Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:20]=[CH:19][C:7]2[N:8]3[C:14](=[O:15])[N:13]=[CH:12][C:11]([C:16]([OH:18])=[O:17])=[C:9]3[S:10][C:6]=2[CH:5]=1.O=P(N(C)C)(N(C)C)N(C)C.[CH2:32](I)[CH3:33]>O>[CH2:32]([O:17][C:16]([C:11]1[CH:12]=[N:13][C:14](=[O:15])[N:8]2[C:7]3[CH:19]=[CH:20][C:4]([O:3][CH3:2])=[CH:5][C:6]=3[S:10][C:9]=12)=[O:18])[CH3:33]
Reactant: CCI
Reactant: COc1ccc2c(c1)sc1c(C(=O)O)cnc(=O)n12
Agent: [Na]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1cnc(=O)n2c1sc1cc(OC)ccc12
Reaction time: 1.33 h

Procedure:
20 g. of the sodium salt of 7-methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxylic acid prepared according to Example 1C are slurried in 200 ml. hexametapol and mixed at ambient temperature with 23.45 g. ethyl iodide. The reaction mixture is stirred for 80 minutes and the resultant solution poured into 3 liters of water. The precipitate obtained is separated off and, while still moist, boiled with 500 ml. ethanol and brought into solution by the addition of some nitromethane. After cooling, 12.9 g. (63.3% of theory) ethyl 7-methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxylate crystallize out; m.p. 231°-232° C.
Reaction SMILES: [CH:1]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]([OH:27])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:1]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([C:16](=[O:27])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:13]=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(OCC2CCCCCC2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)c1cccc(OCC2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-(3-(cycloheptylmethoxy)phenyl)-3-hydroxypropylcarbamate (0.550 g, 1.46 mmol) in dichloromethane (20 mL) was added Celite (est. 3-4 g) and pyridinium chlorochromate (0.377 g, 1.75 mmol). After stirring overnight at room temperature, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (5% EtOAc-hexanes) gave tert-butyl 3-(3-(cycloheptylmethoxy)phenyl)-3-oxopropylcarbamate as a clear oil. Yield (0.50 g, 91%): 1H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J=7.6 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.39 (dd, J=4.4, 2.2 Hz, 1H), 7.18 (dd, J=7.6, 2.4 Hz, 1H), 6.78 (t, J=5.6 Hz, 1H), 3.80 (d, J=6.4 Hz, 2H), 3.24 (dt, J=6.6, 6.0 Hz, 2H), 3.10 (t, J=6.8 Hz, 2H), 1.86-1.97 (m, 1H), 1.77-1.83 (m, 2H), 1.16-1.68 (m, 19H).*
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]1([CH2:29][C:30]([N:32]=[C:33]=[S:34])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCOC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[N:21]=[CH:20][C:19]([NH:22][C:33]([NH:32][C:30](=[O:31])[CH2:29][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[S:34])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cn3)c2cc1OC
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cn3)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 298.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine (85 mg, 0.0285 mmol, 1.0 eq.), and Phenyl-acetyl isothiocyanate (256 mg, 1.44 mmol, 5.0 eq.) dissolved in EtOAc/MeOH 50:50 (2 mL). The reaction mixture was stirred at room temperature for 12 hours, and the solvent was evaporated via rotary evaporation. Purification was done on Biotage with solvent system 95% EtOAc, 4% TEA and 1% MeOH. The combined pure fractions were concentrated and dried under vacuum overnight to yield 1-[6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-3-phenylacetyl-thiourea as a light yellow solid (40.4 mg, 29.7%). 1H NMR (400 MHz, CDCl3): 8.65 (d, 1H), 8.33 (d, 1H), 8.27 (dd, 1H), 7.35 (m, 7H), 7.15 (d, 1H), 6.92 (d, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 3.76 (s, 2H); MS (EI) for C25H22N4O4S: 475 (M+H+).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:15]1[O:17][CH2:16]1.C.[CH2:19]([C:23](C)=[O:24])C(C)C>>[OH:24][CH2:23][CH2:19][O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:14][CH2:16][CH2:15][OH:17])=[O:13]
Reactant: O=C(O)CCCCCCCCC(=O)O
Reactant: C1CO1
Reactant: CC(=O)CC(C)C
Agent: C
Product: O=C(CCCCCCCCC(=O)OCCO)OCCO
Temperature: 150 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
Sebacic acid (50.5g, 0.25 mole), the catalyst of Example II (0.5g), and methyl isobutyl ketone (250 ml) were charged to the autoclave and heated to 150° C. Ethylene oxide (24.23g, 0.55 mole) was introduced from a nitrogen-pressurized cylinder to the autoclave. The temperature rose to 160° C and the pressure increased from 25 psi to 100 psi. After 60 minutes at 160° C, the pressure dropped to 88 psi and the system was vented. The light yellow green reaction mixture was mixed with carbon black, heated to boiling, and filtered through a sintered-glass funnel containing some Al2O3. Upon cooling to -30° C, the precipitated material was filtered, washed with cold hexane, dried in a vacuum desiccator for 48 hours and weighed (31.0g). The product was isolated in 44.0% yield and melted at 47° C. The infrared bands at 3350 cm-1 (OH), 2970 cm-1 (CH2) and 1730 cm-1 (C=O) were characteristic of the expected ester. Anal. Calcd. for C14H26O6 : C, 57.93; H, 8.97; O, 33.10, Found: C, 58.00; H, 9.02. Molecular weight by hydroxyl number. Theory: 290. Found: 289.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:26])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: Cc1noc(-c2sc(NC(=O)C3CCCCC3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and cyclohexanecarbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:19].[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>ClCCl>[Br:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]4)=[CH:37][CH:36]=3)[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:19]
Reactant: CS(=O)(=O)c1ncc2ccc(=O)n(Cc3ccccc3Br)c2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3ncc4ccc(=O)n(Cc5ccccc5Br)c4n3)cc2)CC1
Yield: 9.3 %

Procedure:
8-(2-bromobenzyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.17 g, 0.43 mmol) and 4-(4-methylpiperazino)aniline (0.08 g, 0.43 mmol) were stirred at 140° C. for 4 h. The reaction mixture was dissolved in dichloromethane (20 mL) and washed with 10% sodium hydroxide solution (1×10 mL) then with water (1×10 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using dichloromethane:methanol (95:5) and the product was recrystallized from isopropanol to give the title compound (19 mg, 0.04 mmol, 9.3%). ESMS m/z 505 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.53 (s, 1H), 7.64 (dd, J=7.7, 1.4 Hz, 1H), 7.61 (d, J=9.3 Hz, 1H), 7.06-7.25 (m, 5H), 6.82 (d, J=8.8 Hz, 2H), 6.66 (br. s., 1H), 6.54 (d, J=9.3 Hz, 1H), 5.59 (s, 2H), 3.14-3.21 (m, 4H), 2.55-2.63 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH3:14][N:15]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C1COCC1>[OH:36][C:31]([C:28]1[CH:27]=[CH:26][C:25]([N:15]([CH3:14])[S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])=[CH:30][CH:29]=1)([C:32]([F:33])([F:34])[F:35])[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(c1ccc(C(O)(C#Cc2ccccc2)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.18 g of phenylacetylene (1.75 mmol) in 5 mL of THF was added dropwise 0.76 mL of n-BuLi (2.5M in hexane) at −78° C. The color of the solution turned dark blue and the mixture was stirred at −78° C. for 30 min. Then 0.5 g of N-methyl-N-(4-trifluoroacetyl-phenyl)-benzenesulfonamide (Example 22, Step A) in 5 ml of THF was added and the resultant mixture stirred at −78° C. for 2 h. After this time the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 7:3) to give the title compound. 1H NMR (CDCl3) δ 3.19 (s, 3H), 3.26 (br s, 1H), 7.17 (d, J=8.7 Hz, 2H), 7.34–7.60 (m, 10H), 7.74 (d, J=8.7 Hz, 2H). Mass Spectrum (CI+) m/e=446.0 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:10]([CH:14]=1)[C:11](O)=[O:12]>C(O)C>[CH3:4][O:5][C:6]1[CH:14]=[C:10]2[C:9]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:2][NH:3][C:11]2=[O:12])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)c3cc(OC)ccc23)cc1
Yield: 89.7 %

Procedure:
18.5 mL (380 mmol) of hydrazine hydrate are added to a solution of 21.6 g (75 mmol) of 5-methoxy-2-(4-methoxybenzoyl)benzoic acid in 150 mL of ethanol and the mixture is refluxed for 2 hours. The reaction medium is cooled and then filtered. The precipitate obtained is washed with ethanol and then dried under reduced pressure at 40° C. 19 g of a white solid are obtained (90% yield).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH2:12][N:13]1[C:22](=[O:23])[C:21]2[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29]3)=[N:18][C:17]=2[N:16]([CH3:42])[C:14]1=[O:15])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:1]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]=1[CH2:12][N:13]1[C:22](=[O:23])[C:21]2[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29]3)=[N:18][C:17]=2[N:16]([CH3:42])[C:14]1=[O:15])#[N:2]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1OCC#N)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1c(C#N)oc3ccccc13)c(=O)n2C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 215 mg of 1-{2-[2-cyanomethoxy-phenyl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine and 244 mg of caesium carbonate in 4 ml of N,N-dimethylformamide is stirred for two hours at 50° C., then a further three hours at 70° C. For working up the reaction mixture is combined with water and the precipitate formed is suction filtered and dried.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:13])[CH2:4][CH3:5])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:29]=O.Cl.[C:36]([C:39]1[O:40][CH:41]=[CH:42][CH:43]=1)(=[NH:38])[NH2:37].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:25][C:26]1[CH:27]=[C:28]([CH:29]2[C:11]([C:12]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])=[C:10]([CH2:9][O:8][CH2:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[NH:38][C:36]([C:39]3[O:40][CH:41]=[CH:42][CH:43]=3)=[N:37]2)[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: N=C(N)c1ccco1
Reactant: CCN(CC)CCOCC(=O)CC(=O)OCCCc1ccccc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOCC1=C(C(=O)OCCCc2ccccc2)C(c2ccc(Cl)c(Cl)c2)N=C(c2ccco2)N1
Temperature: 60 °C
Yield: 1.9 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(N,N-diethylamino)ethoxy)acetoacetate (2.0 g, 5.96 mmol), 3,4-dichlorobenzaldehyde (1.15 g, 6.56 mmol), 2-amidinofuran hydrochloride (0.962 g, 6.56 mmol) and sodium hydrogen carbonate (0.551 g, 6.56 mmol) was stirred in N,N-dimethylformamide (10 mL) for 24 h at room temperature and then heated to 60° C. for 5 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (66.3 mg) as an oil. Electrospray MS m/z 584/586 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: OB(O)c1cncnc1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 192.1) and pyrimidin-5-ylboronic acid to afford an off-white solid. HPLC (Condition 4) tR=5.26 min, UPLC-MS (Condition 3) tR=1.00 min, m/z=450.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.69 (s, 3H) 3.40-3.62 (m, 4H) 4.67 (t, J=1.00 Hz, 1H) 7.69 (d, J=8.60 Hz, 2H) 7.90 (d, J=1.00 Hz, 2H) 8.14 (d, J=2.30 Hz, 1H) 8.76 (d, J=2.50 Hz, 1H) 8.95 (s, 2H) 9.17 (s, 1H) 10.32 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[O:19][CH2:18]3)=[N:7]1)=[O:5].[Li+].[OH-].[CH:35]1[CH:40]=[CH:39][C:38](CBr)=[CH:37][CH:36]=1.C1C[O:46][CH2:45]C1>O.CCOC(C)=O>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:23]=[CH:22][C:21]([C:20]([O:19][CH2:18][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:24])=[C:17]([CH2:45][OH:46])[CH:16]=2)=[N:7]1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: C1CCOC1
Reactant: O=C1OCc2cc(-c3nn(C(=O)c4c(Cl)cccc4C(F)(F)F)c4ccccc34)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1ccc(-c2nn(C(=O)c3c(Cl)cccc3C(F)(F)F)c3ccccc23)cc1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)isobenzo furan-1(3H)-one (G-2) (0.6 g, 1.32 mmol) and LiOH (0.16 g, 6.58 mmol) in THF (6 mL) and H2O (3 mL) was stirred at rt for 3 h. The solvent was removed under reduced pressure, and the residue was dissolved in DMF (10 mL), followed by the addition of BnBr (0.78 mL, 6.6 mmol). The resulting mixture was stirred at rt for 3 h. The mixture was diluted with H2O, and EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (PE:EA=4:1) to give the title compound as a colorless oil. LCMS (ESI) calc'd for C30H19ClF5N2O3 for [M+H]+: 585. found: 585.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](O)=[O:8].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([Cl:15])=[O:8]
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1cccc(Br)c1
Yield: 99.8 %

Procedure:
Trans m-bromocinnamic acid (11.4 g) in dry benzene (75 ml) was heated to reflux and then a mixture of thionyl chloride (12 g) in dry benzene (50 ml) was added at such a rate as to maintain constant reflux. The reaction mixture was heated at reflux for an additional 2 hr. after the addition of thionyl chloride. The solvent and excess thionyl chloride were then removed under reduced pressure to give trans 3-bromocinnamoyl chloride (ca. 12.3 g). A solution of the 3-bromocinnamoyl chloride in toluene (150 ml) was added dropwise with stirring to a solution of isopropylamine (10 g) in ether (200 ml). The reaction mixture was stirred at room temperature for 1 hour and then heated at reflux for 1 hour. The solvent and excess amine were removed under reduced pressure. The crude residue was triturated with water, filtered, and recrystallized from ethanol-water to give white, crystalline trans 3-bromo-N-isopropylcinnamamide, m.p. 85°-86° C. Elemental analysis, NMR and IR spectra all confirmed the identity of the product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=2)=[O:10])[CH:2]=1>CCOC(C)=O.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=2)=[O:10])[CH:2]=1
Reactant: CC(C)(C)OC(=O)COc1cccc(C(=O)C=Cc2cccnc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)CCc2cccnc2)c1
Reaction time: 15 h
Yield: 99.6 %

Procedure:
A mixture of 17 (1.70 g, 5.0 mmol) and 10% Pd/C (85 mg) in EtOAc (70 mL) was hydrogenated in a Parr under H2 at 42 psi for 15 h. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. Chromatography on silica (50-60% EtOAc/hexanes) gave 1.70 g (100%) of a colorless oil. 1H NMR (CDCl3, 300 MHz) 8.54 (d, J=2.0 Hz, 1H), 8.48 (dd, J=4.8, 1.5 Hz, 1H), 7.70-7.10 (m, 6H) 4.58 (s, 2H), 3.31 (t, J=7.3 Hz, 2H), 3.09 (t, J=7.4 Hz, 2H), 1.50 (s, 9H); 13C NMR (CDCl3, 75 MHz) 198.3, 168.0, 158.6, 150.4, 148.1, 138.4, 136.9, 136.4, 130.2, 123.7, 121.8, 120.7, 113.5, 83.0, 66.1, 40.2, 28.4, 27.5.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13](O)=O)=[CH:7][CH:6]=1.[CH2:20]([OH:22])C>>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:19]3[C:13](=[CH:12][CH:16]=[CH:17][CH:18]=3)[C:20](=[O:22])[NH:2][N:1]=2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: CCO
Reactant: COc1ccc(-c2ccccc2C(=O)O)cc1
Product: COc1ccc(-c2n[nH]c(=O)c3ccccc23)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
4.10 ml (81.2 mmol) of hydrazine was added to an ethanol solution (100 ml) of 17.33 g (67.6 mmol) of the obtained 2-(4-methoxyphenyl)-benzoic acid, and the reaction liquid was stirred at 60° C. for 4 hours. The reaction liquid was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether to obtain 9.46 g (yield: 55%) of 4-(4-methoxyphenyl)-2H-phthalazin-1-on as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[NH:4][N:3]=1.[C:12]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O-:29])=O)=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18]([O-:20])=O)=[CH:14][CH:13]=1>>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[NH:4][N:3]=[C:2]([NH:1][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([NH:1][C:2]4[CH:6]=[C:5]([C:7]5[S:8][CH:9]=[CH:10][CH:11]=5)[NH:4][N:3]=4)=[O:20])=[CH:16][CH:17]=3)=[CH:26][CH:25]=2)=[O:29])[CH:6]=1
Reactant: O=C([O-])c1ccc(-c2ccc(C(=O)[O-])cc2)cc1
Reactant: Nc1cc(-c2cccs2)[nH]n1
Product: O=C(Nc1cc(-c2cccs2)[nH]n1)c1ccc(-c2ccc(C(=O)Nc3cc(-c4cccs4)[nH]n3)cc2)cc1

Procedure:
Compound 469 was prepared from 3-amino-5-(2-thienyl)pyrazole and 4,4′-biphenyldicarboxylate. [M+H]+ calcd for C28H21N6O282: 537.12; found: 536.93.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][CH:5]([C:8]2[S:33][C:11]3[N:12]=[C:13]([CH3:32])[N:14]=[C:15]([CH2:16][N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]4([CH3:31])[CH3:30])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.Cl.CCOC(C)=O>O1CCOCC1>[CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][CH:5]([C:8]2[S:33][C:11]3[N:12]=[C:13]([CH3:32])[N:14]=[C:15]([CH2:16][N:17]4[CH2:22][CH2:21][NH:20][CH2:19][C:18]4([CH3:30])[CH3:31])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2(C)C)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(CN2CCNCC2(C)C)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To tert-butyl 4-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-3,3-dimethylpiperazine-1-carboxylate (645 mg) and dioxane (6.45 mL) was added 4 M HCl/EtOAc (1.66 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added EtOAc, followed by stirring. The precipitate was filtered and dried under reduced pressure to obtain 6-(4,4-dimethylcyclohexyl)-4-[(2,2-dimethylpiperazin-1-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (422 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC(=O)C)(=O)C>C(Cl)(Cl)Cl>[C:9]1([C:8]2[O:20][C:18](=[O:19])[C:17](=[CH:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: O=Cc1cccs1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccccc2)=CC1=Cc1cccs1
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
Thiophene-2-carboxaldehyde (27.4 cc), 3-benzoylpropionic acid (44.5 g), acetic anhydride (71 cc) and fused potassium acetate (20.5 g) are heated overnight at 80° C. The mixture is cooled to 40° C., chloroform is added and then poured onto crushed ice. Extraction is carried out with chloroform, the organic phase is washed with a decinormal sodium hydroxide solution, it is dried over magnesium sulfate and evaporated under reduced pressure. The residue is stirred for 45 minutes in 40°-60° petroleum spirit, filtered and dried. 5-Phenyl-3-(2-thienylmethylene)-2-furanone (45.3 g), m.p. 141° C., is thereby isolated.