Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[N:12][C:11]=1[C:19]([OH:21])=O.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:19]([C:11]1[N:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:23]
Reactant: O=C(O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
A mixture of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (110 mg, 0.28 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (45.6 mg, 0.44 mmol, 1.6 eq.), HATU (157.6 mg, 0.41 mmol, 1.5 eq.), and DIPEA (96.0 μL, 0.55 mmol, 2.0 eq.) in anhydrous DMF (4.2 mL) was stirred for 18 hours under N2 at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate followed by water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 15%, methanol in dichloromethane) to afford the desired product as a yellow solid (24 mg, 18%). LCMS (method D1): RT=1.00 min, [M+H]+=484.
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([CH2:15][N+:16]([CH3:19])([CH3:18])C)=[N:3]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[N:30]1[CH2:35]CNC[CH2:31]1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[N:30]1[CH2:35][CH2:18][N:16]([CH2:15][C:4]2[C:5]3[CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[C:10]=3[NH:2][N:3]=2)[CH2:19][CH2:31]1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: C[N+](C)(C)Cc1n[nH]c2c1CCc1ccccc1-2
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CCc1c(CN3CCN(c4ccc5ccccc5n4)CC3)n[nH]c1-2

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethylammonium iodide (0.4 g), 1-(quinolin-2-yl)piperazine (0.23 g) and diisopropylethylamine (0.30 cm3) in DMF (10 cm3) was heated under argon at 80° C. for 48 hours. The mixture was cooled, poured into water (50 cm3) and extracted with 10% ethyl acetate-diethyl ether (2×25 cm3). The extracts were dried (MgSO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 5% methanol-dichloromethane+1% ammonia, removed baseline material. Preparative thin layer chromatography on silica, eluting with 3% methanol-dichloromethane+1% ammonia, gave the title compound, which was crystallised as the oxalate salt from ethanol to give brown granules (0.026 g; 5%), m.p. 154°-155° C. (from EtOH); Found: C, 64.6; H, 5.5; N, 13.7. C25H25N5.1.25(CO2 H)2.0.15(H2O) requires C, 64.7; H, 5.5; N, 13.7%. δH (360 MHz; d6 -DMSO) 2.73 (2H, t, J 7.7, --CH2 --), 2.84 (4H, broad s, 2 x NCH2CH2N), 2.90 (2H, t, J 7.7, --CH2 --), 3.79 (4H, broad s, 2 x NCH2CH2N) 7.18-7.30 (5H, m, 5 of ArH), 7.51-7.59 (2H, m, 2 of ArH), 7.65 (1H, d, J 7.6, 1 of ArH), 7.71 (1H, d, J 7.9, 1 of ArH) and 8.06 (1H, d, J 9.2, 1 of ArH); m/z (CI+ ; NH3) 396 (MH+ ; 40%) and 214 (100).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.[N:16]#[C:17]Br>C(#N)C>[CH:7]1([N:6]=[C:2]2[N:3]([C:17]#[N:16])[CH2:4][CH2:5][S:1]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: c1ccc2c(c1)CCC2NC1=NCCS1
Reactant: N#CBr
Solvent: CC#N
Product: N#CN1CCSC1=NC1CCc2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
A suspension of 0.70 g (3.2 mmol) (4,5-Dihydro-thiazol-2-yl)-indan-1-yl-amine, 0.52 g (4.8 mmol) cyanogen bromide and 1.56 g (4.8 mmol) CsCO3 in 10 ml acetonitrile—was stirred at 20° C. for 16 hours. The suspension was filtered and the solvent evaporated. The crude product was purified by flash chromatography using EtOAc/n-hexane (1:5) as eluent to yield 0.50 g of 2-(Indan-1-ylimino)-thiazolidine-3-carbonitrile (white crystals, m.p. 90-91° C.). 1H-NMR (400 MHz, CDCl3): 2.0-2.15 (1H, m); 2.40-2.50 (1H, m); 2.85-2.95 (1H, m); 3.0-3.10 (1H, m); 3.35-3.45 (2H, m), 3.90-4.0 (2H, m), 4.65 (1H, t), 7.10-7.30 (4H, m).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:26](=[O:27])[CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
To a cold (−78° C.), stirred solution of (4R)-4-benzyl-1,3-oxazolidin-2-one (4.17 g, 23.53 mmol) in THF (100 mL) under nitrogen atmosphere was added n-BuLi (9.5 mL, 23.75 mmol) dropwise via syringe over 10 min. After stirring for 10 min, a solution of 2-phenylacetyl chloride (3.2 mL, 24.20 mmol) in THF (20 mL) was added via cannula over 10 min. After the addition was complete, the reaction mixture was placed in an ice-water bath and was stirred at 0° C. for 1 hr, then removed from the ice bath. To the reaction mixture was added aqueous saturated NH4Cl and was extracted with EtOAc (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent hexanes/EtOAc, REDISEP® SiO2 120 g). Concentration of appropriate fractions provided Preparation 4E (6.19 g, 89%) as a colorless viscous oil: 1H NMR (400 MHz, CDCl3) δ 7.32-7.39 (4H, m), 7.21-7.32 (4H, m), 7.10-7.17 (2H, m), 4.67 (1H, dddd, J=10.29, 6.34, 3.45, 3.26 Hz), 4.30 (2H, q, J=15.56 Hz), 4.15-4.22 (2H, m), 3.26 (1H, dd, J=13.30, 3.26 Hz), 2.76 (1H, dd).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[O:19])=[N:6][CH:5]=1)([O-])=O.[Sn](Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[CH3:39][O:40][C:41](Cl)=[O:42]>C1COCC1.Cl>[CH3:39][O:40][C:41](=[O:42])[NH:1][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:6][CH:5]=1
Reactant: COc1cccc(C(=O)c2ncc([N+](=O)[O-])c3cc(OC)c(OC)cc23)c1
Reactant: COC(=O)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)Nc1cnc(C(=O)c2cccc(OC)c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
The above [4-nitro-6,7-dimethoxy-isoquinolin-1-yl]-(3-methoxy-phenyl)-methanone (150 mg, 0.407 mmol) was treated with tin chloride (459 mg, 2.03 mmol) in THF (30 mL) and 6N HCl (19 mL) at room temperature overnight. The reaction mixture was treated with ice-cold saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and dried to a crude solid. 75 mg (0.203 mmol) of this crude solid was dissolved in dry THF (5 mL) and treated with pyridine (24.6 uL, 0.364 mmol) and methylchloroformate (18.7 uL, 0.243 mmol) under argon at 0° C. The reaction was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate, filtered, and evaporated to crude product. Preparative HPLC purification yielded 23 mg of [6,7-dimethoxy-1-(3-methoxy-benzoyl)-isoquinolin-4-yl]-carbamic acid methyl ester; trifluoro-acetic acid salt as an off-white solid: APCI-MS (M+H+) m/e calcd for C21H20N2O6 397.4, found 397.4; 1H NMR (300 MHz) compatible.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.C1(C)C=CC=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[CH2:35][CH3:36])=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(Br)nc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCc1ccccc1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To a stirred slurry of 1.75 g (3.35 mmol) of (S)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-bromo-pyridin-3-yl)propanoate and 1.005 g (6.70 mmol, 2 eq.) of 2-ethylphenylboronic acid in 50 mL of 1:1 isopropanol/toluene was added 25.0 mL of 2 M aqueous sodium carbonate solution. The reaction mixture was purged twice with argon and evacuated and then 124 mg (0.167 mmol, 0.05 equivalents) of bis(tricyclohexylphosphine)palladium (II) chloride was added and the mixture was again purged with argon and evacuated. The rapidly stirred mixture was heated at 80° C. under argon. After 20 h, the reaction mixture was cooled to room temperature and partially concentrated to remove isopropanol. The residue was partitioned between ethyl acetate and water and the aqueous phase was extracted once more with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated to give a brown oil. Purification by chromatography on silica gel using ethyl acetate/dichloromethane (1:9) as eluant (5×15 cm column), gave the desired compound as a colorless oil, 1.25 g, 77% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:19]N(CN(C)C)C.C(OC(=O)C)(=O)C.O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11](=[CH2:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CN(C)CN(C)C
Reactant: CC(C)(C)OC(=O)Cc1ccc([N+](=O)[O-])cc1F
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C=C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1F
Reaction time: 0.5 h

Procedure:
To a solution of t-butyl 2-fluoro-4-nitrophenylacetate (11.3 g) in dimethyl sulfoxide (70 mL) was added bis(dimethylamino)methane (6.80 g) and acetic anhydride (14.9 g) at room temperature, and the mixture was stirred at the same temperature for 30 min. The mixture was poured to water, and the mixture was extracted with toluene. The organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=9:1) of the residue gave t-butyl 2-(2-fluoro-4-nitrophenyl)acrylate. To a solution of the above t-butyl 2-(2-fluoro-4-nitrophenyl)acrylate and trimethylsulfoxonium iodide (11.7 g) in dimethyl sulfoxide (70 mL) was added potassium t-butoxide (5.96 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After quenching the reaction by the addition of 5% hydrochloric acid, the mixture was extracted with ethyl acetate. The organic extracts were washed with 3% sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=9:1) of the residue gave t-butyl 1-(2-fluoro-4-nitrophenyl)cyclopropane-1-carboxylate. MS (EI+) m/z: 281 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[N:16]=[C:15]([C:26]([OH:28])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:50]3[CH2:54][C:53](=[O:55])[NH:52][CH2:51]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[N:16]=[C:15]([C:26]([N:50]3[CH2:54][C:53](=[O:55])[NH:52][CH2:51]3)=[O:28])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: COc1cc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: COc1cc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1

Procedure:
18 mg (0.04 mmol) of the compound of Example 49A is reacted analogously to the synthesis of the compound of Example 1 with 5 mg (0.04 mmol) of 4-imidazolinone-hydrochloride. 4 mg (14% of theory, 82% purity) of the title compound is obtained.
Reaction SMILES: C[O:2][CH2:3][CH:4]([OH:6])[CH3:5].C(O)(=[O:9])C>>[CH3:5][CH2:4][C:3]([OH:9])=[O:2].[CH2:3]([OH:2])[CH:4]([OH:6])[CH3:5]
Reactant: CC(=O)O
Reactant: COCC(C)O
Product: CC(O)CO
Product: CCC(=O)O

Procedure:
A straight batch distillation employing a 20 tray Oldershaw column at a reflux ratio of 10/1 at atmospheric pressure with a pot temperature of 140°-146° C. and an overhead temperature of 115°-140° C. was carried out on a reaction mixture resulting from an acid catalyzed esterification of propylene glycol monomethyl ether (PM) and acetic acid to produce propylene glycol monomethyl acetate (PMA). The reaction mixture contained on a percent by weight basis 97.2% propylene glycol monomethyl ether acetate, 2.0% unreacted acetic acid, 0.1% unreacted propylene glycol monomethyl ether and 0.7% p-toluene sulfonic acid catalyst. The distillation was carried out for 1 hour and a 14% overhead cut taken. The results were as follows:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH3:12][C:13]([CH3:39])([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][C:25]([Br:30])=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:19]=[C:18]1[CH2:31][O:32][CH2:33][CH3:34].[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH3:39][C:13]([CH3:12])([S:35]([NH2:38])(=[O:36])=[O:37])[CH2:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][C:25]([Br:30])=[CH:24][C:23]=3[N:22]=[C:21]([NH2:41])[C:20]=2[N:19]=[C:18]1[CH2:31][O:32][CH2:33][CH3:34]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloroperoxybenzoic acid (0.126 g of 70% pure material, 0.73 mmol) was added in one portion to a stirred solution of dimethyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.30 g, 0.63 mmol) in chloroform (7 mL), and the solution was stirred for two hours at ambient temperature. Ammonium hydroxide (2 mL) and p-toluenesulfonyl chloride (0.15 g, 0.76 mmol) were sequentially added, and the mixture was stirred at ambient temperature for one hour. Dichloromethane (100 mL) was added, and the mixture was washed sequentially with 2 M aqueous sodium hydroxide (2×30 mL), saturated aqueous sodium bicarbonate (2×30 mL), and brine (30 mL); dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with ethyl acetate:ethanol in a gradient from 100:0 to 80:20) followed by recrystallization from dichloromethane:heptane. The crystals were dried for two hours under vacuum at 40° C. to provide 0.185 g of dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide as a white solid, mp 193° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[N:22]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[N:23]=[CH:24][CH:25]=1>>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:14][CH:15]4[CH:19]([CH2:18][N:17]([C:28]([C:27]5[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=5[N:22]5[N:23]=[CH:24][CH:25]=[N:21]5)=[O:29])[CH2:16]4)[CH2:20]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: O=C(O)c1ccccc1-n1nccn1
Product: O=C(c1ccccc1-n1nccn1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and Intermediate 2. MS (ESI): mass calculated for C25H23N7O, 437.50; m/z found 438.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.46-8.31 (m, 1H), 8.21-7.91 (m, 3H), 7.82-7.59 (m, 2H), 7.58-7.39 (m, 6H), 7.01-6.97 (m, 1H), 4.04-3.31 (m, 7H), 3.17-2.86 (m, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[C:52]([Cl:57])[C:51]=1[S:58](Cl)(=[O:60])=[O:59].O>ClCCl>[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[C:52]([Cl:57])[C:51]=1[S:58]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[NH:8][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:60])=[O:59]
Reactant: CC(C)(C)OC(=O)[C@@H](CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](CCCOS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a solution of di-tert-butyl (4S)-4-(3-hydroxypropyl)-N-trityl-L-glutamate (438 mg, 0.78 mmol) and triethylamine (327 μL, 2.35 mmol) in dichloromethane (7.0 mL) was added 2,4,6-trichlorobenzenesulfonyl chloride (328.6 mg, 1.17 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then water was added. The organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/n-hexane=10/90) to give the desired product (415 mg, 66%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.C(NN)C.C(CC(OCC)=O)#N.[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH:26]=O.[C:32]1(=O)[CH2:36][CH2:35][C:34](=[O:37])[CH2:33]1>C(O)C>[Br:22][C:23]1[CH:24]=[C:25]([CH:26]2[C:3]3[C:4](=[O:9])[NH:5][N:6]([CH2:7][CH3:8])[C:2]=3[NH:1][C:32]3[CH2:36][CH2:35][C:34](=[O:37])[C:33]2=3)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: O=C1CCC(=O)C1
Reactant: CCn1[nH]c(=O)cc1N
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: CCNN
Solvent: CCOC(=O)CC#N
Solvent: CCO
Product: CCn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(F)c(Br)c1
Yield: 58.6 %

Procedure:
5-Amino-1-ethyl-1,2-dihydropyrazol-3-one (0.13 g, 1 mmol), prepared by the method of (A. Weisberger and A. Porter, J. Amer. Chem. Soc, (1944) 66,1849) from ethylhydrazine and ethyl cyanoacetate, 3-bromo-4-fluorobenzaldehyde (0.2 g, 1 mmol), and 1,3-cyclopentanedione (0.1 g, 1 mmol) in ethyl alcohol (2 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was cooled and the resulting precipitate was filtered off to provide 0.23 g (58%) of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (t, 3H), 2.28 (t, 2H), 2.68 (m, 2H), 3.82 (q, 2H), 4.7 (s, 1H), 7.17 (m, 1H), 7.2 (t, 1H), 7.4 (dd,1H), 9.64 (bs, 1H), 10.4 (s, 1H); MS (ESI−) m/z 392 (M−H)−; Anal. calcd for C17H15N3BrFO2.0.5H2O: C, 50.89; H, 4.02; N, 10.47. Found: C, 50.85; H, 3.72; N, 10.25.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1B(O)O.C([O-])(O)=O.[Na+].Br[C:25]1[CH:30]=[CH:29][N:28]([CH2:31][CH2:32][CH2:33][CH3:34])[C:27](=[O:35])[C:26]=1[C:36]#[N:37]>O1CCOCC1.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>[CH2:31]([N:28]1[CH:29]=[CH:30][C:25]([C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=3)=[CH:7][C:2]=2[F:1])=[C:26]([C:36]#[N:37])[C:27]1=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCn1ccc(Br)c(C#N)c1=O
Reactant: Cc1cc(Oc2ccc(B(O)O)c(F)c2)ccn1
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: C1COCCO1
Product: CCCCn1ccc(-c2ccc(Oc3ccnc(C)c3)cc2F)c(C#N)c1=O
Yield: 67.4 %

Procedure:
To a solution of intermediate 14 (1.77 mmol) in 1,4-dioxane ml) and a saturated solution of NaHCO3 (6 ml) was added intermediate 6 (0.451 g, 1.77 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.204 mg, 0.177 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 3% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 4 (0.45 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:21](=[O:24])[CH2:22][CH3:23])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: CCC(=O)Cl
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: CCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 88.1 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added propanoyl chloride (0.37 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.58 g (88%) of product as an off-white solid: mp 221–223° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 5.16 (dd, J=5.2 and 12.6 Hz, 1H), 2.99–2.85 (m, 1H), 2.66–2.45 (m, 4H), 2.11–2.07(m, 1H), 1.14 (t, J=7.5 Hz, 3H); 13C NMR (DMSO-d6) δ 172.69, 172.65, 169.71, 167.79, 166.62, 136.65, 136.09, 131.35, 125.93, 118.12, 116.66, 48.91, 30.91, 29.73, 21.97, 9.13; Anal. Calcd. For C16H15N3O5: C, 58.36; H, 4.59; N, 12.76. Found: C, 58.01; H, 4.45; N, 12.61.