Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]([C:10](C#N)=C)=[O:9].[C:14]1(C)C=CC=C[CH:15]=1>>[C:8]([O:7][C:6]1[CH:1]=[CH:2][C:3]([CH:14]=[CH2:15])=[CH:4][CH:5]=1)(=[O:9])[CH3:10]
Reactant: Cc1ccccc1
Reactant: C=C(C#N)C(=O)OCCCCCC
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
The purpose of this prophetic Example is to demonstrate the chemical derivatization of pHS in the organic extractant from the biphasic reaction medium to form the derivatized compound para-acetoxystyrene. The pHCA is first produced by fermentation using a recombinant strain of E. coli. The bio-produced pHCA is then converted to pHS in a biphasic reaction medium, consisting of fermentation supernatant and toluene, using PDC2 cell-free extract. After the toluene layer is separated from the pHCA-depleted fermentation supernatant, the bio-produced pHS is reacted with acetic anhydride to form para-acetoxystyrene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([N:18]2[CH2:23][C:22](=[O:24])[NH:21][C:20](=[O:25])[CH2:19]2)[CH:3]=1.[NH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([N:18]3[CH2:23][C:22](=[O:24])[NH:21][C:20](=[O:25])[CH2:19]3)[CH:3]=[C:2]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(N2CC(=O)NC(=O)C2)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(=O)NC(=O)C2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
119 mg of (S)-4-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}piperazine-2,6-dione, 34 mg of 2-aminopyrazine, 19 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 139 mg of tripotassium phosphate and 17 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added to 2.5 ml of degassed 1,4-dioxane, and then the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 26 mg of the objective compound as pale yellow powder.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[N:12]1([CH2:25][CH2:26][C:27]([NH:29][CH3:30])=[O:28])[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[CH:13]1.[OH-].[NH4+:32].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:32][C:16]1[C:15]2[N:14]=[CH:13][N:12]([CH2:25][CH2:26][C:27]([NH:29][CH3:30])=[O:28])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: [NH4+]
Reactant: CNC(=O)CCn1cnc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CNC(=O)CCn1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
mCPBA (8.95 g, 38.9 mmol) was added to a solution of 3-(1H-imidazo[4,5-c]quinolin-1-yl)-N-methylpropanamide (4.4 g, 15.6 mmol) in chloroform (100 mL); the reaction was stirred for one hour at ambient temperature. Ammonium hydroxide (40 mL) was added, and the mixture was stirred vigorously for 15 minutes. p-Toluenesulfonyl chloride (5.94 g, 31.2 mmol) was added over a period of ten minutes, and the reaction was stirred for two hours. The reaction mixture was filtered to remove a precipitate, and the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from methanol to provide 0.535 g of 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-N-methylpropanamide as off-white needles, mp>260° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH3:35])[CH2:30][CH2:29]2)=[CH:23][C:22]=1[CH3:36])=[O:19])=[O:12].C(=O)[C:38]1[CH:43]=[CH:42]C=[CH:40][CH:39]=1.N1C2C=CC=CC=2N=C1NC(C1NC=NC=1C(NC1C=CC(OC2CCNCC2)=CC=1C)=O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=3)[CH2:30][CH2:29]2)=[CH:23][C:22]=1[CH3:36])=[O:19])=[O:12]
Reactant: O=Cc1ccccc1
Reactant: CCN1CCC(Oc2ccc(NC(=O)c3nc[nH]c3C(=O)Nc3nc4ccccc4[nH]3)c(C)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1cc(OC2CCNCC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OC2CCN(Cc3ccccc3)CC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N5-1H-Benzimidazol-2-yl-N4-(2-methyl-4-{[1-(phenylmethyl)piperidin-4-yl]oxy}phenyl)-1H-imidazole-4,5-dicarboxamide was prepared in a similar manner as N5-1H-benzimidazol-2-yl-N4-{4-[(1-ethylpiperidin-4-yl)oxy]-2-methylphenyl}-1H-imidazole-4,5-dicarboxamide. Benzaldehyde and N5-(1H-benzo[d]imidazol-2-yl)-N4-(2-methyl-4-(piperidin-4-yloxy)phenyl)-1H-imidazole-4,5-dicarboxamide (0.1 mmol) were treated with a DMF solution of sodium triacetoxyborohydride. The reaction mixture was stir at room temperature over night (16 hours). The reaction mixture was then treated with 1 mL of 1N hydrochloric acid and concentrated under reduced pressure. The resulting crude material was purified by reverse phase HPLC (ammonium acetate/acetonitrile) to give 31 mg of N5-1H-benzimidazol-2-yl-N4-(2-methyl-4-{[1-(phenylmethyl)piperidin-4-yl]oxy}phenyl)-1H-imidazole-4,5-dicarboxamide as its acetate salt. 1H-NMR (400 MHz, DMSO-d6): 12.12 (s, 1H), 8.06 (s, 1H), 7.38 (m, 3H), 7.25 (m, 4H), 7.19 (m, 1H), 7.04 (m, 2H), 6.85 (d, 1H), 6.79 (dd, 1H), 4.34 (m, 1H), 3.43 (s, 2H), 2.60 (m, 2H), 2.44 (t, 2H), 2.18 (s, 3H), 1.88 (m, 2H), 1.58 (m, 2H); MS (EI): 550.9 (MH+).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]([OH:12])=O)[CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2].ClC(OCC(C)C)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([OH:34])[C:31]([C:35]([OH:37])=[O:36])=[CH:30][N:29]=2)=[CH:24][CH:23]=1>CN(C)C=O.C(N(CC)CC)C.ClCCl>[C:1]([NH:4][CH:5]([C:10]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:33]=[C:32]([OH:34])[C:31]([C:35]([OH:37])=[O:36])=[CH:30][N:29]=2)=[CH:26][CH:27]=1)=[O:12])[CH2:6][CH:7]([CH3:8])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CC(C)C)C(=O)O
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NC(CC(C)C)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
A solution of 13.0 g (75 mmol) of N-acetyl-DL-leucine, 10.5 ml (75 mmol) of triethylamine, and 150 ml of dichloromethane is stirred at -10° and 9.75 ml (75 mmol) of isobutyl chloroformate is added. The reaction mixture is stirred for 1/2 hour at -10° C. and a cold solution of 11.6 g (50 mmol) of 2-[4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid and 7.7 (55 mmol) of triethylamine in 200 ml of dimethylformamide is added. The mixture is stirred at 5° C. for 3 hrs and overnight at room temperature. The reaction mixture is evaporated and the residue treated with water. The pH is lowered to 2.5 with dilute hydrochloric acid and the solid filtered, washed with water, and dried to give 13.8 g of 2-[4-(N-acetyl-DL-leucylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid; mp 233°-235° C. dec.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[CH2:6][N:7]=[C:8]=[O:9])[CH3:2].[Br:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:28]=1[C:22]1([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:21][CH:20]2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[Br:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:28]=1[C:22]1([CH2:23][CH2:24][N:25]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[O:3][CH2:1][CH3:2])[CH2:26][CH2:27]1)[CH2:21][CH:20]2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Br)cccc21
Reactant: CCOc1ccccc1CN=C=O
Product: CCOC(=O)CC1CC2(CCN(C(=O)NCc3ccccc3OCC)CC2)c2c(Br)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 19 using 2-ethoxybenzyl isocyanate and ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. 1H NMR (CDCl3) [selected resonances] 1.28 (t, 3H), 1.44 (t, 3H), 4.11 (q, 2H), 4.19 (q, 2H), 4.45 (s, 2H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1ccc(C)cc1Br
Product: CCSc1ncc(C(=O)c2cc(C)ccc2OC)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-4-methylanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-methoxy-5-methyl-phenyl)-methanone as a white solid. MS (M+H)+, 304.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: CC(C)CC(O)c1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CC(Oc1ccccc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-bromophenyl)-3-methylbutan-1-ol (500 mg, 2.06 mmol), phenol (252 mg, 2.69 mmol) and triphenyl phosphine (1.06 g, 4.04 mmol) in anhydrous tetrahydrofuran (20 mL) was stirred at room temperature under nitrogen atmosphere. After 1 hour, the mixture was cooled to 0° C. Diisopropyl azodicarboxylate (500 mg, 2.48 mmol) was added dropwise and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, pure ether) to 1-bromo-4-(3-methyl-1-phenoxybutyl)benzene (300 mg, 46%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C@@H:7]([CH3:23])[C@H:8]([N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)C.[BH4-].[Li+].CCOC(C)=O>C1COCC1>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C@@H:8]([N:14]([CH3:15])[C:16](=[O:17])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C@H:7]([CH3:23])[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC[C@@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of compound 2.12d (0.6 g, 1.77 mmol) in THF (3.5 mL) was added lithium borohydride (2.0 M in THF, 8.8 mL, 17.7 mmol, 10.0 equiv) and the resulting mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled at room temperature and EtOAc (2.0 mL) was added. After stirring for 10 minutes, the reaction mixture was quenched by addition of 1.0 N HCl aqueous solution. The phases were separated and the aqueous layer was extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated to give product 2.19.1a (0.54 g) which was used in the next step with no further purification. MS m/z (M+Na) 320.2
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]=2)[C:3]=1[C:24]([NH2:26])=[O:25].[C:27](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:27][O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]=2)[C:3]=1[C:24]([NH2:26])=[O:25]
Reactant: CCCCCCCCCCCCc1ccc2c(C(N)=O)c(O)ccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCc1ccc2c(C(N)=O)c(OC)ccc2c1
Yield: 82.8 %

Procedure:
3.6 g of 2-hydroxy-6-n-dodecyl aminocarbonylnaphthalene obtained in example 2 was dissolved in 36 g of dimethylformamide. To this solution, 1.7 g of potassium carbonate and 2.2 g of methyl iodide were added, and allowed to react at 40° C. for 8 hours. The reaction liquid was poured to 180 g of water, and then precipitate was filtrated, washed thoroughly with methanol and water, dried to give 3.1 g of 2-methoxy-6-n-dodecyl aminocarbonylnaphthalene (Decomposition point: 324° C.). The infrared absorption spectrum (KBr) of the compound is shown in FIG. 3. The triboelectric charge was measured by blow-off method as described in example 1. The triboelectric charge of the compound was +17.6 μC/g.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:35][CH2:34][C@@H:10]1[CH2:9][NH:8][CH2:12][C@H:11]1[CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CO)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of (3S*,4R*)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (85 mg, 0.172 mmol) in 2 mL CH2Cl2, TFA (85 μL, 2.23 mmol) is added. The mixture is stirred 4.5 h at RT, and poured into a saturated solution of NaHCO3. The layers are separated, and the aqueous one is back-extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on Isolute SPE Flash NH2 column (eluent: CH2Cl2/MeOH 100:0 to 99:1) to give the title product. MS (LC-MS): 395.1 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 3.75 min.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:6]=1[CH2:7][OH:8].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:6]=1[CH2:7][O:8][C:14](=[O:16])[CH3:15]
Reactant: OCc1c(Cl)cccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(Cl)cccc1Cl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
Add 500 mL of dichloromethane to 100 g of 2,6-dichlorobenzyl alcohol followed by 117 mL of triethylamine. Cool the solution to 5° C. and add 65 mL of acetic anhydride. After 2.5 hr at room temperature, add another 10 mL of acetic anhydride, 20 mL of triethylamine and 0.5 g of 4-dimethylaminopyridine. Wash the organic layer with 1N HCl followed by saturated aqueous sodium bicarbonate and brine. Dry the organic layer (sodium sulfate) and evaporate to afford 131.5 g of the titled compound as an oil.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 70 %

Procedure:
7 g (30.56 mmol) of ethyl 4-bromobenzoate are dissolved in 60 ml of 1,2-dimethoxyethane and, under argon, 6.96 g (36.67 mmol) of 4-trifluoromethylphenylboronic acid, 271 mg of bis(triphenylphosphine)palladium(II) chloride and 40.7 ml of a 2 M solution of sodium carbonate in water are added. The reaction mixture is then heated under reflux for 12 hours. The mixture is subsequently cooled, filtered through 1 g of Extrelut, washed with dichloromethane and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/dichloromethane 2:1). 6.31 g (21.4 mmol, 70% yield) of a colorless solid are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:18])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:17]=1.[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2[CH2:25][CH2:26][CH2:27][CH2:28][C:20]1=2.O>C(O)(=O)C>[CH2:15]([O:14][C:12]([CH2:11][N:7]1[C:6]2[CH:17]=[C:2]([N:1]3[C:22](=[O:23])[C:21]4[CH2:25][CH2:26][CH2:27][CH2:28][C:20]=4[C:19]3=[O:24])[C:3]([F:18])=[CH:4][C:5]=2[S:9][C:8]1=[O:10])=[O:13])[CH3:16]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCOC(=O)Cn1c(=O)sc2cc(F)c(N)cc21
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)sc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 19.1 %

Procedure:
5-Amino-3-ethoxycarbonylmethyl-6-fluoro-2(3H)benzothiazolone (140 mg) and 3,4,5,6-tetrahydrophthalic anhydride (90 mg) were suspended in acetic acid (3 ml), and the resultant suspension was heated under reflux for 5 hours. After being allowed to cool, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The extract was washed with water and sodium bicarbonate solution, dried and concentrated. The residue was purified by silica gel thin layer chromatography with a mixture of ethyl acetate and hexane (1:2) to give 2-[3-ethoxycarbonylmethyl-6-fluoro-2(3H)-benzothiazolon-5-yl]4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (40 mg). m.p., 155.5°-156.5° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]3[N:20]([C:23]4[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=4[CH3:30])[N:21]=[CH:22][C:15]=23)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH2:31]([NH2:34])[CH2:32][CH3:33].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu](I)I>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]3[N:20]([C:23]4[CH:28]=[CH:27][C:26]([NH:34][CH2:31][CH2:32][CH3:33])=[CH:25][C:24]=4[CH3:30])[N:21]=[CH:22][C:15]=23)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1cc(I)ccc1-n1ncc2c(OC3CCN(C(=O)OC(C)C)CC3)ncnc21
Reactant: CCCN
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCCNc1ccc(-n2ncc3c(OC4CCN(C(=O)OC(C)C)CC4)ncnc32)c(C)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
4-[1-(4-Iodo-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (78 mg, 0.15 mmol), propyl amine (0.75 mmole, 5 eq), proline (0.27 mole, 1.8 eq), copper iodide (0.15 mmole, 1 eq), and potassium carbonate (0.15 mmole, 1 eq) were dissolved in DMSO (2 mL) and then stirred at 100° C. for 30 mins in microwave. The crude was purified through Prep-TLC (Hexane:Ethyl Acetate=1:1, Rf=0.7) to provide compound A215 as white solid (36 mg, 53%). 1H NMR 400 MHz CDCl3 δ (ppm): 8.51 (s, 1H); 8.20 (s, 1H); 7.40-7.36 (m, 1H); 7.30-7.21 (m, 2H); 5.63-5.58 (m, 1H); 4.95 (sep, 1H); 3.89 (m, 2H); 3.41-3.35 (m, 2H); 3.23-3.19 (m, 2H); 2.16-2.03 (m, 4H); 1.89-1.86 (m, 2H); 1.27 (d, 6H); 1.04 (t, 2H). Exact mass calculated for C24H32N6O3 452.2, found LCMS (ESI) m/z 453.4 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]2[NH:7][C:8]3[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=3[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:13]3)[C:5]=2[CH:4]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:28]=[CH:27][C:6]2[NH:7][C:8]3[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=3[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][N:15]([CH3:33])[C@@H:14]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:13]3)[C:5]=2[CH:4]=1
Reactant: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1C
Temperature: 25 °C

Procedure:
Add (S)-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.167 g, 0.399 mmol), formaldehyde (40.8 mg, 0.499 mmol, 37%), and sodium triacetoxyborohydride (0.127 g, 0.598 mmol) in dichloromethane (3 mL). Stir at ambient temperature over night. Dilute the mixture with water and extract with dichloromethane. Wash the organic with brine twice, dry over sodium sulfate, filter, and concentrate under reduced pressure to give crude residue. Purify the residue by flash chromatography, eluting with 2M ammonia in methanol:dichloromethane (5:95) to give the title compound: mass spectrum (m/e):433.08 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]1)[CH3:2].[H][H]>C(O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH2:11]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=C1CCN(C(C)(C)C)CC1
Solvent: CCO
Product: CCOC(=O)CC1CCN(C(C)(C)C)CC1
Yield: 78 %

Procedure:
To a solution of (1-tert-butyl-piperidin-4-ylidene)-acetic acid ethyl ester (5.1 g, 22.7 mmol) in ethanol (50 mL) 10% Pd/C (0.6 g) was added and the mixture was stirred under the hydrogen atmosphere (42 psi) at ambient temperature for 14 hours. The catalyst was removed by filtration, and the filtrate was concentrated to give the title (4.03 g, yield 78%), which was used in the next step directly.