Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:10]([O:13][CH2:14][CH3:15])(=[O:12])[CH3:11].[CH2:16](O)[CH3:17]>>[CH3:16][C:17]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[S:8][C:11]=1[C:10]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(C)=O
Reactant: NC(=S)c1ccncc1
Reactant: CCO
Product: CCOC(=O)c1sc(-c2ccncc2)nc1C

Procedure:
2.76 g (20 mmol) of thioisonicotinamide and 3.6 g (22 mmol) of ethyl 2-chloroacetacetate were heated under reflux in 30 ml of ethanol for 20 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=O)[CH2:17][CH2:18][C:19]2[S:20][C:21]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:22]=3[C:23]=2[CH2:24][CH2:25][CH3:26])=[CH:4][C:5]([CH3:15])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl.[NH2:37][OH:38].C([O-])(=O)C.[Na+]>CCO.O>[OH:1][C:2]1[C:3]([C:16](=[N:37][OH:38])[CH2:17][CH2:18][C:19]2[S:20][C:21]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:22]=3[C:23]=2[CH2:24][CH2:25][CH3:26])=[CH:4][C:5]([CH3:15])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCCc1c(CCC(=O)c2cc(C)c(OCC(=O)OCC)cc2O)sc2cc(C(F)(F)F)ccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(CCC(=NO)c2cc(C)c(OCC(=O)OCC)cc2O)sc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Yield: 37.6 %

Procedure:
To a solution of Ethyl 5-hydroxy-2-methyl-4-[3-[3-propyl-6-(trifluoromethyl)benzothiophen-2-yl]propionyl]-phenoxyacetate (obtained in Example 22-(4), 19 mg, 0.0381 mmol) in EtOH (0.4 mL) was added hydroxylamine hydrochloride (2.9 mg, 0.0419 mmol) and sodium acetate (3.8 mg, 0.0457 mmol) in water (0.3 mL). The mixture was heated for 10 hours under reflux and cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from chloroform-hexane, to give the titled compound as a white crystal (7.5 mg, yield 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:6]([OH:8])=O.[CH3:19][C:20]1[N:25]=[CH:24][C:23]([C@H:26]([NH2:28])[CH3:27])=[CH:22][N:21]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:6]([NH:28][C@@H:26]([C:23]1[CH:22]=[N:21][C:20]([CH3:19])=[N:25][CH:24]=1)[CH3:27])=[O:8]
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: COc1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N[C@H](C)c2cnc(C)nc2)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round-bottom flask were charged 3-methoxy-5-(5-methylpyridin-2-yl)benzoic acid (26 mg, 0.11 mmol), (R)-1-(2-methylpyrimidin-5-yl)ethanamine (29 mg, 0.21 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (41 mg, 0.21 mmol), 1-hydroxybenzotriazole hydrate (33 mg, 0.21 mmol), triethylamine (22 mg, 0.21 mmol) and methylene chloride (3 mL). The mixture was stirred at room temperature overnight, and then concentrated. The residue was purified via preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford the desired product as a white solid.
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@H:17]2[CH2:18][C@H:14]([CH:15]=[CH:16]2)[C@H:13]1[C:19]([O:21][CH3:22])=[O:20])=O)C1C=CC=CC=1.[ClH:23]>C(OCC)(=O)C.[Pd].C(OCC)C.O1CCOCC1>[ClH:23].[NH2:11][C@H:12]1[C@H:17]2[CH2:18][C@H:14]([CH2:15][CH2:16]2)[C@H:13]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H]1[C@@H](NC(=O)OCc2ccccc2)[C@@H]2C=C[C@H]1C2
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl (1R,2R,3S,4S)-3-{[(benzyloxy)carbonyl]amino}bicyclo[2.2.1]hept-5-ene-2-carboxylate (1 g, 3.32 mmol) was dissolved in ethyl acetate (15 mL). 5% Palladium on carbon (120 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil was dissolved in diethyl ether (10 mL) and added dropwise, with vigorous stirring, to a mixture of 4.0 M hydrochloric acid solution in 1,4-dioxane (1.8 mL) in diethyl ether (18 mL). The desired product began to precipitate as a white solid. Additional diethyl ether (10 mL) was added and the mixture was stirred for 10 min. The precipitate was collected by vacuum filtration, washed with additional diethyl ether (2×8 mL). The solid was further dried in vacuo for 1 h to afford the desired product, methyl (1S,2R,3S,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (0.64 g, 3.11 mmol, 94%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.17-1.27 (3H, m), 1.40-1.61 (2H, m), 1.91 (1H, d, J=10.7 Hz), 2.36 (1H, d, J=4.1 Hz), 2.44 (1H, d, J=3.1 Hz), 2.75 (1H, d, J=7.8 Hz), 3.30-3.38 (1H, m), 3.61 (3H, s), 8.05 (3H, bs). LC-MS (ESI) calcd for C9H15NO2 (free amine) 169.11, found 170.3 [M+H+] (100%), 339.3 [2M+H+] (50%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])C>O1CCCC1.O>[C:12]1(=[O:13])[N:8]([CH2:7][CH2:6][CH2:5][CH:4]=[O:3])[C:9](=[O:14])[CH:10]=[CH:11]1
Reactant: CCOC(CCCN1C(=O)C=CC1=O)OCC
Solvent: C1CCOC1
Solvent: O
Product: O=CCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Maleimidobutyraldehyde diethylacetal (2 g, 8.29 mmol) in tetrahydrofuran (20 ml) and water (0.5 ml) was stirred under argon and DOWEX 50×8 ion exchange resin (H+, 2 g, ®Dow Chemical Co.) was added. After 12 hours stirring at room temperature, the solvent was decanted, dried (MgSO4) and evaporated in vacuo to afford 4-maleimidobutyraldehyde (formula III) as a yellow oil which rapidly solidified on standing (1.38 g, 99%); TLC Rf=0.4, ethyl acetate/hexane 1:1. The 4-maleimidobutyraldehyde turned out to be extremely unstable, so that it was necessary to do all work-up at low temperatures (0° C.) and under complete exclusion of oxygen (inert atmosphere).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH2:25])(=[O:24])=[O:23])[CH:13]=[CH2:14]>C(Cl)Cl>[O:9]1[CH2:14][CH:13]1[CH2:12][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH2:25])(=[O:23])=[O:24]
Reactant: C=CCOc1ccccc1S(N)(=O)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1OCC1CO1
Yield: 78 %

Procedure:
To a mixture of 15.3 g of 3-chloroperbenzoic acid in 270 ml of absolute methylene chloride are added 14.2 g of 2-allyloxyphenylsulfonamide over 2 minutes. The solution is then heated to reflux for 3 hours, cooled, and then washed three times with saturated sodium carbonate solution and once with water. The organic phase is dried and concentrated, affording 11.9 g of 2-oxiranylmethoxyphenylsulfonamide with a melting point of 132°-133° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:41]([C:35]3[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=3[F:33])(=[O:43])=[O:42])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluoroaniline (1.24 g, 3.17 mmol) in DCM (31.7 mL) was added pyridine (0.269 mL, 3.33 mmol) and 2,5-difluorobenzenesulfonyl chloride (0.448 mL, 3.33 mmol). The reaction was stirred 18 h at rt. The reaction mixture was concentrated onto silica gel. Purification by chromatography (5 to 100% EtOAc:DCM) afforded the title compound (1.21 g, 2.13 mmol, 67.3% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 7.37-7.67 (m, 5H), 7.32 (t, J=7.9 Hz, 1H), 6.90 (d, J=5.3 Hz, 1H), 3.93 (dd, J=11.4, 2.0 Hz, 2H), 3.39-3.58 (m, 2H), 3.26-3.40 (m, 1H), 1.98-2.09 (m, 2H), 1.63-1.86 (m, 2H). MS (ESI): 567.06 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][CH2:23][CH:24]1[CH:29]([OH:30])[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:26]4[CH2:27][CH2:28][CH:29]([OH:30])[CH:24]([CH2:23][NH2:22])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: NCC1CNCCC1O
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: Cc1c(F)c(N2CCC(O)C(CN)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 45.9 %

Procedure:
The condensation of 1-cyclopropyl-6,7,8-trifluoro-5-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3-aminomethyl-4-hydroxy-piperidine was carried out in a similar manner as described in example 1 gave the titled product. Yield 45.9%, m.p 270–75° C., C20H23F2N3O4, m/z 408 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.O>O1CCCC1>[O:15]=[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: CCCCC(=O)Cc1ccccc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1ccc(C#N)cc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
240 mg of sodium hydride as a suspension at 50% in oil were added to a solution of 0.81 g of 1-phenyl-2-hexanone of Step A of Example 7 in 20 ml of tetrahydrofuran and the mixture was stirred for 90 minutes at 40° C. Then, a solution of 900 mg of 4-(bromo-methyl)-benzonitrile in 10 ml of tetrahydrofuran was added and after stirring for 2 hours at ambient temperature, the reaction mixture was poured into water. Extraction was carried out with ethyl acetate and the extracts were washed with water, dried, and evaporated to dryness. The residue was chromatographed on silica (eluant: methylene chloride - hexane (1-1)) to obtain 1.1 g of the desired product melting at 70° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1(=O)[C:19]2=[C:20]3[C:15](=[CH:16][CH:17]=[CH:18]2)[CH:14]=[CH:13][CH:12]=[C:11]3[C:10]1=O>O>[CH:12]1[C:11]2[C:10]3[C:9]([C:19]4[C:20]=2[C:15]([CH:16]=[CH:17][CH:18]=4)=[CH:14][CH:13]=1)=[N:8][C:1]1[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=1)[N:7]=3
Reactant: Nc1ccccc1N
Reactant: O=C1C(=O)c2cccc3cccc1c23
Solvent: O
Product: c1cc2c3c(cccc3c1)-c1nc3ccccc3nc1-2

Procedure:
To a reaction vessel equipped with a stirrer, 5-liter of glacial acetic acid and 490 g of purified acenaphthenequinone were added and stirred for 15 minutes under nitrogen bubbling to obtain an acenathphenequinone solution. Similarly, to another reaction vessel equipped with a stirrer, 7.5-liter of glacial acetic acid and 275 g of o-phenylenediamine were added and stirred for 15 minutes under nitrogen bubbling to obtain an o-phenylenediamine solution. Thereafter, while stirring under nitrogen atmosphere, the o-phenylenediamine solution was added to the acenaphthenequinone solution gradually over one hour, and then allowed to react by continuing to stir for 3 hours. After ion exchange water was added to the obtained reaction liquid, the precipitate was filtrated to obtain a crude product. This crude product was recrystallized with a heated glacial acetic acid for purification.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:20])#[N:2].[CH2:21]([C:23]1([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[CH2:29][CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)[CH3:22].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[CH2:21]([C:23]1([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][N:25]([C:15](=[O:17])[CH2:14][CH2:13][C:12]2[N:8]([CH2:7][C:6]3[CH:18]=[CH:19][C:3]([C:1]#[N:2])=[C:4]([F:20])[CH:5]=3)[CH:9]=[N:10][CH:11]=2)[CH2:24]1)[CH3:22]
Reactant: N#Cc1ccc(Cn2cncc2CCC(=O)O)cc1F
Reactant: CCC1(c2cccc(O)c2)CCCCNC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCC1(c2cccc(O)c2)CCCCN(C(=O)CCc2cncn2Cc2ccc(C#N)c(F)c2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-[3-(4-Cyano-3-fluoro-benzyl)-3H-imidazol-4-yl]-propionic acid, as described above in Step E, (0.56 g, 0.78 mmol) and 3-(3-ethyl-azepan-3-yl)-phenol, as described above in Step J, (0.182 g, 0.78 mmol), HOBT (0.126 g, 0.936 mmol), EDC (0.179 g, 0.936 mmol) and N-methylmorpholine (0.257 mL, 2.34 mmol) were dissolved in DMF (15 mL) and stirred at ambient temperature for 18 h. The DMF was removed in vacuo and the residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was washed with H2O, brine, dried (MgSO4), filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:41]=[CH:40][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22](OS(C(F)(F)F)(=O)=O)=[N:21]2)=[CH:17][CH:16]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:42][C:43]1[CH:48]=[CH:47][C:46]([C:22]2[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]4[N:4]=[C:5]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)[O:6][C:2]=4[CH3:1])=[CH:41][CH:40]=3)[N:21]=2)=[CH:45][CH:44]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccc(F)cc1
Yield: 45.3 %

Procedure:
Tetrakis(triphenolphosphine)palladium (130 mg) was added to a mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-trifluoromethanesulfonyloxy-1H-pyrazol-4-yl]propionate (1.31 g), 4-fluorophenylboronic acid (0.31 g), 2N aqueous sodium carbonate solution (2.9 ml), ethanol (3 ml), and toluene (50 ml). This mixture was refluxed under an argon atmosphere for 13 hours. Ethyl acetate was added to this reaction mixture, and the mixture was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-(4-fluorophenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (540 mg, yield 45%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 93–94° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31]>O1CCOCC1.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>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])=[C:24]([Cl:23])[CH:25]=2)=[CH:9][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: O=C(c1ccc(B(O)O)cc1Cl)N1CCOCC1
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
Solvent: O
Product: CC(C)n1cc(-c2cc(-c3ccc(C(=O)N4CCOCC4)c(Cl)c3)cnc2N)nn1
Temperature: 120 °C
Yield: 22.8 %

Procedure:
Cs2CO3 (682 mg, 2.10 mmol) was added to a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and (3-chloro-4-(morpholine-4-carbonyl)phenyl)boronic acid (229 mg, 0.85 mmol) in dioxane: water (7 mL: 3 mL) degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (40 mg, 0.035 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 70-80% ethyl acetate in pet-ether to afford 68 mg (Yield: 22.5%) of the title compound as a pale yellow solid. Product was converted to its HCl salt by using HCl in ether (2M) to afford 60 mg of the HCl salt of the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH:13]([O:15][CH3:16])[CH3:14])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[Br:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH:13]([O:15][CH3:16])[CH3:14])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2c(Nc3c(Br)cc(C#CC(C)OC)c4c3OCO4)ncnc2cc1OCCCCl
Reactant: C1COCCN1
Product: COc1cc2c(Nc3c(Br)cc(C#CC(C)OC)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[5-bromo-7-(3-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.12 g, 0.22 mmol) in morpholine (2 ml) was heated at 40 C for 5 hours and then stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue purified directly by flash chromatography on silica eluting with increasingly polar solutions of methanol 0-8% in dichloromethane followed by trituration with diethyl ether to give the product as a racemate and in the form of a pale yellow solid (0.040 g). NMR Spectrum: (d6DMSO) 1.54 (d, 3H), 2.02-2.13 (m, 2H), 2.46-2.53 (m, 4H), 2.54-2.60 (m, 2H), 3.47 (s, 3H), 3.67-3.73 (m, 4H), 4.04 (s, 3H), 4.27-4.33 (m, 2H), 4.51 (q, 1H), 6.27 (s, 2H), 7.30 (s, 1H), 7.40 (s, 1H), 7.94 (s, 1H), 8.43 (s, 1H), 9.62 (s(broad), 1H). Mass Spectrum: M+H+ 599/601.
Reaction SMILES: [O:1]=[O+][O-].[Si:4]([O:11][CH:12]([C:14]1[O:15][C:16](=[O:26])[C:17]2[C:22]([C:23]=1[CH:24]=C)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O=O.C(Cl)Cl>[Si:4]([O:11][CH:12]([C:14]1[O:15][C:16](=[O:26])[C:17]2[C:22]([C:23]=1[CH:24]=[O:1])=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])([C:7]([CH3:10])([CH3:8])[CH3:9])([CH3:6])[CH3:5]
Reactant: C=Cc1c(C(C)O[Si](C)(C)C(C)(C)C)oc(=O)c2ccccc12
Reactant: O=[O+][O-]
Agent: O=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1C=O
Reaction time: 8 h

Procedure:
A slow stream of O3 in O2 was passed through a −78° C. cooled solution of 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-vinyl-1H-isochromen-1-one (intermediate B59.1, 2.967 g of crude) in DCM (100 ml) for 1.5 hrs. The excess of 03 was purged by N2 bubbling, then a solution of PPh3 (2.316 g, 8.83 mmol) in DCM (20 ml) was added. The solution was allowed to reach 25° C. and it was stirred overnight. The solvent was removed in vacuo and the crude material was purified by flash chromatography on Biotage silica gel cartridge (cyclohexane to cyclohexane:EtOAc=90:10) to afford 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-1H-isochromene-4-carbaldehyde (Intermediate B59.2, 1.453 g, 4.38 mmol).
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.[CH3:12][C:13]([CH3:15])=[O:14].[OH-].[Na+].O>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:13](=[O:14])[CH:15]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(C=CC(=O)C=Cc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
4-Dimethylaminobenzaldehyde (1g, 1.00 g, 6.7 mmol) and acetone (19, 0.24 ml, 3.2 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethanol to give 0.53 g (51%) of an orange solid: mp 179-181° C. [expected mp 174-176° C.]; 1H NMR: δ 3.01 (s, 12H), 6.69 (d, 4H, J=8.7 Hz), 6.87 (d, 2H, J=15.7 Hz), 7.50 (d, 4H, J=8.7 Hz), 7.67 (d, 2H, J=15.7 Hz); 13C NMR: δ 40.2, 98.9, 111.8, 121.2, 122.9, 129.9, 142.8, 151.6.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22]O)[C:8]2=[O:24])=[CH:4][CH:3]=1.P(Br)(Br)[Br:28]>CC#N.O>[Br:28][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:8](=[O:24])[N:7]([CH2:6][C:5]2[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10]1
Reactant: COc1nn(-c2ccccc2CO)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Reactant: BrP(Br)Br
Solvent: CC#N
Solvent: O
Product: COc1nn(-c2ccccc2CBr)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 60 °C
Yield: 84.4 %

Procedure:
According to Scheme 9 Step 1: To a stirred solution of 4-(4-chlorobenzyl)-2-(2-(hydroxymethyl)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione (70 mg, 0.19 mmol) in CH3CN (10 mL) was added phosphorus tribromide (76 mg, 0.28 mmol) and the mixture was heated at 60° C. during two hours. The reaction mixture was diluted with 100 mL of water and the aqueous layer was extracted with DCM (×2). The combined organic layers were successively washed with water, with brine, dried over MgSO4, filtered and concentrated to afford 70 mg (Yield=86%) of 2-(2-(bromomethyl)phenyl)-4-(4-chlorobenzyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione. The product was pure enough to be used in the next step without any purification