Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][N:11]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:8]=3[N:9]=[CH:10][C:5]2=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[N:3]=1.C1C(=O)N([Br:41])C(=O)C1>C(Cl)Cl>[Br:41][C:13]1[C:7]2[N:6]3[C:2]([CH3:1])=[N:3][C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:28][CH:29]=4)=[C:5]3[CH:10]=[N:9][C:8]=2[N:11]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[CH:12]=1
Reactant: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)n12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3c(c(Br)cn3[Si](C(C)C)(C(C)C)C(C)C)n12
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 36.9 %

Procedure:
To a solution of 2-(4-(1-methyl-6-(triisopropylsilyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (1.5 g, 3.2 mmol, Preparation #AX.1) in DCM (32.4 ml) at about −20° C. was added NBS (0.46 g, 2.6 mmol). The mixture was stirred at about −20° C. for about 40 min. The mixture was diluted with DCM (100 mL) and washed with saturated aqueous NaHCO3 (75 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (120 g silica gel column; 0 to 50% EtOAc/heptane) to give 2-(4-(8-bromo-1-methyl-6-(triisopropylsilyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.52 g, 29%). LC/MS (Table 2, Method h) Rt=2.51 min; MS m/z 543 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:9][CH:10]=1)[OH:5].[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[O:9][CH:10]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[N:7]=2)=[CH:12][CH:13]=1
Reactant: NCCC(O)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCC(O)c1coc(-c2ccc(F)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 19 %

Procedure:
This compound was synthesized from 3-amino-1-(2-(4-fluorophenyl)oxazol-4-yl)propan-1-ol and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (35 mg, yield 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8.80-8.77 (t, J=5.3 Hz, 1H), 8.51 (s, 1H), 8.20-8.18 (d, J=7.6 Hz, 1H), 8.13-8.11 (d, J=7.9 Hz, 1H), 8.00 (s, 1H), 7.99-7.96 (dd, J=8.8 Hz, 5.5 Hz, 2H), 7.72-7.68 (t, J=7.8 Hz, 1H), 7.37-7.32 (t, J=8.8 Hz, 2H), 5.44-5.43 (d, J=5.2 Hz, 1H), 4.69-4.65 (m, 1H), 3.47-3.42 (m, 2H), 2.17-2.08 (m, 1H), 1.99-1.90 (m, 1H). MS (ESI) m/z: Calculated for C22H16F4N4O4: 476.11. found: 477.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH:25]=[CH2:26])[CH3:23])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.O.[OH-].[Na+]>C(O)C>[CH2:24]([N:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH:9]=[CH:10]2)[CH3:23])[CH:25]=[CH2:26]
Reactant: C=CCN(C)CCCCCc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCN(C)CCCCCc1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
To 1.3 g (3.5 mmol) 5-[5-(Allyl-methyl-amino)-pentyl]-indole-1-carboxylic acid tert-butyl ester in 20 ml ethanol were added 1.5 ml water and 3 ml conc. NaOH, and stirred at 60° C. for 1.5 h. The slurry was concentrated and dissolved in ether/water. The organic layer was washed with water and dried over Na2SO4 and evaporated to yield 900 mg (quantitative) Allyl-[5-(1H-indol-5-yl)-pentyl]-methyl-amine as light yellow oil, MS: 257 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[N:13][C:12]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]2=3)[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][C:15](=[O:16])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]4[CH:31]=[CH:30][C:27]5[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=5[N:33]=4)[CH2:7][CH2:6]3)[C:11]=2[N:20]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2n1
Reaction time: 24 h
Yield: 52 %

Procedure:
A solution of 4-[2-(4-amino-1-piperidinyl)ethyl]-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (50 mg, 0.1648 mmoles) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e)) (29.4 mg, 0.1648 mmoles) in anhydrous DCM (5 ml) and anhydrous MeOH (0.5 ml) was stirred at rt for 5 mins. Sodium triacetoxyborohydride (104.7 mg, 0.494 mmoles) was added and the mixture was stirred, under argon, for 24 h. The reaction was treated with sat. aq. NaHCO3 solution (2 ml) and 9:1 DCM:MeOH (5 ml). The layers were separated and the aqueous layer was washed with 9:1 DCM:MeOH (10 ml) and 5:1 DCM:MeOH (2×20 ml). The organic extracts were combined, passed through a hydrophobic frit and evaporated to an orange gum. Purification on a 10 g silica column eluted with an 80:20 DCM:MeOH elution gave the product as a yellow gum (39.8 mg, 52%).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[CH3:10][CH2:9][CH2:8][CH:2]([P:14]([O:15][CH2:16][CH3:17])([O:13][CH2:11][CH3:12])=[O:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOP(OCC)OCC
Reactant: CCCC(Br)C(=O)OCC
Product: CCCC(C(=O)OCC)P(=O)(OCC)OCC

Procedure:
In analogy to the procedure given in Example 3: Ethyl 2-bromovalerate was treated with triethylphosphite to give triethyl 2-phosphonovalerate as a colorless clear liquid, b.p.=95°-110° C. (0.175 mm of Hg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]Cl)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)=[O:23])=[CH:29][CH:30]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(OCC1CC1)c1ccc(O)cc1
Reactant: ClCCC1CCN(c2ccc(Cl)nn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(OCC1CC1)c1ccc(OCCC2CCN(c3ccc(Cl)nn3)CC2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A mixture of 2.6 parts of 3-chloro-6-[4-(2-chloroethyl)-1-piperidinyl]pyridazine, 1.9 parts of (cyclopropylmethyl) 4-hydroxybenzoate 1.1 parts of sodium carbonate and 94 parts of N,N-dimethylacetamide was stirred overnight at 110° C. After cooling, the reaction mixture was poured into water. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2.9 parts (69.7%) of (cyclopropylmethyl) 4-[2-[1-(6-chloro-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate; mp. 134.0° C. (comp. 129).
Reaction SMILES: [Br:1][C:2]1[S:18][C:5]2[C:6](=[O:17])[NH:7][CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[CH3:19]N(C)C=O.[H-].[Na+].CI>>[Br:1][C:2]1[S:18][C:5]2[C:6](=[O:17])[N:7]([CH3:19])[CH2:8][CH:9]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C1NCC(c2ccc(Cl)cc2)c2cc(Br)sc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN1CC(c2ccc(Cl)cc2)c2cc(Br)sc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
To a 20 mL vial was added a solution of 2-bromo-4-(4-chlorophenyl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (0.0800 g, 0.233 mmol) in anhydrous N,N-dimethylformamide (3.00 mL, 38.7 mmol) and cooled to 0° C. NaH 60% in mineral oil (60:40, sodium hydride:Mineral Oil, 0.0500 g, 1.25 mmol) was added in portions and stirred for 10 minutes. Methyl iodide (0.0876 mL, 1.41 mmol) was added and the reaction mixture was slowly warmed to room temperature and allowed to stir for 1 hour. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (5.00 mL) and diluted with EtOAc (10.00 mL). The mixture was successively washed with water (10.0 mL×2) and brine (10.0 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was wet loaded onto silica gel and then purified using a ISCO (4 g cartridge, gradient hexanes to 75% EtOAc over 30 min) to afford the product (0.0812 g, 78%) as a yellow oil. LC/MS (AA) ES+ 356, 358, 360. 1H NMR (dmso-d6, 400 MHz): d 7.43-7.37 (2H, m), 7.25-7.19 (2H, m), 6.98 (1H, s), 3.81-3.73 (1H, m), 3.66-3.58 (1H, m), 2.85 (3H, s).
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[C:16]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=2)=[CH:9][CH:8]=1)=[O:6].Cl>C(O)C.O>[C:5]([C:7]1[C:16]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=2)=[CH:9][CH:8]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1ccc2cccc(C(C)C)cc1-2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1cccc2ccc(C(=O)O)c-2c1
Temperature: 25 °C

Procedure:
Potassium hydroxide (10.5 g) was dissolved in a mixture of ethanol (80 ml) and water (15 ml). The compound (17) (12.43 g) was added thereto and the mixture was heated under reflux for 50 minutes in an oil bath. The reaction solution was cooled to room temperature, and then poured into water (400 ml). The solution was made acidic (pH 3) with conc. HCl. The precipitate was filtered, washed with water and dried to obtain 1-carboxy-7-isopropylazulene (18), at a yield of 2.1 g (92.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCSc1cccc(Br)c1
Reactant: O=C1NC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCSc1cccc(Br)c1

Procedure:
Mitsunobu coupling of 2-(3-bromophenylthio)ethanol (125) with phthalimide according to the method used in Example 17, followed by flash chromatography (5-20% ethyl acetate/hexanes gradient) gave 2-(2-(3-bromophenylthio)ethyl)isoindoline-1,3-dione (126) as a white solid. Yield (4.04 g, 72%): 1H NMR (400 MHz, CDCl3) δ 7.77-7.84 (m, 2H), 7.66-7.72 (m, 2H), 7.50 (t, J=2.0 Hz, 1H), 7.30 (ddd, J=0.8, 1.6, 7.6 Hz, 1H), 7.19 (ddd, J=0.8, 1.6, 7.6 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 3.93 (t, J=7.2 Hz, 2H), 3.22 (J=7.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:5]=[CH:6][C:7]=1[Cl:8].C(OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CS(C)(=O)=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 148.2 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-7-(3,4-dichlorophenyl)-6-[(methylsulfonyl)methyl]-1,4-oxazepane-4-carboxylate (111 mg) in ethyl acetate (1 ml) was added 4 N hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The crystals obtained by concentration under reduced pressure were recrystallized from ethanol-water to give the title compound (70.3 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.O1CCCC1>C(O)C.[C].[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.5 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (20 g) in ethanol (200 ml)-tetrahydrofuran (125 ml) was added 10% palladium carbon (6.0 g), followed by stirring under a hydrogen atmosphere at room temperature for 4.5 hrs. The mixture was filtered to remove the catalyst, which was washed with ethanol. The filtrate was concentrated under a reduced pressure to provide the titled compound (16.1 g, 100%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].O>CN(C=O)C>[CH3:15][C:6]1[C:7]([O:14][CH2:30][CH:29]=[CH2:28])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]([C:2]([F:20])([F:1])[F:21])=[N:4][C:5]=1[C:16]([F:19])([F:18])[F:17]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1c(C)c(C(F)(F)F)nc(C(F)(F)F)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of 10 g (0.03 mol) of product of Example 35 with 9.7 g (0.07 mol) of K2CO3 in 100 ml of DMF was charged 8 g (0.07 mol) of allyl bromide. The resulting mixture was stirred at 25° C. for 4 days. The reaction mixture was poured into H2O, and extracted with duethyl ether. The ether phase was dried (MgSO4), and concentrated in vacuo to 10.2 g (95%) of product as a yellow oil: nD25 1.4334
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:9]([CH2:18][N+:19]([O-:21])=[O:20])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.Cl[CH2:23][NH:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33].Cl>CN(C)C=O>[Cl:7][C:8]1[C:9]([CH:18]([N+:19]([O-:21])=[O:20])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:33])([F:35])[F:34])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=1
Reactant: O=C(NCCl)c1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])Cc1ncc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCC(c1ncc(C(F)(F)F)cc1Cl)[N+](=O)[O-])c1ccccc1C(F)(F)F
Yield: 56.7 %

Procedure:
To 10.26 g of potassium tert-butoxide in 80 ml of N,N-dimethylformamide, 20.00 g of 3-chloro-2-nitromethyl-5-(trifluoromethyl)pyridine was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at the same temperature for another 30 minutes. Then, to the reaction mixture, 18.77 g of the N-chloromethyl-2-(trifluoromethyl)benzamide prepared in Step 2 in Synthetic Example 19 in 20 ml of N,N-dimethylformamide was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 3 hours. After completion of the reaction, the reaction mixture was carefully poured into 150 ml of 5% aqueous hydrochloric acid under cooling with ice and extracted with ethyl acetate (100 ml×2). The resulting organic layers were combined, washed with water (100 ml×2) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The precipitated solid was purified with 30 ml of diisopropyl ether to obtain 19.80 g of the desired product as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[C:8]([CH:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13])(=O)[CH3:9].C(O)(=O)C>C1(C)C=CC=CC=1>[OH:14][CH2:15][CH2:16][C:11]1[C:8]([CH3:9])=[N:1][C:2]2[N:3]([N:4]=[C:5]([CH3:7])[CH:6]=2)[C:12]=1[OH:13]
Reactant: CC(=O)C1CCOC1=O
Reactant: Cc1cc(N)n[nH]1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc2nc(C)c(CCO)c(O)n2n1
Temperature: 25 °C
Yield: 85788 %

Procedure:
A solution of 3-amino-5-methylpyrazole (25.0 g, 0.26 mole), α-acetyl-γ-butyrolactone (34.5 g, 0.27 mmol) and acetic acid (5 mL) in toluene (350 mL) was heated under reflux for three hours. After cooling to room temperature, the resulting crystals were collected by filtration and washed with ethyl acetate, to give the title compound (48.0 g) as white crystals.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH:6]1([CH2:9][N:10]2[CH:15]=[CH:14][C:13](O)=[C:12]([C:17]([F:20])([F:19])[F:18])[C:11]2=[O:21])[CH2:8][CH2:7]1>CN(C=O)C>[Br:3][C:13]1[CH:14]=[CH:15][N:10]([CH2:9][CH:6]2[CH2:8][CH2:7]2)[C:11](=[O:21])[C:12]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=P(Br)(Br)Br
Reactant: O=c1c(C(F)(F)F)c(O)ccn1CC1CC1
Solvent: CN(C)C=O
Product: O=c1c(C(F)(F)F)c(Br)ccn1CC1CC1
Temperature: 110 °C
Yield: 42 %

Procedure:
Phosphorus oxybromide (7.03 g, 24.5 mmol) was added to a solution of intermediate D8 (2.60 g, 11.1 mmol) in DMF (50 ml) and the mixture was heated at 110° C. for 1 hour. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D9 (1.38 g, 42%).
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10]C)=[O:8])=[CH:4][CH:3]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][O:9][C:7]([C:5]1[N:6]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:15])[C:2]([Br:1])=[CH:3][CH:4]=1)=[O:8]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)c1ccc(Br)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)n1CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A mixture of ethyl 5-bromo-1H-pyrrole-2-carboxylate (0.13 g, 0.64 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (160 mg, 0.69 mmol) and potassium carbonate (132 mg, 0.95 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature overnight. At this time, the light brown reaction mixture was quenched with water. The resulting precipitate was collected by filtration and dried in vacuo. The resulting solid was dissolved in methylene chloride, concentrated in vacuo and then triturated with diethyl ether. The resulting solid was collected by filtration and dried in vacuo to afford 5-bromo-1-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester (155 mg, 69%) as light brown solid. 1H NMR (chloroform-d) δ ppm 8.00 (d, J=8.8 Hz, 2H), 6.96-7.07 (m, 3H), 6.85 (d, J=1.8 Hz, 1H), 5.71 (s, 2H), 3.91 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(F)(F)F)=[C:4]([CH3:15])[CH:3]=1.[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24][C:25]2[CH:26]=[C:27]([O:40][CH2:41][CH3:42])[C:28](I)=[C:29]([O:31][S:32]([CH2:35][CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:33])[CH:30]=2)=[CH:19][N:18]=1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[C:27]([O:40][CH2:41][CH3:42])=[CH:26][C:25]([CH2:24][C:20]3[C:21]([NH2:23])=[N:22][C:17]([NH2:16])=[N:18][CH:19]=3)=[CH:30][C:29]=2[O:31][S:32]([CH2:35][CH:36]([CH3:37])[CH3:38])(=[O:33])=[O:34])=[CH:3][C:4]=1[CH3:15]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1I
Reactant: Cc1cc(Br)ccc1NC(=O)C(F)(F)F
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1-c1ccc(N)c(C)c1
Yield: 66 %

Procedure:
Starting from 191 mg (0.68 mmol) N-(4-bromo-2-methyl-phenyl)-2,2,2-trifluoro-acetamide and 173 mg (0.34 mmol) 2-methyl-propane-1-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 109 mg of the title compound are obtained as a brown solid after chromatography and stirring in 5 ml ether.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[NH:7][C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[C:25]([F:31])[CH:24]=1.Cl>CN(C)C=O>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:7]2[C:6](=[O:19])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2=[O:18])=[C:25]([F:31])[CH:24]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To a solution of ethyl 2-(7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)acetate (176 g) in N,N-dimethylformamide (3.5 l) was added sodium hydride (60% in mineral oil, 32.3 g) at 0° C. and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added a solution of 4-bromo-2-fluorobenzyl bromide (200 g) in N,N-dimethylformamide (100 ml) below 20° C. over a 20-minute period and the resulting mixture was stirred at room temperature for 1 hour. 3N Aqueous hydrochloric acid (62.2 ml) was added to the mixture below 15° C. and the solvent was evaporated in vacuo. The residue was poured into a mixture of ethyl acetate (3 l) and water (3 l), and the resulting mixture was stirred for 15 minutes. The precipitates were filtered off and the organic layer was separated. The solution was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized with addition of isopropyl ether and the crystals were collected by filtration and washed with isopropyl ether. The crude crystals and the precipitates were mixed and recrystallized from a mixture of ether acetate (0.9 l) and n-hexane (0.9 l) to give ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (251 g).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]([CH2:10][C:11](=[O:13])[CH3:12])(=[O:9])[CH3:8].[Na]>>[CH3:6][O:5][C:1](=[O:4])[CH2:2][CH2:3][CH:10]([C:11](=[O:13])[CH3:12])[C:7](=[O:9])[CH3:8]
Reactant: C=CC(=O)OC
Reactant: CC(=O)CC(C)=O
Agent: [Na]
Product: COC(=O)CCC(C(C)=O)C(C)=O

Procedure:
4-acetyl-5-oxohexanoic acid methyl ester was prepared through the Michael addition of methyl acrylate to acetyl acetone in the presence of metallic sodium. The crude product was purified by vacuum distillation and received in a purity of approximately 99%.
Reaction SMILES: CC1C=CC=C(C)N=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18](Br)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1.[OH:24][CH2:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][N:32]2[CH3:35])=[CH:28][CH:27]=1>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18]([C:30]3[C:29]4[C:33](=[CH:34][C:26]([CH2:25][OH:24])=[CH:27][CH:28]=4)[N:32]([CH3:35])[CH:31]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: Cn1ccc2ccc(CO)cc21
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO)ccc12
Temperature: 80 °C
Yield: 77.3 %

Procedure:
2,6-Dimethylpyridine (0.12 ml) was added to a stirred solution of methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from step (c), 273 mg, 1 mmol) and 6-(hydroxymethyl)-1-methylindole (from step (a), 161 mg, 1 mmol) in anhydrous dimethylformamide (2 ml) at ambient temperature, under a nitrogen atmosphere. The solution was heated to 80° C. for 3 hours. The reaction mixture was cooled, and partitioned between diethylether and water, separated and the organic layer dried (magnesium sulphate) and evaporated in vacuo. The residue was flash chromatographed (using diethyl ether as eluant) to give the subtitle compound as a colourless foam (273 mg).