Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(O)C.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Nc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask charged with 5-bromopyridin-3-amine (0.400 g, 2.3 mmol) in ethanol (10 ml, 171 mmol), was added 4-methylbenzene-1-sulfonyl chloride (0.880 g, 4.6 mmol) into the mixture. The mixture was allowed to stir at ambient temperature overnight, while under inert atmosphere. The progress of the reaction was monitored by LC/MS, which showed mostly desired product. The mixture was diluted with DCM and saturated sodium bicarbonate solution, then extracted the organic layer with DCM (3×25 ml). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by ISCO silica-gel chromatography, in a gradient of 10-30% EtOAc/DCM. The fractions with desired product were combined and concentrated. This gave N-(5-bromopyridin-3-yl)-4-methylbenzenesulfonamide (0.350 g, 46% yield) as a light-yellow crystalline solid. MS (ESI pos. ion) m/z: 328 (MH+). Calc'd exact mass for Cl2H, BrN2O2S: 327. 1H NMR (400 MHz, chloroform-d): 2.43 (d, J=18.57 Hz, 3H), 7.35 (d, J=6.53 Hz, 2H), 7.69 (d, J=6.02 Hz, 2H), 7.80 (d, J=5.02 Hz, 2H), 8.13-8.20 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:15])[NH:8][C:7]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:5])[CH3:4].Br[CH2:22][CH2:23][O:24][CH3:25].[CH3:26]N(C)C=O>>[CH:3]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:26])=[O:12])=[C:9]([CH3:15])[N:8]([CH2:22][CH2:23][O:24][CH3:25])[C:7]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:5])[CH3:4]
Reactant: COCCBr
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OC)c1C(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(C(C)C)c(C(=O)OCC)n(CCOC)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Sodium hydride (55%; 555 mg, 12.7 mmol) was added to a solution of 2-ethyl 4-methyl 3-isopropyl-5-methyl-1H-pyrrole-2,4-dicarboxylate (1.8 g, 6.74 mmol) in dry dimethylformamide (10 mL) at 0-5° C. and stirred for 30 min. 1-Bromo-2-methoxy-ethane (1.0 mL, 10.1 mmol) was added dropwise to the mixture which was stirred at 90° C. for 2 h. Additional sodium hydride (55%; 275 mg, 6.37 mmol) was added followed by 1-bromo-2-methoxy-ethane (1.0 mL, 10.1 mmol) and stirring continued at 90° C. for 5 h. The reaction mixture was cooled to room temperature, quenched with ice water and extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with water (2×50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford diethyl 3-isopropyl-1-(2-methoxyethyl)-5-methyl-pyrrole-2,4-dicarboxylate (2.2 g, 100%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[O:4].CCO[CH2:37][CH3:38]>N1C=CC=CC=1>[Cl-:1].[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][N:5]1[C:6]2[C:7](=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:2]([N+:5]2[CH:38]=[CH:37][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:4]
Reactant: COc1ccc(CN(C(=O)CCl)c2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Reactant: CCOCC
Solvent: c1ccncc1
Product: COc1ccc(Cn2c(=O)c(-[n+]3ccccc3)c(-c3cccc(F)c3)c3cc(OC)ccc32)c(OC)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-chloro-N-(2,4-dimethoxybenzyl)-N-[2-(3-fluorobenzoyl)-4-methoxyphenyl]acetamide (229 mg, 0.485 mmol) in 3 mL of pyridine was heated to reflux. A precipitate formed while the mixture stirred overnight. After cooling the mixture to room temperature, ether was added (10 mL), and the mixture was cooled further using an ice bath. The suspension was filtered, and the filtrate was washed with cold ether and dried in vacuo to provide the titled salt as a dark brown solid which was used in the next step without further purification. HRMS (ES) exact mass calculated for C30H25FN2O4 (M+): 497.1871. Found 497.1884.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH2:15][CH2:16][CH2:17][N:18]=[C:7]3[C:6]=2[CH:5]=1.[CH2:21](Br)[CH:22]=[CH2:23]>>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:23][CH:22]=[CH2:21])[C:9](=[O:14])[N:8]3[CH2:15][CH2:16][CH2:17][N:18]=[C:7]3[C:6]=2[CH:5]=1
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C2=NCCCN12
Reactant: C=CCBr
Product: C=CCN1C(=O)N2CCCN=C2c2cc(OC(F)(F)F)ccc21

Procedure:
Preparation analogously to Example 29 from 10-trifluoromethoxy-6-oxo-2,3,4,5,6,7-hexahydropyrimido-[1,2-c]-quinazoline and allyl bromide.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[CH3:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:28]=[CH:29][C:30]([CH2:31][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:33][CH:34]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: Cc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2ccc(Cn3cnc4c3c(=O)n(C)c(=O)n4C)cc2)cc1
Yield: 45.9 %

Procedure:
A solution of 1,3-dimethylxanthine (99 mg), potassium carbonate (135 mg), 4-(4-methylbenzoyl)benzyl bromide (201 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:5) and recrystallized from ethyl acetate-isopropyl ether to provide the title compound as colorless solid (98 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].[N:35]1([CH2:41][C:42]2[CH:43]=[C:44]([CH:50]=[CH:51][CH:52]=2)[O:45][CH2:46][CH2:47][CH2:48][NH2:49])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[C:17]1([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:9][CH2:8][N:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:23]([NH:49][CH2:48][CH2:47][CH2:46][O:45][C:44]2[CH:50]=[CH:51][CH:52]=[C:42]([CH2:41][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:43]=2)=[O:24])[CH3:1])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(CCCCN)CCC(c1ccccc1)c1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Product: CN(CCCCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.7 g (2.3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,4-butanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.7 g (2.8 mmol) of 3-[3-(piperidinomethyl)phenoxy]propaneamine. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of an oil; MS (EI-80 eV): m/z (rel. int.[%])=571 ([M]+, 4), 84 (22), 169 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[H-].[Na+].COC1C=C2C(=CC=1OC)N=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43](NC(NC2CCNCC2)=O)=[CH:42][CH:41]=1.[C:56](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:32][CH2:31][CH2:30][O:39][C:40]2[CH:41]=[CH:42][C:43]([CH3:56])=[CH:44][CH:45]=2)=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(O)cc3)c2cc1OC
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCNCC4)cc3)c2cc1OC
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(OCCCOc4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenol (100 mg) was dissolved in dimethylformamide (2 ml) to prepare a solution. Sodium hydride (16 mg) was then added to the solution, and the mixture was stirred at room temperature for 10 min. A solution of the compound (1) (85 mg) in dimethylformamide was added thereto, and the mixture was further stirred at room temperature for 4 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing three times with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (142 mg, yield 95%).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[N:31]1[CH2:37][CH2:36][C@H:35](O)[C@H:34]([NH:39][C:40](=[O:46])[O:41]C(C)(C)C)[CH2:33][CH2:32]1)=[O:23])=O)(C)(C)C.[H-].[Na+].CO>CN(C=O)C.Cl.O1CCOCC1>[O:46]=[C:40]1[NH:39][C@@H:34]2[CH2:33][CH2:32][N:31]([C:26]3[N:27]([CH3:30])[N:28]=[CH:29][C:25]=3[NH:24][C:22]([C:10]3[N:11]=[C:12]([C:14]4[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=4[F:21])[S:13][C:9]=3[NH2:8])=[O:23])[CH2:37][CH2:36][C@@H:35]2[O:41]1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CC[C@H](O)[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H]2OC(=O)N[C@@H]2CC1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a stirred solution of tert-butyl N-((4R,5S)-1-(4-((5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl)amino)-2-methyl-pyrazol-3-yl)-5-hydroxy-azepan-4-yl)carbamate (199 mg, 0.30 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 26 mg, 0.66 mmol). The mixture was allowed to warm to room temperature over 2 hr, quenched with water (3 mL) and the resulting precipitate filtered off and dried under reduced pressure. The aqueous layer was extracted with EtOAc (3×3 mL) and the combined organic layers were passed through a phase separation cartridge, concentrated under reduced pressure and the residue combined with the precipitate collected earlier. A solution of this material (159 mg, 0.27 mmol) in HCl in dioxane (4 M, 10 mL) and MeOH (5 mL) was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure. Purification via preparative HPLC gave 486 as a white solid (55 mg, 41% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.79 (s, 1H), 7.37-7.28 (m, 1H), 7.05 (t, J=8.8 Hz, 2H), 6.14 (s, 2H), 5.08-5.00 (m, 1H), 4.87 (s, 1H), 4.26 (td, J=9.3, 3.5 Hz, 1H), 3.75 (s, 3H), 3.45-3.33 (m, 2H), 3.16-3.07 (m, 2H), 2.34-2.27 (m, 2H), 2.20-2.09 (m, 1H), 2.06-1.97 (m, 1H). LCMS (ES+) m/z 490 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][CH:29]([CH3:33])[C:30](Cl)=[O:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:30](=[O:31])[CH:29]([CH3:33])[CH3:28])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: CC(C)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and 2-methylpropanoyl chloride (21 mg, 150 μmol). Yield 18 mg (84%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([F:13])[C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:2]>[Pd].C(OCC)(=O)C>[CH2:1]([NH:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([F:13])[C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:2]
Reactant: CCNc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCNc1c(N)ccc(F)c1-c1ccccn1
Temperature: 20 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
A mixture of ethyl-(3-fluoro-6-nitro-2-pyridin-2-yl-phenyl)amine (1.00 g, 3.82 mmol) and 10% palladium on carbon (0.10 g) in ethyl acetate (15 mL) was stirred under an atmosphere of hydrogen at atmospheric pressure and 20° C. for 3 days. The catalyst was removed by filtration and the resultant solution was concentrated in vacuo. The residue was purified by silica gel chromatography eluting (Si—PPC, gradient 0-100% EtOAc/cyclohexane) to give the title compound as yellow oil (0.61 g, 69%). 1H NMR (CDCl3) δ: 8.71 (1H, ddd, J=6.6, 2.5, 1.3 Hz), 7.78 (1H, ddd, J=10.5, 10.1, 2.5 Hz), 7.58 (1H, ddt, J=10.6, 5.0, 1.4 Hz), 7.27 (1H, ddd, J=10.0, 6.5, 1.6 Hz), 6.76-6.66 (2H, m), 5.24 (1H, br s), 3.82 (2H, br s), 2.76 (2H, t, J=9.5 Hz), 0.82 (3H, t, J=9.5 Hz)
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:33])[N:27]([CH2:29][CH2:30][O:31][NH2:32])[CH3:28])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:33])[N:27]([CH2:29][CH2:30][O:31][NH:32][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])[CH3:28])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CN(CCON)C(=O)OC(C)(C)C
Product: CN(CCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 55 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl(2-(aminooxy)ethyl)(methyl)carbamate (436 mg) described in Reference Example 16, 347.8 mg of the title compound was afforded (yield 55%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[NH:12][CH:13]=2)[O:3]1.Br[CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:24]([O:23][CH2:22][CH2:21][CH2:20][N:12]1[CH:13]=[C:9]([B:4]2[O:3][C:2]([CH3:18])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=[C:11]1[C:14]([O:16][CH3:17])=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCCOCc1ccccc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1CCCOCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
A mixture of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (Compound 38F, 600 mg, 2.39 mmol) and 1-bromo-3-benzyloxypropane (575 mg, 2.51 mmol) in DMF (2.19 mL) was charged with cesium carbonate (778 mg, 2.39 mmol). The reaction mixture was allowed to stir at 70° C. for 16 hrs. The reaction mixture was diluted with water and then extracted with EtOAc (2×). The organic layer was washed with water (2×), brine (1×), dried over Na2SO4, filtered, concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→4% Ethanol in DCM] to afford 442 mg of the title compound (46%). 1H NMR (400 MHz, CD3OD) δ 7.26-7.37 (m, 5H), 7.25 (d, J=1.8 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 4.45 (s, 2H), 4.42 (t, J=6.8 Hz, 2H), 3.78 (s, 3H), 3.38 (t, J=5.9 Hz, 2H), 2.01 (t, J=6.2 Hz, 2H), 1.31 (s, 12H). MS (ESI): m/z 440.59 [M+H]+. UPLC: tR=1.60 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)CCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 4-bromophenol (2.2 g, 12.7 mmol) and 4-bromo-1,1,1-trifluorobutane (2.4 g, 12.7 mmol) in anhydrous DMF (15 mL) was added K2CO3 (3.5 g, 25.4 mmol). The mixture was stirred at rt overnight. The mixture was diluted with EtOAc (120 mL) and the solids were removed by filtration. The filtrate was washed with water and sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (40 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 11A (3.05 g, 85%) as a colorless oil.
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[S:34][CH:35]=[C:36]([C:38](O)=[O:39])[N:37]=1>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:38]([C:36]2[N:37]=[C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[S:34][CH:35]=2)=[O:39])[CH2:6][CH2:7]1
Reactant: O=C(O)c1csc(-c2ccccc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3ccccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2-fluorophenyl)thiazole-4-carboxylic acid (see Bioorg. Med. Chem. Lett. 2010, 20, 1758) gave 318. 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.53 (s, 1H), 8.35-8.28 (m, 1H), 7.81 (s, 1H), 7.66-7.58 (m, 1H), 7.53-7.41 (m, 2H), 5.02-4.81 (m, 2H), 4.24-4.09 (m, 1H), 4.09-3.92 (m, 1H), 3.77 (s, 3H), 2.20-2.09 (m, 1H), 2.07-1.92 (m, 1H), 1.87-1.74 (m, 2H), 1.66 (d, J=13.1 Hz, 1H). LCMS (ES+) m/z 434 (M+1).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:30]4[C:29]5[CH:28]=[C:27]([C:31]6[CH:32]=[N:33][C:34]7[C:39]([CH:40]=6)=[CH:38][CH:37]=[CH:36][CH:35]=7)[CH:26]=[CH:25][C:24]=5[N:23]=[CH:22][C:21]=4[C:20](=[O:41])[O:19][C:18]3=O)=[CH:13][C:12]=2[C:43]([F:46])([F:45])[F:44])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[CH3:47][NH2:48]>C1COCC1.C(Cl)Cl>[CH3:47][N:48]1[C:20](=[O:41])[C:21]2[CH:22]=[N:23][C:24]3[CH:25]=[CH:26][C:27]([C:31]4[CH:32]=[N:33][C:34]5[C:39]([CH:40]=4)=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:28][C:29]=3[C:30]=2[N:17]([C:14]2[CH:15]=[CH:16][C:11]([N:8]3[CH2:7][CH2:6][N:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:10][CH2:9]3)=[C:12]([C:43]([F:46])([F:44])[F:45])[CH:13]=2)[C:18]1=[O:19]
Reactant: CN
Reactant: CCC(=O)N1CCN(c2ccc(-n3c(=O)oc(=O)c4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(=O)N1CCN(c2ccc(-n3c(=O)n(C)c(=O)c4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
To a solution of compound 5.6 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)-1H-[1,3]oxazino[5,4-c]quinoline-2,4-dione (20 mg, 0.032 mmol, 1 equiv.) in THF/CH2Cl2 (5 mL, 1:1) at room temperature was added MeNH2 (5 mg, 0.16 mmol, 5 equiv.). The resulting solution was heated to 40° C. and stirred for 2h. Upon concentration, the mixture was purified via preparative LC-MS (CH3CN:H2O) to furnish the desired compound 5.7 3-methyl-1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)pyrimido[5,4-c]quinoline-2,4(1H,3H)-dione (3 mg). LC-MS(M+H): 639.49
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:14]=[CH:13][C:12]2=[C:15]3[C:5]=1[O:6][CH2:7][C@H:8]([CH3:34])[N:9]3[C:10]([C@@H:16]([NH:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]3[C:20]=1[N:21]=[CH:22][N:23]3C1CCCCO1)[CH3:17])=[N:11]2>O1CCOCC1.CO>[F:3][C:4]1[CH:14]=[CH:13][C:12]2=[C:15]3[C:5]=1[O:6][CH2:7][C@H:8]([CH3:34])[N:9]3[C:10]([C@@H:16]([NH:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]3[C:20]=1[N:21]=[CH:22][NH:23]3)[CH3:17])=[N:11]2
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Hydrogen chloride HCl (340 μL of a 4M solution in dioxane) was added to a solution of [(S)-1-((S)-6-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethyl][9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (117 mg, 0.27 mmol) in MeOH (1 mL) and the reaction was stirred at RT for 30 min. The crude reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give 441 (88 mg, 92%) as an off-white solid. LCMS (Method K): RT 2.61 min [M+H]+ 354.0. 1H NMR (CD3OD, 400 MHz): δ 8.23 (1H, s), 8.05 (1H, s), 7.08 (1H, dd, J=8.8, 3.1 Hz), 6.93 (1H, dd, J=12.1, 8.8 Hz), 5.77 (1H, br s), 5.19 (1H, qdd, J=6.7, 2.6, 1.8 Hz), 4.48 (1H, dd, J=11.5, 1.8 Hz), 4.20 (1H, dd, J=11.5, 2.6 Hz), 1.80 (3H, d, J=7.0 Hz), 1.47 (3H, d, J=6.7 Hz)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:16]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>CN(C)C=O>[CH2:34]([N:36]([CH2:37][CH3:38])[C:19](=[O:21])[CH2:18][CH2:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:16]=1)[CH3:35]
Reactant: O=C(O)CCc1nc(-c2ccccn2)nc2ccccc12
Reactant: CCNCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCc1nc(-c2ccccn2)nc2ccccc12

Procedure:
The procedure is as in Example 7, starting with 2-(2-pyridyl)-4-quinazolinepropanoic acid (1.34 g), carbonyldiimidazole (0.93 g) and diethylamine (1 cc) in dimethylformamide (25 cc). After chromatography on silica gel with a chloroform/methanol (95:5 by volume) mixture as eluant, and crystallization in ethyl acetate, N,N-diethyl-2-(2-pyridyl)-4-quinazolinepropanamide (0.58 g), m.p. 130° C. is obtained.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[C:8]([F:15])[C:7]=1[CH:16]([CH3:18])[CH3:17])=[O:4].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[C:8]([F:15])[C:7]=2[CH:16]([CH3:18])[CH3:17])=[O:4])[CH2:24][CH2:23]1
Reactant: OCCN1CCNCC1
Reactant: CC(C)c1ccc(F)c(C(C)C)c1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1ccc(F)c(C(C)C)c1NC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.2 %

Procedure:
To a solution of this acetamide (498 mg, 1.57 mmol) in acetonitrile (10 ml) were added 1-(2-hydroxyethyl)piperazine (371 mg, 2.85 mmol) and potassium carbonate (469 mg, 3.39 mmol) successively with ice-cooling, and stirred at room temperature for 12 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting reside was purified by a silica gel column chromatography (silica gel 50 g, developing solvent; chloroform:methanol=25:1 10:1) and recrystallized from ether-hexane to provide 575 mg (yield 99%) of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-(2,6-diisopropyl-3-fluorophenyl)acetamide as colorless needles.