Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][OH:10].[K].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[OH:10][CH2:9][C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][CH2:2][N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cccc(OCCCCl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CO)c1
Yield: 76.9 %

Procedure:
m-(3-Chloropropyloxy)benzyl alcohol (14 g), phthalimide potassium salt (13 g) and tetra-n-butyl ammonium hydrogen sulfate (2 g) were suspended in 200 g of acetonitrile. The suspension was refluxed for 18 hours. After cooling, the insoluble matter was removed by filtration, and the filtrate was concentrated. The concentrate was taken into ethyl acetate, washed with a 1N aqueous solution of sodium hydroxide and water, and then dried. The solvent was evaporated, and the residue was recrystallized from ethanol to give 16.7 g (yield 76.9%) of N-[3-(3-hydroxymethylphenoxy)propyl]phthalimide.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(-c2ccccc2F)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 94.4 %

Procedure:
A mixture of 6-Chloro-nicotinonitrile (7.26 g, 52.4 mmol) and 2-fluorophenyl boronic acid (11 g, 78.6 mmol) and Na2CO3 (11 g, 103 mmol) in toluene (200 mL) and water (10 mL) is degassed and filled with nitrogen for three times, then Pd(PPh3)4 (0.73 g) is added under nitrogen. The reaction mixture is heated at 90° C. After 12 hrs, the reaction mixture is cooled to room temperature, diluted with ethyl acetate, washed with water, dried, concentrated. Column chromatography on silica gel (Hexane/ethyl acetate as eluent) gave 9.8 g of 6-(2-Fluoro-phenyl)-nicotinonitrile.
Reaction SMILES: [Li].[F:2][CH:3]([F:21])[O:4][C:5]1[CH:6]=[C:7]([C:11]([O-])=[CH:12][C:13](=O)[C:14]([O:16]CC)=[O:15])[CH:8]=[N:9][CH:10]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:45][C:46]1[CH:47]=[C:48]([NH:53][NH2:54])[CH:49]=[CH:50][C:51]=1[F:52]>>[Cl:45][C:46]1[CH:47]=[C:48]([N:53]2[C:11]([C:7]3[CH:8]=[N:9][CH:10]=[C:5]([O:4][CH:3]([F:2])[F:21])[CH:6]=3)=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[N:54]2)[CH:49]=[CH:50][C:51]=1[F:52]
Reactant: NNc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cncc(OC(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cncc(OC(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
220 mg (0.64 mmol) of the compound of Example 17A is reacted analogously to the synthesis of the compound of Example 20A with 188 mg (0.96 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, 120 mg (49% of theory) of the title compound is obtained.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1.[CH3:18][C:19]1[C:28]2[CH:27]=[N:26][C:25](S(C)=O)=[N:24][C:23]=2[N:22]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=2)[C:21](=[O:43])[CH:20]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]3[N:26]=[CH:27][C:28]4[C:19]([CH3:18])=[CH:20][C:21](=[O:43])[N:22]([C:32]5[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=5)[C:23]=4[N:24]=3)=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Reactant: COc1cc(NC2CN(CCF)C2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(NC5CN(CCF)C5)cc4OC)nc32)c1
Temperature: 80 °C
Yield: 48.6 %

Procedure:
To a suspension of N1-(1-(2-fluoroethyl)azetidin-3-yl)-3-methoxybenzene-1,4-diamine (11c; 373 mg, 1.56 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 440 mg, 1.194 mmol) in tert-butanol (10 mL) was added DIEA (0.62 mL, 3.58 mmol). The mixture was heated in an oil bath at 80° C. for 1 h. The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was purified on silica gel on an ISCO Combiflash RF (40 g Redisep column, using a gradient of 5-10% 2M NH3/MeOH in DCM) affording enriched product. It was then repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The desired fractions were collected, and concentrated to dryness in a genevac overnight. The resulting solid was dissolved in 9:1=DCM:MeOH and was then passed through a Silicycle SPE-R66030B-20× SiliaSep OT, 5 g/25 mL carbonate column using 10% MeOH/DCM then concentrated and dried under vacuum affording N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (317 mg, 0.58 mmol, 49% yield) as a yellow solid. m/z (ESI, +ve ion) 544.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (1H, s), 8.78 (1H, br. s.), 8.05 (1H, br. s.), 7.84 (1H, d, J=7.0 Hz), 7.60 (1H, s), 7.50 (1H, t, J=8.0 Hz), 7.15 (1H, d, J=9.0 Hz), 6.99 (1H, d, J=9.0 Hz), 6.41-6.51 (1H, m), 6.23-6.34 (2H, m), 6.16 (1H, d, J=2.2 Hz), 5.85 (1H, br. s.), 5.73-5.81 (1H, m), 5.57 (1H, br. s.), 4.49 (1H, t, J=4.8 Hz), 4.37 (1H, t, 1=4.8 Hz), 3.90 (1H, br. s.), 3.73 (5H, br. s.), 2.76-2.88 (2H, m), 2.74 (1H, t, J=4.9 Hz), 2.63-2.71 (1H, m), 2.46 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:30])=[O:24])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(N)=O)cn2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.203 mmol) in DMF (3 mL) was added CDI (40 mg, 0.244 mmol) and the resulting mixture stirred at 60° C. for 1 h. After cooling to room temperature ammonium hydroxide (320 μL, 2.03 mmol) was added and reaction mixture was stirred for 30 min and then evaporated. Purification by chromatography (reverse phase HPLC) afforded the title compound (58 mg, 74%) as a white solid. MS: m/e=364.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[O:23][C:24]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:40]([N:43]([CH:47]([CH3:49])[CH3:48])[CH2:44][CH2:45]Cl)([CH3:42])[CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[O:23][C:24]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:45][CH2:44][N:43]([CH:47]([CH3:49])[CH3:48])[CH:40]([CH3:42])[CH3:41])=[CH:34][CH:33]=4)=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=23)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2ccnc3oc(-c4ccc(O)cc4)c(-c4ccccc4)c23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N(CCOc1ccc(-c2oc3nccc(NCCN4CCN(C(=O)OC(C)(C)C)CC4)c3c2-c2ccccc2)cc1)C(C)C
Temperature: 85 °C
Reaction time: 17 h

Procedure:
A resealable tube was charged with 4-{2-[2-(4-hydroxy-phenyl)-3-phenyl-furo[2,3-b]pyridin-4-ylamino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester 8a (0.070 g, 0.136 mmol), 2-diisopropylaminoethylchloride hydrochloride 9a (0.029 g, 0.143 mmol), cesium carbonate (0.222 g, 0.680 mmol), and DMF (2.0 mL). The system was purged with argon and the tube was sealed. The mixture stirred at 85° C. for 17 h. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a green oil. This oil was purified via preparative thin layer chromatography (eluting with 95:5:0.5, dichloromethane/methanol, ammonium hydroxide) to afford 4-(2-{2-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridin-4-ylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester 10a as a yellow oil. MS (MH+) 642.4; Calculated 641 for C38H51N5O4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)=O)([O-])=O.C(O)(C(F)(F)F)=O>[Pd].CN(C=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2
Reactant: O=C1Cc2cc(C(=O)c3cccc([N+](=O)[O-])c3)ccc2N1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1cccc(Cc2ccc3c(c2)CC(=O)N3)c1
Reaction time: 0.75 h
Yield: 69.9 %

Procedure:
The PARR apparatus was charged with was charged with 5-(3-Nitro-benzoyl)-1,3-dihydro-indol-2-one (50 g, 0.18 mol), 10% Pd/C (5 g) and DMF (500 mL). The reactor was evacuated, purged with N2(g) then filled with H2(g) (60 psi) at room temperature. After hydrogenating at 60 psi for 45 min thin layer chromatographic analysis (TLC) (Hexanes/EtOAc 1:1) indicated that the reaction had caused the reduction of the nitro group to an amine and the reduction of the keto group to the alcohol. Subsequently, TFA 926 mL, 0.35 mol) was added and the reaction was continued for 4 h. The reaction was filtered through celite and the solvent from the filtrate was removed in vacuo. The solids obtained were washed with saturated NaHCO3(aq) (500 mL), and H2O (500 mL) then triturated with Methyl-t-Butyl Ether (500 mL) and then triturated again with methanol to afford 5-(3-Amino-benzyl)-1,3-dihydro-indol-2-one (30 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Li+].[Br:13][C:14]1[C:27]2=[N:28][O:29][C:25]3=[C:26]2[C:17]([C:18](=[O:30])[C:19]2[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:16](Br)[CH:15]=1.CC(OC)(C)C>CC(N(C)C)=O>[Br:13][C:14]1[C:27]2=[N:28][O:29][C:25]3=[C:26]2[C:17]([C:18](=[O:30])[C:19]2[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:16]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:15]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1c2ccccc2-c2onc3c(Br)cc(Br)c1c23
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(Nc2cc(Br)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Reaction time: 19 h

Procedure:
Mixing 4-amino benzoic acid and lithium hydroxide in DMAc, then adding 3,5-dibromo-6H-anthra[1,9-cd]isoxazol-6-one into the mixture and raising the temperature to about 45° C. to 55° C. Stirring the reaction mixture for 18-20 hours. Slowly adding MTBE to the reaction mixture and then cooling to 0 to 10° C. Filtering the solid and drying at room temperature to get 4-((3-bromo-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid (Intermediate 5).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:3][N:2]=1.[OH-].[Na+]>CO.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:3][N:2]=1
Reactant: CCOC(=O)CCCCCCCc1cncc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
Ethyl 8-(isoquinolin-4-yl)octanoate (0.8 g) was dissolved in a mixture of methanol (10 ml) and water (5 ml) followed by addition of sodium hydroxide (1 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was adjusted to pH 5 with 2N-HCl and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure, and the resulting crude crystalline crop was recrystallized from ethyl acetate to provide the title compound (0.6 g).
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:7]=[N:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:4]1.C(O[C@@H:18]1[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:19]1[O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C.ClCCCl>C1C=CC=CC=1>[C:21]([O:20][C@@H:19]1[C@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:40][C@H:18]1[N:3]1[CH:7]=[N:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:4]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)n1cnc(CC(=O)O)n1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: ClCCCl
Product: O=C(O)Cc1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Yield: 85.5 %

Procedure:
55 mmoles of 1-trimethylsilyl-3-carboxymethyl-1,2,4-triazole and 55 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose were combined, in 100 ml. of 1,2-dichloroethane, with 5 mmoles of (CH3)3Si--O--SO2CF3 in 20 ml. of C6H6 and refluxed for 4 hours at a bath temperature of 100° C. After working up the mixture as usual, 24 g. (85.5%) of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-3-carboxymethyl-1,2,4-triazole was produced.
Reaction SMILES: [CH2:1]([P:3](=[S:5])=[S:4])[CH3:2].[CH3:6][C:7]([CH3:11])([SH:10])[CH2:8][CH3:9].C(N(CC)CC)C>O1CCCC1>[CH3:6][C:7]([S:10][P:3]([CH2:1][CH3:2])([SH:5])=[S:4])([CH3:11])[CH2:8][CH3:9]
Reactant: CCP(=S)=S
Reactant: CCC(C)(C)S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(C)SP(=S)(S)CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 16.5 grams (g) of ethylthionophosphine sulfide in tetrahydrofuran, under nitrogen at room temperature, was added 13.8 g (0.133 mole) 1,1-dimethyl-1-propanethiol (tertiary amyl mercaptan). To this mixture was added 18.5 milliliters (ml) (0.133 mole) triethylamine, dropwise. The mixture was stirred one hour at room temperature, then refluxed for 1/2 hour and stripped of solvent. There was obtained 30.1 g (87% of theoretical yield) of the triethylamine salt of S-(1,1-dimethylpropyl)ethylphosphonotrithioic acid).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=O)=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (93 mg, 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][N:14]=1.C(OC(=O)C)(=O)C>O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccncn1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(C=Cc2ccncn2)cc1
Temperature: 120 °C
Yield: 77 %

Procedure:
The starting compound is prepared as follows. p-Nitrobenzaldehyde (24.2 g), 4-methyl-pyrimidine (15.5 g) and acetic anhydride (16.7 g) are mixed at room temperature, and the mixture is heated at 120° C. for 5 hours. After cooling, the mixture is poured into water (500 ml), and the aqueous mixture is extracted several times with chloroform. The combined chloroform extracts are dried over magnesium sulfate and concentrated until crystals separated. Addition of ether gives 4-[2-(p-nitrophenyl)ethenyl]pyrimidine (28 g), m.p. 213°-215° C.
Reaction SMILES: [C:1](NC1C=C(B(O)O)C=CC=1)(=O)C=C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[CH:29]=2)[NH:24]N=1>C(O)C.C(Cl)Cl>[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[CH:29]=2)[NH:24][CH:1]=1
Reactant: C=CC(=O)Nc1cccc(B(O)O)c1
Reactant: C=CC(=O)Nc1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2cnc3[nH]cc(C)c3c2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A solution of 19 (50 mg, 0.2369 mmol) and 2 (50 mg, 0.2369 mmol) in ethanol and toluene (1:4 mL) was added sodium carbonate (49.74 mg, 0.4738 mmol). The reaction was degassed and purged with nitrogen for 15 min. Pd(dppf)Cl2.DCM (9.06 mg, 0.0114 mmol), and again degassed for 15 min. The reaction mixture was stirred for 2 h at 90° C. and the reaction mixture allowed to cool to rt and diluted with DCM (25 mL). The organic layer was filtered through Celite and concentrated to get the crude. The resulting oil was purified via silica gel chromatography using a gradient of 30% ethyl acetate:hexane to afford Compound 20. MS-ES+277 1H NMR (400 MHz, DMSO-D6) 20: 11.37 (d, 1H), 10.24 (d, 1H), 8.45 (d, 1H), 8.09 (d, 2H), 7.68 (d, 1H), 7.43 (d, 2H), 7.28 (d, 1H), 6.46 (d, 1H), 6.44 (d, 1H), 5.79 (d, 1H), 2.30 (d, 1H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH2:10])[CH2:4][C:3]1([CH3:12])[CH3:11].C(N(CC)CC)C.[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[OH:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([NH:10][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC1(C)CC(N)CC(C)(C)N1O
Reactant: CCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)NC1CC(C)(C)N(O)C(C)(C)C1
Temperature: 25 °C

Procedure:
To a stirred 0° C. solution of 1.0 g of 1-oxyl-4-amino-2,2,6,6-tetramethylpiperidine and 0.65 g of triethylamine in 10 mL of methylene chloride is added dropwise a solution of 0.95 g of octanoyl chloride in 5 mL of methylene chloride. After the addition is complete, the reaction mixture is allowed to warm to ambient temperature. After two more hours, the reaction mixture is washed with 1% aqueous sodium hydroxide and finally water. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated. The title compound is isolated as a red oil after column chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH2:17]([O:16][C:12](=[O:15])[CH:13]=[CH:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:18]
Reactant: Brc1ccc2ncccc2c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc2ncccc2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 87.3 %

Procedure:
A vial under nitrogen atmosphere was charged with 6-bromo-quinoline (1 g, 4.8 mmol) and dimethylformamide (15 mL), followed by ethyl acrylate (2.1 mL, 19.2 mmol), triethylamine (6.7 mL, 48 mmol), and palladium (II) acetate (32 mg, 0.142 mmol). The reaction mixture was stirred at 100° C. for 5 h, then the hot mixture was filtered over celite and the filtrate was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous solution of ammonium chloride, saturated aqueous solution of sodium bicarbonate, then brine. The organic layer was then adsorbed on silica gel. Purification on silica gel with 10-80% gradient of ethyl acetate in hexane provided 952 mg of product as a yellow oil. 1H NMR 500 MHz (DMSO) δ 1.28 (t, 3H), 4.20 (q, 2H), 6.82 (d, 1H), 7.58 (d, 1H), 7.84 (d, 1H), 8.01 (d, 1H), 8.16 (dd, 1H), 8.30 (d, 1H), 8.37 (dd, 1H), 8.93 (dd, 1H); MS (m/z) 228 [M+H+]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:17])[NH:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[H][H]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:15])[NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Reactant: [H][H]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(=N)N)CC1
Yield: 114.6 %

Procedure:
Dissolve 4-(N-Hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.7 g 1.00 equiv; 39.9 mmoles) in methanol (300 mL) and add acetic acid (2 equiv, 79.73 mmoles; 4.6 mL), and methanol washed Raney Nickel (2.7 g). Heat the reaction to 50° C., then hydrogenate with 1 ATM hydrogen gas for 4.5 hours. Filter the reaction mixture through Celite and concentrate under reduced pressure. Suspend the solid in diethyl ether, filter and dry under reduced pressure to give 10.39 g of 4-carbamimidoyl-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](S(O)(=O)=O)=[CH:6][CH:7]=1.O.[CH2:13]([NH:20][C:21]1[C:22]([NH2:28])=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC(OC)(OC)C1C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:20]1[C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[N:28]=[C:13]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Br)ccc1NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(OC)(OC)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: Brc1ccc2c(c1)nc(-c1ccccc1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
p-TsOH.H2O (311.7 mg, 1.606 mmol) was added to a DCM (50 ml) solution of N1-benzyl-4-bromobenzene-1,2-diamine (4451 mg, 16.06 mmol) and trimethyl orthobenzoate (3096 μl, 17.66 mmol) and the resulting mixture was stirred at rt under an atmosphere of Nitrogen for 40 h. The reaction mixture was then concentrated in vacuo to give a yellow solid which was triturated with 40% MeOH/water (375 mL), filtered, washed with saturated NaHCO3 (20 ml)+H2O (80 ml) twice and 40% MeOH/H2O (2×50 ml), and dried to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm=5.44 (s, 2H), 7.05-7.08 (m, 3H), 7.30-7.36 (m, 4H), 7.44-7.50 (m, 3H), 7.66-7.68 (m, 2H) and 7.99 (dd, 1H, J=0.4 & 1.6 Hz). MS (ES+): m/z 363.20 and 365.26 [MH+].