Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1.[Cl:15]OC(C)(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:11]1[CH:10]=[C:9]([C:13]#[N:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Reactant: CC(C)(C)OCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(-n2cc(Cl)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a stirred mixture of 1-(4-methylphenyl)pyrrole-2-carbonitrile (10 g), silica gel (46 g) and carbon tetrachloride (150 ml) was added dropwise a solution of tertbutyl hypochlorite (8.1 g) in carbon tetrachloride (15 ml). After stirring for 1 hour at ambient temperature, the precipitate was filtered off and the filtrate was evaporated in vacuo to give an oily residue which was crystallized from n-hexane. The crystals were further purified by silica gel column chromatography (SiO2 100 g, n-hexane-toluene=1:1) and subsequent crystallization from n-hexane to give colorless crystals (3.92 g) of 4-chloro-1-(4-methylphenyl)pyrrole-2-carbonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1)#[N:2].Cl.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.O1CCOCC1>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(C#N)cc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.8 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[2-(7-cyano-2-oxo-1(2H)-quinolinyl)ethyl]-4-piperidinyl}carbamate (1.1 g, 2.8 mmol) in chloroform (15 ml) was added 4N HCl in 1,4-dioxane (15 ml) and the reaction stirred at rt for 45 mins. Toluene was then added and the solution was evaporated, dissolved in MeOH and treated with Amberlyst A21 basic resin for 30 m until pH of the solution is basic. The resine was filtered off and the solvent removed; the residue was subjected to column chromatography on silica gel eluting with 0-15% 2M ammonia in methanol-DCM to afford the desired compound (0.82 g, 99%).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH:14][C@H:15]([C:37]([N:39]3[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH2:41][CH2:40]3)=[O:38])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]S(C4C5C=CN=CC=5C=CC=4)(=O)=O)=[CH:19][CH:18]=3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[OH-].[K+].[Cl-].[Na+]>CO>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH:14][C@H:15]([C:37]([N:39]3[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH2:41][CH2:40]3)=[O:38])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=C([C@H](Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)NS(=O)(=O)c1cccc2cnccc12)N1CCN(CCCc2ccccc2)CC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=C([C@H](Cc1ccc(O)cc1)NS(=O)(=O)c1cccc2cnccc12)N1CCN(CCCc2ccccc2)CC1
Yield: 46 %

Procedure:
216 mg of the amorphous compound obtained in Example 32 was dissolved in 3 ml of methanol, and to the solution was added 0.6 ml of 2N potassium hydroxide aqueous solution. The mixture was refluxed for 10 hours, and after the addition of 30 ml of saturated sodium chloride aqueous solution, extracted twice with 20 ml of a mixed solvent of chloroform/isopropanol (5:1). The extract was dried over magnesium sulfate and concentrated under a reduced pressure, and a resulting residue was applied to a silica gel column and eluted with chloroform/methanol (40:1 to 10:1) to obtain 74 mg of the title compound in a colorless amorphous form.
Reaction SMILES: [CH:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17]1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][C:12]([C:7]3([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(O)C1(C2CCCCC2)CCCC1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1(C2CCCCC2)CCCC1

Procedure:
1-Cyclohexyl-1-cyclopentanecarboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-cyclohexyl-1-cyclopentanecarboxamide.
Reaction SMILES: [NH2:1][C:2]([C:4]1([CH2:17][CH2:18][C:19]#[N:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:3].[H][H]>[Pt]=O.C(O)(=O)C>[NH2:20][CH2:19][CH2:18][CH2:17][C:4]1([C:2]([NH2:1])=[O:3])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: [H][H]
Reactant: N#CCCC1(C(N)=O)c2ccccc2-c2ccccc21
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NCCCC1(C(N)=O)c2ccccc2-c2ccccc21

Procedure:
A 3.3 g. portion of 9-aminocarbonyl-9-(2-cyanoethyl)fluorene from Example 27 was hydrogenated in 95 ml. of glacial acetic acid under 4 atmospheres of hydrogen pressure for two hours at 24° C. in the presence of 1.5g. of platinum oxide catalyst. The reaction mixture was filtered to remove the catalyst and the solvent was removed by evaporation under reduced pressure. The product which remained was dissolved in ethyl acetate and then extracted into 1 N hydrochloric acid. The aqueous acid layer was separated, made alkaline with 50% sodium hydroxide, and extracted several times with fresh ethyl acetate. The extracts were combined, washed with water and with brine, dried, and the solvent was removed by evaporation under reduced pressure to provide 2.3 g of a white solid. The solid was dissolved in 1 N hydrochloric acid, filtered, and diluted with water to 100 ml. The aqueous acid solution was lyophilized to provide a white solid, which when crystallized from methanol and ethyl acetate was identified as 1.0 g. of 9-(3-aminopropyl)-9-aminocarbonylfluorene. m.p. 198°-200° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[OH:14])=[CH:5][N:6]=1.CS([C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1)(=O)=O.C(=O)([O-])[O-]>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]([C:7]2[C:8]([O:14][C:19]3[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=3)=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])=[CH:5][N:6]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cc1ncc(-c2c(O)cccc2F)o1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(F)c2-c2cnc(C)o2)n1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
4 ml DMF solution containing 0.12 g 2-(2-methyloxazole-5-yl)-3-fluorophenol, 0.12 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.18 g pottasium carbonate was stirred for 14 hours at 50° C. After completing the reaction, the solution reacted was poured into ice water and then extracted with ethyl acetate. The organic layer obtained was washed with water and then dried by using anhydrous magnesium sulfate. After filtration, the solvent used was removed by distillation under reduced pressure, and the residue obtained was treated with petroleum ether, affording the objective substance in an amount of 0.1 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.C([O-])(O)=O.[Na+].C1COCC1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>C(Cl)Cl>[C:8]([C:6]1[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:30](=[O:31])[O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:7]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1c(NC(=O)Oc2ccccc2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under N2 was charged the product of step (ix) above (167.0 g, 613 mmol), NaHCO3 (77.3 g, 920 mmol), THF (870 mL) and DCM (1440 mL). Phenyl chloroformate (82.6 mL, 659 mmol) was added dropwise, while maintaining the temperature below 20° C., and the reaction was stirred at room temperature for 4 h. HPLC analysis of the reaction mixture indicated 98.6% product and 0.03% starting material. The reaction mixture was filtered and the cake was washed with THF (˜50 mL). The filtrate was concentrated to ˜900 mL and cyclohexane (2400 mL) was added, then the mixture was left to stir overnight. The resulting solid was collected via vacuum filtration and washed with cyclohexane (500 mL). The pale pink solid produced was dried, under vacuum, at 40° C. for 4 h. Yield=232.6 g (96.7%). HPLC purity 94.5%. 1H NMR purity >95%.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([N:13]=[C:14]=[S:15])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:1]([NH:4][C:14]([NH:13][C:5](=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[S:15])[CH2:2][NH:3][C:14]([NH:13][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:15]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCN
Solvent: ClCCl
Product: O=C(NC(=S)NCCNC(=S)NC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To an ice cold solution of ethane-1,2-diamine (2.23 g, 37.1 mmol) in CH2Cl2 (100 mL) is added benzoyl isothiocyanate (12.41 g, 76 mmol) dropwise and the resulting suspension is stirred at room temp for 18 h. The reaction is filtered thru a ground glass frit and the resulting solid is washed with CH2Cl2 to give 10.2 g (71%) of the title compound as a white solid. LC/MS (Condition A): ret. T=3.67 min, (M+H)+ 387.13. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (2 H, br. s.), 7.86-8.01 (4 H, m), 7.60-7.72 (2 H, m), 7.47-7.58 (4 H, m), 3.88-4.09 (4 H, m).
Reaction SMILES: FC1C=CC(CC2C3C(=CC=CC=3[N+]([O-])=O)C(=O)NN=2)=CC=1C(N1CCC(OC)CC1)=O.[F:33][C:34]1[CH:54]=[CH:53][C:37]([CH2:38][C:39]2[C:48]3[C:43](=[C:44]([N+:49]([O-])=O)[CH:45]=[CH:46][CH:47]=3)[C:42](=[O:52])[NH:41][N:40]=2)=[CH:36][C:35]=1[C:55]([N:57]1[CH2:62][CH2:61][CH:60]([O:63][CH3:64])[CH2:59][CH2:58]1)=[O:56]>C(O)C.[Pd]>[NH2:49][C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:43]=1[C:42](=[O:52])[NH:41][N:40]=[C:39]2[CH2:38][C:37]1[CH:53]=[CH:54][C:34]([F:33])=[C:35]([C:55]([N:57]2[CH2:58][CH2:59][CH:60]([O:63][CH3:64])[CH2:61][CH2:62]2)=[O:56])[CH:36]=1
Reactant: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c([N+](=O)[O-])cccc34)ccc2F)CC1
Agent: [Pd]
Agent: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cccc([N+](=O)[O-])c34)ccc2F)CC1
Solvent: CCO
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(N)cccc34)ccc2F)CC1
Temperature: 20 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
A mixture of 4-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzyl)-5-nitrophthalazin-1 (2H)-one (34b) with 4-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzyl)-8-nitrophthalazin-1 (2H)-one (34a) (6 mg, 6.81 μmol) in ethanol (2 ml) was added to 5% palladium on carbon (2 mg, 0.94 μmol) in ethanol (5 mL) at 20° C. and the resulting mixture stirred at 20° C. for 5 hours, under an atmosphere of hydrogen. The catalyst was filtered and washed with ethanol and the solvent evaporated to a foam. Further ethanol and 5% palladium on charcoal (10 mg) were added and mixture stirred for a further 5 hours, under an atmosphere of hydrogen. The catalyst was filtered and washed with ethanol. Evaporation gave a gum, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a colourless gum (1.700 mg, 60.8%); 1H NMR (400.132 MHz, CDCl3) δ 1.25-1.31 (1H, m), 1.51-1.82 (2H, m), 1.89-1.98 (1H, m), 3.09-3.17 (1H, m), 3.38 (3H, s), 3.46-3.51 (2H, m), 3.55-3.63 (1H, m), 3.98-4.05 (1H, m), 4.16 (2H, s), 6.43 (2H, s), 6.79 (1H, d), 6.85 (1H, d), 7.00-7.04 (1H, m), 7.25-7.31 (2H, m), 7.41-7.45 (1H, m), 9.56 (1H, s); m/z (LC-MS, ESI+), RT=1.71 (M+H 411.5).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].Cl>C(OCC)(=O)C.CS(C)=O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76.9 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 100 ml were charged 3.40 g (62.9 mmol) of sodium methoxide and 20 ml of dimethyl sulfoxide under argon atmosphere, and then, while stirring at room temperature, 8.31 g (62.3 mmol) of dimethyl malonate with a purity of 99% was gradually added dropwise to the mixture over 5 minutes. After cooling the mixture to 20° C., 5.10 g (31.4 mmol) of 2,4-difluoronitrobenzene was gradually added dropwise to the mixture over 5 minutes, and the temperature of the mixture was raised to 80° C. and the mixture was reacted for one hour. After completion of the reaction, the mixture was cooled to room temperature, and then, 100 ml of ethyl acetate was added to the mixture, and 5.25 ml (31.4 mmol) of 6 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 30 ml of water and 30 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting concentrate was purified by silica gel column chromatography (filler:Daisogel 1002W, eluent:hexane:ethyl acetate=9:1 (volume ratio)) to obtain 6.55 g of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate (isolation yield: 75%) as a white crystal with a purity of 97.2% (areal percentage by high performance liquid chromatography).
Reaction SMILES: [CH:1]12[O:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].O=[O+][O-].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH3-]C#N.[Na+]>CO.C(Cl)Cl.CO>[C:20]1([CH2:19][N:26]2[CH2:6][CH:1]3[O:7][CH:4]([CH2:3][CH:2]3[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:5]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CC2C=CC1O2
Reactant: NCc1ccccc1
Agent: O=[O+][O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC2CN(Cc3ccccc3)CC1O2
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a solution 1,1-dimethylethyl 7-oxabicyclo[2.2.1]hept-5-en-2-ylcarbamate (1.0 g, 4.74 mmol) in MeOH/DCM (48 mL, 1:1) at −78° C. was bubbled through O3 until the solution maintained a blue color. N2 was then bubbled through until the blue color dissipated and a solution of benzylamine (0.49 mL, 4.5 mmol) and NaBH3CN (1.19 g, 19.0 mmol) in MeOH (22 mL) was added dropwise. After gradually warming to 25° C. over 12 hr, the mixture was partitioned between 6N NaOH and DCM. The aqueous layer was back-extracted several times with DCM and the combined organic fractions were concentrated and purified by column chromatography (silica, 0-1% MeOH in DCM (1% NH4OH )) affording the title compound as a clear oil (560 mg, 37%): LC/MS (ES) m/e 319 (M+H)+.
Reaction SMILES: [CH3:1][PH:2](=[O:10])[CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH3:11]I>>[CH3:1][P:2](=[O:10])([CH3:11])[CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCOC(OCC)[PH](C)=O
Product: CCOC(OCC)P(C)(C)=O

Procedure:
Following a procedure analogous to that of Example 12, but using methyl(diethoxymethyl)phosphine oxide instead of tert-butyl(diethoxymethyl)phosphine oxide and using methyl iodide instead of benzyl bromide, there is obtained dimethyl(diethoxymethyl)phosphine oxide.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[C:22]1([C@@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:30][C@H:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:29])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: C[C@H](N)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C)c1ccccc1
Temperature: 140 °C
Yield: 26.3 %

Procedure:
2-Chloro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (100 mg, 0.3238 mmol, prepared as described in WO 2007/095188) was dissolved in n-butyl alcohol (1 mL). To the butyl alcohol solution thus obtained were then added (1S)-1-phenylethanamine (750 μL, 5.830 mmol) and DIPEA (167.4 mg, 225.6 μL, 1.295 mmol). The resulting solution was heated at 140° C. in microwave for 90 minutes. Additional (1S)-1-phenylethanamine (500 μL, 3.887 mmol) was added and the reaction mixture heated for 90 minutes in microwave at 140° C. The solvent was removed in vacuo and the residue dissolved in dichloromethane and washed sequentially with 0.5M HCl (three times, 5 mL each), saturated aqueous sodium hydrogen carbonate solution (three times, 5 mL each), and brine (once, 5 mL). The washed solution was dried over MgSO4, filtered, and concentrated in vacuo to give yellow oil. The oil was purified by mass directed HPLC and the product fractions passed through a bicarbonate cartridge and lypholized to afford the title compound as a white solid (33.5 mg, 26% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[C:8](=[CH:13][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[C:8](=[CH:13][C:14]=1[N+:19]([O-:21])=[O:20])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(NC(C)=O)cc1C(=O)OC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)OC
Reaction time: 2.5 h

Procedure:
Dimethyl 4-acetamidophthalate (100.4 g, 0.400 mol) is added to fuming nitric acid (90%, 600 mL) at 0° C. to 5° C. When the addition is completed (0.5 hour), the mixture is stirred 2.5 hours at 0° C. to 10° C., combined with cold methylene chloride and shaken with crushed ice. The aqueous layer is separated and extracted further with methylene chloride. The combined organic layers are washed with ice water, sodium bicarbonate solution and cold water, dried (MgSO4) and concentrated in vacuo to give a solid residue. The residue is recrystallized twice from methanol to afford the title product I as orange-brown needles, mp 119°-120° C. The original mother liquor is concentrated in vacuo, and the residue is recrystallized several times from carbon tetrachloride to afford the title compound II as light yellow needles, mp 124°-125° C. The yield of compound I is 38.9 g (32.9%), and the yield of compound II is 33.1 g (28.1%).
Reaction SMILES: Br[C:2](C)([C:6]1[C:7](=[C:11](C)[CH:12]=[CH:13][CH:14]=1)[C:8]([O-])=[O:9])C([O-])=O.[C:17]([C:19]1[C:20]([OH:26])=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=1)#[N:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:25][C:22]1[N:21]=[C:20]2[C:19]([C:17]3[NH:18][C:8](=[O:9])[C:7]4[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=4[C:2]=3[O:26]2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(C#N)c(O)n1
Reactant: Cc1cccc(C(C)(Br)C(=O)[O-])c1C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)oc1c3ccccc3c(=O)[nH]c21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of α-bromodimethylhomophthalate (2.00 g, 6.97 mmol) in DMF (15 mL) was added 3-cyano-2-hydroxy-6-methylpyridine (1.03 g, 1.1 eq) and potassium carbonate (4.82 g, 5 eq). The resulting mixture was allowed to stir at 100° C. for 4 h under inert atmosphere. The reaction was cooled to room temperature and concentrated in vacuo. The resulting solid residue was diluted with 1 N aqueous HCl (60 mL) and stirred for 30 min. The resulting suspension was filtered and the solids were washed with water. The aqueous filtrate was extracted with EtOAc (2×50 mL). The collected solids were added to the combined EtOAc extracts, and the resulting solution was dried over sodium sulfate, filtered and concentrated in vacuo to afford a crude residue. The crude residue was recrystallized from toluene at −20° C. over 18 h, vacuum filtered and dried to provide compound 26a as a yellow solid. Yield=500 mg (29%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[C:18](Br)[N:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH:6][CH:5]=1)([OH:3])=[O:2].[N:21]1[O:22][N:23]=[C:24]2[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][C:25]=12.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([C:29]4[C:24]5[C:25](=[N:21][O:22][N:23]=5)[CH:26]=[CH:27][CH:28]=4)[N:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: OB(O)c1cccc2nonc12
Reactant: O=C(O)c1ccc(-c2cc3cccnc3c(Br)n2)cc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2cc3cccnc3c(-c3cccc4nonc34)n2)cc1
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of 6-(4-carboxyphenyl)-8-bromo-1,7-naphthyridine (100 mg, 0.304 mmol) in DMF (2.5 ml) is added 4-benzo[c]furazanyl boronic acid (60 mg, 0.36 mmol), bis(dibenzylidenacetone) palladium (7 mg, 0.0122 mmol), tri-o-tolylphosphine (7.4 mg, 0.024 mmol) and aqueous Na2CO3 (0.9 ml, 2N). The reaction mixture is stirred at 80° for 2 h. The hot solution is filtred through cellit and the solution evaporated to dryness. The residue is stirred in ethyl acetate (20 ml), the suspension is filtered and the organic solvent is removed. The residue is dissolved in hot DMF (7 ml) and the crude product is precipitated by carefully adding aqueous HCl (2N, 1 ml). The crude product in recrystallized from hot DMF to yield the title compound (68 mg). MH+369; Melting point >300° C. M+H=369. Retention time HPLC=10.40 min (column: LiChroCart 125-4, Supersphere 60 RP-select B, 40°; eluent: acetonitril-water (0.1% TFA)=45:55; 1 ml/min; detection at 254 nm).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].N1C=CC=CC=1.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[O:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[O:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28]([O:4][CH2:1][CH:2]=[CH2:3])=[O:29])=[CH:24][CH:23]=1
Reactant: C=CCO
Reactant: CC(Oc1ccc(Oc2cnc3ccccc3n2)cc1)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)C(C)Oc1ccc(Oc2cnc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.2 g allyl alcohol and 1.6 g pyridine in 50 cc methylene chloride, add 6.6 g of 2-[4-(2-quinoxalinyloxy)phenoxy]propionyl chloride in 60 cc methylene chloride. Stir the mixture at room temperature overnight. Wash the methylene chloride solution with water and dry the solution over magnesium sulfate concentrate under vacuum to give allyl 2-[4-(2-quinoxalinyloxy)phenoxy]propanoate.