Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O1C=CC=C1>C(Cl)Cl>[O:5]1[CH:6]=[CH:7][CH:2]=[C:3]1[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14])=[O:22]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(O)CCCCCCBr
Solvent: c1ccoc1
Solvent: ClCCl
Product: O=C(CCCCCCBr)c1ccco1
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A solution of 135 mmol of trifluoroacetic anhydride in 50 ml of dry methylene chloride was added to a stirred solution of 130 mmol of 7-bromoheptanoic acid in 200 ml of dry methylene chloride. After 15 minutes, a solution of 390 mmol of furan in 25 ml of dry methylene chloride was added in a steady stream to the reaction mixture, and the resultant mixture stirred at 25° C. for 2.0 hrs. The methylene chloride and trifluoroacetic acid were removed by evaporation in vacuo. The residue was dissolved in ether, washed with water and distilled in vacuo to afford the title compound, bp 114° (0.01 mm Hg), 89.7% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].N12CCCN=C1CCCCC2.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>C(#N)C.[Cu]>[CH3:25][C:22]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:26])[C:23]#[CH:24]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CC(C)(C)Cl
Agent: [Cu]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Temperature: 12.600000381469727 °C

Procedure:
To a solution of 4-cyanophenol (9.0 g, 75.55 mmol, commercially available) and anhydrous acetonitrile (120 mL) at ~0° C. under argon was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, 14.0 mL, 93.61 mmol, 1.24 eq based on the input of 4-cyanophenol). A temperature increase to 12.6° C. was observed. After the solution had cooled to 0° C., copper bronze (cooper powder, 49.8 mg, 0.783 mmol, 0.0104 eq, 1.04 mol %) was added followed by the addition of a portion of the cuprous chloride in acetonitrile solution prepared above (600 μL, 15.49 μmole, 0.000205 eq., 0.0205 mol %). To the resulting mixture was added, dropwise over 12 minutes, 3-chloro-3-methyl-1-butyne (7.03 g, 68.54 mmol, 0.907 eq. based on the input of 4-cyanophenol). The resulting mixture was allowed to stir at 0° C. under argon. After stirring for 10 hours, the reaction mixture was filtered through a small pad of Celite (to remove the remaining copper bronze) using additional acetonitrile to complete the transfer and to wash the filter bed. The filtrate was concentrated at reduced pressure (bath temperature 40° C.) and the residue was partitioned between 1N HCl (100 mL) and toluene (400 mL). The organic fraction was washed with 1N HCl (2×60 mL), 1N NaOH (2×60 mL), and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a pale yellow oil (10.68 g). Distillation of the crude material (bulb-to-bulb, ~70°-90° C., ~0.15 mm Hg) afforded the title compound as a colorless, low melting (mp 28°-29° C.) solid (10.40 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].C1(C(C2C=CC=CC=2)CC(O)=O)C=CC=CC=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(c2ccccc2)c2ccccc2)CCN1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)C1CNCCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 4-Benzhydryl-piperazine-2-carboxylic acid ethyl ester (0.5 g, 1.54 mmol) in dry CH2Cl2 (25 ml) was added 3,3-diphenylpropanoic acid (0.35 g, 1.54 mmol) under nitrogen. To the reaction was added EDC (0.59 g, 3.08 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (20 ml, 2×) and 10% NaOH (20 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane: ethyl acetate (3:1) to give title compound in 73% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[SH:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[S:18][C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(S)n1-c1ccc(F)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (3) (4.09 g, 15.34 mmol) in THF (70 mL) was added triethyl amine (4.50 mL, 32.29) and triphenylmethyl chloride (4.67 g, 16.76 mmol) and the solution was stirred for 1 hour at room temperature. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10%-40% EtOAc in hexanes) to give ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate. A solution of ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate (6.34 g, 12.47 mmol), sodium hydroxide (0.74 g, 18.39 mmol), methanol (10 mL), THF (20 mL), and water (10 mL) was stirred at room temperature for 16 hour and was then concentrated in vacuo. The aqueous was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to yield 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylic acid (6).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[K+]>C1COCC1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Yield: 86.7 %

Procedure:
Methyl 4-chlorobenzoate (171 mg, 1.00 mmol) reacted with 4-methoxyphenylboronic acid (200 mg, 1.31 mmol) using 1/2 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (180 mg, 3.10 mmol) in THF at 100° C. for 4 h to give the title compound (210 mg, 89%) as a white solid: 1H-NMR (500 MHz, CDCl3): δ 8.09 (d, 2H, J=8.35 Hz), 7.63 (d, 2H, J=8.30 Hz), 7.59 (d, 2H, J=8.71 Hz), 7.01 (d, 2H, J=8.73 Hz), 3.95 (s, 3H), 3.88 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 167.02, 159.77, 145.14, 132.32, 130.05, 128.31, 128.16, 126.40, 114.31, 55.32, 52.03. GC/MS (EI): m/z 242 (M+), 211, 139.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH2:18][CH2:19][C:20](O)=[O:21])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:36][NH:37][O:38][CH3:39]>ClCCl>[CH3:39][O:38][N:37]([CH3:36])[C:20](=[O:21])[CH2:19][CH2:18][CH:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1CCC(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)CCC1Cc2ccccc2CN1C(=O)OC(C)(C)C
Reaction time: 0.67 h
Yield: 97.9 %

Procedure:
A solution of 3-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)propanoic acid (7.7 g, 25.2 mmol) in dichloromethane (200 mL, 0.13 M) was treated with CDI (6.1 g, 37.8 mmol) in three portions over 10 min with vigorous stirring. After the addition was complete, the mixture was stirred for an additional 40 min and treated with N,O-dimethylhydroxylamine hydrochloride (3.7 g, 37.2 mmol) and stirred overnight. The resulting solution was washed successively with water, 1 M HCl, 1 M NaOH, sat'd aq sodium chloride, dried over anhydrous MgSO4, filtered and concentrated to give tert-butyl 3-(3-(methoxy(methyl)amino)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a yellow oil (8.6 g, 98%). LCMS, C19H28N2O4 m/z [371.4 (M+23)]. The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][CH2:64][C@@H:65]1[CH2:69][CH2:68][CH2:67][NH:66]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][CH2:69][C@H:65]1[CH2:64][OH:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3CO)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2S)-2-hydroxymethyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[NH:24][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: COc1cnc(-c2ccccn2)nc1Cl
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2nc(-c3ccccn3)ncc2OC)c1

Procedure:
The title compound was prepared from 4-chloro-5-methoxy-2-(2-pyridinyl)pyrimidine (100 mg, 0.451 mmol) and m-anisidine (51 μl, 0.451 mmol) similar to Example 13 and isolated as a tan oily liquid (63 mg, 45%). 1H NMR (CDCl3): 8.76-8.74 (m, 1H), 8.37 (dd, J=1.1, 8.0 Hz, 1H), 8.05 (s, 1H), 7.79-7.73 (m, 2H), 6.65-6.62 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2](OCC)=O.[O-]CC.[K+].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1C)([O-:17])=[O:16]>CCOCC>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[C:19]=1[CH2:2][C:1]([OH:8])=[O:7]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)O
Yield: 45 %

Procedure:
Diethyl oxalate (30 mL) in 20 mL dry ether was added with stirring to 19 g potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternately with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered and the filtrate acidified with 6 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 2-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of 4-methyl-2-oxindole as a white solid.
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8]3[C:9](=[CH:10][CH:11]=[C:12]4[C:20]=3[NH:19][C:18]3[C:13]4=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:6]=1[NH:7][C:8]1[C:9]2=[CH:10][CH:11]=[C:12]2[C:20]=1[NH:19][C:18]1[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1ccccc1I
Reactant: c1ccc2c(c1)[nH]c1c2ccc2c3ccccc3[nH]c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1I)c1cccc2c1[nH]c1c2ccc2c3ccccc3[nH]c21
Temperature: 40 °C
Reaction time: 12 h

Procedure:
43 g (169 mmol) of 11,12-dihydroindolo[2,3-a]carbazole are initially introduced in 1000 ml of THF, and 8.9 g (223.3 mmol) of NaH (60% in oil) are added at 0° C. 24 g (80 mmol) of 2-iodobenzenesulfonyl chloride are subsequently added to the mixture, which is then stirred at 40° C. for 12 h. The organic phase is dried over MgSO4, and the solvent is removed in vacuo. The residue is recrystallised from acetone and finally sublimed in a high vacuum. Yield: 29 g (574 mmol), 72% of theory, purity according to HPLC 99.9%.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4].[CH3:22]I.O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][O:21][CH3:22])=[CH:18][CH:19]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1cnn(-c2ccc(CO)cc2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc(COC)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (129 mg) was added to a solution of 1-[4-(hydroxymethyl)phenyl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (700 mg) in N,N-dimethylformamide (13 ml) at room temperature and stirred at the same temperature for 0.5 hour. Methyl iodide (0.3 ml) was added therein and stirred at 80° C. for two hours. Methyl iodide (0.2 ml) was further added and stirred at the same temperature for an hour. After completion of the reaction, the reaction solution was cooled to room temperature, water was added therein and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-[4-(methoxymethyl)phenyl]-5-methyl-1H-pyrazol-4-carboxylic acid ethyl ester (401 mg) as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]([C:20]4[NH:24][C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[N:21]=4)=[O:19])=[CH:14][CH:13]=3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH2:2]1.C(N(CC)CC)C.N1([C:41](=[O:43])[CH3:42])C=CN=C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[C:5]([CH:3]3[CH2:4][N:1]([C:41](=[O:43])[CH3:42])[CH2:2]3)=[N:10][CH:9]=[CH:8][N:7]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: CC(=O)n1ccnc1
Reactant: O=C(c1ccc(Oc2nccnc2C2CNC2)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 36 %

Procedure:
To a solution of (4-(3-(azetidin-3-yl)pyrazin-2-yloxy)phenyl)(1H-benzo[d]imidazol-2-yl)methanone in DMF (1.0 mL) is added triethylamine (104 μL, 0.743 mmol) and 1-(1H-imidazol-1-yl)ethanone (60.0 mg, 0.545 mmol). The reaction was stirred at rt 7 h. The reaction mixture was added to saturated NaHCO3 (5 mL) and extracted with Teac (3×5 mL). The combined organic layers were washed with water (5 mL), saturated NaCl (5 mL), dried (MgSO4) and concentrated. Purification by RPHPLC gives 1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidin-1-yl)ethanone (55.4 mg, 36.0% over 3 steps) as a white solid. MS (ESI, pos. ion) m/z: 414.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:17]([O:18][C:19](=[O:22])[CH2:20][CH3:21])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1.[N+:30]([O-])([OH:32])=[O:31].S(=O)(=O)(O)O>ClCCl.O>[NH2:1][C:2]1[C:3]2[C:10]([N+:30]([O-:32])=[O:31])=[CH:9][N:8]([C@@H:11]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:17]([O:18][C:19](=[O:22])[CH2:20][CH3:21])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2ccc3c(N)ncnc32)O[C@@H]1COC(C)=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc([N+](=O)[O-])c3c(N)ncnc32)O[C@@H]1COC(C)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of the product from Step 4 (1.5 g, 3.69 mmol) in dichloromethane (25 mL) was cooled to 0° C. and a 1:1 mixture of fuming nitric acid and sulfuric acid (4 mL) was added dropwise and the reaction was vigorously stirred at 0° C. for 20 min. The reaction was quenched with ice cold saturated sodium bicarbonate solution. The quenched reaction was diluted with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by plating on silica gel with dichloromethane and eluded by ramping to 5% methanol in dichloromethane to give 600 mg (36%);
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15]CC)=O)[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[NH3:18].CO>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([NH2:18])=[O:15])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2c(=O)[nH]1
Solvent: CO
Product: NC(=O)c1cc2ccc(Cl)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Ethyl 7-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (580 mg, 2.30 mmol) was dissolved in NH3/MeOH(4.0M, 15 mL) and the reaction mixture was stirred at RT overnight. The solvent was removed in vacuo. The resulting residue was washed with petroleum ether and dried to give the title compound (200 mg, 38%). ESI-MS m/z [M+H]+223.1.
Reaction SMILES: C[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6]O.S(Cl)(Cl)=O>ClC1C=CC=CC=1>[S:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[CH:5]=[N:6]1
Reactant: CSc1ccccc1C=NO
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1
Product: c1ccc2sncc2c1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
In a 300 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 100 g of monochlorobenzene was placed in advance, to which 33.4 g (0.2 mol) of 2-(methylthio)benzaldehyde oxime was added under nitrogen atmosphere. 25.2 g (0.21 mol) Of thionyl chloride was added dropwise thereto while stirring at a temperature of from -10° to -15° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, the reaction mixture was heated to room temperature and subjected to distilling off of the solvent and then to distillation under reduced pressure to give 26.2 g of 1,2-benzisothiazole (boiling point: 115° to 116° C./15 mm Hg, melting point: 39° to 40° C.). The yield was 97% to the 2-(methylthio)benzaldehyde oxime.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:30])=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[C:24]([CH3:30])=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c(C)n1
Solvent: C1CCOC1
Product: CCn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)c(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A small screw cap test tube was charged with 1-Ethyl-3-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.2401 mmol) and THF (2.5 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (45.7 mg, 0.240 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was redissolved in EtOAc (˜5 mL) and Hexane (˜40 mL) was added to the solution. The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (10 mL) to afford the title compound in 58% yield (0.0821 g, 0.139 mmol).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O>[O:28]1[CH2:29][CH2:30][N:25]([C:2]2[C:3]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]4[NH:20][C:19]5[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=5[N:17]=4)=[CH:13][CH:14]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:26][CH2:27]1
Reactant: C1COCCN1
Reactant: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3[nH]2)cc1
Solvent: CS(C)=O
Product: c1ccc2[nH]c(Nc3ccc(Oc4nccnc4N4CCOCC4)cc3)nc2c1
Reaction time: 3 h

Procedure:
N-(4-(3-chloropyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (191 mg, 565 μmol) and morpholine (74 μL, 848 μmol) in DMSO was heated to 80° C. After 3 h, starting material remained so additional morpholine (74 uL, 848 umol) was added and the mixture was heated overnight. The hot solution was then poured onto ice water which caused a brown solid to precipitate. The solid was collected by filtration, washed and dried to give the desired product. MS (ESI, pos. ion) m/z: 389.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].N1C=CC=CC=1.[C:15](Cl)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])O.[Na+]>C(OCC)C>[C:15]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCOC(=O)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(OC(=O)CCCCCCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
While ethyl pyruvate (174 g, 1.5 mol) was being stirred at 0° C., pyridine (120 g, 1.5 mol) was dropped into the ethyl pyruvate. After it was stirred at 0° C. for 10 minutes, octanoyl chloride (243 g, 1.5 mol) was slowly dropped into this mixture. After the temperature of the reaction solution reached room temperature, the reaction solution was stirred for 48 hours. An aqueous solution of saturated sodium hydrogencarbonate and diethyl ether were added to the reaction solution, and an organic layer was separated by use of a separating funnel. Diethyl ether was again added to an aqueous layer and an organic compound was extracted. The obtained organic layer was then mixed with the organic compound, and sodium sulfate was added for dehydration. Thereafter, the sodium sulfate was removed by filtration and the solvent was removed by use of an evaporator under a reduced pressure. The concentrate was distilled under a reduced pressure (1 mmHg, 95 to 100° C.) to give ethyl α-octanoyloxyacrylate (126 g, yield: 34%).