Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41]([OH:43])=O)[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23].CCN(C(C)C)C(C)C.[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH2:57]>C(Cl)Cl>[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH:57][C:41]([C:26]1[CH:27]=[C:28]2[C:33](=[C:24]([CH:22]([OH:21])[CH3:23])[CH:25]=1)[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])=[O:43]
Reactant: CN(C)CCN
Reactant: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.3 %

Procedure:
TSTU (104 mg, 0.34 mmol) at 25° C., was added portionwise to 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (110 mg, 0.34 mmol) and DIPEA (0.066 mL, 0.38 mmol) suspended in DCM (1 mL) under nitrogen. The resulting mixture was stirred at 25° C. for 1.5 hrs. N1,N1-dimethylethane-1,2-diamine (0.038 mL, 0.34 mmol) was then added and the mixture stirred at 25° C. for 30 minutes. The mixture was poured onto a silica gel column and purified by flash chromatography eluting with 5% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness, the residue was triturated in diethyl ether, collected by filtration and dried to afford N-(2-(dimethylamino)ethyl)-8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (80 mg, 0.205 mmol, 59.6%) as a off-white solid. Mass Spectrum: M+H+ 390.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[NH2:19])=[CH:12][CH:11]=2)=[CH:5][C:4]=1[O:23][CH3:24])#[N:2].C(N(CC)CC)C.Cl[C:33]([O:36]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>C(Cl)Cl>[CH3:21][C:18]1([CH3:20])[C:17](=[O:22])[N:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([O:23][CH3:24])[CH:5]=3)=[CH:15][CH:14]=2)[C:33](=[O:36])[NH:19]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccc(NC(=O)C(C)(C)N)cc2)ccc1C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cc2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
N1-(4-{[4-cyano-3-(methyloxy)phenyl]oxy}phenyl)-2-methylalaninamide (Intermediate 191, 77.0 mg) was dissolved in DCM (10 mL). Triethylamine (0.218 mL, 1.57 mmol) was added and the obtained mixture was cooled at 0° C. Bis(trichloromethyl)carbonate (68.1 mg, 0.22 mmol) was dissolved in 5 mL of DCM and the obtained solution was added dropwise to the reaction mixture. The reaction mixture was stirred at 0° C. After 15 min, the reaction mixture was evaporated in vacuo to obtain the crude product that was purified by silica gel chromatography (from 100:0 to 50:50 Cyclohexane/EtOAc in 10 CV; then 50:50 Cyclohexane/EtOAc for 10 CV) to obtain 65.1 mg of the title compound as a white solid
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:22][CH2:23][C@H:24]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.CC#N>[C:28]([O:27][C:25](=[O:26])[C@@H:24]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:23][NH:22][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[CH:20][CH:19]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
To a stirred solution of 1-4 (200 mg, 0.71 mmol), 2-1 (260 mg, 0.85 mmol), NMM (313 μL, 2.8 mmol), and CH3CN (4 mL) at ambient temperature was added BOP reagent (473 mg, 1.1 mmol). After 20 h the reaction mixture was diluted with EtOAc and then washed with H2O, sat. NaHCO3, 10% KHSO4 and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes) gave 2-3 as a white solid. Rf 0.19 (silica, 40% EtOAc/hexanes).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])#[N:2].[NH2:13][OH:14]>CCO>[NH2:2]/[C:1](=[N:13]/[OH:14])/[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: NO
Reactant: CC(C)(C)OC(=O)NCCC#N
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC/C(N)=N\O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Tert-butyl N-(2-cyanoethyl)carbamate (40 g; 235 mmol; 1 eq.) and hydroxylamine (41.6 ml; 705 mmol; 3 eq.) are dissolved in EtOH (800 ml). The resulting solution is heated under reflux for 2 hours. The reaction progression is followed by 1H NMR. After 2 hours, the reaction mixture is cooled down to RT, concentrated under high vacuum to afford the title compound as a white solid (47.5 g, 99%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=3)[CH:5]=[CH:4][N:3]=1.[CH3:22][NH2:23]>C(O)C>[CH3:22][NH:23][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=3)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc2[nH]c(-c3ccnc(Cl)n3)cc2c1
Reactant: CN
Solvent: CCO
Product: CCOC(=O)c1ccc2[nH]c(-c3ccnc(NC)n3)cc2c1
Yield: 105.1 %

Procedure:
30 g (95.4 mmol) of ethyl 2-(2-chloropyrimidin-4-yl)-1H-indole-5-carboxylate were initially charged and suspended in 150 ml of ethanol. 53.9 g of methylamine solution in ethanol (8 M) were added to this suspension which was heated to from 75° C. to 80° C. in an autoclave for 4 h. After concentration and washing with ethanol, 29.7 g of ethyl 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylate were obtained (97.6 HPLC area %).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[C:38](\[F:41])/[CH2:39]O)=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:39]/[C:38](/[F:41])=[CH:37]/[C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:36][CH:35]=1)=[O:9]
Reactant: OC/C(F)=C/c1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C(F)=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methyoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 219 mg (1 mM) of (Z)-3-[4-(1-imidazolylmethyl)phenyl]-2-fluoro-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 506 mg (92.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].[CH3:18][Si](C)(C)N[Si](C)(C)C.[Na].IC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:18])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a −78° C. stirred solution of Intermediate 53 (2.22 g, 9.13 mmol) in dry THF (30 ml) was added NaHMDS (sodium hexamethyldisilazane) (1.0 M in THF, 10.03 mmol) dropwise. The reaction was stirred at this temperature for 30 minutes and then iodomethane (0.682 ml, 10.95 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight with good stirring. The reaction was cooled and then quenched with saturated NH4Cl. The layers were separated and the aqueous layer was extracted three times with 20 ml of EtOAc and the organic extracts were combined. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The oil was purified by silica chromatography using hexanes/EtOAc (0>15%) to yield 2.25 g (95.8%) of 3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (Intermediate 54). 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (s, 3 H), 1.3 (s, 9 H), 1.4 (m, 2 H), 1.9 (m, 2 H), 3.0 (d, J=13.2 Hz, 1 H), 3.1 (m, 1 H), 3.3 (m, 1 H), 3.5 (s, 3 H), 3.7 (d, J=13.4 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([CH2:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.CO.O.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1>>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH3:27])=[O:17])=[C:9]([CH2:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2.5 g of (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid in 50 ml (1.234 mol) of methanol is added 0.125 g of p-toluenesulfonic acid monohydrate. The solution is stirred at room temperature for 2 days and then concentrated to a small volume, and the residue partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated to give methyl (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH2:9][NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]2)=[O:12])=[CH:4][CH:3]=1.C[CH2:24][OH:25].C(=O)(O)[O-].[Na+].C=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:22])[CH:9]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18]2)=[O:12])[CH2:24][OH:25])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)cc2)CC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCC(C(=O)NC(CO)C(=O)c2ccc(F)cc2)CC1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
To a 250 mL 3-neck flask under n2 is added 8.00 g (26.1 mmol) of 1-Acetyl-piperidine-4-carboxylic acid [2-(4-fluoro-phenyl)-2-oxo-ethyl]amide, prepared as in Part A, to a 3:1 solution of EtOH:H2O (40 mL). While stirring the resultant solution at room temperature, 500 mg (5.95 mmol) of sodium bicarbonate is added followed by subsequent addition of 4.24 mL (52.23 mmol) of 37% formaldehyde over 5 min. The mixture is stirred for 1.5 h and then 20 mL of H2O is added. The reaction is cooled to -5° C. at which point a precipitate formed and is filtered. The mother liquor is again cooled to give a second crop of product and the combined lots are dried in-vacuo overnight at 65° C. to yield 1-Acetyl-piperidine-4-carboxylic acid [2-(4-fluoro-phenyl)-1-hydroxymethyl-2-oxo-ethyl]-amide as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[C:4]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[I:38]I>O1CCCC1>[F:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[C:4]2[C:10]([C:11]#[N:12])=[C:9]([I:38])[N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: II
Reactant: COc1ccc(F)cc1-c1c(F)cnc2c1c(C#N)cn2COCC[Si](C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1c(F)cnc2c1c(C#N)c(I)n2COCC[Si](C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 263D (0.72 g, 1.7 mmol) in tetrahydrofuran (50 mL) was cooled to −75° C. and 2N lithium diisopropylamide (2.6 mL, 5.2 mmol) was added dropwise. The mixture was stirred at −75° C. for 30 minutes and a solution of iodine (0.88 g, 3.47 mmol) in tetrahydrofuran (2.5 mL) was added. The mixture was slowly brought to room temperature, quenched with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (twice). The organic phase was concentrated and purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound. MS (ESI+) m/z 542 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:4]=1[CH2:5][OH:6].Cl[Sn]Cl.O.[OH-].[Na+]>CCO>[OH:6][CH2:5][C:4]1[CH:7]=[C:8]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[NH2:11].[NH2:11][C:8]1[CH:9]=[CH:10][CH:3]=[CH:4][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1CO
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1CO
Product: Nc1ccccc1
Temperature: 70 °C
Yield: 293.6 %

Procedure:
A mixture of 2-methoxy-5-nitrobenzylalcohol (1.02 g, 6.03 mmol) and SnCl2.H2O (6.8 g, 30.15 mmol) in EtOH (20 mL) was heated at 70° C. for 1 hour. After cooling, the mixture was treated with 2M NaOH and extracted with ether. The organic layer was washed with water, dried, and evaporated under vacuum to provide 2.18 g (84%) of the aniline 3-hydroxymethyl-4-methoxyaniline: 1H NMR (DMSO-d6, 500 MHz) δ 6.66 (d, 1H, J=2.2 Hz), 6.61 (d, 1H, J=8.6 Hz), 6.38 (dd, 1H, J=2.4 and 8.2 Hz), 4.81 (t, 1H, J=5.5 Hz), 4.54 (br, 2H), 4.37 (d, 2H, J=5.8 Hz), 3.61 (s, 3H). 3-hydroxymethyl-4-propyloxyaniline
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][NH:32][CH2:33]4)=[CH:28][CH:27]=3)[N:23]=[C:22]([NH2:36])[N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:44][C:45]1[C:46]([N:51]2[CH2:56][CH2:55][CH:54]([NH2:57])[CH2:53][CH2:52]2)=[N:47][CH:48]=[CH:49][CH:50]=1>C(#N)C>[NH2:36][C:22]1[N:23]=[C:24]([C:26]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][N:32]([C:1]([NH:57][CH:54]4[CH2:55][CH2:56][N:51]([C:46]5[C:45]([CH3:44])=[CH:50][CH:49]=[CH:48][N:47]=5)[CH2:52][CH2:53]4)=[O:2])[CH2:33]3)=[CH:28][CH:27]=2)[CH:25]=[C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]2)[N:21]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: Cc1cccnc1N1CCC(N)CC1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cc1cccnc1N1CCC(NC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 20% phosgene in toluene (Phosgene:Toluene=1:4, 20.1 uL, 0.0380 mmol) was added a solution of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (15 mg, 0.034 mmol) and triethylamine (14.4 uL, 0.104 mmol) in acetonitrile (0.5 mL). The resulting mixture was stirred for 10 min A mixture of 1-(3-methylpyridin-2-yl)piperidin-4-amine (9.8 mg, 0.051 mmol) (Alfa Aesar, Cat. #H50779) and triethylamine (14 uL, 0.10 mmol) in acetonitrile (0.3 mL) was added to above mixture. The reaction mixture was stirred at r.t. for 30 min., and then purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=542.3.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: OB(O)c1cccnc1
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4cccnc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (7%-10% methanol in CH2Cl2 gradient) afforded 1-isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 244-246° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.Cl.[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]([NH2:41])[CH3:40].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]([NH:41][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=1)=[O:22])[CH3:40]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(N)c1ncco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (210 mg, 0.48 mmol) and 1-oxazol-2-yl-ethylamine dihydrochloride (198 mg, 0.86 mmol). DMF (2.2 ml) was added followed by N,N-diisopropylethylamine (0.55 ml, 3.15 mmol) and HATU (199 mg, 0.52 mmol). The light yellow solution was stirred at room temperature overnight. Water was added and the resulting suspension was filtered. The solid was washed with water and petroleum ether then dried under high vacuum to afford 248 mg (97%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide as a light yellow powder.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH:37]([OH:41])[CH2:36]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:35]2[CH2:40][CH2:39][CH2:38][CH:37]([OH:41])[CH2:36]2)=[O:18])[N:8]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:12]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: OC1CCCNC1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N2CCCC(O)C2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and (3RS)-3-piperidinol, the title compound was obtained in 79% purity by HPLC. MS(ESI+): m/z=458.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]1=[O:12].C[O:20][C:21]([C:23]1[C:28]([C:29](OC)=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1)=O.[H-].[Na+].Cl>O1CCCC1.CCOCC.CO>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[C:7](=[O:12])[C:8]2[C:21]([OH:20])=[C:23]3[C:28]([CH:27]=[CH:26][CH:25]=[N:24]3)=[C:29]([OH:30])[C:9]=2[C:10]1=[O:11]
Reactant: COC(=O)c1cccnc1C(=O)OC
Reactant: COc1ccc(CN2C(=O)CCC2=O)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)c3c(c(O)c4ncccc4c3O)C2=O)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To 1-(2,4-dimethoxy-benzyl)-pyrrolidine-2,5-dione 299 (1.4 g, 5.6 mmol) and pyridine-2,3-dicarboxylic acid dimethyl ester (1.13 g, 5.8 mmol) dissolved in tetrahydrofuran (60 ml) and methanol (7.0 ml) was added a 60% dispersion of sodium hydride in mineral oil (NaH, 492 mg, 12.3 mmol). The reaction mixture was warmed to 80° C. and kept at 80° C. with stirring overnight. The reaction mixture was placed in an ice bath and titrated to a pH of 4 with 1 M HCl. 200 ml of ether was added and the resulting yellow solid was collected by filtration. The solid was washed twice with ether, twice with water, and dried under high vacuum with heating to provide 7-(2,4-dimethoxy-benzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione 300 (1.1 g, 52%). 1H NMR (d-DMSO) δ 10.8 (broad, 2H), 9.0 (d, 1H), 8.67 (d, 1H), 7.72 (m, 1H), 6.90 (d, 1H), 6.5 (d, 1H), 6.38 (dd, 1H), 4.58 (s, 2H), 3.76 (s, 3H), 3.66 (s, 3H). MS: 382.1 (M+1)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Br[CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2c(Br)cccc21

Procedure:
Add sodium hydride (4.89 g, 122.4 mmol, 60% dispersion in mineral oil) to a solution of 4-Bromo-1H-indole (12 g, 61.2 mmol) in dimethylformamide (100 ml). Cool the reaction to 0° C. and add (2-bromo-1-(tert-butyldimethylsilyloxy)ethane (17.04 g, 67.32 mmol). Stir the reaction for 1 hour at room temperature, quench with aqueous saturated sodium bicarbonate, and extract into ethyl acetate. Combine the organic layers and wash with saturated aqueous sodium chloride, dry over magnesium sulfate. Concentrate under reduced pressure to obtain the title compound, as a clear oil.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]([Br:14])[CH:7]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>>[CH2:3]([NH+:29]([CH2:28][CH3:27])[CH2:30][CH3:31])[CH3:4].[NH2:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]([Br:14])[C:9]([O:13][CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:10]([Br:12])[CH:11]=1)[C:3]([O-:2])=[O:23]
Reactant: COC(=O)C(Cc1cc(Br)c(O)c(Br)c1)NC(=O)OC(C)(C)C
Reactant: ClCc1ccncc1
Product: CC[NH+](CC)CC
Product: NC(Cc1cc(Br)c(OCc2ccncc2)c(Br)c1)C(=O)[O-]
Yield: 13 %

Procedure:
Methyl-2-tert-butoxycarbonylamino-3-(3,5-dibromo-4-hydroxyphenyl)propionate (0.035 mmol) was coupled with 4-chloromethylpyridine and hydrolyzed using the method described in “General procedure for the preparation of Examples 8-22”. This gave 13% yield of 2-amino-3-[3,5-dibromo-4-(pyridin-4-ylmethoxy)phenyl]propionate triethylammonium. LC/MS (electrospray): m/z 429 (M−1).