]=[C:21]([CH3:22])[CH2:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:5]
Reactant: CC(=O)C(=C=O)C(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)CC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Yield: 18 %

Procedure:
A solution of (2R)-benzyl 2-(2-(carbonyl)-3-oxobutanoyl)pyrrolidine-1-carboxylate in TFA (50 mL) and dichloromethane (50 mL) was stirred at room temperature for 1 hr and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% EtOAc) to afford (R)-benzyl 2-(3-oxobutanoyl)pyrrolidine-1-carboxylate (2.1 g, 18% over two steps). LCMS: 6.9 min calculated: 289, found (MH+): 290.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH-].[Na+]>CN1CCCC1=O.CCOC(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[N:12]=1
Reactant: Brc1cccc(Br)n1
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2cccc(Br)n2)cc1F
Temperature: 100 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
A mixture of 3,4-difluorophenol (1.55 g, 11.9 mmol), 2,6-dibromopyridine (2.82 g, 11.9 mmol), and Cs2CO3 (3.88 g, 11.9 mmol) in N-Methyl-2-pyrrolidinone (10 mL) was stirred at 100° C. for 18 h, then was cooled to rt. EtOAc (10 mL) and 1N aq. NaOH (20 mL) were added to the reaction mixture. The organic layer was separated and washed with water (3×) and brine, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo. The crude product was chromatographed (SiO2; continuous gradient of EtOAc/hexanes from 0% to 10% over 12 min) to give the title compound (2.90 g, 10.1 mmol, 85% yield) as a clear oil, which eventually became a white solid. 1H NMR (CDCl3) δ: 7.56 (t, J=7.8 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.18 (q, J=9.1 Hz, 1H), 7.06-7.00 (m, 1H), 6.92-6.87 (m, 1H), 6.85 (d, J=8.1 Hz, 1H); 19F NMR (CDCl3) δ: −134.55 (d, J=21.4 Hz), −142.14 (d, J=21.3 Hz).
Reaction SMILES: [O:1]1CCCO[CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([F:21])[F:20])=[CH:15][CH:16]=2)[C:11]([C:22]2[N:23]=[C:24]3[C:30]([C:31]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][N:28]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:25]3=[N:26][CH:27]=2)=[N:10]1.Cl.C(=O)([O-])O.[Na+]>CC(C)=O>[C:34]([NH:33][C:31]([C:30]1[C:24]2[C:25](=[N:26][CH:27]=[C:22]([C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=4)[N:9]([CH2:8][CH2:7][CH:2]=[O:1])[N:10]=3)[N:23]=2)[N:28]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:29]=1)=[O:32])([CH3:36])([CH3:35])[CH3:37]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC4OCCCO4)c4ccc(OC(F)F)cc34)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC=O)c4ccc(OC(F)F)cc34)nc12
Temperature: 50 °C
Reaction time: 120 h
Yield: 29.7 %

Procedure:
2-(1-(2-(1,3-dioxan-2-yl)ethyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 155 μmol) was dissolved in acetone (3 mL), and HCl 3N (1.2 g, 1 mL, 3.00 mmol9.3) was added. Heated to 50° C. with stirring and continued for 5 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (5×30 mL). The combined organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate 0 to 100% over 20 min) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-oxopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (27 mg, 46.0 μmol, 29.7%) and a small amount of the SEM group de-protection product 2-(1-(2-(1,3-dioxan-2-yl)ethyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (5 mg, 9.72 μmol, 6.27%) as light yellow needles. MS (M+H)+=515; 1H NMR (DMSO-d6) δ: 12.80 (br. s., 1H), 9.08 (s, 1H), 8.37 (s, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.39 (dd, J=9.1, 2.3 Hz, 1H), 7.19 (t, J=74.4 Hz, 1H), 4.45-4.72 (m, 3H), 3.99 (dd, J=11.3, 4.5 Hz, 2H), 3.55-3.75 (m, 2H), 2.07-2.22 (m, 2H), 1.79-1.97 (m, 1H), 1.49 (s, 9H), 1.38 (s, 9H), 134 (m, 1H). Unreacted starting material (34 mg, 34%) was also obtained.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][N:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]3)[CH:3]=1.[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O.ClCCl>[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][N:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]3)[CH:3]=1)([O-:18])=[O:17]
Reactant: Oc1ccc2ncc3c(c2c1)CCCC3
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1COc1ccc2ncc3c(c2c1)CCCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
A mixture of Compound 275 (57.17 g, 287 mmol) , 2-nitrobenzyl bromide (68.19 g, 316 mmol), powdered potassium carbonate (142.0 g, 1.03 mol) and tetra-n-butylammonium iodide (3.18 g, 8.61 mmol) in dry DMF (400 mL) was stirred at 25° C. for 3 hours and then poured into a mixture of ethyl ether (200 mL), dichloromethane (1500 mL), and water (200 mL) with stirring. After allowing this mixture to settle, the aqueous layer was discarded. The organic layer was washed with water (3×1500 mL), dried (MgSO4), and filtered through a 8 cm×8 cm plug of silica with rinsing with ethyl ether (300 mL). The combined filtrates were evaportated in vacuo, and the residue was purified by recrystallization from chloroform-ethyl ether to give 90.41 g (94 percent) of Compound 276: off-white crystalline solid; mp 153°-154° C. Rf=0.48 (silica, 40 percent ethyl acetate in dichloromethane); IR (CHCl3) νmax 2939, 1619, 1526, 1508, 1433, 1342 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1 H, H6), 8.19 (dd, J=7.4, 1.0 Hz, 1 H, aromatic), 7.99 (d, J=9.1 Hz, 1 H, H4), 7.97 (dd, J=7.4, 1.0 Hz, 1 H, aromatic), 7.71 (td, J=7.4, 1.0 Hz, 1 H, aromatic), 7.52 (td, J=7.4, 1.0 Hz, 1 H, aromatic), 7.39 (dd, J=9.1, 2.8 Hz, 1 H, H3), 7.24 (d, J=2.8 Hz, 1 H, H1), 5.61 (s, 2 H, benzylic), 2.99 (t, J= 6.1 Hz, 2 H, H7 or H10), 2.88 (t, J=6.1 Hz, 2 H, H7 or H10), 2.01-1.84 (m, 4 H, H8 and H9); --C NMR (125 MHz, CDCl3) δ 156.0, 150.3, 146.9, 142.4, 140.0, 134.0, 133.9, 133.4, 131.5, 130.1, 128.5, 128.4, 124.9, 119.8, 102.7, 66.7, 27.1, 24.9, 22.3, 22.2; MS (FAB+) m/e (rel intensity) 335 (M+H, 100), 200 (13); HRMS for C20H19N2O3 (M+H), calcd 335.1396, found 335.1394.