Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:25]([F:31])=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>O1CCOCC1.C(#N)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([Cl:23])[C:25]=3[F:31])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
4.0 M HCl in Dioxane (4.0 ml) was added to a stirred suspension of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (CAS Registry No162364-72-9, prepared as described in WO98/13354, Example 1) (60 g, 0.2 mol) and 3-chloro-2-fluoroaniline (31.96 g, 0.22 mol) in acetonitrile (1200 ml). The reaction mixture was heated at 80° C. for 1 hour then left to stand overnight. Acetonitrile (500 ml) was added and the resulting precipitate filtered, washed with acetonitrile (3×500 ml) and dried under vacuum to give 7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine hydrochloride as a beige solid (85.45 g, 96%); 1H NMR Spectrum: (DMSO d6) 4.02 (s, 3H), 5.35 (s, 2H), 7.30-7.60 (m, 9H), 7.65 (m, 1H), 8.38 (s, 1H), 8.85 (s, 1H), 11.8 (s, 1H); Mass Spectrum: (M+H)+ 410.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=3)=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cnc(-c3ccc(OC(F)(F)F)cc3)nc2)cc1
Yield: 44.2 %

Procedure:
4-(2-Chloropyrimidin-5-yl)-benzaldehyde (0.92 mmol), 4-trifluoromethoxyphenyl boronic acid (1.10 mmol), dichlorobis(triphenylphosphine)-palladium(II) (0.01 mmol), 2M potassium carbonate (0.92 mL) and dioxane (5 mL) were combined in a vial and irradiated by microwave for 10 min at 150° C. The organic layer from the reaction mixture was loaded directly onto silica and dried in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded the product (140 mg) as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 9.07 (s, 2H), 8.57 (d, J=9.0 Hz, 2H), 8.07 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H); EIMS m/z 344 (M+).
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][CH2:10][CH:9]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:8]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:10][CH:9]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[C:8]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C(=O)Cl
Reactant: O=C(NC1CNc2ccccc2N(c2ccccc2)C1=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)N1CC(NC(=O)OCc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 84.7 %

Procedure:
1-Phenyl-2-oxo-3-benzyloxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (300 mg) was dissolved in methylene chloride (15 ml), isobutyryl chloride (107 mg), pyridine (79 mg) and 4-(N,N-dimethyl)aminopyridine (1 mg) were added, the mixture was refluxed for 2 hours. The reaction mixture was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 300 mg of the title compound (Yield: 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O=[C:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13]([C:12]1[C:11]([CH3:18])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:14])[CH3:17]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccccc1N
Product: CCOC(=O)c1c(C)nc2ccccc2c1N

Procedure:
Prepared as in Example 2a from 2-aminobenzonitrile and ethyl 3-oxobutanoate as a yellow solid (32%). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=8.0 Hz, 3H), 2.61 (s, 3H), 4.34 (q, J=8.0 Hz, 2H), 7.41 (m, 1H), 7.66 (m, 2H), 7.74 (bs, 2H), 8.27 (d, J=8.0 Hz, 1H). MS 231 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N+:9]([O-])=[CH:10]2)=[O:4].O=P(Cl)(Cl)[Cl:18]>ClCCl>[Cl:18][C:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=2[CH:7]=[CH:8][N:9]=1
Reactant: COC(=O)c1cccc2c[n+]([O-])ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc2c(Cl)nccc12
Temperature: 90 °C
Yield: 86 %

Procedure:
5-(Methoxycarbonyl)isoquinoline 2-oxide (2 g, 9.84 mmol) obtained in Step (4) of Preparation Example 1 was dissolved in dichloromethane (20 mL), added with POCl3 (20 mL) at room temperature, and stirred for 4 hours or more at 90° C. The temperature of the reaction mixture was lowered to room temperature, followed by quenching with distilled water. The reaction mixture was diluted with dichloromethane, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.86 g, 86%).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[C:21]#[N:22].[Na].[F:24][C:25]([F:29])([F:28])[CH2:26][OH:27]>>[F:24][C:25]([F:29])([F:28])[CH2:26][O:27][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[C:21]#[N:22]
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c2c1Cl
Agent: [Na]
Product: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c2c1OCC(F)(F)F

Procedure:
4-Chloro-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole is reacted with the sodium salt of 2,2,2,-trifluoroethanol to obtain 4-(2,2,2-trifluoroethoxy)-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole, m.w., 404.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:18])=[C:14]([CH2:16][OH:17])[N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH3:2].[H-].[Na+].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1>C(#N)C>[CH2:1]([C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:18])=[C:14]([CH2:16][O:17][C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CCc1cccc(C)c1CNc1cccn2c(C)c(CO)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1cccc(C)c1CNc1cccn2c(C)c(COC(=O)CCC(=O)O)nc12
Reaction time: 0.08 h
Yield: 82 %

Procedure:
To a suspension of 8-(2-ethyl-6-methylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine (0.47 g, 1.5 mmol) in acetonitrile (20 ml) was added sodium hydride (50% in oil) (0.081 g, 1.7 mmol) and the mixture was stirred for 5 min. To the mixture was added succinic anhydride (0.23 g, 2.3 mmol) and the reaction mixture was refluxed for 20 h. The solvent was evaporated under reduced pressure. The residue was suspended in water and the pH was adjusted to 6 with 2M HCl and the solid that formed was isolated by centrifuging. Washing with water and with acetonitrile gave 0.51 g, (82%) of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=2)[N:3]=1.Cl.[CH:31]1([C:34]2([F:38])[CH2:37][NH:36][CH2:35]2)[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH:31]1([C:34]2([F:38])[CH2:37][N:36]([C:2]3[CH:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[N:5]=[C:4]([S:15][C:16]4[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=4)[N:3]=3)[CH2:35]2)[CH2:33][CH2:32]1
Reactant: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Nc3ccccn3)n2)cc1
Reactant: FC1(C2CC2)CNC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Nc3ccccn3)cc(N3CC(F)(C4CC4)C3)n2)cc1
Temperature: 140 °C
Yield: 3.9 %

Procedure:
N-(4-(4-chloro-6-(pyridin-2-ylamino)pyrimidin-2-ylthio)phenyl)-3,3,3-trifluoropropanamide (2b, 620 mg, 1.4 mmol) and 3-cyclopropyl-3-fluoroazetidine hydrochloride (598 mg, 3.94 mmol, 2.8 eq.) were dissolved in 1,4-dioxane and transferred to a microwave vial. DiPEA (437 mg, 3.38 mmol, 2.4 eq.) was added. The mixture was flushed with N2 for 10 minutes while stirring and heated at 140° C. for 30 minutes in the microwave. HPLC-MS analysis showed 27-40% product in the mixture. The mixture was concentrated and purified by preparative HPLC and lyophilized, yielding 28 mg (3.8%) of a light-yellow solid with a purity of 98+% (HPLC method B: Rf=5.855 minutes).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:7]1[C:8]([I:21])=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[OH:6])[CH3:2].C(O[C:27]([CH3:30])([CH3:29])[CH3:28])(=O)C.S(=O)(=O)(O)O>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:7]1[C:8]([I:21])=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[O:6][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:2]
Reactant: CCOC(=O)C(O)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: CC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 25 °C
Yield: 35.8 %

Procedure:
Ethyl-2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl]-2-hydroxyacetate (3 g, 7 mmol) was taken up in 20 mL dichloromethane and tert-butyl acetate (20 mL, 170 mmol) and the mixture coiled to 3° C. in an ice/water bath. Concentrated sulphuric acid (1.14 mL, 21 mmol) was then added dropwise and the mixture allowed to warm to room temperature over 3 hours. The reaction was quenched by the addition of 100 mL of 1M NaOH and 100 mL water and the organic layer separated. The organics were washed with brine (100 mL), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash chrmoatography using a gradient of EtOAc in heptane as eluant (0:100 to 30:70) to afford the title compound as a white solid (1.22 g, 36%). 1H NMR (400 MHz, CDCl3) δ 1.20 (t, 3H), 1.23 (s, 9H), 1.81-1.94 (m, 4H), 2.66 (s, 3H), 2.80-2.87 (m, 2H), 3.22-3.31 (m, 2H), 4.10-4.22 (m, 2H), 5.90 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH3:12])[O:4][CH2:3][CH2:2][N:32]1[CH2:33][CH2:34][N:29]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:30][CH2:31]1
Reactant: O=C(CCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCNCC1
Reactant: COc1ccc(OCCBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(OCCN2CCN(C(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 4-(2-bromo-ethoxy)-1,2-dimethoxy benzene (1.41 g, 4.86 mmol) and 6,6-bis-(4-fluorophenyl)-1-piperazin-1-yl-hexan-1-one (1.81 g, 4.86 mmol.) in dry DMF (40 ml) was added K2CO3 (0.8 g, 5.83 mmol.) and the mixture stirred at 120° C. overnight. EtOAc was added, washed with water (2×30 ml), brine (3×10 ml), dried over MgSO4, and evaporated under reduced pressure. The produce was purified by column chromatography on silica (hexane:EtOAc 1:1), followed by EtOAc to give the desired product in 57% yield.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:17])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22]Br)[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:5][CH:4]([CH2:13][CH3:12])[CH2:3][CH2:2][CH2:15][CH3:14])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1)[CH3:20]
Reactant: CCCCC(CC)CBr
Reactant: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc2c(c1)C(=O)c1ccc(OCC(CC)CCCC)cc1C2=O
Temperature: 90 °C
Yield: 128.3 %

Procedure:
2,6-Dihydroxyanthraquinone (100.0 g, 0.42 mol) and 2-ethylhexyl bromide (165.0 g, 0.86 mol) were dissolved in 1 L of DMF. To this solution was added anhydrous K2CO3 (120.0 g, 0.87 mol). The reaction was heated at 90° C. overnight. Most of DMF was removed and 500 mL of water was added. The reaction was extracted with ether (3×400 mL), washed with brine (1×200 mL), and dried over MgSO4. Solvent was removed and the crude product was recrystallized from methanol to give yellow powdery product 125.21 g (65% yield). 1H NMR (CDCl3) δ (Ppm): 0.92-0.98 (m, 12H, CH3), 1.34-1.54 (m, 16H), 1.75-1.81 (m, 2H, CH(CH3)), 4.02 (d, J=5.5 Hz, 4H, OCH2), 7.19 (d, J=8.4 Hz, 2H), 7.70 (s, 2H), 8.19 (d, J=8.5 Hz, 2H); 13C NMR (CDCl3): 11.12, 14.06, 23.04, 23.88, 29.08, 30.51, 39.34, 71.34, 110.64, 120.84, 127.00, 129.62, 135.88, 164.29, 182.27. M.p. 49-51° C.; FD-MS: m/z 464 (M+).
Reaction SMILES: [Br:1][CH:2]([C:4]1[N:5]=[C:6]2[S:13][CH:12]=[C:11]([CH3:14])[N:7]2[C:8](=[O:10])[CH:9]=1)[CH3:3].C(#N)C.[Br:18]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>O>[Br:18][C:9]1[C:8](=[O:10])[N:7]2[C:11]([CH3:14])=[CH:12][S:13][C:6]2=[N:5][C:4]=1[CH:2]([Br:1])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2nc(C(C)Br)cc(=O)n12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1csc2nc(C(C)Br)c(Br)c(=O)n12
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
Under nitrogen, a suspension of 7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(13.2 g, 48.3 mmol) in acetonitrile (100 mL, 2000 mmol) was stirred until a clear solution was obtained. N-Bromosuccinimide (9.891 g, 55.57 mmol) was then added and the reaction mixture was stirred at 50° C. After 20 minutes, HPLC indicated that the reaction was complete. A solution of sodium sulfite (3.046 g, 24.16 mmol) in water (50 mL) was added and the mixture was stirred at room temperature for 20 minutes. Water (200 mL) was added slowly and the mixture stirred at room temperature for 30 minutes and then filtered. The solid was washed with water (100 mL×3) and dried to give 6-bromo-7-(1-bromoethyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one as an off-white solid (15.61 g, 91%). LCMS calculated for C9H9Br2N2OS (M+H)+: m/z 352.87, 354.87; Found: 352.65, 354.60. 1H NMR (400 MHz, DMSO-d6) δ 7.15 (q, J=1.3 Hz, 1H), 5.51 (q, J=6.7 Hz, 1H), 2.66 (d, J=1.2 Hz, 3H), 1.90 (d, J=6.7 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[S:5]([CH3:8])(=[O:7])=[O:6].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:21]1([CH2:20][O:19][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=2[N:4]([CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[S:5]([CH3:8])(=[O:7])=[O:6])[C:13]([O:15][CH3:16])=[O:14])[CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(N(CCBr)S(C)(=O)=O)c(OCC2CC2)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(N(CCN2CCN(C)CC2)S(C)(=O)=O)c(OCC2CC2)c1
Temperature: 130 °C
Yield: 79 %

Procedure:
The mixture of methyl 4-(N-(2-bromoethyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoate (630 mg, 1.551 mmol), 1-methylpiperazine (155 mg, 1.551 mmol) and K2CO3 (321 mg, 2.326 mmol) in dry CH3CN (14 ml) was heated at 130° C. under microwave irradiation for 3 hours. After cooling the inorganic salts were filtered, the solvent was evaporated and the residue was purified by flash chromatography on silica gel (eluent: DCM/MeOH/32% NH4OH 95/5/0.5) to give methyl 3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)-methylsulfonamido)benzoate as a light brown oil (520 mg, 1.222 mmol, 79% yield, MS/ESI+ 426.0 [MH]+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:19][CH3:20]>CN(C)C=O>[CH2:19]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11])[CH3:20]
Reactant: CCI
Reactant: O=Cc1cc2cccnc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1c(C=O)cc2cccnc21
Temperature: 20 °C

Procedure:
In a separate reaction: To a suspension of 1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (600 mg, 4.11 mmol) and Cs2CO3 (2675 mg, 8.21 mmol) in N,N-Dimethylformamide (DMF) (20 mL) stirred under nitrogen at 20° C. was added iodoethane (0.498 mL, 6.16 mmol) dropwise during 0.5 min. The reaction mixture was stirred at r.t. for 1 h, TLC showed complete conversion.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: FC(F)(F)c1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and 4-trifluoromethylphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 374.0 (M+H)+, retention time 1.47 minutes.
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].Cl.[Br:16][C:17]1[C:22]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:21][C:20]([NH:27][NH2:28])=[C:19]([F:29])[CH:18]=1>O>[Br:16][C:17]1[C:22]([O:23][CH:24]([CH3:25])[CH3:26])=[CH:21][C:20]([NH:27][N:28]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[C:19]([F:29])[CH:18]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: CC(C)Oc1cc(NN)c(F)cc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Br
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
First, 50 g (0.61 mol) of sodium acetate and 41 g (0.14 mol) of 1,1-dibromo-3,3,3-trifluoroacetone were mixed with 500 ml of water, and the mixture was stirred at 80° C. for 30 minutes and then cooled to 0° C. Then, 45 g (0.14 mol) of 4-bromo-2-fluoro-5-isopropoxyphenylhydrazine hydrochloride was added at 10° C. or lower, and the mixture was stirred at 10° C. or lower for 3 hours. The precipitated crystals were collected by filtration and dried, which afforded 35 g (94.3 mmol) of 3,3,3-trifluoro-2-oxopropanal 1-(4-bromo-2-fluoro-5-isopropoxyphenylhydrazone).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH3:8][C@H:6]1[NH:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([NH:14][S:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[CH:28][CH:27]=3)(=[O:30])=[O:31])[CH:15]=2)[CH2:5]1
Reactant: O=S(=O)(Cl)c1ccc(-c2cccs2)cc1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: c1ccncc1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (200 mg, 0.85 mmol) in pyridine (5 ml) was treated 4-(2-thienyl)benzenesulfonyl chloride (WO 9827069) (258 mg, 1.0 mmol). The solution was stirred at room temperature for 24 hours and concentrated in vacuo. The residue was co-evaporated with methanol and toluene (×3). The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (1:40 to 1:20 2M ammonia in methanol:dichloromethane) to afford the title product (E17). MS (ES+) m/e 458 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:16])[C:5]([C:8]([OH:15])([CH:12]([OH:14])[CH3:13])[C:9]([OH:11])=[O:10])(O)[N:6]=1>C(O)C>[NH2:1][C:2]1[N:6]=[C:5]([C:8]([OH:15])([CH:12]([OH:14])[CH3:13])[C:9]([OH:11])=[O:10])[C:4](=[O:16])[N:3]=1
Reactant: CC(O)C(O)(C(=O)O)C1(O)N=C(N)NC1=O
Solvent: CCO
Product: CC(O)C(O)(C(=O)O)C1=NC(N)=NC1=O
Yield: 22 %

Procedure:
A solution of 2 g of the crude compound of Example 18 (8.23 mmol), solubilized in 80 ml of anhydrous ethanol, is refluxed for one hour. After evaporation and purification on silica gel (eluent: 35% MeOH/5% H2O/CH2Cl2 then 40% MeOH/5% H2O/CH2Cl2) 400 mg are obtained with a yield of 22%.
Reaction SMILES: [NH2:1][NH2:2].[F:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13](O)=[O:14])=O)=[CH:6][CH:5]=1>>[F:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]([OH:14])=[N:2][N:1]=2)=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(O)c1ccccc1C(=O)Cc1ccc(F)cc1
Product: Oc1nnc(Cc2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 3 M ethanolic solution of hydrazine (20 ml, 60 mmol) is added to 2-(4-fluorobenzyl carbonyl)benzoic acid (5.5 g, 20 mmol), and the mixture is stirred at room temperature for 5 hours. Precipitation gives 4-(4-fluorobenzyl)-1-hydroxy-phthalazine.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:22])=[O:21].CC(C)([O-])C.[K+]>CS(C)=O.O>[C:2]1([C:1]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:27][CH2:26][CH2:25][CH2:24][CH2:23][C:20]([OH:22])=[O:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc2ccccc2n1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCCCC=C(c1ccccc1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a solution of 2-benzoylquinoline (4.0 g) and (5-carboxy-l-pentyl)triphenylphosphonium bromide (11.8 g) in DMSO (50 ml) was added potassium t-butoxide (5.8 g) gradually and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was poured in iced water and washed with toluene. The aqueous layer was neutralized with 3N HCl and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried and the solvent was distilled off. The crude residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) to give 0.90 g of 7-phenyl-7-(2-quinolyl)-6-heptenoic acid as a mixture of its (E) and (Z) forms. This mixture (0.90 g) and 5% palladium-on-carbon (0.90 g) were suspended in methanol (10 ml) and stirred in a hydrogen atmosphere at room temperature for 3 hours. The catalyst was then filtered off and the filtrate was concentrated to provide the title compound (1.0 g).