Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=2)[C:56]=1[CH3:73].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=4)[C:56]=3[CH3:73])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2cccnc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccnc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.024 g, 0.05 mmol), 2,5-dimorpholinopyridin-3-amine (0.098 g, 0.37 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-3-yl)quinoline (0.090 g, 0.31 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.074 g, 0.77 mmol) in toluene (3.1 mL) at 120° C. for 5 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.86 (1H, d, J=2.3 Hz), 8.73 (1H, dd, J=4.9, 1.8 Hz), 7.99 (1H, dt, J=7.8, 2.0 Hz), 7.76 (1H, d, J=11.2 Hz), 7.67 (1H, d, J=2.7 Hz), 7.62 (1H, br d, J=9.0 Hz), 7.50 (1H, dd, J=7.8, 4.9 Hz), 7.04 (1H, ddd, J=13.3, 8.4, 2.4 Hz), 6.37 (1H, d, J=2.2 Hz), 3.91 (4H, m), 3.82 (4H, app t, J=4.1 Hz), 3.23 (4H, br. s.), 3.05 (4H, app t, J=4.3 Hz), 2.18 (3H, s). Mass Spectrum (ESI) m/e=519.2 (M+1).
Reaction SMILES: C[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]3OCO[C:7]=3[CH:8]=2)[C:3]1=[O:14]>CC1C2C(=C(O)C=CC=2C)C(=O)C1.C(O)C>[C:3]1(=[O:14])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:2]1
Reactant: CC1Cc2cc3c(cc2C1=O)OCO3
Agent: Cc1ccc(O)c2c1C(C)CC2=O
Solvent: CCO
Product: O=C1CCc2ccccc21

Procedure:
The above-described aromatic composition according to the present process is added in an amount of 1 ppm to the materials of cookies, and this materials are baked to form cookies. Likewise, the mixture (in the ratio 2:1) of 2-methyl-5,6-methylenedioxyindan-1-one and 3,4-dimethyl-7-hydroxyindan-1-one is dissolved in ethanol in an amount of 5 %, and the solution is added to the materials of cookies in an amount to give 10 ppm by weight of said indanone compounds mixture to the materials of cookies, and the materials are baked.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.CN(C=O)C.Br[CH2:36][CH3:37].O.[OH-].[Cs+]>>[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:3]2[N:2]([CH2:36][CH3:37])[N:1]=[CH:5][CH:4]=2)[N:8]=1)[CH3:29]
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CCBr
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccnn2CC)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 1 h
Yield: 4.8 %

Procedure:
To N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.10 mmol) in dry DMF (519 μl, 0.10 mmol) was added bromoethane (11 mg, 0.10 mmol), cesium hydroxide hydrate (17 mg, 0.10 mmol) and 4 angstrom molecular sieves. The reaction mixture was stirred for one hour, filtered through an Acrodisk, rinsed with DCM and MeOH, and concentrated under a nitrogen stream to a residue. Preparative thin layer chromatography eluting with 10% MeOH, 0.5% NH4OH in CHCl3 provided the desired product (2 mg). MS (ES+APCI) m/z=414 (M+H). (The other regioisomer, N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide, was also isolated and was utilized in Example 40).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li:16])CCC.CCCCCC.[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Li:16])=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9].[CH2:26]1[CH2:27][O:23][CH2:24][CH2:25]1
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]c1ccc(C(C)(C)C)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Under an argon stream, 1-bromo-4-tert-butylbenzene (125 g, 587 mmol) and tetrahydrofuran (470 mL) were charged in a reactor, and cooled to −70° C. An n-butyl lithium/hexane solution (1.6 M, 367 mL, 587 mmol) was dropped to this solution over 90 minutes at −70° C. After dropping was completed, the solution was stirred at −70° C. for 2 hours to obtain a 4-tert-butylphenyllithium/THF solution. Under an argon stream, cyanuric chloride (50.8 g, 276 mmol) and tetrahydrofuran (463 mL) were charged in another reactor, and cooled to −70° C. The 4-tert-butylphenyllithium/THF solution prepared previously was slowly dropped to this solution while the solution was cooled so that the reaction temperature might be not more than −60° C. After dropping was completed, the reaction solution was stirred at −40° C. for 4 hours, and stirred at room temperature for 4 hours. Water (50 mL) was added to this reaction mixture to complete the reaction, and tetrahydrofuran was distilled off. Water (1 L) and chloroform (2 L) were added to this residue, and an organic layer was extracted. The organic layer was further washed with water (1 L), and subsequently the solvent was distilled off. This residue was dissolved in acetonitrile (600 mL), and an insoluble solid was removed by filtration at the time of heating. The obtained filtrate was condensed to approximately 100 mL, and cooled to −70° C. to filter and collect the solid deposited. The collected solid was dissolved in a mixed solvent of chloroform (200 mL)/hexane (600 mL), and purified with silica gel column chromatography (developing solvent: chloroform/hexane). The solvent was distilled off, and this residue was recrystallized from acetonitrile. Thereby, 4,6-bis(4′-tert-butylphenyl)-2-chloro-1,3,5-triazine (41.3 g, 109 mmol) was obtained.
Reaction SMILES: N#N.[N:3]([C@@H:6]([C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=1)[CH3:11])[C:7]([OH:9])=[O:8])=[N+]=[N-]>CO.[Pd]>[NH2:3][C@@H:6]([C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH:13]=1)[CH3:11])[C:7]([OH:9])=[O:8]
Reactant: C[C@@H](c1cn(C(=O)OC(C)(C)C)c2ccccc12)[C@H](N=[N+]=[N-])C(=O)O
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: C[C@@H](c1cn(C(=O)OC(C)(C)C)c2ccccc12)[C@H](N)C(=O)O
Reaction time: 2 h

Procedure:
10% Pd on carbon (1.19 g, 1.118 mmol) was placed in a flask under a blanket of N2 (g). The catalyst was wet with MeOH (5 mL). To the flask was added (2S,3S)-2-azido-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid (2.38 g, 6.91 mmol) as a solution in MeOH (69.1 ml). The flask was evacuated then charged with H2 (g). The reaction was stirred for 2 h. The flask was evacuated and purged with N2 (g) 2×. The reaction was filtered through CELITE® and the filter cake washed with MeOH. The organics were concentrated under vacuum to give (2S,3S)-2-amino-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid which was used in Step 7 as is. ESI-MS(+) m/z 319.4 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:25])=[C:4]([F:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]3[O:42][CH:41]=[CH:40][C:39]=3[CH:43]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].ClCCl>[O:42]1[C:38]2[CH:37]=[CH:36][C:35]([C:2]3[C:7]([F:8])=[CH:6][C:5]([N:9]4[C:13]([CH2:14][C@@H:15]5[CH2:19][CH2:18][N:17]([C:20]([CH:22]6[CH2:24][CH2:23]6)=[O:21])[CH2:16]5)=[N:12][NH:11][C:10]4=[O:25])=[C:4]([F:26])[CH:3]=3)=[CH:43][C:39]=2[CH:40]=[CH:41]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2cc(F)c(Br)cc2F)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2cc(F)c(-c3ccc4occc4c3)cc2F)C1
Temperature: 100 °C
Yield: 46 %

Procedure:
To a microwave vial were added 4-(4-bromo-2,5-difluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.117 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (42.8 mg, 0.176 mmol), cesium carbonate (114 mg, 0.351 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (6.0 mg, 0.00735 mmol). The mixture was purged with nitrogen followed by the addition of 1,4-dioxane (1 mL) and water (0.5 mL). The suspension was heated overnight at 100° C. and analysis by LCMS indicated desired product formation and consumption of starting material. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH˜6 with 1N aq HCl. The aqueous phase was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title product as a white solid (25 mg, 46%). MS(ES)+ m/e 465.2 M+H]+.
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH:41]4[CH2:43][CH2:42]4)[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:46](Cl)(=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48]>CC#N>[CH:41]1([N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[C:25]([C@H:23]2[CH2:22][C@@H:21]([NH:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:20][NH:19][CH2:24]2)=[O:44])[CH2:42][CH2:43]1
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1C
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)C(C)(C)C)C2)C2CC2)ccc1C

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{cyclopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (Example 98A.) and pivaloyl chloride. MS: 460.6 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.07 min.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2)([OH:3])=[O:2].[OH-].[Na+].[H][H]>O.[Pt].[C]>[C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: O=C(O)c1cccc2[nH]c(=O)ccc12
Agent: [Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCc2c(cccc2C(=O)O)N1

Procedure:
2 Grams of 5-carboxycarbostyril was suspended in 30 ml of water, then 10N-sodium hydroxide aqueous solution was added to dissolve the crystals. To this solution was added 500 mg of 10% platinum-carbon and this mixture was catalytically reduced with hydrogen gas under condition of 3-4 kg/cm2 at 70° C. After the completion of the reaction, the catalyst was removed from the reaction mixture by filtration, then the pH of the filtrate was adjusted to about pH=1 by adding concentrated hydrochloric acid. The precipitated crystals were collected by filtration, recrystallized from methanol to obtain 820 mg of 5-carboxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([OH:12])[CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:14]([CH3:31])[CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO>[C:1]1([S:7][CH2:8][CH:9]([OH:12])[CH2:10][NH:11][CH:14]([CH3:31])[CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC(O)CSc1ccccc1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)CSc1ccccc1
Yield: 36.3 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 2.95 g of 3-phenylthio-2-hydroxypropylamine (prepared as described in Preparation 87), 3 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione, 1.0 g of sodium cyanoborohydride and 100 ml of anhydrous methanol were used, to give 1.74 g of the title compound, melting at 176° C. to 177° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
Ethyl 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylate (240 mg) and 27 mg of lithium hydroxide monohydrate were dissolved in 4 mL of THF and 4 mL of H2O. The reaction was stirred for 2 h at room temperature. The mixture was evaporated, and then added H2O. The mixture was acidified with 1N HCl to pH=2˜3. The resulting solid was filtered and washed with H2O to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (250 mg).
Reaction SMILES: [Cl:1][CH:2]([C:10](=O)[CH3:11])[C:3](=[O:9])[C:4]([O:6]CC)=[O:5].Cl.[NH2:14]O.O.[OH-].[Na+]>CO>[CH3:11][C:10]1[C:2]([Cl:1])=[C:3]([C:4]([OH:6])=[O:5])[O:9][N:14]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)C(Cl)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.8 %

Procedure:
A solution of ethyl 3-chloro-2,4-dioxovalerate (3.0 g, 15.6 mmol) and hydroxylamine hydrochloride (1.08 g, 15.6 mmol) in a mixuture of 1.5 mL of H2O and 1 mL of CH3OH was heated to reflux. After four hours TLC analysis indicated that all of the starting material had been consumed. Sodium hydroxide (0.31 g, 7.8 mmol) was added to the hot solution. After four hours the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was taken up in a 1:1 mixture to ethyl acetate/H2O. The aqueous layer was made basic with 2N NaOH and separated. The aqueous layer was then acidified with 2M HCl and extracted with ethyl acetate (125 mL). The ethyl acetate extract was washed with H2O (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 600 mg (24% yield) of the desired product a gummy tan solid: 1H NMR (CDCl3) δ8.8 (bs, 1H), 2.3 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:11]2[N:10]=[C:9](Cl)[NH:8][C:7]=2[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[F:19][C:20]([F:34])([F:33])[C:21]1[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]([F:18])([F:17])[C:3]1[C:11]2[N:10]=[C:9]([N:30]3[CH2:31][CH2:32][N:27]([C:22]4[C:21]([C:20]([F:34])([F:19])[F:33])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:28][CH2:29]3)[NH:8][C:7]=2[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1
Reactant: FC(F)(F)c1cc(C(F)(F)F)c2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: FC(F)(F)c1cc(C(F)(F)F)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The benzoimidazole from step (b) above (115 mg, 0.4 mmol) and 1-(3-trifluoromethylpyridin-2-yl)piperazine (140 mg, 0.6 mmol, Maybridge) reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 142° C. MS (ESI, pos. ion) m/z: 484 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](N(OC)C)=[O:14])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]=CN(C)C)=[CH:21][CH:20]=3)[C:9]=2[CH3:33])=[CH:4][CH:3]=1.[CH2:34]1COC[CH2:35]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:14])[CH2:34][CH3:35])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:26])(=[O:31])=[O:32])=[CH:21][CH:20]=3)[C:9]=2[CH3:33])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Reactant: C1CCOC1
Product: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 72.5 °C

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene) sulfamoyl)phenyl)-N-methoxy-N,4-dimethylthiophene-2-carboxamide (compound 1d, 2.3 g, 4.55 mmol) in anhydrous THF (40 ml) at 25° C., Grignard reagent (ethyl magnesium bromide, 3.04 g, 22.8 ml, 22.77 mmol) was added dropwise and the reaction mixture was heated at 70-75° C. for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., the reaction mixture was quenched by adding a solution of saturated ammonium chloride (40 ml) and the resulting mixture was extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product; which was purified by column chromatography over silica gel (100-200 mesh) using 30-35% ethyl acetate in hexane as an eluent to obtain the title compound which was further purified by precipitation by dissolving 1.1 g of the compound in dichloromethane (10 ml) and precipitating it by slow addition of diisopropyl ether. (0.89 g, 47%)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-].[K+].[I-].[Na+]>O.CN(C)C=O>[CH2:25]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCBr
Reactant: NC(=O)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(N)=O)cc1
Temperature: 110 °C
Reaction time: 72 h
Yield: 47.7 %

Procedure:
A mixture of 50 g of 4-hydroxybenzamide, 106.1 g of 1-bromotetradecane, 75.59 g of potassium hydroxide, 5.46 g of sodium iodide and 600 ml of dimethylformamide is heated at 110° C. for 24 hours; followed by stirring at room temperature for 72 hours. The reaction is poured into water, the resulting solid collected and washed with water. The solid is recrystallized first from chloroform then ethyl acetate to give 58 g of the desired product.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.O=C1N(C2C=CC(C3CCNCC3)=CC=2)CC(CCC(N)=O)O1.[C:48]([O:51][CH2:52][C:53](Cl)=[O:54])(=[O:50])[CH3:49].C(OCC(Cl)=O)C1C=CC=CC=1>>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][N:16]([C:53](=[O:54])[CH2:52][O:51][C:48](=[O:50])[CH3:49])[CH2:17][CH:18]=3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)c(F)c2)C(=O)O1
Reactant: CC(=O)OCC(=O)Cl
Agent: NC(=O)CCC1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Agent: O=C(Cl)COCc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)COC(C)=O)CC3)c(F)c2)C(=O)O1

Procedure:
Following the general procedure of EXAMPLE 18, and making non-critical variations but substituting (S)-(-)-N-[[2-oxo-3-[4-(3,6-dihydro-2H-pyridin-4-yl)-3-fluorophenyl]-5-oxazolidinyllmethyl]acetamide (EXAMPLE 38) for (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl acetamide and acetoxyacetyl chloride for benzyloxyacetyl chloride, the title compound is obtained, mp 188-191° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17].[CH3:19][O:20][C:21]1[CH:29]=[C:28]([S:30][CH3:31])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([NH:12][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([S:30][CH3:31])=[CH:29][C:21]=3[O:20][CH3:19])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17]
Reactant: COc1cc(SC)ccc1C(=O)Cl
Reactant: CC1(C)C(=O)NC(=O)c2c1ccc(N)c2[N+](=O)[O-]
Product: COc1cc(SC)ccc1C(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C

Procedure:
Prepared analogous to Example 2a from 5 gm of 4,4-dimethyl-7-amino-8-nitro-2H,4H-isoquinoline-1,3-dione and 2-methoxy-4-methylmercapto-benzoyl chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[O:15])[S:8][C:7]=12.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(#N)C>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:11]([C:9]3[S:8][C:7]4=[C:2]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[N:3]=[N:4][CH:5]=[C:6]4[CH:10]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(Cl)c2s1
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(N3CCOCC3)c2s1
Temperature: 150 °C

Procedure:
A 2.5 ml glass microwave reaction vessel was charged with 3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide: (0.020 g, 0.058 mmol), acetonitrile (1 ml), morpholine (0.015 g, 0.17 mmol). The reaction mixture was heated in a Smith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 50 min. The solvent was evaporated under reduced pressure and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide N-cyclopropyl-4-methyl-3-(7-morpholinothieno[2,3-d]pyridazin-2-yl)benzamide (0.016 g) MS (ES+): 395 (M+H)+.