Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:34]1[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(Cl)c(Cl)cc4nc3OC)CC2)c1
Yield: 68 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-di methoxyphenyl)piperazine were reacted by the same way with the example 176 to obtain the titled compound (yield, 68%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.74-3.78 (m, 4H), 3.79 (s, 6H), 4.15 (s, 3H), 6.07 (s, 1H), 6.11 (s, 2H), 7.33 (br s, 1H), 7.85 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: I[CH3:2].[Si:3]([O:10][CH2:11][C:12]1[C:13]2[N:14]([N:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[C:15]([CH2:18][OH:19])=[CH:16][CH:17]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(#N)C.[Ag]=O>[Si:3]([O:10][CH2:11][C:12]1[C:13]2[N:14]([N:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=2)[C:15]([CH2:18][O:19][CH3:2])=[CH:16][CH:17]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CO)n2nc(C(F)(F)F)cc12
Agent: O=[Ag]
Solvent: CC#N
Product: COCc1ccc(CO[Si](C)(C)C(C)(C)C)c2cc(C(F)(F)F)nn12
Temperature: 25 °C
Reaction time: 85 h

Procedure:
Silver oxide (30.0 g) and iodomethane (16.1 mL) were added to a solution of the compound of Example 324 (9.53 g) in acetonitrile (300 mL). The mixture was stirred at room temperature for 85 hours. Subsequently, the mixture was filtered through Celite. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to afford the title compound as a pale yellow powder (8.76 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(O)(=O)C.[Zn]>[NH2:21][C:17]1[CH:16]=[C:15](/[CH:14]=[C:11](/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)\[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(/C(C#N)=C/c2cccc([N+](=O)[O-])c2)cc1OC
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(/C(C#N)=C/c2cccc(N)c2)cc1OC
Yield: 79.9 %

Procedure:
Compound 33 (1.80 g) was dissolved in acetic acid. Zinc powder was added to the resultant solution, and the resultant mixture was stirred for four hours. The mixture was concentrated to dryness under reduced pressure, followed by purification by use of a silica gel column, to thereby produce the target product (1.30 g, yield: 80%).
Reaction SMILES: Cl[Si:2]([Cl:12])([Cl:11])[CH2:3][CH:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8].[CH2:13]([Mg]Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1.C(OCC)C>[Cl:12][Si:2]([Cl:11])([CH2:3][CH:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(CC)C[Si](Cl)(Cl)Cl
Reactant: CCCCCCCC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCC[Si](Cl)(Cl)CC(CC)CCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Trichloro(2-ethylhexyl)silane (synthesized in accordance with J. Am. Chem. Soc. 2008, 130, 16144-16145, 24.8 g) was placed in a 300 mL four-necked flask in a nitrogen atmosphere, and dissolved in tetrahydrofuran (100 mL). The resulting solution was cooled to 0° C., and a solution of n-octyl magnesium bromide in diethyl ether (Sigma-Aldrich Co. LLC., 2.00 M, 50.0 mL) was added dropwise. The reaction solution was agitated for about 30 minutes at 7° C., and then agitated for about 3 hours at room temperature. The solvent was then distilled off with an evaporator. Hexane was added to the resulting crude product, which was then filtered, after which the solvent was again distilled off. Finally, distillation purification (111° C., 0.61 torr) was performed to obtain the target dichloro(2-ethylhexyl)n-octylsilane (Compound G6, 15.9 g, yield 49%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](O)=[C:11]2[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:27]>>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([Cl:27])=[C:11]2[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ncnc2c1c(Nc1ccccc1)nn2Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2c1c(Nc1ccccc1)nn2Cc1ccccc1
Temperature: 25 °C

Procedure:
Under argon, 200 mg of 1-benzyl-4-hydroxy-3-phenylamino-pyrazolo[3,4-d]-pyrimidine are heated under reflux for 5 hours with 2 ml of POCl3, during which time the suspension slowly becomes a solution. The light-brown solution is cooled to room temperature, concentrated to dryness by evaporation and stirred with ice-water. The crude product is filtered off with suction and recrystallized from ethanol/water, yielding fine needles of 1-benzyl-4-chloro-3-phenylamino-pyrazolo[3,4-d]pyrimidine; m.p. 135° C., FAB-MS: (M+H)+ =336 (C18H14ClN5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:25])[CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([CH:23]=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.O.CN([CH:35]=[O:36])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([C:23]([CH:35]=[O:36])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:25])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CN(C1CCc2cc3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C1CCc2c(C=O)c3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
To a solution of the product from Step 9 of Example 1 (15 mg) in 2 mL of DMF was added 15 μL of POCl3. After stirring for 10 min, 2 mL of water was added and the reaction mixture was stirred for 24 h. The solid was collected by filtration to give the title compound (˜16 mg). 1H NMR (500 MHz, acetone-d6) δ 10.11 (s, 1H), 8.15 (m, 1H), 8.10 (m, 2H), 7.48 (t, 2H), 7.45 (m, 1H), 7.27 (m, 2H), 4.68 (m, 1H), 4.30 (m, 1H), 4.06 (t, 1H), 3.62-3.68 (m, 1H), 3.18-3.27 (m, 1H), 3.10 (s, 3H), 2.10 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[Si:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=1[CH2:32][CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[F:34][C:35]([F:44])([F:43])[C:36](N1C=CN=C1)=[O:37]>C1COCC1>[Si:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH2:30][C:36](=[O:37])[C:35]([F:44])([F:43])[F:34])=[CH:25][C:24]=1[CH2:32][CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: CCc1cc(C(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Reactant: O=C(n1ccnc1)C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C(=O)CC(=O)C(F)(F)F)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred solution of 1,1,1,3,3,3-hexamethyldisilazane (1.79 g, 11.1 mmol) in THF (37 ml) was added n-butyl lithium (1.52 M solution in hexane; 7.3 ml, 11.1 mmol) dropwise at 0° C., and the mixture was stirred at 0° C. for 30 minutes, then cooled at −78° C. A solution of 1-(4-[[tert-butyl(dimethyl)silyl]oxy]-3-ethylphenyl)-1-ethanone (2.57 g, 9.23 mmol) in THF (40 ml) was added dropwise, and the mixture was stirred at −78° C. for 1 hour. 1-(Trifluoroacetyl)imidazole (2.0 g, 12.2 mmol) was added, and the mixture was stirred at −78° C. for 3 hours, and quenched with water., The reaction mixture was warmed up to room temperature, and diluted with ethyl acetate. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over. MgSO4, and concentrated in vacuo. The residue was used for next reaction without further purification. (3.45 g, 99% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]#[N:11])[CH2:5][OH:6].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C(OC)(C)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]#[N:11])[CH:5]=[O:6]
Reactant: N#Cc1ccc(CO)cc1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: N#Cc1ccc(C=O)cc1F

Procedure:
A solution of 22 g of 3-fluoro-4-cyanobenzyl alcohol in 50 ml of methylene chloride is added, with stirring, to 48 g of PCC in 150 ml of methylene chloride. After one hour 300 ml of methyl tert.-butyl ether are added to the reaction mixture and the latter is filtered, with the addition of Celite. Removing the solvent and recrystallising the residue from aqueous ethanol gives 3-fluoro-4-cyanobenzaldehyde, m.p. 83°-85°, IR (cm-1): 3089, 2880, 2239, 1699, 1571, 1499, 1486, 1428, 1392, 1299, 1251, 1140, 1111, 971, 900, 839, 753; 1H-NMR (200 MHz): (ppm): 7.7-8.0 (m, 3H, aromatic), 10.1 (s, 1H, CHO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C(OC([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40]O)[CH2:35]1)=O)(C)(C)C.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:40][CH:36]5[O:37][CH2:38][CH2:39][NH:34][CH2:35]5)=[C:19]([O:24][CH3:25])[CH:18]=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OCC1CNCCO1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (103 mg, 0.267 mmol), 2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Pharmacore, CAS: 135065-69-9) (70 mg, 0.324 mmol), and PBu3 (84 μl, 0.324 mmol) in dry toluene (1.2 mL). Cool to 0° C. then add 1,1′-(azodicarbonyl)piperidine (84 μl, 0.324 mmol). Let stir for 10 min at 0° C., then warm to ambient temperature overnight. Reaction mixture thickens and turns gel like. Add hexanes and collect solid via vacuum filtration. Wash the solid with hexanes several times. Dissolve the crude material in dry CH2Cl2 (500 μL) and TFA (200 μl) and stir overnight. Add 1N NaOH until the reaction is pH=10 and extract with EtOAc (3×10 mL). Dry the combined organic portions with Na2SO4, filter, and concentrate to give the title compound. MS (ES+) 486.0 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O.N1C=CC=CC=1.C(OC(=O)C)(=O)C>CCCCCC.CCOCC.C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]([Br:13])=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(C)c(N)c1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
A mixture of 16.5 g (100 mmol) of methyl 3-amino-4-methylbenzoate and 300 ml of CCl4 was treated with 18.6 g (105 mmol) of N-bromosuccinimide and stirred at ambient temperature for four hours. The reaction mixture was filtered, and the filtrate was evaporated at reduced pressure to afford an amber oil. To remove material resulting from bromination at the 6-position, the crude product was taken up in 100 ml of hexane and 60 ml of ether and treated with 3.96 g (50.0 mmol) of pyridine and 3.06 g (30.0 mmol) of acetic anhydride. After stirring for three hours at 25° C., the precipitate was removed by filtration. The filtrate was evaporated at reduced pressure to yield an amber oil. The crude product was purified by HPLC to afford 14.5 g (59%) of the desired product as an amber oil. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][C@@H:8]2[N:10](CC3NC(C4SC=CN=4)=N[C@@H](C4C=CC(F)=CC=4Cl)C=3C(OC)=O)[C@@H:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1.[Br:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C@H:43]1[C:48]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:47]([CH2:54]Br)[NH:46][C:45]([C:56]2[S:57][CH:58]=[CH:59][N:60]=2)=[N:44]1>>[NH2:1][CH:2]1[CH2:3][C@@H:4]2[N:10]([CH2:54][C:47]3[NH:46][C:45]([C:56]4[S:57][CH:58]=[CH:59][N:60]=4)=[N:44][C@@H:43]([C:37]4[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=4[Br:35])[C:48]=3[C:49]([O:51][CH2:52][CH3:53])=[O:50])[C@@H:8]([CH2:7][O:6][CH2:5]2)[CH2:9]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Reactant: COC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(N)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(N)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br

Procedure:
Compound 71a was prepared in analogy to 60b in Example 60 by using ethyl (4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 70a instead of compound C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)=[O:2].[BH4-].[Na+]>C1COCC1.CO>[OH:2][CH2:1][C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a chilled (0° C.) solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-formyl-pyridin-4-yl)-propyl]-amide (95 mg, 0.24 mmol) in THF (2 mL) and methanol (2 mL) was added sodium borohydride (17.8 mg, 0.47 mmol). The mixture was then warmed to room temperature. After 1.5 hours, the mixture was quenched with water (5 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The mixture was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: [Cl:1]CC1C=CC2OC(C3C=CC=CC=3)OC=2C=1.[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C1(C)C(C)=CC=CC=1>[ClH:1].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: ClCc1ccc2c(c1)OC(c1ccccc1)O2
Agent: c1cnc(N2CCNCC2)nc1
Solvent: Cc1ccccc1C
Product: Cl

Procedure:
A solution of 8.5 g (0.0344 mole) of 5-chloromethyl-2-phenyl benzo [d]-1,3-dioxole (BP/0.05 mm = 135°-137° C) and 11.3 g (0.0689 mole) of 1-(2-pyrimidinyl) piperazine in 250 ml of anhydrous xylene was refluxed for 9 hours. The precipitate of 1-(2-pyrimidinyl) piperazine hydrochloride formed was suction-filtered off and the xylene was evaporated off under reduced pressure.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([S:39][CH3:40])[N:34]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:40][S:39][C:35]1[N:36]=[C:37]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH:38]=[CH:33][N:34]=1
Reactant: CSc1nccc(Cl)n1
Reactant: CC1(C)OB(c2ccccc2Oc2ccc([N+](=O)[O-])cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CSc1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1

Procedure:
To a mixture of 4,4,5,5-tetramethyl-2-(2-(4-nitrophenoxy)phenyl)-1,3,2-dioxaborolane (0.936 g, 2.7 mmol), Pd(dppf)Cl2 (0.10 g, 0.14 mmol) in dioxane and Sodium carbonate (2.0 M in water, 2.7 ml, 5.5 mmol) was added 4-chloro-2-methylthiopyrimidine (0.38 ml, 3.3 mmol). The brown mixture was sealed and heated to 80 deg. C. overnight. In the morning the reaction was partitioned between EtOAc/1N NaOH. The aqueous layer was extracted once with EtOAc. The combined organics were dried over anhyd. Na2SO4, filtered, and concentrated to a brown oil. This material was treated with CH2Cl2 and purified by silica gel chromatography eluting with 0-25% EtOAc/hexane. The product-containing fractions were concentrated to afford 2-(methylthio)-4-(2-(4-nitrophenoxy)phenyl)pyrimidine as a clear oil. MS m/z=340 [M+1]+. Calc'd for C17H13N3O3: 339.37.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:25]([O:27]C)=[O:26].[I-].[Li+]>N1C=CC=CC=1>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:25]([OH:27])=[O:26]
Reactant: COC(=O)c1cnc2c3cc(NC(=O)C4CCCCC4)ccc3ncn2c1=O
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1cnc2c3cc(NC(=O)C4CCCCC4)ccc3ncn2c1=O
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
A mixture of methyl 4-oxo-10-cyclohexanecarboxamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (4.7 g) and anhydrous lithium iodide (11.75 g) in dry pyridine (47 ml) was stirred at 100° C. for 1 hour and 20 minutes and cooled to ambient temperature. The resulting solid was collected by filtration and washed with ethanol. The solid was suspended in water (100 ml). The suspension was adjusted to pH 1-2 with conc. hydrochloric acid to give yellow crystals which were separated by filtration, washed with water and dried. The crude crystals were washed with a mixture of chloroform and methanol and dried. There was obtained 4-oxo-10-cyclohexanecarboxamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (2.75 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])[C:5]2=[CH:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.[O:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].CN(C)C=O>[O:31]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])[C:5]3=[CH:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)=[CH:32]1
Reactant: OB(O)c1ccoc1
Reactant: COc1cc2c(cc1Br)C(=CNc1ccc(N3CCN(C)CC3)cc1)C(=O)NC2=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(cc1-c1ccoc1)C(=CNc1ccc(N3CCN(C)CC3)cc1)C(=O)NC2=O
Temperature: 110 °C
Yield: 68.9 %

Procedure:
A mixture of 6-Bromo-7-methoxy-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (241 mg, 0.51 mmole), N,N-dimethylformamide (2 mL), furan-3-boronic acid (143 mg, 1.28 mmole), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (64 mg, 0.062 mmole), tri(t-butyl)phosphine (25 mg, 0.124 mmole) and cesium carbonate (334 mg, 1.02 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator. The reaction mixture is evaporated to dryness, taken up in 5% methanol in chlororform and passed through a short pad of Florisil eluting with 5% methanol in chloroform. The eluate is evaporated in vacuo and treated with acetonitrile, filtered and dried to give a brown solid 161 mg (68%), mp 198-220° C.; MS (ESI): m/z 459.2, 461.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.CN(C)C=O.O.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH2:16]([NH:15][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:5]2[C:6]([N:8]=1)=[N:7][C:2]([C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:24])[CH:30]=1)=[CH:3][N:4]=2)=[O:14])[CH3:17]
Reactant: OB(O)c1cccc(O)c1
Reactant: CCNC(=O)Nc1ccc2ncc(Cl)nc2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc2ncc(-c3cccc(O)c3)nc2n1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
100 mg 1-(3-chloropyrido[2,3-b]pyrazine-6-yl)-3-ethyl-urea (0.40 mmol) was presented in a dimethylformamide/water mixture under nitrogen as protective gas. Then 60.3 mg 3-hydroxyphenyl boronic acid (0.44 mmol), 126 mg sodium carbonate (1.19 mmol) and 23 mg tetrakis(triphenylphosphine) palladium(0) (0.02 mmol) were added. The reaction mixture was stirred at 90° C. for 4 hours. The mixture was filled with water for reprocessing and the deposited solid rewashed with dichloromethane. The resulting raw product was stirred again in warm DCM, filtered off and dried. A yellow solid was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7](=[O:12])[NH:8][CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1.Br>>[OH:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7](=[O:12])[NH:8][CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OCCNC2=O
Agent: Br
Product: O=C1NCCOc2cc(O)ccc21
Temperature: 110 °C
Yield: 117 %

Procedure:
A mixture of 8-(methyloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (Preparation 25) (7.98 g, 41.3 mmol) and hydrobromic acid (100 ml, 1842 mmol) was stirred and heated at 110° C. for 7 hours. Then the reaction mixture was evaporated and azeotroped twice with 150 ml of ethanol to give the title compound (8.66 g) light brown solid which was used without purification. MS (ES) C9H9NO3 requires 179; found 180 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C=O)C>C1COCC1>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(C3C(=O)Nc4ccccc43)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
A solution of oxindole (1.2 g, 9 mmol) in THF (10 ml) was added dropwise to a suspension of sodium hydride (360 mg of a 60% suspension in paraffin oil, 9 mmol) in THF (15 ml) over 15 minutes under nitrogen. The resulting white suspension was stirred for 15 minutes at ambient temperature and a solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (900 mg, 3 mmol) in THF (10 ml) was added followed by DMF (5 ml). The resulting reddish solution was stirred for 30 minutes at ambient temperature followed by 1 hour at 65° C. The mixture was concentrated to half its volume by evaporation and was partitioned between ethyl acetate and water. The aqueous layer was separated, adjusted to pH7 with 2M hydrochloric acid and the resulting precipitate was collected by filtration, washed with water, followed by ethyl acetate and ether and dried under vacuum to give 7-benzyloxy-6-methoxy4-(oxindol-3-yl)quinazoline (1 g, 83%) as a yellow solid.