Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[Cl:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42](O)=[O:43])[CH:38]=[CH:39][CH:40]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[Cl:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:43])[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1cccc(Cl)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-chloro-phenylacetic acid (0.41 g, 2.4 mmol) were added. The reaction was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol) and was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 30% EtOAc in CH2Cl2 for 10 min, then increase to 60% EtOAc in CH2Cl2 over 20 min) to afford 2-(3-chloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide as a white solid (0.73 g, 76%): mp, 185-187° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.2 min. (99%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.86-2.91 (m, 1H), 3.56 (s, 2H), 4.73 (d, J=6.0 Hz, 2H), 5.12-5.18 (dd, J=5, 13 Hz, 1H), 7.23-7.82 (m, 7H), 8.70 (t, J=6 Hz, 1H), 11.13 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.90, 37.87, 41.53, 48.83, 121.93, 126.40, 127.15, 127.82, 128.94, 130.04, 131.52, 132.74, 133.25, 134.66, 138.54, 139.01, 166.88, 167.41, 169.77, 170.03, 172.73. Anal Calcd for C22H18ClN3O5: C, 60.08; H, 4.12; N, 9.55; Cl, 8.06. Found: C, 59.92; H, 3.85; N, 9.55; Cl, 8.37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([CH3:21])[CH:3]=1.C1(N)CCCCC1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1ccc(C(=O)CCC(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: NC1CCCCC1
Product: Cc1cc(Cl)ccc1-c1ccc(CCCC(=O)O)cc1
Yield: 76 %

Procedure:
Prepared analogous to Example 1 by reduction of 4-(4'-chloro-2'-methyl-4-biphenylyl)-4-oxo-butyric acid. Yield: 76%. Melting point of the cyclohexylamine salt: 145.5°-147° C. (from ethyl acetate).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH2:7].[C:9]([O:13][C:14](=O)[O:15]C(C)(C)C)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH:7][C:14](=[O:15])[O:13][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CN(CCN)CCN
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CN(CCN)CCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 118.5 %

Procedure:
N1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. A solution of di-tert-butylcarbonate (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0° C. over a period of 15 mm. The resulting reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 1.1 g of tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:20][C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[N:25][CH:26]=1>CN(C=O)C.O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:24]2[N:23]=[CH:22][C:21]([CH2:20][O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]4)=[CH:26][N:25]=2)=[CH:33][CH:32]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: ClCc1cnc(Nc2ccc(Cl)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2cc(OCc3cnc(Nc4ccc(Cl)cc4)nc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.8 %

Procedure:
A mixture of 6-hydroxyquinolin-2(1H)-one (0.057 g, 0.354 mmol), Cs2CO3 (0.192 g, 0.590 mmol) and 5-(chloromethyl)-N-(4-chlorophenyl)pyrimidin-2-amine (0.1 g, 0.394 mmol) in DMF (2.5 mL) was stirred at room temperature for 18 h. The reaction was diluted with water and the resulting suspension filtered. The bright yellow filter cake was taken up in methanol and the mixture was stirred for 1 h. The suspension was filtered and the yellow solid was washed with methanol and dried. The solid was further stirred in DCM/MeOH for 2 days. The mixture was filtered, and the filter cake washed with methanol and dried to give 6-((2-(4-chlorophenylamino)pyrimidin-5-yl)methoxy)quinolin-2(1H)-one as a brown solid (0.04 g, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68 (1H, s), 9.95 (1H, s), 8.64 (2H, s), 7.72-7.92 (3H, m), 7.12-7.47 (5H, m), 6.52 (1H, d, J=9.54 Hz), 5.04 (2H, s). LCMS: R.T.=3.77 min; [M+H]+=378.93.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:14]([O:16][CH3:17])=[O:15]>CN(C=O)C.C(OCC)C.C(OCC)(=O)C.O.C(=O)(O)[O-]>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Br)CC(C)C
Reactant: OCc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C)C)OCc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
4-Bromobenzylalcohol (1.1 g, 5.9 mmoles) in 12 mL of DMF was treated with sodium hydride (260 mg, 60% oil dispersion, 6.5 mmoles) and stirred for 30 minutes. Methyl 2-bromo-4-methylpentanoate (1.1 mL, 6.8 mmoles) was added in one portion and the reaction was stirred overnight. The reaction was diluted with diethyl ether, ethyl acetate, water and sat. aq. bicarbonate. The phases were separated and the organic phase was washed with 2 portions of 1.2 N hydrochloric acid and then brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford methyl 2-[(4-bromobenzyl)oxy]-4-methylpentanoate.
Reaction SMILES: [C:1]([Br:4])(=O)[CH3:2].[N+](C1C=[C:12]([CH2:14][C:15]([F:18])([F:17])[F:16])[N+:11]([O-:19])=[C:10]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH:9]=1)([O-])=O.[OH-].[Na+]>CC(O)=O>[Br:4][C:1]1[CH:9]=[C:10]([CH2:20][C:21]([F:22])([F:23])[F:24])[N+:11]([O-:19])=[C:12]([CH2:14][C:15]([F:16])([F:17])[F:18])[CH:2]=1
Reactant: CC(=O)Br
Reactant: O=[N+]([O-])c1cc(CC(F)(F)F)[n+]([O-])c(CC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: [O-][n+]1c(CC(F)(F)F)cc(Br)cc1CC(F)(F)F
Temperature: 90 °C
Yield: 72 %

Procedure:
Acetyl bromide (14 mL) was added to a solution of 4-nitro-2,6-bis-(2,2,2-trifluoro-ethyl)-pyridine 1-oxide (2.7 g, 8.9 mmol) dissolved in AcOH (25 mL). The reaction mixture was heated to 90° C. for 5 hours. The reaction was cooled to room temperature, poured into ice, made basic with NaOH pellets and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 30% EtOAc in hexanes) gave the product as a yellow oil (2.18 g, 72%). 1H NMR (400 MHz, CDCl3): δ 3.92 (t, J=10.1 Hz, 4 H), 7.59 (s, 2 H).
Reaction SMILES: [ClH:1].C(O[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=1)C.[NH3:22]>C(O)C>[ClH:1].[C:6]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=1)(=[NH:5])[NH2:22]
Reactant: N
Reactant: CCON=Cc1ccc(C=CC=CC(=O)OCC)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C=CC=Cc1ccc(C(=N)N)cc1
Temperature: 25 °C

Procedure:
To a mixture of ethyl 5-[4-{(1-ethoxy)iminomethyl}phenyl]-2,4-pentadienoate hydrochloride (22.00 g) in ethanol (220 ml) was poured 9N-ethanol solution of ammonia (19.7 ml) and refluxed for 15 hours. After cooled to room temperature, the reaction mixture was evaporated in vacuo, and the resulting precipitate was washed with diisopropyl ether to give ethyl 5-(4-amidinophenyl)-2,4-pentadienoate hydrochloride (20.15 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[F:25][C:26]([CH3:33])([CH2:30][CH2:31][CH3:32])[C:27](O)=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:25][C:26]([CH3:33])([CH2:30][CH2:31][CH3:32])[C:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1)=[O:28]
Reactant: CCCC(C)(F)C(=O)O
Reactant: CCCCOc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCOc1ccc(-c2ncc(-c3ccc(OC(=O)C(C)(F)CCC)cc3)cn2)cc1
Yield: 15.1 %

Procedure:
3.6 g (0.01 mol) of 5-(4-hydroxyphenyl)-2-(4-butyloxyphenyl)pyrimidine, 1.5 g (0.01 mol) of (-)-2-fluoro-2-methylpentanoic acid, 2.1 g (0.01 mol) of N,N'-dicylohexylcarbodiimide (DCC) and 130 mg (1.0×10-3 mol) of 4-dimethylaminopyridine were dissolved in 190 ml of dried methylene chloride, which were stirred under reflux for 6 hours. After the completion of the reaction, the precipitate was removed by filtration and then the filtrate was washed with 1 normal hydrochloric acid and further with water and thereafter dried on anhydrous magnesium sulfate. After the removal of magnesium sulfate by filtration, the filtrate was purified through a column chromatography of silica gel with a developing solvent (toluene: ethyl acetate=10:1 (V/V)) and recrystallized from 30 ml of ethanol to obtain 660 mg (yield: 15%) of a white crystal. The thus obtained compound has the aforementioned physical and chemical properties.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([CH3:14])[C:5](=[O:13])[C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[Cs+].[Cs+].O.CC1(C)C(C)(C)OB([C:31]2[CH:48]=[CH:47][C:34]([O:35][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)=[CH:33][CH:32]=2)O1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][N:4]1[C:3](=[O:15])[C:2]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)=[CH:47][CH:48]=2)=[C:6]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[C:5]1=[O:13]
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Reactant: CN1C(=O)C(Br)=C(N2CCOCC2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C(N2CCOCC2)C1=O
Temperature: 80 °C
Yield: 42.9 %

Procedure:
To a stirred solution of 3-bromo-1-methyl-4-morpholino-1H-pyrrole-2,5-dione (100 mg, 0.36 mol) in DMF (40 mL) were added Cs2CO3 (415 mg, 1.27 mmol), water (5 mL), and Pd(Ph3P)4 (84 mg, 0.072 mmol). 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (138 mg, 0.38 mmol) was then added and the reaction mixture was heated at 80° C. for 3 h, filtered through a pad of Celite® and the filtrate was then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 60% EtOAc in hexanes to afford 1-methyl-3-morpholino-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (70 mg, 45%). 1H NMR (500 MHz, d6-DMSO): δ 8.42 (d, J=7.2 Hz, 1H), 8.1 (t, J=7.2 Hz, 2H) 7.78 (t, J=7.8 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.28 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.4 Hz, 2H), 5.38 (s, 2H), 3.62-3.58 (m, 4H), 3.45-3.39 (m, 4H), 2.96 (s, 3H); MS: M+H: m/z=430.2 HPLC: 96%, (Condition-C).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH3:21])[CH:5]=[CH:6][CH:7]=1.[C:40](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:40][O:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[CH3:21])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(O)c3)c(=O)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(-n2c(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)nc3cccc(C)c3c2=O)c1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
A 100-mL, one-neck, round bottomed flask equipped with a magnetic stirrer was charged with compound 126 (370 mg, 0.68 mmol), potassium carbonate (235 mg, 1.70 mmol), and DMF (4 mL). The resulting mixture was stirred for 5 min, and methyl iodide (435 mg, 3.10 mmol) was then added. After stirring for a further 1 h at ambient temperature, the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give an 82% yield of compound 127 as a light yellow oil. 1H NMR (CD3OD) δ (ppm) 8.20 (m, 2H), 6.99-7.66 (m, 7 H), 5.58 (s, 2H), 5.15 (bs, 1H), 3.62 (dt, 2H, J=1.8, 8.0 Hz), 3.32 (s, 3H), 2.78 (s, 3H), 1.55 (m, 3H), 0.88 (m, 2H), −0.07 (s 9H); m/z=558 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[O:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:23]1[CH:27]=[CH:26][C:25]([C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)=[CH:24]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1-c1ccoc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
A solution of 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 425; 37.7 mg, 0.121 mmol), furan-3-ylboronic acid (Boron Molecular, Research Triangle, N.C.; 20.23 mg, 0.181 mmol), Na2CO3 (38.3 mg, 0.362 mmol), and Pd(PPh3)4 (Strem Chemicals, Inc.; 6.96 mg, 6.03 μmol) in a mixture of 1,4-dioxane (1.5 mL) and water (0.500 mL) was stirred under argon at 100° C. for 20 min. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(3-(furan-3-yl)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (37.0 mg, 0.107 mmol, 89% yield) as a yellow-orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, br. s.), 8.52 (1H, s), 8.02 (1H, dd, J=7.2, 1.4 Hz), 7.95 (1H, t, J=1.7 Hz), 7.83 (1H, dd, J=8.2, 1.4 Hz), 7.74-7.80 (1H, m), 7.25 (1H, s), 7.24 (1H, dd, J=1.8, 0.8 Hz), 7.00 (1H, br. s.), 3.45 (2H, td, J=6.7, 2.3 Hz), 2.90-2.94 (2H, m), 2.90 (3H, s). m/z (ESI, +ve) 344.9 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[Cl:10].[C:11]([S:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([S:15][C:16](=[O:21])[CH:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[Cl:10])[C:18](=[O:20])[CH3:19])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)CC(=O)SC(C)(C)C
Reactant: Fc1ccc(CBr)c(Cl)c1
Product: CC(=O)C(Cc1ccc(F)cc1Cl)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-2-chloro-4-fluorobenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)=[O:4].Cl.O1CCOCC1.[N:25]#[C:26][NH2:27]>CCO.C(#N)C>[CH3:1][N:2]([CH3:17])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:26]([NH2:27])=[NH:25])=[CH:14][CH:15]=1)=[O:4]
Reactant: CN(C)C(=O)[C@@H]1CCCN1c1ccc(N)cc1
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: CC#N
Product: CN(C)C(=O)[C@@H]1CCCN1c1ccc(NC(=N)N)cc1
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
To (S)-1-(4-Amino-phenyl)-pyrrolidine-2-carboxylic acid dimethylamide (Method 53; 0.67 g) was added acetonitrile (20 ml) and EtOH (2 ml). HCl in dioxane (0.86 ml, 3.48 mmol) was added and the reaction was stirred for 10 minutes, HCl salt precipitated. Cyanamide (0.2 g, 4.9 mmol) was added and the reaction was heated at reflux over the weekend. The black reaction was filtered and the black HCl salt was dissolved in water (5 ml) and basified with NaHCO3 (20 ml) solution. No solid was observed; the aqueous was further basified to pH 14 with KOH, extracted with DCM (2×100 ml), dried and solvent removed in vacuo to yield the title compound as a black gum (0.50 g, 63%). M/z 276.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@H:50]([OH:57])[CH2:51][N:52]2[CH:56]=[N:55][CH:54]=[N:53]2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:27][O:26][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]([CH2:15][O:14][C@H:12]2[CH2:13][NH:8][CH2:9][C@@H:10]([O:48][CH2:49][C@H:50]([OH:57])[CH2:51][N:52]3[CH:56]=[N:55][CH:54]=[N:53]3)[C@@H:11]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=2)[CH:25]=1
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H](O)Cn3cncn3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12
Agent: Cl
Solvent: CO
Product: COc1cc(CO[C@H]2CNC[C@@H](OC[C@H](O)Cn3cncn3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (l) the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-[1,2,4]triazol-1-yl-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the (R)-1-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-3-[1,2,4]triazol-1-yl-propan-2-ol as colorless oil; MS: 684 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:6][CH:7]([O:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)[CH3:8])[CH3:5].Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:35][CH2:34][C@@H:33]([F:36])[C@@H:32]3[C@H:28]2[CH2:29][NH:30][CH2:31]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:1][CH2:2][CH2:3][N:4]([CH2:6][CH:7]([O:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([N:30]1[CH2:29][C@@H:28]2[C@@H:32]([C@H:33]([F:36])[CH2:34][CH2:35][C:27]2([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:31]1)=[O:13])[CH3:8])[CH3:5]
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CC(CN(C)CCO)OC(C(=O)O)c1ccccc1
Agent: Cl
Product: CC(CN(C)CCO)OC(C(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Yield: 43.7 %

Procedure:
By carrying out the procedure as in Example 2, but using 1.37 g of {3-[N-(2-hydroxyethyl)-N-methylamino]-2-propoxy}phenylacetic acid and 1.2 g of (3aR, 7R, 7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, 0.86 g of (3aR,7R,7aR)-2-{{3-[N-(2-hydroxyethyl)-N-methylamino]-2-propoxy}phenylacetyl}-4,4-diphenyl-7-fluoroperhydroisoindole is obtained, after purification by chromatography on a silica gel column, in the form of a white meringue.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH2:20]([NH:23][C:24](=[O:27])[O:25][CH3:26])[C:21]#[CH:22]>CN(C=O)C.CCN(CC)CC.[Cu]I.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>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[N:5]=[C:6]([C:22]#[C:21][CH2:20][NH:23][C:24](=[O:27])[O:25][CH3:26])[CH:7]=[CH:8][C:9]=2[C:10](=[O:16])[C:11]=1[C:12](=[O:13])[NH:14][CH3:15]
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CCNC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CCNC(=O)OC)nc21

Procedure:
A suspension of 0.8 g (2.85 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide in 22 ml of a DMF/Et3N (v/v; 2.2/1) mixture is placed in a 10 ml microwave tube. Argon is sparged into this suspension for 10 minutes and then 0.98 g of methyl (prop-2-yn-1-yl)carbamate (8.66 mmol), 0.076 g of CuI (0.40 mmol) and 0.139 g of bis(triphenylphosphine)palladium(II) dichloride (0.20 mmol) are successively added.
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[C:39]([CH3:42])[CH:40]=O)=[CH:34][CH:33]=1)[CH3:30].O>O1CCCC1.CCCCCC>[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][C:35](/[CH:38]=[C:39](\[CH3:42])/[CH:40]=[CH:4]/[CH:3]=[O:2])=[CH:34][CH:33]=1)[CH3:30]
Reactant: OCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C=C(C)C=O)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(/C=C(C)/C=C/C=O)cc1
Temperature: -40 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of 2-hydroxyethyltriphenylphosphonium bromide (30 g, 0.077 mol) in dried tetrahydrofuran (300 ml) cooled to −40° C. under an atmosphere of nitrogen was added a solution of n-butyllithium in hexane (2.5M, 58.5 ml) dropwise. The resulting orange suspension was then stirred at 50° C. with occasional ultrasonication for 3 h, cooled to −60° C. and a solution of 3-(4-ethoxyphenyl)-2-methylpropenaldehyde (7.4 g, 0.039 ml) in dried tetrahydrofuran (25 ml) added dropwise and allowed to warm to 0° C. After ½ h, water was added and the organic phase separated. The aqueous phase was extracted with diethyl ether and the combined organic phases washed four times with water and then brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to an oil. The oil was dissolved in a minimum of diethyl ether and chromatographed on flash silica eluting with hexane then hexane-diethyl ether (3:2) to give 5-(4-ethoxyphenyl)-4-methylpent-2E,4E-dienal as a white solid.