Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[C:2]1[C:11]1[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[C:12]=1[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:20]=1.II>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:17][N:14]1[C:13](=[O:18])[C:12]2[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:20]=3[C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[O:1][C:2]=3[C:11]=2[C:15]1=[O:16]
Reactant: CN1C(=O)C(C2=COc3ccccc3O2)=C(c2cn(C(=O)OC(C)(C)C)c3ccccc23)C1=O
Agent: II
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c3oc4ccccc4oc3c3c(c4ccccc4n3C(=O)OC(C)(C)C)c2c1=O

Procedure:
218.1 μmol of the compound obtained in Step A above and 5.91 mmol of double-sublimed iodine are dissolved in 500 ml of toluene inside the cell of an irradiation apparatus. After irradiating for 30 minutes, with stirring, the reaction mixture is cooled and then diluted with ethyl acetate. Washing with 80 ml of 20% aqueous sodium thiosulphate solution is carried out until the organic phase is decolourised. The aqueous phase is extracted with ethyl acetate three times, and then the organic phases are combined and directly concentrated in vacuo. A brown, semi-oily, semi-solid residue is collected. The procedure is repeated a further five times in the same manner, using the same amounts. The crude reaction products of the six procedures are combined. Washing with ethyl acetate is carried out on the six crude reaction products, which are then filtered. The filtrate is evaporated and then taken up in methanol, filtered, rinsed with methanol and then dried in vacuo, allowing the expected product to be isolated.
Reaction SMILES: [OH:1][CH:2]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:31]1(=[O:36])[O:35][CH2:34][CH2:33][CH2:32]1>>[CH2:19]([N:18]([CH2:17][CH:2]([OH:1])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:34](=[O:35])[CH2:33][CH2:32][CH2:31][OH:36])[C:31](=[O:36])[CH2:32][CH2:33][CH2:34][OH:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCCCCCNCC(O)CNCCCCCCCCCCCC
Product: CCCCCCCCCCCCN(CC(O)CN(CCCCCCCCCCCC)C(=O)CCCO)C(=O)CCCO
Temperature: 160 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
A reactor was charged with 9.5 g (0.02 mole) of 15-hydroxy-13,17-diazanonacosan and 11.7 g (0.13 mole) of γ-butyrolactone, and the contents were heated to 160° C. and kept for 5 hours at this temperature, thereby reacting them. After completion of the reaction, the product was purified by column chromatography (on 500 g of silica gel, developing solvent: chloroform/methanol=97/3), thereby obtaining 6 g (yield: 45%) of the title compound as a viscous liquid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:20]=1[C:21]([N:23]=[C:24]=[O:25])=[O:22]>C(Cl)Cl>[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:20]=1[C:21]([NH:23][C:24]([N:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:25])=[O:22]
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(C#N)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)NC(=O)c1c(F)cccc1Cl)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92414.5 %

Procedure:
To a solution of tert-butyl 2-(4-cyanophenyl)hydrazinecarboxylate (2.5 g, 0.01 mmol) in DCM (15 mL) was added 2-chloro-6-fluorobenzoyl isocyanate (Intermediate-8, 2.56 g, 0.012 mmol). The reaction mass was stirred at RT for 2 h. Excess of solvent was removed under vacuum to afford 4.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.42 (s, 9H), 7.25-7.38 (m, 2H), 7.47-7.60 (m, 3H), 7.82-7.85 (m, 2H), 9.96 (br s, 1H), 11.43 (br s, 1H); MS (m/z): 431.02 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.CCN(CC)CC.[C:22](Cl)(=[O:24])[CH3:23]>O>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:22](=[O:24])[CH3:23])[CH2:3]1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
A solution of 3,3-dimethyl-6-nitroindoline (Example 4, 190.5 g) in 1200 mL IPAC, Et3N (200.6 g) was charged to a 1-L jacketed reactor, followed by the drop-wise addition of acetyl chloride (155.4 g) while maintaining reaction temperature<25° C. The reaction contents were stirred for 1 h at 20-25° C. 1200 mL D.I. water was charged slowly at T<30° C. to form a suspension. The product was isolated by filtration. Wet cake was washed with D.I. water (200 mL×2) and heptane (200 mL), and was dried at 50° C. under vacuum until constant weight. (193 g, 83.2 wt % adjusted yield, 99.15 A %, 99.5 wt % (dry))
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>>[CH2:1]([N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[Br:20])[C:24]([CH:21]1[CH2:23][CH2:22]1)=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: FC(F)(F)c1ccc(Br)c(CNCc2ccccc2)c1
Product: O=C(C1CC1)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1Br

Procedure:
Benzyl-(2-bromo-5-trifluoromethyl-benzyl)-amine and cyclopropanecarbonyl chloride were reacted as described in Example 11, Step 2 to provide cyclopropanecarboxylic acid benzyl-(2-bromo-5-trifluoromethyl-benzyl)-amide.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1)#[N:2].C[Si]([N:37]=[N+:38]=[N-:39])(C)C.C([Sn](=O)CCCC)CCC.C(O)CO>C1(C)C=CC=CC=1>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:11]3[C:10]([O:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][C:1]4[NH:39][N:38]=[N:37][N:2]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCOCCC#N)c23)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: OCCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCOCCc4nnn[nH]4)c23)cc1

Procedure:
Stir 200 mg (0.47 mmol) 4-[3-(2-cyanoethoxy)propoxy]-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]-pyrimidine, 804 mg (7.0 mmol) trimethylsilylazide and 174 mg (0.70 mmol) di-n-butyltin oxide in 10 ml toluene overnight at 80° C. Concentrate the mixture by evaporation, take up the residue in water and acidify with dilute hydrochloric acid. Next, extract with methylene chloride. Wash the organic extracts with sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. Purify the residue that remains by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). To remove organotin compounds, dissolve the beige foam obtained in 10 ml toluene and add 1 ml ethylene glycol. After heating for 1 h under reflux, remove the solvent under vacuum. Dissolve the residue in methylene chloride, wash with dilute hydrochloric acid and with sodium chloride solution, dry, and concentrate by evaporation. Purification of the residue by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-34 min 5%→98% acetonitrile, 34-38 min 98% acetonitrile) gives 46 mg (21% of theor.) of the title compound as a beige foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([CH3:14])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH3:13])[C:7](=[O:9])[CH:8]=1.CO[CH:17]=[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([I:28])[CH:26]=2)[C:21](=[O:29])[NH:20][C:19]1=[O:30]>CN(C)C=O>[I:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:29])[NH:20][C:19](=[O:30])[C:18]2=[CH:17][NH:1][CH2:2][C:3]1[N:4]([CH3:14])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH3:13])[C:7](=[O:9])[CH:8]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: CCCOc1cn(C)c(CN)cc1=O
Solvent: CN(C)C=O
Product: CCCOc1cn(C)c(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1=O

Procedure:
A mixture of 2-aminomethyl-1-methyl-5-propoxy-1H-pyridin-4-one (196 mg, 1.0 mmole), 10 mL of N,N-dimethylformamide is stirred, 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (329 mg, 1.0 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give an off-white solid, 124 mg, (24%); m.p. 176-96° C. dec; MS (ES+): m/z 494.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C([N-]C(C)C)(C)C.[Li+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:23]([C:22]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([O:19][CH3:18])[CH:21]=1)=[O:24]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1c(Cl)cncc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Temperature: 0 °C
Yield: 50.4 %

Procedure:
A solution of 3,5-dichloro-4-methyl-pyridine (2.06 g, 12.7 mmol) in dry tetrahydrofuran (30 ml) was cooled down to −78° C., then a 1.8 M solution of lithium diisopropylamide in tetrahydrofuran (7.4 ml, 13.3 mmol) was added dropwise under stirring, keeping the temperature below −70° C. The resulting solution was stirred for 30 min., then a solution of 3,4-dimethoxy-benzoyl chloride (2.55 g, 12.7 mmol) in dry tetrahydrofuran (20 ml) was added dropwise, maintaining the temperature below −70° C. After stirring for 15 minutes, ice (20 g) was added, followed by further 500 ml of water. The mixture was extracted with ethyl acetate (2×50 ml), the combined organic layers were dried over sodium sulphate and evaporated under reduced pressure to give an oil that was purified by flash chromatography (Eluent: ethyl acetate/petroleum ether from 10/90 to 30/70 v:v). 2.1 grams (6.4 mmol, 52% yield) of the title compound were obtained as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:44])[CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:41]3[CH2:42][CH2:43][CH:38]([N:37]([CH3:44])[CH3:36])[CH2:39][CH2:40]3)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCC(N(C)C)CC1

Procedure:
cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted 4-dimethylamino-piperidine (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-dimethylamino-piperidin-1-yl)-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H41N6O2Cl2 [(M+H)+] 623.2663, observed 623.2665.
Reaction SMILES: CO[C:3](=[O:32])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:31])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([Br:30])[CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2([CH3:15])[C:3](=[O:32])[C:4]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][C:9]=3[Cl:10])[NH:12][C:13]2=[O:31])=[CH:17][C:18]=1[Br:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OCc2ccccc2)c(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(c2ccc(OCc3ccccc3)c(Br)c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Yield: 67.3 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 2-[2-(4-benzyloxy-3-bromo-phenyl)-propionylamino]-4,6-dichloro-benzoic acid methyl ester (0.80 g, 1.50 mmol) and LiHMDS (3.20 mmol, 1M THF solution). After normal workup, the objective compound (0.51 g, 67%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.71 (s, 3H, CH3), 5.09 (s, 2H, CH2Ph), 6.78 (d, J=2.0 Hz, 1H, ArH), 6.85 (d, J=9.0 Hz, 1H, ArH), 7.04 (dd, J=8.6, 2.4 Hz, 1H, ArH), 7.11 (d, J=2.4 Hz, 1H, ArH), 7.33-7.43 (m, 5H, ArH); m.p. 189-190° C.; MS(EI) m/e 503 [M+], 91; HRMS m/e cacld. for C23H16NO3Br1Cl2 502.9691, found 502.9696.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.Cl>C(O)(=O)C>[Br:2][C:3]1[C:4]2[NH:9][C:15]3[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][C:14]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccccc1Br
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCc2[nH]c3c(Br)cccc3c2C1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of (2-bromophenyl)hydrazine hydrochloride (1.1 g, 4.92 mmol; Aldrich) and 1-methyl-4-piperidone (0.56 g, 4.92 mmol; Aldrich) was combined with a solution of HCl in acetic acid (1.0 M, 30 mL; Aldrich) and stirred at 70° C. for 18 hours in a sealed tube. The reaction mixture was concentrated under vacuum. The residue was taken up in toluene (100 mL) and concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure was repeated a second time). The residue was dissolved in dimethyl sulfoxide (20 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.54 (s, 3H), 2.85-2.90 (m, 2H), 2.93-2.98 (m, 2H), 3.66 (t, J=1.5 Hz, 2H), 6.88 (t, J=7.8 Hz, 1H), 7.19 (dd, J=7.8, 0.8 Hz, 1H), 7.32 (dd, J=7.8, 0.8 Hz, 1H); MS (DCI) m/z 265/267 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][CH:7]=[C:8]([CH2:9][C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=3[O:20][CH3:21])[C:4]=2[CH:3]=1.CN1[CH2:30][CH2:29][O:28]CC1.O>ClCCl>[C:29]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][CH:7]=[C:8]([CH2:9][C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=3[O:20][CH3:21])[C:4]=2[CH:3]=1)(=[O:28])[CH2:30][CH2:23][CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc(Cc2csc3ccc(N)cc23)c(OC)c1
Reactant: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2scc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 1 h
Yield: 75 %

Procedure:
Hexanoyl chloridc (0.024 g.) was added to a stirred solution of methyl 4-(5-aminobenzo[b]thien-3-ylmethyl)-3-methoxybenzoate (H) (0.06 g.), and N-methylmorpholine (0.1 ml.) in dichloromethane (3 ml.). The mixture was stirred for 1 hour and then poured into water (20 ml.). The aqueous mixture was extracted with dichloromethane (2×20 ml.). The combined extracts were dried (MgSO4), and evaporated. The mixture was recrystallized from a mixture of ethyl acetate and hexane to give the title compound (0.05 g., 75%) as a colorless solid NMR (250 MHz, DMSO-d6): 0.87(t,3H, CH2CH3), 1.28(m,4H, CH2.CH2.CH3), 1.59 (quintet,2H, CH2CH2CON), 2.29(t,2H, CH2CON), 3.84(s, 3H, OCH3), 3.91(s,3H, OCH3), 4.11(s,2H, CH2 -Ar), 7.14 (d,1H), 7.34 (s,1H), 7.49(m,3H), 7.86(d,1H), 8.11(d, 1H), 9.95(s,1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2]
Reactant: CCOc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCN(Cc3ccccc3)CC2)ncn1
Temperature: 60 °C
Yield: 21.5 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #1A) (0.60 g, 1.84 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in DMF (40 mL) was added benzyl bromide (0.31 g, 0.22 ml, 1.84 mmol) at room temperature. The reaction mixture was heated at 60° C. for one hour and the progress of the reaction was monitored by TLC. The mixture was poured onto ice water and extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with dry diethyl ether and the solid was filtered to obtain 1-benzyl-piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #5A) (0.165 g. 21%) as a yellow solid.
Reaction SMILES: C[C:2]1([CH3:20])[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](O)=O)=[C:4]([C:17](O)=O)[CH2:3]1.[OH2:21]>>[CH3:7][C:6]1[CH:20]=[CH:2][C:3](=[O:21])[C:4]2[C:5]=1[C:8]1[C:16](=[CH:15][CH:14]=[CH:13][C:9]=1[CH3:10])[CH:17]=2
Reactant: CC1(C)C=CC(c2ccccc2C(=O)O)=C(C(=O)O)C1
Reactant: O
Product: CC1=C2C(=Cc3cccc(C)c32)C(=O)C=C1
Temperature: 60 °C

Procedure:
4,4-Dimethyldiphenic acid (20.0 g, 74.0 mmol) was charged with polyphosphoric acid (83.4 g) at room temperature. The mixture was heated in an oil bath at 120°-121° C. for 6.5 hr until decarboxylation was over (no gas evolved). The reaction mixture was cooled down to 60° C., diluted with water (150 mL) then cooled down to room temperature. The precipitate was filtered off, washed with water, 10% sodium bicarbonate solution until the filtrate became colorless, extracted with 25% solution of ethyl acetate in hexane and dried over magnesium sulfate. Evaporation of the solvents gave the crude ketone which was purified by short path chromatography (5% ethyl acetate in hexane). This afforded 10.8 g (70.4%) of 4,5-dimethylfluorenone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1.[NH3:26]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:26])=[O:24])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: N
Reactant: COC(=O)c1cccc2nc(-c3cccc(-c4ccccn4)c3)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3cccc(-c4ccccn4)c3)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
Methyl 2-(3-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate (150 mg, 0.43 mmol) was added to ammonia in methanol (30 mL) and the mixture was stirred at room temperature for 3 days. Then the solid was filtered, washed with methanol, dried in vacuum. 100 mg of 2-(3-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 74%. 1H-NMR (400 MHz, DMSO-d6) δ 7.44-7.47 (t, J=5.2 Hz, 1H), 7.50-7.54 (t, J=8.0 Hz, 1H), 7.76-7.88 (m, 3H), 7.96-8.01 (m, 3H), 8.12-8.14 (d, J=7.6 Hz, 1H); 8.35-8.39 (t, J=8.0 Hz, 2H); 8.76-8.77 (d, J=2.8 Hz, 1H); 9.01 (s, 1H); LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12](Br)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([C:18]2[CH:17]=[CH:16][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccc3ccccc3c2)c1
Yield: 75 %

Procedure:
A solution of 5-bromoisophthalic acid dimethylester (544 mg, 2 mmol), 2-naphthaleneboronic acid (342 mg, 2 mmol), Pd(OAc)2 (8 mg), tri-o-tolylphosphine (30 mg) and 5 ml Et3N (5 ml) in 10 ml DMF was stirred at 100° C. for overnight The reaction mixture was purified by silica gel column eluted by 20% EtAc in hexane to afford the product (75% yield). 1H NMR (Acetone-d6, 400 MHz), 8.55 (s, 1H), 8.45 (s, 2H), 8.17 (d, 1H), 7.91 (d, 1H), 7.88 (d, 1H), 7.77 (t, 1H), 7.67 (t, 1H), 7.38 (m, 2H), 4.03 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[CH:7](O)[N:8]([CH3:14])[C:9](=[O:13])[C:10]=3[CH:11]=[CH:12][C:4]=2[CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[CH2:7][N:8]([CH3:14])[C:9](=[O:13])[C:10]=3[CH:11]=[CH:12][C:4]=2[CH:3]=1
Reactant: CN1C(=O)c2ccc3cc(Br)ccc3c2C1O
Agent: [Zn]
Solvent: CC(=O)O
Product: CN1Cc2c(ccc3cc(Br)ccc23)C1=O
Temperature: 100 °C
Yield: 86.3 %

Procedure:
7-Bromo-1-hydroxy-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one (1.03 g) was dissolved in acetic acid (25 ml) and zinc (3.0 g) was added. The mixture was stirred with heating at 100° C. for 3 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated. The obtained residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extracted layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (carrier: silica gel, developing solvent: hexane-ethyl acetate, 2:1-1:1). The obtained crystals were washed with diisopropyl ether to give the title compound (0.84 g) as colorless crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([O:19][C:20]1[C:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][C:28]=2[O:35][CH3:36])=[C:24]([CH3:37])[N:23]=[C:22]([NH2:38])[N:21]=1)(=[O:18])=[O:17])([CH3:3])[CH3:2].[F:39][C:40]([F:52])([F:51])[CH2:41][NH:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(#N)C.O>[NH2:38][C:22]1[N:23]=[C:24]([CH3:37])[C:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][N:42]([CH2:41][C:40]([F:39])([F:51])[F:52])[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:29][C:28]=2[O:35][CH3:36])=[C:20]([O:19][S:16]([C:5]2[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][C:8]([CH:10]([CH3:11])[CH3:12])=[CH:7][C:6]=2[CH:13]([CH3:15])[CH3:14])(=[O:18])=[O:17])[N:21]=1
Reactant: CC(C)(C)OC(=O)CNCC(F)(F)F
Reactant: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(CN(CC(=O)OC(C)(C)C)CC(F)(F)F)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Yield: 154.6 %

Procedure:
The mixture of 2-amino-5-(4-chloromethyl-2-methoxybenzyl)-6-methylpyrimidin-4-yl 2,4,6-triisopropylbenzenesulfonate (6.0 g), tert-butyl 2-(2,2,2-trifluoroethylamino)acetate (2.7 g), sodium carbonate (3.4 g) and potassium iodide (0.5 g) in acetonitrile (48 g) was refluxed for 8 h. After cooling to RT, water (30 g) was added to the mixture and extracted with toluene (48 g). The organic layer was washed with water (30 g) and concentrated in vacuo. The residue was precipitated with n-heptane (18 g) to afford the sub-title compound (12.2 g).