Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[Br:13]NC(=O)CCC(N)=O>CN(C)C=O>[Br:13][C:11]1[C:2]([F:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5][CH2:4]2
Reactant: NC(=O)CCC(=O)NBr
Reactant: O=C1CCc2c(F)cccc2N1
Solvent: CN(C)C=O
Product: O=C1CCc2c(ccc(Br)c2F)N1
Reaction time: 8 h

Procedure:
To a stirred solution of 5-fluoro-3,4-dihydroquinolin-2(1H)-one (146-4; 0.45 g, 0.00272 mol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinamide (0.53 g, 0.0029 mol). Reaction mass was allowed to stir for overnight. Ice cold water was added to reaction mass. The solid separated was filtered and dried thoroughly to obtain the title compound. MS (M+1): 246.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([CH:17]=3)[NH2:16])[N:10]=2)[CH:7]=1.C(#N)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([NH:16][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[CH:17]=3)[N:10]=2)[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(-c2cn3cc(Cl)ccc3n2)ccc1C(F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Cl)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
A 20 mL vial is charged with 5-(6-chloroimidazo[1,2-a]pyridin-2-yl)-2-(trifluoromethyl)aniline (0.156 g, 0.5 mmol), acetonitrile (4.12 mL) and pyridine (0.081 mL). The mixture is added trimethylacetyl chloride (0.123 mL, 0.001 mol) and stirred for 20 min at 80° C. The solution is concentrated, taken into EtOAc (10 mL) and washed once with HCl (10 mL, 1M) and NaOH (10 mL, 1M). Organics are dried, concentrated purified on silica (0-100% EtOAc in Hexanes) to give the title compound (106 mg, 54% yield). LCMS m/z=396.4 [M+H]+, tR=2.54 min. (compound same as Example 81)
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ClCCl.C(C1C=C(CC[N:26]2[CH2:31][CH2:30][C:29]([CH2:33][N:34]([CH3:45])[C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)([OH:32])[CH2:28][CH2:27]2)C=CC=1)#N.[CH3:46][S:47]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([OH:59])=O)=[CH:52][CH:51]=1)(=[O:49])=[O:48]>O>[OH:32][C:29]1([CH2:33][N:34]([CH3:45])[C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)[CH2:30][CH2:31][N:26]([C:57](=[O:59])[CH2:56][C:53]2[CH:52]=[CH:51][C:50]([S:47]([CH3:46])(=[O:48])=[O:49])=[CH:55][CH:54]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc(N(C)CC2(O)CCN(CCc3cccc(C#N)c3)CC2)cc1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C)CC2(O)CCN(C(=O)Cc3ccc(S(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.8 %

Procedure:
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.68 g) was added to a dichloromethane solution (15 mL) of the compound (0.90 g) obtained in Step 3 of Example 25 and 4-methylsulfonylphenylacetic acid (0.76 g) and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into cold water (80 mL) and then separated, and the aqueous layer was extracted with dichloromethane. The organic layer was combined and washed with water and brine successively, and then dried over anhydrous sodium sulfate. After the solvent was removed under reduce pressure, the residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=8:1) to obtain the titled compound (1.36 g) as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:35]1[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]1=[O:36])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CCl)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Yield: 82.2 %

Procedure:
A solution of 6-benzyloxy-4-butoxy-3-chloromethyl-2-isobutyl-1(2H)-isoquinolinone (6.85 g, 16 mmol) and potassium phthalimide (4.44 g, 24 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-[(6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione (7.08 g, 82.2%) as an amorphous.
Reaction SMILES: [CH2:1]([C@@H:8](/[CH:24]=[CH:25]/[C@H:26]([CH3:42])[C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43]COC(C)=O>[Pd]>[CH2:1]([C@@H:8]([CH2:24][CH2:25][C@H:26]([CH2:42][CH3:43])[C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: C[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Pd]
Product: CC[C@@H](CC[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of (2S,5S,E)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-methylhex-3-ene-1,6-dione (250 mg, 0.431 mmol) in EtOAc (5 mL) was added 10% Pd/C (80 mg, 0.075 mmol). The reaction mixture was purged with nitrogen and stirred under an atmosphere of hydrogen (balloon) overnight. The reaction mixture was filtered through CELITE® and concentrated to afford (2R,5S)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-ethylhexane-1,6-dione (221 mg, 0.379 mmol, 88% yield), which was used without further purification. Anal. Calcd. for C35H38N2O6 m/z 582.3. found 579.2 (M−); 1H NMR (400 MHz, CDCl3) δ ppm 7.35-7.31 (m, 5H), 7.27-7.21 (m, 7H), 7.04-7.02 (m, 3H), 4.68-4.66 (m, 2H), 4.19-4.11 (m, 4H), 4.04 (m, 1H), 3.66 (bs, 1H), 3.32 (m, 1H), 3.05-3.0 (m, 2H), 2.80 (m, 1H), 2.68 (m, 1H), 2.36 (m, 1H), 1.75-1.68 (m, 4H) 1.25 (t, J=7.2 Hz, 2H), 0.92 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[Cl:18])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccccc1Cl
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccc2Cl)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-chlorobenzylamine in DME. ES-MS m/e (%): 328 (M{37Cl}+H+, 30), 326 (M{35Cl}+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-])=O.[CH3:29][O:30][C:31]([NH:33][C:34](=NC(OC)=O)SC)=[O:32]>[Pd].C(O)C>[CH3:29][O:30][C:31]([NH:33][C:34]1[NH:26][C:3]2[CH:4]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]4[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:12]=4[CH:25]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2[nH]1
Temperature: 80 °C
Yield: 79.4 %

Procedure:
1,1-Dimethylethyl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (3.3 g, 8.56 mmol) and 10% palladium on carbon (300 mg) were suspended in ethanol (100 mL) and the mixture was hydrogenated at 50 psi using a Parr apparatus for 12 h. The mixture was filtered through a celite pad and the filtrate concentrated. The residue was taken into acetic acid (25 mL) followed by addition of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (2.3 g, 11.15 mmol) and the resulting mixture heated to 80° C. for 30 minutes. The mixture was cooled to room temperature then concentrated and partitioned with ethyl ether (60 mL) and dilute aqueous sodium bicarbonate. The biphasic mixture was allowed to stand for several minutes until a precipitate formed. The solid was collected by filtration, washed with water then ethyl ether and dried to give 1,1-dimethylethyl 7-(2-{[(methyloxy)carbonyl]amino}-1H-benzimidazol-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (2.98 g, 80% yield) as a white solid. MS (EI) for C23H26N4O5: 439 (MH+).
Reaction SMILES: CC1(C)CC(C)(C)C2C(=C(C)C=C([C:14]([OH:16])=[O:15])C=2)O1.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24](Br)[C:23]([O:33][CH2:34][O:35][CH3:36])=[CH:22][C:21]1=2.[Li]C(C)(C)C>>[CH3:36][O:35][CH2:34][O:33][C:23]1[C:24]([C:14]([OH:16])=[O:15])=[CH:25][C:26]2[C:27]([CH3:31])([CH3:30])[CH2:28][CH2:29][C:20]([CH3:37])([CH3:19])[C:21]=2[CH:22]=1
Reactant: Cc1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C
Reactant: COCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: [Li]C(C)(C)C
Product: COCOc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C

Procedure:
Using the same procedure as for the synthesis of 2,2,4,4,8-pentamethyl-6-chromanoic acid (Compound A1) but using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxymethoxy-2-bromonaphthalene (Compound J, 722 mg, 2.21 mmol) and 2.86 ml of t-BuLi (4.87 mmol, 1.7 M solution in hexane), the title compound was obtained as a white solid (143 mg).
Reaction SMILES: [Br-:1].C1(C(C2C=CC=CC=2)(C)C(O[C@@H:12]2[CH:17]3[CH2:18][CH2:19][N+:14]([CH2:20][C:21](=[O:28])[NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)([CH2:15][CH2:16]3)[CH2:13]2)=O)C=CC=CC=1.[CH:36]1([C:41]([C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)([OH:45])[C:42]([OH:44])=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[Br-:1].[CH:36]1([C:41]([C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)([OH:45])[C:42]([O:44][C@@H:16]2[CH:17]3[CH2:18][CH2:19][N+:14]([CH2:20][C:21](=[O:28])[NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)([CH2:13][CH2:12]3)[CH2:15]2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C(=O)O[C@H]1C[N+]2(CC(=O)Nc3ccon3)CCC1CC2)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(O)(c1ccco1)C1CCCC1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccco1)C1CCCC1)C2)Nc1ccon1

Procedure:
This compound is prepared analogously to (R)-3-(2,2-Diphenyl-propionyloxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (See Example 4) by replacing 2,2′-diphenylpropionic acid with cyclopentyl-furan-2-yl-hydroxy-acetic acid.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH2:7][CH3:8])[S:4][C:3]=1[CH2:9][CH3:10].[Li]CCCC.CN([CH:19]=[O:20])C>CCOCC>[CH2:9]([C:3]1[S:4][C:5]([CH2:7][CH3:8])=[CH:6][C:2]=1[CH:19]=[O:20])[CH3:10]
Reactant: CN(C)C=O
Reactant: CCc1cc(Br)c(CC)s1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1cc(C=O)c(CC)s1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-2,5-diethyl thiophene, C6, (9.1 g, 41 mmol) in 100 mL of dry Et2O cooled to -78° C. was added n-BuLi (26.2 mL, 42 mmol) dropwise. The bath temperature was allowed to rise to -20° C. and DMF (6.3 mL, 82 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with NH4Cl (aq) and extracted with Et2O. The organic layer washed twice with water and brine and then dried (MgSO4). After evaporation of solvent, the crude product was purified on flash silica gel (98:2 hexane/Et2O) to afford 2,5-diethylthiophene-3-carboxaldehyde, D6, as a light yellow oil (5.0 g, 72%). 1H NMR (CDCl3) supported the assigned structure. ##STR51##
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[C:12]1([CH2:11][O:18][C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccnc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-isonicotinic acid [CAS Reg. No. 6313-54-8] (4 g) and benzyl alcohol (3.3 g) were added to dry toluene (50 mL). Sodium hydride (2.66 g, 50% in mineral oil) was added in 2 portions and the mixture was allowed to stir at room temperature for 30 minutes. 18-Crown-6 (906 mg) was added and the mixture was then heated to 125° C. for 12 hours. An unstirrable, yellow mixture was obtained. This was diluted with more toluene (80 mL) and stirring was continued for another 4 hours at 125° C. TLC analysis confirmed that there was still 2-chloro-isonicotinic acid left. More benzyl alcohol (3.3 g) and sodium hydride was (2.66 g) added and the mixture was heated for another 12 hours. The mixture was cooled and quenched with 1M aqueous HCl (100 mL). Hexane (200 ml) was added and the mixture was stirred at 0° C. for 1 hour; a light brown solid was obtained. The solid was filtered off and washed with hexane. To remove residual water from the solid, toluene was added and removed again. A colorless solid was obtained (4.8 g). MS (m/e, ISP neg ion): 228.3 (M−H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH:14]=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][C:22]#[N:23]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[C:21](=[CH:14]/[C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[O:13][N:12]=2)/[C:22]#[N:23])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COc1ccc(-c2cc(C=O)no2)cc1
Product: COc1ccc(-c2cc(/C=C(\C#N)c3ccc(OC)c(OC)c3)no2)cc1
Yield: 35.7 %

Procedure:
5-(4-Methoxyphenyl)-isoxazole-3-carboxaldehyde (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (174 mg) through Method A (production step 2), to thereby yield the target product (yield: 127 mg, 36%).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[CH:15]2[CH2:17][CH2:16]2)=[CH:4][C:3]=1[F:24].[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26].CC(C)([O-])C.[K+].Cl>O1CCOCC1>[C:25]([CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[CH:15]2[CH2:16][CH2:17]2)=[CH:4][C:3]=1[F:24])#[N:26]
Reactant: CCOC(=O)c1cn(C2CC2)c2c([N+](=O)[O-])c(Cl)c(F)cc2c1=O
Reactant: CCOC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c([N+](=O)[O-])c(C(C#N)C(=O)OCC)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g of ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinoline-carboxylate and 1.92 g of ethyl cyanoacetate are initially introduced into 30 ml of dioxane. 1.91 g of potassium tert-butoxide are added in portions at room temperature. The mixture is stirred overnight and then heated to 50° for a further 4 hours. After cooling to room temperature, the mixture is diluted using ice-water and rendered acidic using HCl. The mixture is extracted using methylene chloride, and the organic phase is dried and concentrated. The residue is recrystallized from isopropanol.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>>[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Cn1ccnc1-c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(-c2nccn2C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1-methyl-imidazol-2-yl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C27H22N4O3
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH3:28])[CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)=[C:21]([CH3:28])[CH:20]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Cc1cc(F)ccc1-n1cnc2ccc(O)nc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 4-fluoro-2-methylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=244.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[N:3]=1
Reactant: Cc1n[nH]c2ncccc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nn(C(=O)OC(C)(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 692 mg (5.20 mmol) of 3-methyl-1H-pyrazolo[3,4-b]pyridine in 25 mL of acetonitrile under nitrogen was cooled to 0° C. in an ice bath, and was treated with 635 mg (5.20 mmol) of DMAP and 761 μL (5.46 mmol) of triethylamine. A solution of 1.36 g (6.24 mmol) of (BOC)2O in 5 mL acetonitrile was then added dropwise using an addition funnel. Upon completion of addition, the ice bath was removed and the mixture was stirred for an additional 18 hours at room temperature. Solvent was removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to an orange oil. This crude material was purified by flash chromatography over silica gel with 1:1 ethyl acetate/hexanes to give the title product as a clear oil. 1H NMR (CDCl3): δ 1.74 (s, 9H), 2.60 (s, 3H), 7.29 (m, 1H), 8.02 (dd, 1H), 8.74 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C(B(CC)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.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>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: COc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2cccnc2)c1
Temperature: 25 °C
Yield: 103 %

Procedure:
3-bromo anisole (17.4 g, 93.03 mmol) was dissolved in 650 mL tetrahydrofuran and 210 mL water in a 2 L round bottom flask equipped with a magnetic stirrer. Diethyl-(3-pyridyl)borane (15.73 g, 106.99 mmol), sodium carbonate (44.4 g, 418.64 mmol) and dichlorobis(triphenylphosphine)palladium (II) (9.8 g, 13.95 mmol) were added and the mixture heated at reflux for 4 h then cooled to ambient temperature. The mixture was diluted with 300 mL water and extracted with diethyl ether (2×300 mL). The extracts were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was purified by flash chromatography (1:1 ethyl acetate/hexanes). Product fractions were concentrated under reduced pressure to yield 17.75 g (99%) of the desired compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:20])[CH2:17][CH2:18]Br)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(OCC)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH2:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:20])[CH:3]=1
Reactant: CCOC(=O)CCBr
Reactant: N#Cc1ccc2[nH]cc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CCn1cc(Cl)c2cc(C#N)ccc21
Temperature: 80 °C
Yield: 90.3 %

Procedure:
A mixture of 3-chloro-1H-indole-5-carbonitrile (D94) (1.8 g, 10 mmol), ethyl-3-bromopropionate (1.92 ml, 15 mmol), cesium carbonate (6.5 g, 20 mmol) and DMF (50 ml) was heated at 80° C. for 4 hours to give complete reaction. After allowing mixture to cool to room temperature diethyl ether (300 ml) was added and the solution washed with water (3×300 ml). Dried over MgSO4 and evaporated off the solvent to give a brown solid. The solid was triturated with a mixture of diethyl ether and hexane to obtain 2.5 g of the title compound as a tan solid. Crude product used in the next stage (synthesis of D96).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N+:17]([O-])=O>CO.[Pd]>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]1[C:8]([NH2:17])=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=1
Reactant: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1N

Procedure:
To N-(3-(dimethylamino)propyl)-N-methyl-2-nitro-4-(trifluoromethyl)benzenamine (1.46 g, 5.05 mmol) in dry MeOH (50 mL) was added Pd/C (10%, 535 mg). H2 gas was bubbled through the solution at room temperature overnight with vigorous stirring. The reaction mixture was filtered through celite to provide, after concentration, the title compound as an orange solid. MS m/z (M+H)+=276; Calc'd for C13H20F3N3: 275.32.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([Br:14])=[CH:9][C:8]=1[F:15])(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]([Br:16])[C:7]1[C:8]([F:15])=[CH:9][C:10]([Br:14])=[CH:11][C:12]=1[F:13])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCCc1c(F)cc(Br)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCC(Br)c1c(F)cc(Br)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of 4-bromo-2,6-difluorophenethyl acetate (1.182 mmol) in carbon tetrachloride (3 mL) was degassed with a stream of nitrogen for 5 min and was then treated with N-bromosuccinimide (1.301 mmol) and azobisisobutyronitrile (0.118 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was stirred in an oil bath at 80° C. overnight. The reaction was then cooled and was concentrated to dryness under a stream of nitrogen. The crude material was dissolved in ethyl acetate (50 mL) and was washed twice with water. The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The product was dissolved in dichloromethane and was again concentrated to dryness in vacuo to afford the title compound as a yellow oil (403 mg, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.01 (s, 3 H) 4.55-4.70 (m, 2 H) 5.50 (t, J=7.45 Hz, 1 H) 7.55-7.67 (m, 2 H).