Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1C=CN=C1C1SC=CN=1.ClC1C=CC(OC)=C(NC2S[CH:21]=[C:22]([C:24]3[S:28][C:27]([NH:29]C(=O)C4C=CC=CC=4)=[N:26][C:25]=3[CH3:38])N=2)C=1.ClC(C(=O)C)C(=[O:45])C.NC(N)=S>C(O)C>[C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:38])(=[O:45])[CH3:21]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: COc1ccc(Cl)cc1Nc1nc(-c2sc(NC(=O)c3ccccc3)nc2C)cs1
Agent: NC(N)=S
Agent: c1csc(-c2nccs2)n1
Solvent: CCO
Product: CC(=O)c1sc(N)nc1C
Yield: 90 %

Procedure:
An efficient route for the synthesis bithiazole analogs was developed as follows. Efforts began with a synthesis of N-(2-(5-chloro-2-methoxyphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)benzamide—the putative structure of “Corr-4” corrector 4. This work commenced by treating 3-chloropentane-2,4-dione with thiourea under reflux in absolute ethanol. 5-Acetyl-2-amino-4-methylthiazole (5) was obtained in 90% yield. Surprisingly, attempts to aminoacylate the 2-amino moiety in 5 with benzoyl chloride under various base, solvent and temperature conditions failed to deliver the desired intermediate N-(5-acetyl-4-methyl-thiazol-2-yl)-benzamide (6).
Reaction SMILES: CN1CCOCC1.Cl.[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13].C1C=CC2N(O)N=NC=2C=1.[C:26]([NH:33][C@@H:34]([C:39](O)=[O:40])[CH2:35][CH2:36][S:37][CH3:38])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[NH:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:34]([C:39]([NH:13][C@H:12]([C:11]([O:10][CH3:9])=[O:15])[CH3:14])=[O:40])[CH2:35][CH2:36][S:37][CH3:38]
Reactant: COC(=O)[C@H](C)N
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
N-methylmorpholine (5.6 g), L-alanine methyl ester hydrochloride (3.9 g), HOBt (4.6 g) and 1-(3-dimethlylaminopropyl)-3-ethylcarbodiimide (5.3 g) was added to a solution of Boc-(D)-Methionine (7 g, 0.028 mol) in dry DMF (50 ml). The mixture was stirred overnight. Solvent was removed by evaporation and the residue was partitioned between dichloromethane (100 ml) and 5% aqueous acetic acid (5 ml). On standing HOBt crystallised and was removed by filtration, and the organic layer was separated and washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated. The residue (8.5 g) was purified by flash chromatography in a sinter funnel eluting with a mixture of dichloromethane and ether (0% to 100% ether). The fractions containing product were combined and evaporated to give Boc-(D)-Met-(L)-Ala-OMe (7.2 g) as a gum which crystallised on standing; NMR (CDCl3): 1.4 (d, 3H), 1.45 (s, 9H), 1.95 (m, 1H), 2.1 (s, 3H), 2.1 (m, 1H), 2.6 (m, 2H), 3.75 (s, 3H), 4.3 (bs, 1H), 4.6 (m, 1H), 5.3 (m, 1H), 6.9 (bs, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([NH:11][C:12]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14](OC)[CH:13]=3)[N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:24].[CH3:25][NH:26][C:27]1[N:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[N:28]=1.[C:46](=O)([O-])[O-:47].[Na+].[Na+].CN(C=O)C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:46][O:47][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:6]2[N:7]=[CH:8][CH:9]=[C:10]3[C:2]([C:32]4[CH:33]=[C:34]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([NH:26][CH3:25])[N:36]=[CH:35]5)=[C:3]([CH3:24])[S:4][C:5]=23)=[CH:17][C:16]=1[C:18]([F:20])([F:21])[F:19]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Nc2nccc3c(Br)c(C)sc23)cc(C(F)(F)F)c1
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ncc2cc(-c3c(C)sc4c(Nc5ccc(OC)c(C(F)(F)F)c5)nccc34)ccc2n1
Temperature: 150 °C

Procedure:
3-Bromo-N-(3-methoxy-5-(trifluoromethyl)phenyl)-2-methylthieno[2,3-c]pyridin-7-amine (0.230 g, 0.551 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.189 g, 0.661 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (0.0193 g, 0.0276 mmol), sodium carbonate (0.117 g, 1.10 mmol) were all placed in a clear microwave vial along with 5 ml of 9:1 DMF:water. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 150° C. for 10 minutes. The reaction was diluted with water and extracted with EtAOc. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 50-100% EtOAc in hexanes. The pure fractions were reduced in vacuo and the residue triturated with ether to give 6-(7-(4-methoxy-3-(trifluoromethyl)phenylamino)-2-methylthieno[2,3-c]pyridin-3-yl)-N-methylquinazolin-2-amine as a yellow solid. MS (M+H)+ 496.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:8]([NH2:10])[CH:9]=1)([O-:3])=[O:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:10][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:24])[CH2:15][CH2:16]1
Reactant: Nc1cc([N+](=O)[O-])ccc1N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Yield: 85.9 %

Procedure:
A solution of 5-nitro-2-(piperazin-1-yl)benzenamine (2.4 g, 10.7 mmol), benzoyl chloride (1.2 ml, 12.8 mmol) and triethylamine (6.0 ml, 42.7 mmol) in 40 ml DCM was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. (4-(2-Amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (3.0 g, 86%) was obtained by flash column chromatograph (40% ethyl acetate in hexanes). A solution of (4-(2-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (0.3 g, 0.9 mmol), acetyl chloride (0.065 ml, 0.9 mmol) and sodium hydroxide (0.037 g, 0.9 mmol) in 20 ml THF was stirred at 0° C. for 2 hours. The mixture was concentrated. N-(2-(4-benzoylpiperazin-1-yl)-5-nitrophenyl)acetamide (0.11 g, 32%) was obtained by flash column chromatograph (65% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.29 (s, 3H), 3.00 (s, br, 4H), 3.84 (s, br, 4H), 7.23 (d, J=8.8 Hz, 1H), 7.47-7.51 (m, 5H), 8.00 (dd, J=8.6, 2.6 Hz, 1H), 8.16 (s, br, 1H), 9.24 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 25.3, 52.3, 116.0, 119.9, 120.8, 127.6, 129.2, 130.7, 135.6, 171.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:22]([CH:25]=[CH2:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1>[Pd].C(O)C>[CH2:25]([C:22]1[N:10]2[N:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9]2=[CH:24][CH:23]=1)[CH3:26]
Reactant: C=Cc1ccc2c(-c3ccc(F)cc3)c(C(=O)OCC)c(C(C)C)nn12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(C(C)C)nn2c(CC)ccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100.5 %

Procedure:
A mixture of ethyl 4-(4-fluorophenyl)-2-isopropyl-7-vinylpyrrolo[1,2-b]pyridazine-3-carboxylate (8.9 g) and 10% palladium on carbon (900 mg) in ethanol (180 mL) was stirred under hydrogen atomosphere (3.5 atm) at ambient temperature. After 10 hours, the mixture was stood overnight. To the mixture was added 10% palladium on carbon (900 mg) and was stirred under hydrogen atomosphere (3.5 atm) at ambient temperature. After 12 hours, the mixture was stood overnight. To the mixture was added 10% palladium on carbon (900 mg) and was stirred under hydrogen atomosphere (3.5 atm) at ambient temperature for 8 hours. The mixture was filtered through Celite. The filtrate was concentrated in vacuo to give ethyl 7-ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow oil (9.0 g, 100.5%).
Reaction SMILES: [F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:10]([OH:34])[CH:9]=2)[CH:3]=1.Cl[C:36]([F:41])([F:40])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:40][CH:36]([F:41])[O:34][C:10]1[CH:9]=[C:8]([N:4]2[CH:5]=[C:6]([F:7])[C:2]([F:1])=[CH:3]2)[CH:13]=[CH:12][C:11]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[N:15]1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2O)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OC(F)F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 75.4 %

Procedure:
A mixture of 1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-hydroxyphenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (231 mg), sodium chlorodifluoroacetate (152 mg), potassium carbonate (104 mg), DMF (2.5 mL) and water (0.5 mL) was heated under reflux overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate), and crystallized from hexane/ethyl acetate to give the title compound (193 mg).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.Cl[CH2:30][C:31]#[N:32].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:31]([CH2:30][N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17]1)#[N:32]
Reactant: N#CCCl
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 70 °C

Procedure:
A mixture of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (16 g, 0.052 mole), chloroacetonitrile (8 g, 0.10 mole) and sodium bicarbonate (17 g, 0.20 mole) in DMF (125 ml) was warmed at 70° C. for 2.5 hours. The mixture was concentrated to an oil which was stirred with water and extracted with ethyl acetate. The organic extracts were washed twice with water and dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil (18 g) which solidified upon triturating with petroleum ether to a solid (16.5 g, 92%, m.p. 125°-129° C.). A sample was recrystallized from hexanes to yield 3-cyanomethyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, m.p. 134°-135° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=3[O:23][CH3:24])=[N:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[SH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.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>[CH2:35]([S:34][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=3[O:23][CH3:24])=[N:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: SCc1ccccc1
Reactant: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1n[nH]c(=O)c2cc(SCc3ccccc3)ccc12
Temperature: 80 °C
Yield: 60.1 %

Procedure:
To a pressure tube containing a solution of 7-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazin-1(2H)-one (1.14 g, 2.86 mmol) and N,N-diisopropylethylamine (0.99 mL, 5.71 mmol) in 1,4-dioxane (20 mL) was added XantPhos (0.083 g, 0.143 mmol) and tris(dibenzylideneacetone) dipalladium (0) (0.065 g, 0.071 mmol) followed by (mercaptomethyl)benzene (0.352 mL, 3.00 mmol). The reaction tube was purged with nitrogen. The tube was sealed and heated at 80° C. for 30 min. After cooling to RT, the reaction was filtered over a pad of diatomaceous earth, rinsing well with EtOAc. The filtrate was concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (120 g), eluting with a gradient of 0% to 50% EtOAc in heptane, to provide 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazin-1(2H)-one (0.76 g, 60% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 3.77 (s, 3H), 4.44 (s, 2H), 7.15 (d, J=8.55 Hz, 1H), 7.21-7.28 (m, 1H), 7.32 (t, J=7.43 Hz, 2H), 7.40-7.50 (m, 4H), 7.57 (d, J=7.69 Hz, 1H), 7.72 (dd, J=8.60, 2.08 Hz, 1H), 8.11 (d, J=1.92 Hz, 1H), 12.85 (s, 1H). m/z (ESI) 443.0 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:30]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH:32]=1)[CH2:8][N:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[S:10]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[OH:21])(=[O:12])=[O:11])=[N+]=[N-].C1(C)C=CC=CC=1>CCOC(C)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:30]=[C:31]([O:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH:32]=1)[CH2:8][N:9]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[S:10]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[OH:21])(=[O:12])=[O:11]
Reactant: [N-]=[N+]=NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A mixture of N-(3-(azidomethyl)-5-(4-fluorophenoxy)benzyl)-3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzenesulfonamide (1.0 g, 1.652 mmol) and 100 mg of 20% of Pd(OH)2 on carbon in EtOAc (15 mL) and MeOH (15 mL) was stirred at rt under 1 atm of H2 gas for 3 h. To the mixture was added toluene. The resulting mixture was stirred for a while, and the solid was filtered, washed with methanol. The filtrate was concentrated in vacuo to obtain the desired product (0.88 g, 1.519 mmol, 92% yield) as a white solid. 1H NMR (CD3OD): δ 7.49 (d, J=2.8 Hz, 1H), 7.35 (d, J=2.8 Hz, 1H), 7.21-7.09 (m, 4H), 6.99-6.90 (m, 5H), 6.85 (s, 1H), 6.64 (s, 1H), 4.48 (s, 2H), 4.40 (s, 2H), 3.93 (s, 2H); MS (ESI): (M+H)+=579.0.
Reaction SMILES: [C:1]1([C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12]Br>C(OCC)C>[Br:12][CH:8]([CH2:9][CH3:10])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: BrBr
Reactant: CCCC(=O)c1ccccc1
Solvent: CCOCC
Product: CCC(Br)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
To a solution of 1-phenylbutan-1-one (10.0 g, 67.5 mmol) in diethyl ether (200 ml) was slowly added dropwise bromine (10.8 g, 67.5 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was distilled off under reduced pressure to give the desired product (11.1 g, 72.3%) as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[C:20](=O)([O:28]C1C=CC=CC=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O>C1COCC1>[C:22]1([O:21][C:20](=[O:28])[NH:17][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[N:4]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1nc(OCc2ccc(F)cc2)ncc1F)Oc1ccccc1
Yield: 21 %

Procedure:
To a stirred mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.20 g, 0.84 mmol) in dry THF (3 mL) at ice-bath temperatures was added NaH (0.034 g of 60 wt. % suspension in mineral oil, 0.84 mmol). When bubbling ceased, the resulting mixture was transferred (dropwise) via cannula to an ice-cold, stirred mixture of diphenyl carbonate (1.8 g, 8.4 mmol) in dry THF (5 mL). The mixture was stirred overnight, poured into EtOAc, and washed with saturated aq. NH4Cl solution followed by brine solution. The EtOAc layer was separated, dried over Na2SO4, filtered, and evaporated. The crude material was purified on silica gel using a gradient of EtOAc and hexanes to give 0.063 g (21%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]carbamic acid phenyl ester as a white solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=2.3 Hz, 1H), 7.43 (m, 5H), 7.30-7.20 (m, 2H), 7.02 (t, J=8.6 Hz, 2H), 5.38 (s, 2H); HPLC-MS (ESI) m/z 358 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=2)([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH3:15])[CH:10]=2)[N:3]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH3:15])[CH:10]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:27]3[CH:28]=[N:23][CH:24]=[N:25][CH:26]=3)[CH:17]=2)[N:3]=1
Reactant: CCn1ccc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)c1
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCn1ccc(C2(c3cccc(-c4cncnc4)c3)N=C(N)N(C)C2=O)c1
Yield: 75.7 %

Procedure:
To a solution of 2-amino-5-(3-bromophenyl)-5-(1-ethyl-1H-pyrrol-3-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one (80 mg, 0.22 mmol) in DME (3 mL) is added pyrimidin-5-ylboronic acid (57 mg, 0.44 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmo) and a solution sodium carbonate (93 mg, 0.88 mmol) in H2O (0.5 mL) at room temperature. The reaction mixture is refluxed for 1 h and cooled. After evaporation of the solvent, the crude material is purified by chromatography (silica gel, EtOAc/2M ethanolic NH3: 92/8) to give the title compound (60 mg, 75%) as a solid. mp: 100-102° C.; MS (+) ES: 361 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20][CH2:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]([N:20]([CH2:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:19])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1cc2ccccc2[nH]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1cc2ccccc2[nH]1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (17.10 g, 68.6 mmole) was added to a solution of 2-(methylaminomethyl)-1H-indole (10.00 g, 62.4 mmole), from Preparation 33, and triethylamine (9.60 mL, 68.6 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated. Flash chromatography on silica gel (20% ethyl acetate/hexanes) gave the title compound (14.80 g, 80%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[C:19]2[C:14](=[CH:15][C:16]([F:26])=[C:17]([N:20]3[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21]3)[CH:18]=2)[C:13](=[O:27])[N:12]([OH:28])[C:11]1=[O:29].F[C:31](F)(F)C([O-])=O>>[F:9][C:5]1[CH:4]=[C:3]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:26])=[C:17]([N:20]4[CH2:21][CH2:22][N:25]([CH3:31])[CH2:23][CH2:24]4)[CH:18]=3)[C:13](=[O:27])[N:12]([OH:28])[C:11]2=[O:29])[CH:2]=[CH:7][CH:6]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2cc(F)c(F)cc2F)C1
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2cccc(F)c2)CC1

Procedure:
1-(2,4,5-Trifluorophenyl)-6-fluoro-3-hydroxy-7-(3-aminopyrrolidin-1-yl)-1H-quinazoline-2,4-dione, trifluoroacetate;
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([O:25]CC)=[O:24].O.[OH-].[Li+].Cl>C1COCC1.O>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 0 °C
Reaction time: 17 h
Yield: 102 %

Procedure:
To a suspension of ethyl (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate (10.5 g, 24.5 mmol) in THF (200 mL) and water (100 mL) was added lithium hydroxide monohydrate (3.98 g, 95.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and at ambient temperature for 17 h. The mixture was neutralized with of 4 M HCl (15.0 mL). The residue obtained upon removing the solvent was acidified by the addition of 4 M HCl (6.2 mL) to pH 3. The solid was filtered, washed with water and hexane, and dried under the reduced pressure to give the title compound (8.48 g, 87%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.32-7.06 (m, 4H), 6.79 (d, 1H), 6.49 (s, 1H), 6.23 (s, 1H), 5.84 (m, 2H), 4.92 (m, 1H), 4.69-4.63 (m, 2H), 4.45 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.8, 171.8, 155.8, 149.0, 142.4, 141.2, 132.0, 129.0, 124.1, 124.0, 119.2, 108.3, 103.4, 101.5, 93.5, 80.2, 58.2, 41.1; MS (ES−) m/z 338.2 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][CH2:25][OH:26]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]2[O:26][CH2:25][CH2:24][CH2:23][O:7]2)=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C=O)cc(C)c1Br
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C2OCCCO2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-bromo-3,5-dimethyl-benzaldehyde (8.15 g, 38.25 mmol), p-toluenesulfonic acid (50 mg) and 1,3-propanediol (9.5 mL) in toluene (100 mL) is heated to 110° C. for 3 h. The reaction flask is equipped with a Dean-Stark apparatus and heating is continued at 110° C. for 16 h. The reaction mixture is cooled to rt, washed with sat. aq. NaHCO3 and the solvent is removed in vacuo. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-(4-bromo-3,5-dimethyl-phenyl)-[1,3]dioxane (5.97 g) as a colourless oil.