Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[NH:36][C:21]4[N:22]=[CH:23][N:24]=[C:25]([NH:26][C:27]5[CH:35]=[CH:34][C:30]6[N:31]=[CH:32][S:33][C:29]=6[CH:28]=5)[C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=1.[OH-].[Na+]>CO.O.CCOC(C)=O>[S:33]1[C:29]2[CH:28]=[C:27]([NH:26][C:25]3[C:20]4[CH:19]=[C:18]([C:15]5[CH2:16][CH2:17][N:12]([C:10]([C:6]6[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=6)[C:3]([OH:37])=[O:2])=[O:11])[CH2:13][CH:14]=5)[NH:36][C:21]=4[N:22]=[CH:23][N:24]=3)[CH:35]=[CH:34][C:30]=2[N:31]=[CH:32]1
Reactant: COC(=O)c1cccc(C(=O)N2CC=C(c3cc4c(Nc5ccc6ncsc6c5)ncnc4[nH]3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(C(=O)N2CC=C(c3cc4c(Nc5ccc6ncsc6c5)ncnc4[nH]3)CC2)c1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
3-{4-[4-(Benzothiazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carbonyl}-benzoic acid methyl ester (0.624 mmol) was suspended in a mixture of MeOH (6.0 mL) and water (2.0 mL). 2 M NaOH solution (1.0 mmol) was then added to the above suspension and the reaction temperature increased to 65° C. The resulting suspension was stirred for a further period of 16 h. The mixture was allowed to reach r.t and diluted with EtOAc (30 mL) and washed with 2M NaOH (2×20 mL). The aqueous phase was then acidified by careful addition of conc. HCl solution until pH≈1. The resulting brown precipitate was then filtered and dried under vacuum affording the title compound. 1H NMR (DMSO, 400 MHz): δ=9.45(1H,s), 8.7(1H,s), 8.15(1H,d), 8.1(1H,d), 8.0(1H,s), 7.8(1H,d), 7.7 (1H, d), 7.6(1H, t), 6.9(1H, s), 6.6(1H, m), 6.35(1H, m), 4.35(1H, m), 4.1(1H, m), 3.9(1H, m), 2.6(1H, m). [MH+—CO2]=498.25.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][C:16]1[O:20][N:19]=[CH:18][C:17]=1[C:21](Cl)=[O:22]>O>[C:12]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=2[C:2]=1[NH:1][C:21]([C:17]1[CH:18]=[N:19][O:20][C:16]=1[CH3:15])=[O:22])(=[O:14])[CH3:13]
Reactant: Cc1oncc1C(=O)Cl
Reactant: CC(=O)c1oc2ccc(Br)cc2c1N
Solvent: O
Product: CC(=O)c1oc2ccc(Br)cc2c1NC(=O)c1cnoc1C
Temperature: 27 °C
Reaction time: 0.08 h

Procedure:
To a solution (10 ml) of 1-(3-amino-5-bromobenzofuran-2-yl)ethanone (0.2 g, 0.79 mmol) in water-free THF was added dropwise a solution (5 ml) of 5-methylisoxazole-4-carbonyl chloride (0.10 g, 0.79 mmol) in water-free THF under a nitrogen gas with vigorous stirring at 26-28° C. over 5 min. The reaction solution was heated at 65° C. for 2 hr. The reaction mixture was cooled to room temperature and the precipitate was collected by filtration. The precipitate was recrystallized from ethyl acetate to give N-(2-acetyl-5-bromobenzofuran-3-yl)-5-methylisoxazole-4-carboxamide as pale-yellow needle crystals (0.19 g, yield 68.0%).
Reaction SMILES: C(OC(=O)COC1C=CC(SC2C=CC(C=O)=CC=2)=CC=1C)C.[CH2:24]([O:26][C:27](=[O:39])[CH2:28][O:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([SH:37])=[CH:32][C:31]=1[CH3:38])[CH3:25].Cl[C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][C:42]=1[CH3:49]>>[CH2:24]([O:26][C:27](=[O:39])[CH2:28][O:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([S:37][C:41]2[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][C:42]=2[CH3:49])=[CH:32][C:31]=1[CH3:38])[CH3:25]
Reactant: CCOC(=O)COc1cc(C)c(S)cc1C
Reactant: Cc1cc(C=O)ccc1Cl
Agent: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2)cc1C
Product: CCOC(=O)COc1cc(C)c(Sc2ccc(C=O)cc2C)cc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 7.1, using compound 21.3 and 4-chloro-3-methylbenzaldehyde as the starting materials. 1H NMR (400 MHz) (CDCl3) δ 9.86 (1H, s); 7.62 (1H, s); 7.44 (1H, d, J=8.1 Hz); 7.33 (1H, s); 6.70 (1H, s); 6.62 (1H, d, J=8.1 Hz); 4.68 (2H, s); 4.29 (2H, q, J=7.1 Hz); 2.46 (3H, s); 2.29 (3H, s); 2.26 (3H, s); 1.32 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([NH:17][CH:18]([P:20]([CH:25](Br)[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:24])[O:21][CH2:22][CH3:23])Br)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl-].[NH4+]>C1COCC1>[C:10]([O:14][C:15]([NH:17][CH:18]([P:20]([CH:25]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOP(=O)(C(Br)NC(=O)OC(C)(C)C)C(Br)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOP(=O)(C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 29.4 %

Procedure:
A 2.00N benzylmagnesium chloride solution (1.35 ml; 2.70 mmol) in THF is added dropwise to a solution of the bromide 6 (340 mg; 0.67 mmol) in THF (10 ml), which is stirred at -78° C. under an argon atmosphere. After stirring at -70° C. for 3 hours, the reaction solution is warmed to room temperature and mixed with saturated aqueous ammonium chloride solution (50 ml). The aqueous phase is extracted with ethyl acetate (3×60 ml). The combined organic phase is dried over Na2SO4 and concentrated under reduced pressure. After purification by column chromatography on silica gel (ethyl acetate/heptane), the bisalkylated phosphinic acid ester 10 (105 mg, 30% of theory) is obtained.
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([CH2:17][CH3:18])=[O:16])=[C:11]([Br:19])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([CH2:17][CH3:18])=[O:16])=[C:11]([Br:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(Br)c(OCC(=O)CC)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)COc1c(Br)ccc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.280 g (3.20 mmol) of ethyl 2,4-dibromo-3-(ethylcarbonylmethoxy)benzoate were dissolved in 15 ml of THF and 15 ml of water, and 0.143 g (3.6 mmol) of NaOH was added. The mixture was stirred at RT for 12 h and then evaporated to dryness. The residue was taken up in water, and 6 N HCl was added. The resulting precipitate was filtered off with suction and dried. This gave 2,4-dibromo-3-(ethylcarbonylmethoxy)benzoic acid in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10]S(C)=O.C([Cl:17])(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][Cl:17]
Reactant: CS(=O)COc1ccc(Cl)cc1Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: ClCOc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To an ice-water cooled solution of 2,4-dichloro-1-methanesulfinylmethoxy-benzene (8 g, 33.46 mmol) in DCM (100 mL) was added dropwise a solution of acetylchloride (2.6 mL, 36.80 mmol) in DCM (10 mL). The reaction mixture was allowed to reach room temperature during 2 hrs at which time the volatiles were evaporated in vacuo affording ˜7 g of crude 2,4-dichloro-1-chloromethoxy-benzene which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]1[NH:6][C:5](=[O:7])[N:4]([CH3:8])[C:3]1=[O:9].[N:10]1[C:17]([Cl:18])=[N:16][C:14](Cl)=[N:13][C:11]=1[Cl:12].C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:12][C:11]1[N:10]=[C:17]([Cl:18])[N:16]=[C:14]([NH:1][CH:2]2[NH:6][C:5](=[O:7])[N:4]([CH3:8])[C:3]2=[O:9])[N:13]=1
Reactant: CN1C(=O)NC(N)C1=O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN1C(=O)NC(Nc2nc(Cl)nc(Cl)n2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
An ice-cold suspension of 5-amino-3-methyl-imidazolidine-2,4-dione (Example 1.3, Part C) (266 mg, 2.06 mmol), cyanuric chloride (415 mg, 2.27 mmol) and sodium bicarbonate (191 mg, 2.27 mmol) in acetonitrile (15 mL) was stirred over an ice bath under a nitrogen atmosphere for 1 h, and then allowed to stir at room temperature for 22 h. The solvent was evaporated, and the crude product was extracted with ethyl acetate. The organic layer was dried and evaporated, and the crude product was purified by column chromatography (PS with gradient elution to DCM:EtOAc 1:1) to afford the product as a cream solid (448 mg, 78%). δH (300 MHz, CD3CN) 7.50 (br s, 1H, NH), 6.56 (br s, 1H, NH), 5.60 (dd, J 7.8, 1.8 Hz, 1H, CH), 2.97 (s, 3H, CH3). Mass spectrum (ESI) m/z 259 [M+H(OH for Cl exchanged ion)].
Reaction SMILES: [CH:1]1([S:6][C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]CC)=O)=[CH:19][CH:18]=3)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:29]>CO>[CH:1]1([S:6][C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:29])=[O:26])=[CH:19][CH:18]=3)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(SC3CCCC3)nc3c2CCC3)cc1
Reactant: N
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(SC3CCCC3)nc3c2CCC3)cc1
Yield: 69 %

Procedure:
Following general procedure C, ethyl 2-(4-((2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.51 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL) to afford the title compound (0.130 g, 69% over two steps) as an off-white solid. MW=367.51. 1H NMR (DMSO-d6, 300 MHz) δ 8.00 (s, 1H), 7.44 (s, 1H), 7.23 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 6.87 (s, 1H), 6.52 (s, 1H), 3.82 (quin, J=7.0 Hz, 1H), 3.33 (s, 2H), 2.84-2.67 (m, 4H), 2.12-1.95 (m, 4H), 1.73-1.39 (m, 6H); APCI MS m/z 368 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([CH2:25][C:26]([O:28]CC)=[O:27])[C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([CH2:25][C:26]([OH:28])=[O:27])[C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CN1CCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(CC(=O)O)CC3)CC1

Procedure:
Ethyl [7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl]acetate (1-4) (2.9 g, 6.95 mmol), 1N LiOH (20.9 mL, 20.9 mmol) and MeOH (50 mL) were stirred for 16 hours at room temperature. The solvent was removed, the residue was taken up in EtOAc and washed with 1N HCl. Repeated extraction of the aqueous phase followed by washing of the bulked organic layers with brine (5 mL), drying (MgSO4) and evaporation afforded 1-5 as a solid. 1H NMR (CD3OD): d1.48 (9H, s), 2.99 (2H, t), 3.20 (4H, m), 3.62 (6H, m), 4.31 (2H, s), 7.22 (2H, s), 7.60 (1H, s).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C@H:7]([NH:11][CH2:12][C:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([OH:22])[C:16]=3[NH:15][CH:14]=2)[CH2:8][S:9][CH3:10])[CH2:4][O:3]1.Cl>CO>[OH:6][C@H:5]([CH2:4][OH:3])[C@H:7]([NH:11][CH2:12][C:13]1[C:17]2[N:18]=[CH:19][NH:20][C:21](=[O:22])[C:16]=2[NH:15][CH:14]=1)[CH2:8][S:9][CH3:10]
Reactant: CSC[C@@H](NCc1c[nH]c2c(O)ncnc12)[C@H]1COC(C)(C)O1
Agent: Cl
Solvent: CO
Product: CSC[C@@H](NCc1c[nH]c2c(=O)[nH]cnc12)[C@H](O)CO
Yield: 73.3 %

Procedure:
The product from Example 26.6 (0.055 g, 0.16 mmol) was stirred in a 1% hydrogen chloride solution in methanol (10 ml) for 1.5 h at ambient temperature. The reaction mixture was neutralised with Amberlyst A-21 ion exchange resin. The resin was filtered and the reaction solution concentrated. The residue was chromatographed (methanol [3.5N ammonia solution]-DCM, 1:4) giving a white solid (0.035 g, 72%). 1H NMR (CD3OD) δ ppm 7.98 (s, 1H), 7.60 (s, 1H), 4.44 (ABq, 2H), 3.97 (q, J=3.8 Hz, 1H), 3.76 (dd, J=11.7, 4.2 Hz, 1H), 3.67 (dd, J=11.7, 3.8 Hz, 1H), 3.44 (m, 1H), 2.92 (m, 2H), 2.08 (s, 3H). 13C NMR (CD3OD) δ 156.2, 145.6, 144.0, 130.7, 120.0, 109.8, 70.1, 66.0, 60.0, 41.4, 33.9, 16.0. +ESMS Found 299.1194: (M+H)+ C12H19N4O3S requires 299.1178:
Reaction SMILES: CON(C)[C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:18]=[C:17]1[CH2:29][CH2:30][CH3:31].[C:34]1([Mg]Br)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[C:34]1([C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]=[CH:20][C:19]=3[N:18]=[C:17]2[CH2:29][CH2:30][CH3:31])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)N(C)OC
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)c1ccccc1

Procedure:
The general method described in Step 6 of Example 15 was used to react N-methoxy-N-methyl-12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanamide (6.0 g, 13.3 mmol) with phenylmagnesium bromide (26.5 mmol, 26.5 mL of a 1 M solution in THF) to provide 1-phenyl-12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecan-1-one (6.0 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]([N:11]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[NH:5][C:4](=[O:21])[CH:3]=1.[F:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O1CCOCC1>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH2:13][CH2:12][N:11]2[C:9](=[O:10])[CH2:8][C:6]1[NH:5][C:4](=[O:21])[CH:3]=[C:2]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([F:22])[CH:28]=2)[N:7]=1
Reactant: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
Reactant: CC1(C)OB(c2ccnc(F)c2)OC1(C)C
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: [Cs+]
Solvent: C1COCCO1
Product: O=C(Cc1nc(-c2ccnc(F)c2)cc(=O)[nH]1)N1CCc2c(F)cccc21
Temperature: 100 °C

Procedure:
130 mg of 6-chloro-2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one, 3 ml of 1,4-dioxane, 104 mg of 2-fluoropyridine-4-boronic acid pinacol ester, 50 mg of tetrakis(triphenylphosphine)palladium(0), and 0.58 ml of an aqueous 1.5 M cesium carbonate solution are successively placed in a three-necked round-bottomed flask under argon and with stirring. The mixture is heated at a temperature of 100° C. for 20 hours, and then filtered while hot. After cooling to ambient temperature, the filtrate is concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 20 ml of dichloromethane and 30 ml of water. After settling out, the organic phase is separated and the aqueous phase is extracted with dichloromethane. The aqueous phase is concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 30 ml of ethyl acetate and a few drops of ethanol, and then washed with 5 ml of water. After settling out, the organic phase is separated and the aqueous phase is extracted with 2×20 ml of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is taken up in 1 ml of dioxane and the mixture is refluxed, and then filtered through sintered glass. After drying of the isolated solid, 44 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-fluoropyridin-4-yl)-3H-pyrimidin-4-one are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15]C)=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br.CCCCCC>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1coc2cc(O)ccc12
Temperature: 10 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a cooled (0° C.) solution of 6-methoxy-benzofuran-3-carboxylic acid ethyl ester (90.0 g, 408.67 mmol) in DCM (700 mL) was slowly added BBr3 (159.0 g, 634.67 mmol) in DCM (200 mL) maintaining a controlled temperature (<5° C.). The resulting mixture was stirred (10° C., 6 h). The reaction mixture was slowly poured into ice/water with vigorous stirring followed by stirring in a temperature gradient (0° C.−rt, 18 h). The solids were filtered off and the filtrate was extracted with EtOAc (2×250 mL). The solids were dissolved (required heat) with the combined organic phase. The organic phase was washed with saturated NaHCO3 (700 mL), H2O (700 mL), dried, filtered and concentrated in vacuo to provide a yellow solid. The crude solid was suspended in EtOAc:hexane (20%), stirred (24 h) and filtered to provide the title compound as a solid (75.6 g). The filtrate was concentrated in vacuo and the resulting residue was purified by flash column chromatography using EtOAc:hexanes (20%) to provide the title compound (2.4 g) as a white solid (93% combined yield). MS (ESI): mass calcd. for C11H10O4, 206.2; m/z found, 207.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.15 (s, 1H), 7.88 (d, J=8.5, 1H), 7.01 (s, 1H), 6.90 (dd, J=8.5, 2.3, 1H), 5.05 (s, 1H), 4.4 (q, J=7.1, 2H) 1.42 (t, J=7.2, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([NH2:19])[C:15]=1[CH2:20][CH3:21]>C(O)(=O)C>[Cl-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=3)[C:15]=2[CH2:20][CH3:21])=[CH:5][CH:4]=1
Reactant: CCc1n(N)cc[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 50 h

Procedure:
2.98 g (20 mmol) of p-dimethylaminobenzaldehyde are added to a solution of 3.24 g (20 mmol) of 1,3-diamino-2-ethylimidazolium chloride in 180 ml of glacial acetic acid. The mixture is stirred at room temperatured for 50 hours, the precipitated 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium chloride is then filtered off and washed with ethanol. The mother liquor is evaporated and the residue is placed on a column loaded with 200 g of silica gel (particle size: 0.063-0.200 mm). By elution with methylene chloride/methanol (9:1 v/v) there is obtained a further portion of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-ethyl-imidazolium chloride.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:8]([Cl:14])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1.[F:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]([CH:26]=[CH2:27])[C:17]=1[CH:18]=[O:19].[NH4+].[Cl-]>C(OC(C)C)(C)C.C1C=CC=CC=1>[Cl:14][C:8]1[C:7]([CH:18]([C:17]2[C:20]([CH:26]=[CH2:27])=[CH:21][CH:22]=[C:23]([O:24][CH3:25])[C:16]=2[F:15])[OH:19])=[CH:12][C:11]([Cl:13])=[CH:10][N:9]=1
Reactant: Clc1cnc(Cl)c(Br)c1
Reactant: C=Cc1ccc(OC)c(F)c1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(C)OC(C)C
Product: C=Cc1ccc(OC)c(F)c1C(O)c1cc(Cl)cnc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of nBuLi (1.6 M in hexane, 29.0 mL, 46.4 mmol) in diisopropyl ether (80 mL) was added 3-bromo-2,5-dichloropyridine (10.5 g, 46.4 mmol) in diisopropylether (60 mL) slowly at −78° C. The resulting suspension was treated with 2-fluoro-3-methoxy-6-vinylbenzaldehyde (7.6 g, 42.2 mmol) in diisopropylether (60 mL) and benzene (3 mL), and allowed to stir at −78° C. for 30 min followed by warming to room temperature as the bath did. The mixture was treated with saturated NH4Cl solution and extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound.
Reaction SMILES: Cl.Cl.[CH:3]([NH:6][CH:7]1[CH2:10][NH:9][CH2:8]1)([CH3:5])[CH3:4].[NH2:11][C:12]1[N:17]=[C:16]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([F:30])=[C:25](F)[C:26]=3[Br:28])[C:21](=[O:31])[C:20]([C:32]([OH:34])=[O:33])=[CH:19]2)[C:15]([F:35])=[CH:14][C:13]=1[F:36].CN1CCCC1.[Cl-].[Li+]>C(OCC)C.CS(C)=O>[NH2:11][C:12]1[N:17]=[C:16]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([F:30])=[C:25]([N:9]4[CH2:10][CH:7]([NH:6][CH:3]([CH3:5])[CH3:4])[CH2:8]4)[C:26]=3[Br:28])[C:21](=[O:31])[C:20]([C:32]([OH:34])=[O:33])=[CH:19]2)[C:15]([F:35])=[CH:14][C:13]=1[F:36]
Reactant: CC(C)NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)NC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Br)C1
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 65 %

Procedure:
N-isopropylazetidin-3-ylamine dihydrochloride (374 mg), 1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinolin-3-carboxylic acid (518 mg), N-methylpyrrolidine (0.8 mL), lithium chloride (500 mg) and dimethyl sulfoxide (1.5 mL) were mixed, and the mixture was stirred at 50° C. for 4.5 hours. After the mixture had been left to cool, diethyl ether (10 mL) was added to the mixture and stirred, followed by removing the supernatant. The same procedure was repeated three times. Water (3 mL) was added to the residue, and the pH of the mixture was adjusted to 6 by use of aqueous citric acid solution. The formed solid was collected through filtration, washed three times with water (3 mL), then suspended in ethanol (10 mL), and stirred under heating. The formed solid was collected through filtration, and suspended in diisopropyl ether (10 mL), followed by stirring under heating. The heated suspension was filtrated to yield 410 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[N:5][C:4]([OH:7])=[N:3][C:2]=1[OH:8].[H-].[Na+].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:1]2[CH:6]=[N:5][C:4]([OH:7])=[N:3][C:2]2=[O:8])=[CH:14][CH:13]=1
Reactant: Oc1ncnc(O)n1
Reactant: Clc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1nc(O)ncn1Cc1ccc(Cl)cc1
Yield: 14 %

Procedure:
To an N,N-dimethylformamide solution (200 mL) of 1,3,5-triazine-2,4-diol (5.00 g, 44.2 mmol, synthesized according to the method described in Angew. Chem., 74, 354; 1962), sodium hydride (2.12 g, 48.6 mmol, purity 55%) was added at 0° C. and the resultant solution was stirred for 1 hour. To the reaction solution, 4-chlorobenzyl bromide (9.99 g, 48.6 mmol) was added and the resultant solution was stirred at room temperature for 2 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was added thereto, and extraction with ethyl acetate from the resultant mixture was performed. The organic layer was washed with saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the obtained residue, toluene was added and the solid was collected by filtration, washed with toluene, and dried under reduced pressure to obtain the title compound (1.50 g, yield 14%).