Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:8]2)=[O:4].[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[C:13]([Br:24])[N:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2C)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2C)c1O
Yield: 82.1 %

Procedure:
A mixture of 5-hydroxy-1-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (67 mg, 0.216 mmol) and N-bromosuccinimide (42 mg, 0.238 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH) to give 69 mg of the title compound as a yellow solid. MS: (−) m/z 387.13, 389.15 (M−1, 79/81Br).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[C:12]([F:15])([F:14])[F:13])=[C:7](F)[CH:6]=1>C(O)CCC.O>[Br:4][C:5]1[CH:6]=[C:7]2[C:8]([C:11]([C:12]([F:15])([F:14])[F:13])=[N:2][NH:3]2)=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(Br)cc1F)C(F)(F)F
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: FC(F)(F)c1n[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
Hydrazine hydrate (3.5 mL, 45 mmol) was added to a solution of 1-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (1.00 g, 3.69 mmol) in 1-butanol (15 mL). The reaction was heated to reflux for 5 hours, then cooled to room temperature and left stirring overnight. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-50% ethyl acetate/heptanes) gave the title compound (310 mg, 32%) as an off-white solid. 1H NMR (400 MHz, CDCl3, δ): 7.42 (dd, J=8.58, 1.56 Hz, 1H), 7.72 (d, J=8.58 Hz, 1H), 7.75 (dd, J=1.56, 0.78 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[CH2:14][O:13][CH2:12][CH2:11][C:9]=2[N:10]=1)[CH3:4].[F:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=O)[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]([N:2]([CH3:1])[CH:3]([C:5]3[NH:6][C:7](=[O:15])[C:8]4[CH2:14][O:13][CH2:12][CH2:11][C:9]=4[N:10]=3)[CH3:4])=[O:32])[CH2:27][CH2:28]2)=[O:22])=[CH:33][CH:34]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CNC(C)c1nc2c(c(=O)[nH]1)COCC2
Product: CC(c1nc2c(c(=O)[nH]1)COCC2)N(C)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 24.8 %

Procedure:
The title compound (170 mg) was prepared according to the general procedure of Example 1 from 2-(1-(methylamino)ethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (320 mg, 1.5 mmol) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (450 mg, 1.7 mmol). 1H NMR (400 MHz, CDC3) δ 12.88 (br. s., 1H), 7.97 (dd, J=8.8, 5.3 Hz, 2H), 7.05-7.21 (m, 2H), 4.48-4.70 (m, 2H), 3.95 (t, J=5.5 Hz, 2H), 3.68 (d, J=12.5 Hz, 1H), 3.39 (br. s., 1H), 3.16-3.36 (m, 1H), 3.07-3.16 (m, 1H), 2.83-3.07 (m, 3H), 2.62-2.77 (m, 5H), 2.56 (t, J=9.8 Hz, 1H), 2.27-2.47 (m, 1H), 1.97-2.27 (m, 2H), 1.76-1.94 (m, 1H), 1.46-1.69 (m, 3H). HRMS calculated for C24H23FN4O4 457.2251. found (ESI, [M+H]+), 457.2257. Retention time=1.83 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[CH:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.I[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH:28]=[C:27]2[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[NH:30][C:29](=[O:34])[CH:28]=[C:27]4[CH3:35])=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(=O)[nH]c2ccc(I)cc12
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(=O)[nH]c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.8 g (8.42 mmol) of 5-(4-chlorophenyl)-2-ethynylpyridine and 2.34 mL (16.84 mmol) of triethylamine are added to a suspension of 3.0 g (8.42 mmol) of 6-iodo-4-methyl-1H-quinolin-2-one in 20 mL of DMF and the mixture is evacuated three times and gassed with argon. Then 40.1 mg (0.21 mmol) of CuI and 153.9 mg (0.21 mmol) of PdCl2(dppf)-DCM complex are added and the mixture is evacuated again and gassed with argon. The reaction mixture is stirred overnight at RT, combined with EtOAc, and the precipitated product is filtered off and with washed EtOAc. The residue is stirred with a THF/water mixture (1:1), filtered, washed with THF, and dried in the circulating air dryer at 50° C. until the weight is constant. Yield: 3.10 g (99% of theoretical); C23H15ClN2O (M=370.831); calc.: molpeak (M+H)+: 371/373 (Cl); found: molpeak (M+H)+: 371/373 (Cl).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C@@:20]([OH:32])([CH3:31])[CH2:21][N:22]3[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[N:24]=[C:23]3Cl)=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C@:20]3([CH3:31])[O:32][C:23]4=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:22]4[CH2:21]3)=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: C[C@](O)(COC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COC(=O)N2CCC(Nc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To the solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylphenylamino)piperidine-1-carboxylate prepared in Example 105 (1.44 g, 2.85 mmol) in DMF (10 ml), sodium hydride (0.14 g, 3.42 mmol) was added followed by stirring for 1 hour with cooling on ice-bath. To the reaction mixture, ice-water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from acetonitrile-isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 4-(4-trifluoromethylphenylamino)piperidine-1-carboxylate (0.42 g, yield 31%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:6][CH:7]([CH2:9][C:10](=[O:31])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:12]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:8])[NH2:5].[Li+].[OH-]>C1COCC1.O>[N:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:13]2[C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:11]([CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH:7]([CH3:8])[CH2:6][C@@H:4]([C:3]([OH:32])=[O:2])[NH2:5])=[O:31])=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H](N)CC(C)CC(=O)c1cccc(NCc2ccncc2)c1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CC(=O)c1cccc(NCc2ccncc2)c1-c1ccccc1)C[C@H](N)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
The product of Example 389A (0.22 g, 0.51 mmoles) was dissolved in 10 mL THF/H2O (2:1), cooled to 0° C. and LiOH (0.04 g, 1.02 mmoles) added. The reaction was stirred at 0° C. for 1 h, followed by stirring at room temperature for 2 hours. The solvents were evaporated and the residue passed through a bed of silica gel and eluted with CH2Cl2:CH3OH (9:1) to afford the title compound (0.19 g, 90%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 0.79 (t, 6H), 1.19 (m, 2H), 1.42 (m, 1H), 4.06 (m, 1H), 4.36 (d, 2H), 6.53 (dd, 1H), 6.81 (m, 2H), 7.04 (d, 1H), 7.17-7.31 (m, 6H), 7.59 (d, 1H), 8.46 (d, 2H).
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21](O)=[O:22])[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:22])[N:15]=2)[CH:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)O)nc3c2CCC3)n[nH]1
Reactant: C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
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(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)N3CCCCC3)nc3c2CCC3)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.1 %

Procedure:
A mixture of 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (400 mg, 1.12 mmol), piperidine (143 mg, 1.68 mmol), HATU (512 g, 1.34 mmol) and DIPEA (230 mg, 1.79 mmol) in DMF (4 mL) was allowed to stir at RT overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (8×25 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc gave an oily residue which was purified by reverse phase HPLC followed by chiral HPLC to afford 10 mg of (R)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(piperidin-1-yl)methanone, and its enantiomer. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.30 (d, 6H), 1.40-1.90 (m, 6H), 1.92-2.12 (m, 5H), 2.30-2.42 (m, 1H), 2.65-2.81 (m, 4H), 2.90-3.01 (m, 1H), 3.40-3.90 (m, 6H), 5.00-5.08 (m, 1H), 6.00 (brs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH:6]1[CH2:8][CH2:9]OS(C)(=O)=O)=[O:4].[CH3:23][S-:24].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:7][CH:6]1[CH2:8][CH2:9][S:24][CH3:23])=[O:4]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCOS(C)(=O)=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCSC
Reaction time: 4.75 h
Yield: 79 %

Procedure:
A solution of 1-tert-butoxycarbonylamino-2-(2-methanesulfonyloxyethyl)cyclopropanecarboxylic acid methyl ester (0.52 g, 1.53 mmol) in 5 mL MeOH was added dropwise to a rt solution of sodium thiomethoxide in 3 mL MeOH. After 4.75 h, the solvent was removed in vacuo and the residue was taken up in EtOAc and H2O (15 mL each). The aqueous layer was extracted with 3×10 mL EtOAc. The combined organics were washed with brine and dried over anhydrous MgSO4. Following concentration in vacuo, 1-tert-butoxycarbonylamino-2-(2-methylsulfanylethyl)cyclopropanecarboxylic acid methyl ester (0.350 g, 79%) was obtained as a colorless oil that was used without further purification. LCMS found 312.0 [M+Na]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][CH:18]([NH:23][C:24]1[C:25]([CH3:39])=[C:26]3[C:30](=[CH:31][CH:32]=1)[N:29](C1CCCCO1)[N:28]=[CH:27]3)[CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:8]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][CH:18]([NH:23][C:24]1[C:25]([CH3:39])=[C:26]3[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]3)[CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(NC2CC3CCC(C2)N3Cc2ccccc2)ccc2c1cnn2C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NC2CC3CCC(C2)N3Cc2ccccc2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of the N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (273 mg, 0.634 mmol) obtained in Example 499 in dichloromethane (9 ml), and the resulting mixture was stirred at room temperature for 30 minutes. Then, trifluoroacetic acid (1 ml) was added thereto and stirred for another 30 minutes, and the resulting mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a preparative thin-layer chromatography (200×200×0.5 mm, 6 plates, eluent: chloroform/methanol=6/1) to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine (142 mg, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]3[NH:20][CH:21]=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(=O)OC(=O)CC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]3[N:20]([CH2:6][N:8]([CH3:13])[CH3:9])[CH:21]=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3[nH]cnc3c2)CC1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)O1
Agent: [K+]
Solvent: ClCCl
Product: CN(C)Cn1cnc2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To stirring solution of 1 (1.50 g, 4.54 mmol) in dichloromethane (20 mL) was added potassium carbonate (690 mg, 4.99 mmol, 1.1 eq) and succinic anhydride (500 mg, 4.99 mmol, 1.1 eq) at 23° C. Next, N,N,N′,N′-tetramethylamino methane (0.68 mL, 4.99 mmol, 1.1 eq) was added dropwise and the suspension stirred at room temperature for 6 hr. The reaction mixture was diluted with dichloromethane (50 mL) and quenched with 20% NaOH (aq) (50 mL). The layers were separated and the organic washed with water, dried over Na2SO4, and concentrated to an off white solid (1.76 g, 4.74 mmol, 100%). 1H NMR (CDCl3, 400 MHz): δ 7.94 (s, 1H), δ 7.79-7.71 (m, 1H), δ 7.60 (s, 0.5H), δ 7.50-7.48 (d, 0.5H), δ 7.38-7.35 (d, 0.5H), δ 7.25-7.22 (d, 0.5H), δ 4.80-4.78 (d, 2H), δ 3.80-3.35 (m, 8H), δ 2.28 (s, 6H), δ 1.41 (s, 9H)
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][NH:28][CH:29]6[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:29]6[CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(NCc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
To a solution of 430 (300 mg, 0.496 mmol) in DMF (6 mL) was added ethyl bromoacetate (0.06 mL, 0.546 mmol). The reaction mixture was stirred at RT for 3 days, quenched with water and extracted with DCM. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Biotage (SNAP 10 g cartridge; MeOH/DCM: 0/100 to 10/90), to afford the title compound 431 (93 mg, 27% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.76 (s, 1H), 8.54 (brd, J=1.6 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.35 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.88 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.18 (m, 1H), 6.65 (dd, J=5.2, 0.8 Hz, 1H), 6.61 (brd, J=2.8 Hz, 1H), 4.05 (q, 7.2 Hz, 2H), 3.93-3.75 (m, 5H), 3.79 (s, 2H), 3.31 (s, 2H), 2.58-2.52 (m, 1H), 1.37 (s, 9H), 1.17 (t, J=7.2 Hz, 3H), 0.68-0.62 (m, 2H), 0.47-0.41 (m, 2H). MS (m/z): 691.64 (M+H).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.[CH2:23]([O:30][C:31]1[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][C:32]=1[C:33]([NH:35][C:36]1[CH:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.O>[CH2:23]([O:30][C:31]1[CH:58]=[CH:57][C:56]([O:59][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:55][C:32]=1[C:33]([NH:35][C:36]1[CH:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Reactant: CN1CCN(CCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN1CCN(CCCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 31.2 %

Procedure:
N,N-Dimethylformamide (3.0 mL), potassium carbonate (0.12 g), and 1-(3-bromopropyl)-4-methylpiperazine (0.30 g) were sequentially added to tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate (0.15 g), followed by stirring at 100° C. for 1 hour and 20 minutes. Potassium carbonate (0.12 g) was added to the reaction mixture, followed by stirring at 100° C. for 50 minutes. Water and chloroform were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.060 g of tert-butyl 2-(2-(benzyloxy)-5-(3-(4-methylpiperazin-1-yl)propoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH:21](C1C=C2C(=CC=1)C(NC(=O)C1C=CC=CC=1)=NC=C2)=[O:22]>>[CH:21]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1)=[O:22]
Reactant: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Reactant: O=C(Nc1nccc2ccc(Br)cc12)c1ccccc1
Product: O=Cc1ccc2ccnc(NC(=O)c3ccccc3)c2c1

Procedure:
N-(7-Formylisoquinolinyl)benzamide was prepared from 37e using the procedure described for 1f but was not purified using column chromatography. The crude aldehyde was transformed into the title compound using the procedure described for 1 g folowed by purification using column chromatography on silica gel (toluene/ethyl acetate:2/1). M.p. 137.5-139.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[N:29][CH:28]=1>C1COCC1>[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[N:29][CH:28]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)cncc2c1
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)cncc3c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a flask charged with N-(4-methoxybenzyl)thiazol-2-amine (180 mg, 0.816 mmol) was added THF (3 ml) and the resulting mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide (1M in THF) (855 μl, 0.855 mmol). The resulting light brown solution was stirred for 15 min at 0° C. prior to the addition of a solution of perfluorophenyl 4-bromoisoquinoline-7-sulfonate (353 mg, 0.777 mmol) in THF (2 ml), followed by 1 ml THF wash. The resulting solution was allowed to stir and warm slowly to room temperature (ice melt). After 2 hr LC/MS indicated about 70% conversion fairly cleanly, with starting amine and PFP ester present (no change from 1 hr). The solution was cooled back to 0° C. and 0.5 eq LiHMDS (1 M) was added. After 1 hr LC/MS indicated complete consumption of starting material. To the mixture was added 400 μl acetic acid and the mixture was dried under reduced pressure and purified with a 40 g HP Silicycle column (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0 to 50%, 10% DCM throughout) affording product as a white solid 4-bromo-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide (Intermediate PPPP) (202 mg, 0.412 mmol, 53.0% yield). m/z (ESI) 490.0 (M+H)+.
Reaction SMILES: CC(C)([S@]([NH:6][C@H:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:8]1[CH:9]=[C:10]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])[CH:11]=[CH:12][CH:13]=1)=O)C>Cl.O1CCOCC1>[NH2:6][C@H:7]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:9]=[C:10]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])[CH:11]=[CH:12][CH:13]=1
Reactant: CCOP(C)(=O)c1cccc([C@H](N[S@](=O)C(C)(C)C)c2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(C)(=O)c1cccc([C@H](N)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Ethyl 3-((R)—((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)phenyl(methyl)phosphinate, 24-d, (15 g, 80% purity, 32.3 mmol) was dissolved in HCl/dioxane (70 ml, 4 mol/L) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum and the residue was dissolved with H2O (90 ml) and HCl (10 ml). The aqueous phase was extracted with EA (80 ml*5). The pH of the aqueous layer was adjusted to about pH=12 and extracted with EA (100 ml*3). The organic was dried over Na2SO4 and the crude product was purified with column (DCM/MeOH=100/1˜30/1) to provide the product, 24-e, (6.77 g, 74%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH3:18])[C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:5][CH2:4][O:3]1.[H][H]>[Pd].C(O)C>[O:1]=[C:2]1[N:6]([CH:7]([CH3:18])[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][O:3]1
Reactant: CC(C(=O)OCc1ccccc1)N1CCOC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C(=O)O)N1CCOC1=O
Reaction time: 3 h
Yield: 100.5 %

Procedure:
A 25 mL round bottom flask under an atmosphere of nitrogen was charged with 0.030 g (0.028 mmol) of 10 weight percent palladium on activated carbon and wet with 2 ml of ethanol. Next, a solution of 0.37 g (1.5 mmol) of benzyl 2-(2-oxo-1,3-oxazolidin-3-yl)propanoate from step B above in 10 mL of ethanol was added and the mixture placed under 1 atmosphere of hydrogen. The reaction was stirred for 3 h then filtered through a pad of Celite®. The pad was washed with 20 mL of ethanol and the filtrate was evaporated in vacuo to afford the title compound as a colorless solid (0.24 g, quantitative yield). 1H-NMR (500MHz, CD3OD) δ: 4.60-4.30 (m, 3H), 3.80-3.60 (m, 2H), 1.45 (d, J=3.5, 3H). LC-MS: m/z (ES) 160 (MH)+.