Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][N:21]=[CH:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][CH2:26][CH2:25][CH2:24][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCCCn1ccnc1
Product: O=C(NCCCn1ccnc1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.40 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.60 mmol of 3-imidazol-1-yl-propylamine. LC/MS [4.82 min; 466 (M+1)]
Reaction SMILES: F[B-](F)(F)F.[C:6]1([C:12]2[CH:17]=[CH:16][O+:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]=2C2C=CC=CC=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:30][B-:31]([C:36]#[N:37])([C:34]#[N:35])[C:32]#[N:33].[K+]>C(#N)C>[CH3:30][B-:31]([C:36]#[N:37])([C:34]#[N:35])[C:32]#[N:33].[C:6]1([C:16]2[CH:17]=[C:12]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O+:15]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(-c2cc[o+]c(-c3ccccc3)c2-c2ccccc2)cc1
Agent: C[B-](C#N)(C#N)C#N
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CC#N
Product: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1

Procedure:
A solution of triphenylpyrylium tetrafluoroborate, [TPP][BF4], (100 mg, 0.252 mmol), in acetonitrile (2 ml) and a solution of potassium methyltricyanoborate (36 mg, 0.252 mmol) in acetonitril (2 ml) are combined and mixed. The salt potassium tetrafluoroborate is filtered at 0° C. and all volatile components are removed under reduced pressure resulting in the solid compound 2,4,6-triphenylpyrylium methyltricyanoborate.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[OH:23]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:23][C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[F:15])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1cc(F)ccc1F
Product: COC(=O)c1cc(Cl)ccc1COc1cc(F)ccc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 2,5-difluorophenol:
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30].[O-2].[Mg+2]>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([S:18]([CH3:17])=[N:32][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: CS(N)(=O)=O
Reactant: CSc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: O=Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=NS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 29 %

Procedure:
879 mg (2.73 mmol) of iodosobenzene diacetate are added to a suspension of 300 mg (1.77 mmol) of 1-methylsulphanyl-4-nitrobenzene, 337 mg (3.55 mmol) of methanesulphonamide, 285 mg (7.10 mmol) of magnesium oxide and 78 mg (0.18 mmol) of rhodium(II) acetate dimer in 12 ml of dichloromethane at room temperature. The mixture is stirred for 24 h and then concentrated. The resulting residue is purified by chromatography (dichloromethane/ethanol 95:5). 133 mg (0.51 mmol; yield: 29%) of the product are obtained.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH:18]([C:39]([O:41]C)=[O:40])[NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)=[O:21])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.O.[OH-].[Li+]>O1CCCC1.CO.O>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH:18]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)=[O:21])[C:39]([OH:41])=[O:40])=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)C(Cc1ccc2c(cnn2C(=O)OC(C)(C)C)c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(Cc1ccc2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.5 %

Procedure:
A solution of 5-(2-methoxycarbonyl-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-ethyl)-indazole-1-carboxylic acid tert-butyl ester (168 mg, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL) in methanol (5 mL) was cooled to 0° C. A solution of lithium hydroxide monohydrate (49 mg, 2.04 mmol) in water (5 mL) was added. The reaction mixture was stirred at 0° C. for 6 h and then placed in the freezer for a further 16 h. The solvents were removed in vacuo and the residue dissolved in water (15 mL). The pH of the aqueous solution was adjusted to ca. 1 with 1N hydrochloric acid. The resulting white solid precipitated was collected by filtration. The solid was dried under vacuum to give the title compound (108 mg, 80%). 1H-NMR (DMSO-d6, 300 MHz) δ 12.94 (bs, 1H), 9.19 (s, 1H), 8.01 (s, 1H), 7.61 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.28 (dd, J=8.5, 1.5 Hz, 1H), 7.13-7.06 (m, 2H), 6.86 (t, J=7.0 Hz, 1H), 6.76-6.72 (m, 2H), 4.32-4.24 (m, 2H), 4.09-4.02 (m, 4H), 3.17-2.97 (m, 2H), 2.72-2.59 (m, 2H), 1.57-1.35 (m, 4H). IR (KBr, cm−1) 3424, 2963, 2930, 1660, 1628, 1505, 1474, 1446, 753. Mass spec.: 463 (MH)+.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:37]=[CH:36][C:11]([CH2:12][NH:13][C:14](=[O:35])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]4[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][C:27]([C:33]#[N:34])=[CH:26][C:24]=4[N:25]=3)=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[F:38][C:39]([F:52])([F:51])[C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:50][CH2:49][NH:48][CH2:47]2)=[CH:42][CH:41]=1.CC(C)=O>C1(C)C=CC=CC=1>[C:33]([C:27]1[CH:28]=[C:29]([CH:30]([CH3:32])[CH3:31])[C:23]2[O:22][C:21]([C:18]3[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][C:11]4[CH:36]=[CH:37][C:8]([N:48]5[CH2:49][CH2:50][CH:46]([C:43]6[CH:44]=[CH:45][C:40]([C:39]([F:38])([F:51])[F:52])=[CH:41][CH:42]=6)[CH2:47]5)=[CH:9][CH:10]=4)=[O:35])=[CH:16][CH:17]=3)=[N:25][C:24]=2[CH:26]=1)#[N:34]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCc4ccc(Br)cc4)cc3)oc12
Reactant: FC(F)(F)c1ccc(C2CCNC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCc4ccc(N5CCC(c6ccc(C(F)(F)F)cc6)C5)cc4)cc3)oc12
Temperature: 150 °C
Yield: 52 %

Procedure:
Sodium tert-butoxide (10 mg), N-(4-bromobenzyl)-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (24 mg, EXAMPLE 1), and 3-[4-(trifluoromethyl)phenyl]pyrrolidine (31 mg) were dissolved in toluene (5.0 mL). To this mixture was added bispalladiumtribenzylidene acetone (10 mg) and 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (12 mg). The mixture was heated to 150° C. for 25 min in a microwave reactor. Upon cooling, the mixture was then concentrated in vacuo, taken up in dichloromethane, and purified via flash chromatography on a Biotage Horizon, 40 M column, eluting with 1 column volume of 100% hexanes, followed by a linear gradient of ethyl acetate in hexanes from 0 to 100% over 10 column volumes, followed by 4 column volumes of 100% ethyl acetate to provide the title compound (16 mg, 53%). Mass spectrum (ESI) 609.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.31 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 7.94 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.51 (s, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 6.33 (t, J=4.0 Hz, 1H), 4.59 (d, J=5.3 Hz, 2H), 3.75 (t, J=8.4 Hz, 1H), 3.57 (m, 5H), 2.47 (m, 1H), 2.15 (m, 1H), 1.46 (d, J=6.9, 6H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:38][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:33])([F:35])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (1) (0.015 g, 0.031 mmol) in anhydrous methanol (1.5 mL) were added a 37% aq. solution of formaldehyde (0.005 mL, 0.062 mmol) followed by sodium triacetoxyborohydride (0.033 g, 0.155 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 1.5 hours, the volatiles were removed in vacuo and the residue was diluted with EtOAc (15 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (3) (14.5 mg, 97% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.57 (d, J=9.0 Hz, 2H), 7.43 (s, 1H), 7.26-7.13 (m, 4H), 6.96-6.87 (m, 3H), 3.50 (s, 2H), 3.12-3.03 (m, 6H), 3.03-2.94 (m, 2H), 2.47-2.42 (m, 4H), 2.22 (s, 3H). LCMS Method C: rt 4.74 min; m/z 499.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:13]([CH:14](O)[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:7]3[C:6]=2[CH:27]=1.S(Cl)(Cl)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:13]([CH2:14][C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:7]3[C:6]=2[CH:27]=1
Reactant: CN(C)C(=O)C(O)c1c(-c2ccccc2)nc2n(C)c3ccc(Cl)cc3n12
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)C(=O)Cc1c(-c2ccccc2)nc2n(C)c3ccc(Cl)cc3n12
Reaction time: 6 h
Yield: 94.8 %

Procedure:
16.5 g (0.043 mol) of 6-chloro-α-hydroxy-N,N,9-trimethyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole-3-acetamide are treated with 90 ml of thionyl chloride in 250 ml of dichloromethane. The mixture is stirred for 6 h and allowed to stand overnight. The solvent and excess thionyl chloride are evaporated under reduced pressure. The residue is taken up in toluene and the mixture is again evaporated. The residue is dissolved in 800 ml of dichloromethane and treated with 26.5 g of Rongalite®. The mixture is stirred for 48 h and the insoluble matter is then separated by filtration. The organic phase is washed with sodium bicarbonate and then with water. The solvent is evaporated under reduced pressure and the residue is taken up in pentane. 14.96 g of solid are obtained which are purified by silica gel column chromatography, eluting with a dichloromethane/methanol 95/5 mixture. 8.59 g of product are isolated, of which a sample of 1.4 g is taken and dissolved in dichloromethane. The solution is filtered and the filtrate is concentrated under reduced pressure. The residue is treated with carbon black in methanol, and the product is then recrystallized from an N,N-dimethylformamide/water 2/1 mixture and 0.98 g of solid is obtained. Melting point: 233°-236° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:21])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:20])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]>>[CH2:24]([O:23][P:22]([CH2:2][CH2:3][CH:4]([CH3:21])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:20])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])([O:26][CH2:27][CH3:28])=[O:29])[CH3:25]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCC(C)CCCC(C)CCCC(C)CCCC(C)C)OCC
Temperature: 150 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
A mixture of 21.69 g (60 mmol) of 1-bromo-3,7,11,15-tetramethylhexadecane and 25 g (150 mmol) of triethyl phosphite was heated at 150° C. After 18 h, an additional 20 g (120 mmol) of triethyl phosphite was added, and heating was continued for 24 h. Diethyl ethylphosphonate and other volatiles were distilled, bp 30-50° C. at 0.05 mm Hg, and bulb-to-bulb distillation of the concentrate provided 23.51 g (94%) of 1-(diethylphosphono)-3,7,11,15-tetramethylhexadecane as a clear, colorless liquid, bp 190-230° C. at 0.05 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.O1[CH2:14][CH2:13][NH:12]C1=O>ClCCl.O1CCOCC1>[ClH:1].[NH2:12][CH2:13][CH2:14][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C1NCCO1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCNc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 3-chloroaniline (30 mL) in 500 mL of dichloromethane at 0° C. was added dropwise a solution of 4N HCl in 1,4-dioxane (80 mL). The solution was warmed to room temperature, then concentrated to dryness in vacuo to provide a white powder. A mixture of this powder with 2-oxazolidinone (24.6 g) was heated under nitrogen atmosphere at 160° C. for 10 hours, during which the solids melted, and gas evolution was observed. The reaction was allowed to cool, forming the titled compound as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:49]([O:51][CH2:52][CH:53]([O:55][CH2:56][CH3:57])O)[CH3:50].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:50][CH2:49][O:51][CH2:52][CH2:53][O:55][CH2:56][CH3:57])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCOCC(O)OCC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (164 mg), 2-ethoxy-(2-ethoxy)ethanol (0.09 mL) and diethyl azodicarboxylate (0.10 mL). The mixture is stirred at room temperature overnight. The reaction mixture is again treated with triphenylphosphine (164 mg), 2-ethoxy-(2-ethoxy)ethanol (0.09 mL) and diethyl azodicarboxylate (0.10 mL). After 4 hours, the reaction mixture is concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with acetone and then by recrystallization from ethyl acetate-heptane to afford 0.18 gm of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:18][C:19](=O)[CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[OH:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([C:13](=[O:14])[NH:15][C:19]([CH:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[OH:21])=[N:18]2)=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1NC(=O)C(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c(C(O)c2ccc(F)cc2)nc2cc(OCc3ccccc3)ccc12
Temperature: 80 °C
Reaction time: 20 h
Yield: 89.7 %

Procedure:
To 4-(benzyloxy)-2-(2-(4-fluorophenyl)-2-hydroxyacetamido)benzamide (4.1 g, 10.4 mmol) in absolute EtOH (50 mL) was added 20% aq potassium carbonate (5 mL). After heating and stirring at 80° C. for 20 h, the solution was cooled and concentrated to a solid. The solid was washed with water and dried under vacuum to afford 7-(benzyloxy)-2-((4-fluorophenyl)(hydroxy)methyl)quinazolin-4(3H)-one as a white solid (3.51 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.25 (s, 2 H) 5.55 (s, 1 H) 7.10-7.21 (m, 4 H) 7.36-7.48 (m, 5 H) 7.56-7.61 (m, 2 H) 7.97 (d, J=8.67 Hz, 1 H). LC-MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[C@H:9]([OH:38])[CH2:10][C@H:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([OH:38])[CH2:10][C@H:11]([NH:25][C:26]([C@@H:27]([NH:32][C:33](=[O:34])[O:35][CH3:36])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:37])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 107G (0.042 g, 0.066 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL), stirred at 25° C. for 1 hour, concentrated, and partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]([C:12]1[NH:21][C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[N:13]=1)=[CH:10][CH3:11]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:11][CH:10]=[CH:9][C:12]1[NH:21][C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[N:13]=1
Reactant: CC=Cc1nc2ccc(C)cc2c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2nc(C=CCBr)[nH]c(=O)c2c1
Yield: 43.5 %

Procedure:
16.0 g (0.08 moles) of N-bromosuccinimide, 14.0 g (0.07 moles) of 2-propenyl-6-methyl-4(3H)-quinazolone and 0.05 g of dibenzoylperoxide in 500 mls. of carbon tetrachloride are boiled under a reflux for 16 hours. The reaction mixture is evaporated to dryness in vacuo and the succinimide is remoed from the residue by boiling out with water several times. The residue which has been purified in this way is then purified by dissolving once again in a 9:1 mixture of methyl alcohol/chloroform and in this way one obtains 8.5 g (38% of theory) of 2-(3-bromopropenyl)-6-methyl-4(3H)-quinazolone with a melting point of 197°-198° C. c. 4.0 g (0.0144 moles) of 2-(3-bromopropenyl)-6-methyl-4(3H)-quinazolone are heated for 5 hours to 80° C with 5.4 g (0.0288 moles) of 1-(2-methoxyphenyl) piperazine in 50 mls. of dimethylformamide. The reaction mixture is then distributed between 10% aqueous ammonia and chloroform and the chloroform phase is evaporated to dryness after drying over calcined potassium carbonate. The residue is purified by crystallisation twice from ethyl acetate. In this way one obtains 5.4 g (96.5% of theory) of 2-(3-(1-(2-methoxyphenyl) piperazinyl-4) prop-2-en-1-yl)-6-methyl-4(3H)-quinazolone with a melting point of 169°-170° C. Using the same mode of operation, when choosing suitable initial materials, one obtains the piperazinylalkyl-4-(3H)-quinazolones described in Examples 1 to 24.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:4]([N+:21]([O-])=O)[CH:3]=1.Cl[Sn]Cl.O>CCO>[NH2:21][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CCCCCCC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COC(=O)CCCCCCC(=O)Nc1ccc(Br)cc1N
Yield: 66.9 %

Procedure:
To a solution of methyl 8-(4-bromo-2-nitrophenylamino)-8-oxooctanoate (241 mg, 0.623 mmol) in EtOH was added SnCl2.H2O (490 mg, 2.37 mmol). The reaction was heated to reflux overnight and quenched by water. The mixture was filtered and the filtrate was extracted with ethyl acetate. The combined organic layer was dried, concentrated and purified by biotage column chromatography to afford methyl 8-(2-amino-4-bromophenylamino)-8-oxooctanoate (149 mg)
Reaction SMILES: ClC(OC(Cl)C)=O.[O:8]([CH2:15][C:16]1[S:17][C:18]2[CH2:19][N:20](CC3C=CC=CC=3)[CH2:21][CH2:22][CH2:23][C:24]=2[N:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:8]([CH2:15][C:16]1[S:17][C:18]2[CH2:19][NH:20][CH2:21][CH2:22][CH2:23][C:24]=2[N:25]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(CN2CCCc3nc(COc4ccccc4)sc3C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: c1ccc(OCc2nc3c(s2)CNCCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
1-Chloroethyl chloroformate (0.034 mL, 0.31 mmol) was added to a stirred solution of 5,6,7,8-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-4H-thiazolo[5,4-c]azepine (0.055 mg, 0.16 mmol) and DIPEA (0.08 mL, 0.47 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour. Then, the solvent was evaporated in vacuo and a solution of the crude product in MeOH (1 mL) was stirred at 70° C. for 1 hour. The mixture was treated with a 7M solution of ammonia in MeOH and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM 0/100 to 3 /97). The desired fractions were collected and the solvents evaporated in vacuo to yield 5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepine (0.033 g, 81% yield) as a yellow oil. C14H16N2OS LCMS: Rt 1.13, m/z 302 [M+ACN+H]+ (using method, LC-MS Method 6).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([Sn](CCCC)(CCCC)CCCC)=[N:24][CH:25]=1>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>[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:24][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: COC(=O)c1cc(Br)cc(C(=O)N2CCCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-bromo-5-(pyrrolidine-1-carbonyl)benzoate (1.2 g, 3.8 mmol), 5-methyl-2-(tributylstannyl)pyridine (0.90 mL, 2.6 mmol), tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.086 mmol) under argon was subjected to microwave irradiation at 120° C. for 2 hour. The mixture was cooled to room temperature and the precipitate was collected by filtration and rinsed with hexane to afford the title compound as a white solid. The filtrate was concentrated and purified via flash chromatography to afford another crop of the desired product. LC-MS: 325.1 [M+1]+.