Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.CCN(C(C)C)C(C)C.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:64]1([CH2:70][SH:71])[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>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]>[CH2:70]([S:71][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Reactant: SCc1ccccc1
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
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(Br)cc(SCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
1,3-Dibromo-5-tert-butylbenzene (2.89 g, 10 mmol) in dioxane (160 mL) was stirred under Ar. Then DIPEA (3.09 mL, 16 mmol), Xantphos (0.28 g, 0.48 mmol) and Pd2(dba)3 (0.24 g, 0.24 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (0.94 mL, 8 mmol) was slowly added and the reaction was stirred for 6 h, quenched by the addition of H2O (15 mL) and extracted with EA (3×). The combined organic layers were washed with water, dried over Na2SO4, filtered, evaporated and purified by CC to afford compound P21a (1.7 g, 72%).
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[N:12]=[CH:13]\[CH2:14][CH2:15][C:16]([OH:18])=[O:17])/[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C(O)(=O)C>[O:1]=[C:2]1[N:10]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:12][N:11]=[C:9]2[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2
Reactant: CCCCCn1/c(=N/N=C/CCC(=O)O)[nH]c(=O)c2[nH]cnc21
Solvent: CC(=O)O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCC(=O)O)nnc12
Yield: 79.5 %

Procedure:
The mixture of (4E)-4-[(2E)-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazono]butanoic acid (1.367 g, 5.1 mmol) in acetic acid (70 ml) was refluxed for 1 hour. Evaporation of solvent afforded the desired product (1.29 g, 99%) as yellowish solid. LCMS calculated for C14H19N6O3 (M+H): 319.2. Found: 319.2.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36]>CC#N>[Br-:23].[O:36]=[C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34](=[O:35])[N:26]1[CH2:25][CH2:24][N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 51.6 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0916 g, 0.312 mmol) and 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (0.130 g, 0.512 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0881 g, 51.8%). EI-MS m/z 467 (M+) Rt (1.91 min).
Reaction SMILES: [N:1]1([C:6]([O:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16]3[N:24]=[C:23]4[C:19]([NH:20][C:21](=[O:33])[N:22]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])=[C:18]([C:34]([O:36]CC)=O)[N:17]=3)[CH2:11][CH2:10]2)=[O:7])C=CN=C1.[NH2:39]C1C(C(OCC)=O)=NC(N[C@H]2CC[C@@H](O)CC2)=NC=1NC1C=CC=CC=1OC>ClCCl>[C:6](=[O:7])([O:8][C@H:9]1[CH2:10][CH2:11][C@@H:12]([NH:15][C:16]2[N:24]=[C:23]3[C:19]([NH:20][C:21](=[O:33])[N:22]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[C:18]([C:34](=[O:36])[NH2:39])[N:17]=2)[CH2:13][CH2:14]1)[NH2:1]
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@@H](O)CC2)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@@H](OC(=O)n3ccnc3)CC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@@H](OC(N)=O)CC3)nc21

Procedure:
Ethyl 2-(cis-4-(1H-imidazole-1-carbonyloxy)cyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-2-(cis-4-hydroxycyclohexylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.272 g, 0.678 mmol) and 1,1′-1,1′-carbonyldiimidazole (1.09 g, 6.78 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F and purified using biotage chromatography (60-100% ethyl acetate in hexanes) to afford the title compound and the free hydroxyl derivative (0.250 g, 71%). MS (ESI) m/z 522.4 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:16])[C:13]([CH3:15])([CH3:14])[O:12][BH:11][O:10]1.[CH2:17]([N:21]1[CH2:26][C:25]2([CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH2:24][CH2:23][CH2:22]1)[CH2:18][C:19]#[CH:20]>ClCCl.[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2]>[CH3:8][C:9]1([CH3:16])[C:13]([CH3:15])([CH3:14])[O:12][B:11](/[CH:20]=[CH:19]/[CH2:18][CH2:17][N:21]2[CH2:26][C:25]3([CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[CH2:24][CH2:23][CH2:22]2)[O:10]1
Reactant: C#CCCN1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: CC1(C)OBOC1(C)C
Agent: [Zr+2]
Agent: [Cl-]
Agent: c1cc[cH-]c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(CC/C=C/B3OC(C)(C)C(C)(C)O3)C2)CC1
Temperature: 65 °C
Yield: 86.9 %

Procedure:
Triethylamine (5.62 mmoles; 0.783 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.56 mL, 59.0 mmol) and zirconocene chloride (1.45 g, 5.62 mmoles) are added to tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (17.21 g, 56.16 mmoles). The resulting mixture is heated to 65° C. for 3.5 hours. The mixture is cooled and dissolved in dichloromethane (150 mL). The resulting solution is passed through a ˜4 cm thick pad of silica gel, eluting with dichloromethane (2×200 mL). The filtrate is concentrated under reduced pressure to give the title compound (21.2 g, 87% yield). 1H NMR (300.11 MHz, CDCl3): δ 6.65-6.55 (m, 1H), 5.49-5.43 (m, 1H), 3.42-3.29 (m, 4H), 2.40-2.27 (m, 6H), 2.25-2.08 (m, 2H), 1.70-1.13 (m, 29H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:10]1[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15])[CH2:25]2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: COc1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccc(OC)cc4C3)c(F)c21
Yield: 31.6 %

Procedure:
135 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 104 mg of 5-methoxyisoindoline, 121 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 63 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:31]=[N+:32]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:19])=[CH:16][CH:17]=2)=[N:10][C:9]([Br:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)N3CCOCC3)cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)N3CCOCC3)cc2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 275.9 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinate (2.00 gm, 4.76 mmol) was dissolved in trifluoroacetic acid (26 mL) and the yellow solution was cooled in an ice-bath. Powdered sodium nitrite (0.657 gm, 9.52 mmol) was added with stirring to give a dark red mixture. After 30 minutes, powdered sodium azide (3.09 gm, 47.6 mmol) was added followed by diethyl ether (26 mL). The light red mixture was stirred in the ice-bath for 30 minutes. The reaction was partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to about 50 mL on the rotary evaporator. The resulting solid was collected by filtration and washed three times with EtOAc to give methyl 3-azido-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinate (5.86 gm, 72% yield). Removal of the solvent from the filtrate followed by flash silica gel chromatography (step gradient elution with methylene chloride containing 0 to 2% MeOH) afforded another 1.58 gm of product. MS (ESI) m/z 446 and 448 (M+H). 1H NMR (CDCl3) δ ppm 7.82-7.80 (3H, m), 7.49-7.53 (2H, m), 4.02 (3H, s), 3.69-3.88 (4H, m), 3.57-3.70 (2H, m), 3.40-3.53 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C([O-])(O)=O.[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>CCOCC>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:17](=[O:18])[CH2:16][Cl:15]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cccc(C)c1NC(=O)CCl
Temperature: 25 °C

Procedure:
2,6-dimethylaniline (9.8 g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO3 (100 mL) and the reaction mixture was cooled in an ice/water bath. To the cold solution was added chloroacetyl chloride 2 (9.17 g, 81.2 mmol) dropwise over a period of 2 h. The mixture was allowed to warm to RT over 14 h. The mixture was diluted with 100 mL ether and the organic layer was dried over MgSO4, filtered and concentrated to afford compound 3 as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=3)[C:8]([CH2:10][CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].CS(C)=[O:38].OO.[OH-].[Na+]>O.CO>[CH2:10]([C:8]1[N:7]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:25])=[O:26])=[O:22])=[CH:16][CH:17]=2)[C:6]2[CH:34]=[CH:35][C:3]([C:1]([NH2:2])=[O:38])=[CH:4][C:5]=2[N:9]=1)[CH3:11]
Reactant: CCc1nc2cc(C#N)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2cc(C(N)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 of Example 82, 200 mg, 0.68 mmol), DMSO (0.06 mL, 0.82 mmol) and methanol (10 mL) was added 30% aqueous solution of hydrogen peroxide (0.12 mL, 1.0 mmol) and 0.2 M aqueous NaOH (0.06 mL). The mixture was stirred at 50° C. for 4 h, then cooled. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 2N aqueous NaOH (50 mL) and brine (50 mL), then dried (Na2SO4), and concentrated to afford the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 8.23 (1H, d, J=1.1 Hz), 7.96 (1H, br.s), 7.76 (1H, dd, J=1.1 Hz, 8.4 Hz), 7.42-7.51 (4H, m), 7.25 (1H, br.s), 7.09 (1H, d, J=8.4 Hz), 3.70 (2H, t, J=6.6 Hz), 2.85 (2H, t, J=6.9 Hz), 2.76 (2H, q, J=7.4 Hz), 1.24 (3H, t, J=7.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14]1[N:15]=[C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[S:17][C:18]=1[C:19]([NH2:21])=[O:20].[O:28]([CH2:35][C:36](Cl)=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:14]2[N:15]=[C:16]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[S:17][C:18]=2[C:19](=[O:20])[N:21]=[C:36]1[CH2:35][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1c(CNc2nc(N3CCOCC3)sc2C(N)=O)cccc1C(F)(F)F
Reactant: O=C(Cl)COc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(Cn2c(COc3ccccc3)nc(=O)c3sc(N4CCOCC4)nc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-({[2-methyl-3-(trifluoromethyl)phenyl]methyl}amino)-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.250 mmol) in Tetrahydrofuran (THF) (1249 μl) at 0° C. was added phenoxyacetyl chloride (69.0 μl, 0.499 mmol). The mixture was stirred at room temperature overnight, then quenched with methanol and concentrated. The residue was purified by reversed-phase HPLC to provide 4-{([2-methyl-3-(trifluoromethyl)phenyl]methyl}-2-(4-morpholinyl)-5-[(phenyloxy)methyl][1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (14 mg, 11%); LC/MS: MS (ES+) m/e 517 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3H), 3.48-3.54 (m, 4H), 3.62-3.71 (m, 4H), 5.12 (s, 2H), 5.57 (s, 2H), 6.61 (d, J=7.8 Hz, 2H), 6.85-6.97 (m, 2H), 7.19 (dd, J=8.7, 7.5 Hz, 2H), 7.25-7.33 (m, 1H), 7.60 (d, J=7.8 Hz, 1H).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:18]1[N:19]=[CH:20][C:21]3[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Reactant: CNC
Product: CN(C)c1ccc2oc(-c3cc4ccccc4cn3)cc(=NO)c2c1

Procedure:
6-dimethylamino-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 51% overall yield following the method described in example 35, starting from 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime and dimethylamine (2.0 M in tetrahydrofuran). The title compound was isolated as a pale yellow solid after purification by flash chromatography over silica gel (cyclohexane/ethyl acetate: 0-60%).
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]3[C:27]([CH:28]([OH:30])[CH3:29])=[CH:26][CH:25]=[CH:24][N:23]3[CH:31]=2)=[CH:16][CH:15]=1)[CH2:10][CH2:11][OH:12])[C:6](=[O:8])[O-])(C)C.Cl.O1CCOCC1.C(N(CC)C(C)C)(C)C.[Cl:48][C:49]1[CH:50]=[C:51]([CH:66]=[CH:67][C:68]=1[O:69][CH:70]([CH3:72])[CH3:71])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O>[Cl:48][C:49]1[CH:50]=[C:51]([CH:66]=[CH:67][C:68]=1[O:69][CH:70]([CH3:72])[CH3:71])[C:6]([NH:5][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]3[C:27]([CH:28]([OH:30])[CH3:29])=[CH:26][CH:25]=[CH:24][N:23]3[CH:31]=2)=[CH:16][CH:15]=1)[CH2:10][CH2:11][OH:12])=[O:8]
Reactant: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CCO)N(C(=O)[O-])C(C)(C)C)cc3)nc12
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A mixture of 1,1-dimethylethyl[(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]carbamate (1.08 g, 2.54 mmol) and 4M HCl in 1,4-dioxane (8.0 mL, 32 mmol) was stirred at room temperature for 30 minutes. The reaction was concentrated to dryness redissolved in DMF (25 mL), and to this solution was added N,N-diisopropylethylamine (1.64 g, 12.7 mmol) and pentafluorophenyl 3-chloro-4[(1-methylethyl)oxy]benzoate (0.963 g, 2.54 mmol). The mixture was stirred for 3.0 h at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water and saturated sodium chloride, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (2% MeOH:EtOAc) to give the title compound (0.7 g, 53%) as a pale yellow powder. MS (ES+) m/e 522 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[C:9]([F:18])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][CH2:16][CH3:17])[C:7](=[O:19])[C:6]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:5]1.[SH:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].[I-].[Na+].CN(C=O)C>C(OCC)(=O)C.O>[F:18][C:9]1[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH2:16][CH3:17])=[C:13]2[C:8]=1[C:7](=[O:19])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:5][N:4]2[CH2:3][CH2:2][S:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)CCS
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCl)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCSCCC(=O)OC)c12
Temperature: 80 °C
Reaction time: 5 h
Yield: 75.2 %

Procedure:
1-(2-Chloroethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (3.5 g, 8.98 mmol), methyl 3-mercaptopropionate (1.19 g, 9.88 mmol), and sodium iodide (1.48 g, 9.88 mmol) were added to DMF (30 ml) and stirred at 80° C. for 5 hours. Water and ethyl acetate were added to the reaction mixture, followed by separation. The thus-obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane). The purified product was concentrated to dryness under reduced pressure, giving a pale yellow powder of methyl 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionate (3.2 g, yield: 75%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:26])[C:8]([CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.O>C(OC(C)=O)(C)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:26])[C:8]([CH:19]([O:25][C:5]([CH3:10])([CH3:6])[CH3:4])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate (˜2.78 mmol) in t-BuOAc (14 mL) was added 70% perchloric acid (HClO4) (334 μL, 5.56 mmol). After 3 h, water was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the titled compound. 1H-NMR: 400 MHz, (CDCl3) δ: 7.62 (m, 2H), 7.51 (m, 4H), 7.27 (m, 2H), 5.09 (s, 1H), 4.15 (m, 2H), 2.59 (s, 3H), 1.19 (t, J=7 Hz, 3H), 1.00 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].O.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc(N2CCN(c3ccccc3)C2=O)sc1C(=O)O
Yield: 93 %

Procedure:
To a solution of ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate (1.49 g, 4.49 mmol) in tetrahydrofuran (30 mL), methanol (10 mL) and water (10 mL) was added lithium hydroxide monohydrate (0.38 g, 9.00 mmol) at ambient temperature. The resulting reaction mixture was heated to reflux for 14 hours. The solvent was removed in vacuo, and the residue was neutralized to pH 4˜5 with 10% hydrochloric acid. The resulting precipitate was filtered and dried to afford the title compound in 93% yield (1.27 g): mp 286-289° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.88-7.34 (m, 5H), 4.10-3.76 (m, 4H), 2.49 (s, 3H); MS (ES+) m/z 304.3 (M+1).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:13]=1.C[O:31][B:32](OC)[O:33]C.Cl>C1COCC1>[B:32]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:13]=1)([OH:33])[OH:31]
Reactant: COB(OC)OC
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2ccccc21
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
A 1.7 M solution of tert-butyl lithium (t-BuLi) in pentane (3.8 ml; 6.45 mmol) was added over ~5 minutes, to a solution of the title product of Step (B) (1 g; 3 mmol) in THF at -100° C. The temperature was kept below -84° C. during the addition. After stirring 5 minutes at -100° C., trimethylborate was added in one portion and the reaction mixture was allowed to warm to room temperature over 4 hours. At this time, 10 ml of 10% HCl was added and the mixture was extracted with methylene chloride (3×30 ml). The combined organic layers were washed with water (3×30 ml) and brine (30 ml). Drying (MgSO4), decolorizing (Darco) and concentration afforded a tan foam. Due to apparent decomposition at room temperature, the foam was stored at -80° C. overnight. The residue was then partitioned between ether (20 ml) and 0.5 N NaOH (20 ml). The purple ether layer was extracted with 10 ml of 0.5N NaOH. The combined green basic layer was washed with ether (20 ml), acidified to pH 2 with saturated KHSO4 solution to afford a purple mixture, which was extracted with methylene chloride (2×30 ml). Drying (MgSO4) and concentration afforded 623 mg (69%) of the title product of this step as a purple foam.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:4])=[O:3].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[N:34]=[C:33]([NH:35][CH2:36][CH2:37][C:38]3[NH:39][CH:40]=[N:41][CH:42]=3)[C:32]([Br:43])=[CH:31][N:30]=2)=[CH:24][CH:23]=1>CC(N(C)C)=O>[Br:43][C:32]1[C:33]([NH:35][CH2:36][CH2:37][C:38]2[NH:39][CH:40]=[N:41][CH:42]=2)=[N:34][C:29]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=3)=[CH:27][CH:26]=2)=[N:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Nc3ncc(Br)c(NCCc4cnc[nH]4)n3)cc2)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 23.7 %

Procedure:
4-Methanesulfonyl-3-nitro-benzoic acid (72 mg, 0.29 mmole) was dissolved in DMA (3 ml) and thionyl chloride (0.29 mmole) was added at ambient temperature. After the mixture was stirred for 5 minutes N2-(4-Amino-phenyl)-5-bromo-N4-[2-(3H-imidazol-4-yl)-ethyl]-pyrimidine-2,4-diamine (100 mg, 0.26 mmole, prepared according to procedure 21) was added and the reaction was allowed to stir overnight. After extraction with bicarbonate solution and ethyl acetate (3×) the combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was purified by flashmaster chromatography on silica gel to provide 37 mg of N-(4-{5-Bromo-4-[2-(3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl}-4-methanesulfonyl-3-nitro-benzamide (23% yield). ESI-MS: 602.