Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]COC)[CH:6]=[CH:5][C:4]=1[C:13]1[C:14]([CH2:26][O:27][C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([CH3:24])([CH3:23])[CH:17]=[C:16]2[CH3:25].Cl.O1CCOCC1>O1CCOCC1.C(OCC)(=O)C>[OH:9][C:7]1[CH:6]=[CH:5][C:4]([C:13]2[C:14]([CH2:26][O:27][C:28](=[O:36])[C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH3:24])([CH3:23])[CH:17]=[C:16]3[CH3:25])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COCOc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)cc2)C(C)=CC(C)(C)N3)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
6-(2-Methoxy-4-methoxymethoxyphenyl)-5-(4-methylbenzoyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 2-1, 943 mg, 1.93 mmol) was dissolved in 1,4-dioxane (9 mL), 4N HCl/1,4-dioxane solution (980 μL) was added thereto, and then the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL). The mixture was washed with water (80 mL)-saturated aqueous sodium hydrogen carbonate solution (20 mL), and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (687 mg) as a colorless amorphous product. (Yield 80%)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12].COC(=O)[O-].[CH3:18][C:19]1C=CC2C(=CC=CC=2)[C:20]=1[OH:29].C1(O)C2C(=CC=CC=2)C=CC=1.FC(F)(F)C(OC1C=CC=CC=1)=O.C(=O)=O>>[C:20]([O:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH3:1])(=[O:29])[CH2:19][CH3:18]
Reactant: Cc1ccc2ccccc2c1O
Agent: COC(=O)[O-]
Agent: O=C(Oc1ccccc1)C(F)(F)F
Agent: O=C=O
Product: CCC(=O)Oc1c(C)ccc2ccccc12

Procedure:
To demonstrate the storage stability of the compounds of the present invention, test samples of the title compounds of Examples 1, 2, 3, 4, 5 and 6 were placed in clear glass vials and kept on top of a laboratory desk for the time indicated. Samples of 2-methyl-1-naphthol, 1-naphthol and phenyl trifluoroacetate used as controls were similarly kept. One sample of 2-methyl-1-naphthol was stored under nitrogen and in a dry ice chest (temperature of approximately -50° C). A second sample of 2-methyl-1-naphthol and the remaining test'samples were stored at room temperature.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][S:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>O1CCCC1.C(OCC)(=O)C>[CH3:14][S:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:3][C:1]#[N:2])=[CH:18][CH:17]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(C=CC#N)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A solution of diethyl cyanomethylphosphonate (5.3 ml) in tetrahydrofuran (10 ml) was added dropwise to an ice-cooled mixture of sodium hydride (60%, 1.3 g) in tetrahydrofuran (40 ml). The mixture was stirred at 5° C. for 15 minutes. To the resulting mixture was added a solution of 4-(methylthio)benzaldehyde (5 g) in tetrahydrofuran (10 ml) at 5 to 10° C. The mixture was stirred at ambient temperature for 5 hours, diluted with ethyl acetate, and washed with water. The organic layer was dried and concentrated under reduced pressure. The residue was washed with a small amount of ether and dried to give pale brown crystals of 3-[4-(methylthio)phenyl]acrylonitrile (4.7 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH:36]=[C:37]([C:39]#[CH:40])[CH:38]=3)[C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:24])[N:14]=2)=[CH:4][CH:3]=1.[C:41]([C:45]1[CH:46]=[C:47]([NH:63][S:64]([CH3:67])(=[O:66])=[O:65])[C:48]([O:61][CH3:62])=[C:49]([NH:51][C:52](=O)[O:53]C2C=CC=CC=2)[CH:50]=1)([CH3:44])([CH3:43])[CH3:42].C(OC(C)=O)(C)C>CCN(CC)CC>[C:41]([C:45]1[CH:46]=[C:47]([NH:63][S:64]([CH3:67])(=[O:66])=[O:65])[C:48]([O:61][CH3:62])=[C:49]([NH:51][C:52](=[O:53])[NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[C:22]([CH:36]=[C:37]([C:39]#[CH:40])[CH:38]=4)[C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:24])[N:14]=3)=[CH:4][CH:3]=2)[CH:50]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: C#Cc1cc(Nc2nccc(Oc3ccc(N)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Reactant: COc1c(NC(=O)Oc2ccccc2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)C
Product: C#Cc1cc(Nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under N2 was charged the product of step (vi) above (175.5 g, 0.324 mol), the product of step (x) above (145.0 g, 0.369 mmol) and iPrOAc (8800 mL). The resulting solution was heated to 60° C. and NEt3 (9.3 mL) was charged in one portion, then the mixture was left to stir at 60° C. overnight, following which HPLC analysis indicated 25.77% product of step (vi), 3.60% product of step (x) and 57.85% product of step (xi). Further product of step (x) (36.0 g, 0.092 mol) was charged, then the reaction was left to stir at 60° C. overnight, whereupon HPLC analysis indicated 5.47% product of step (vi), 3.72% product of step (x) and 73.33% product of step (xi). The reaction mixture was cooled to room temperature, before being concentrated to isolate a dark purple solid (522.9 g). This solid was recrystallised from acetonitrile (2615 mL, 5 volumes), before being collected via vacuum filtration and washed with iPrOAc (2×500 mL). The pink solid obtained was dried, under vacuum, at 40° C. overnight, yielding 181.1 g (66.5%) of the title compound with HPLC purity 99.27%. 1H NMR conformed to structure.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1.[I:12]I>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([I:12])=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCOc1cc(Br)ccc1N
Reactant: II
Solvent: CC#N
Product: CCOc1cc(Br)ccc1I
Reaction time: 1.5 h
Yield: 509.8 %

Procedure:
To a solution of 62B (2.5 g, 1.2 mmol) in acetonitrile (30 mL) at 0° C. was added dropwise a solution of iodine (6 g, 2.4 mmol), and t-BuONO (1.44 g, 1.4 mmol) in acetonitrile (100 mL) over 30 min and stirred 1.5 h. The mixture was quenched with aqueous Na2SO3 while maintaining the temperature <10° C. After stirring 1 h the mixture was extracted with hexane (3×100 mL). The combined organics were dried (MgSO4) before concentrating in vacuo and the residue was purified by flash chromatography (0-5% EtOAc/Hexane) to afford 62C (2 g, 53%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (t, J=7.03 Hz, 4 H) 4.06 (q, J=7.03 Hz, 2 H) 6.83 (dd, J=8.35, 1.76 Hz, 1 H) 6.90 (d, J=2.20 Hz, 1 H) 7.59 (d, J=8.35 Hz, 1 H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:27])[CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl>C(Cl)Cl.O1CCOCC1>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:27])[CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([NH2:19])[CH2:17][CH2:18]3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(=O)N2CCN(C3CCC3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1CCN(CC(=O)N2CCN(C3CCC3)CC2)CC1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl {1-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]piperidin-4-yl}carbamate (9.2 mmol) in DCM, is added 4N HCl in dioxane (10 mL) slowly. The mixture is heated at 50° C. for 30 min. The solvent is removed in vacuo to give the title compound as a white solid (trihydrochloric acid salt).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:21]=[O:22])[N:17]=[C:16]([Cl:23])[C:15]=1[NH:24][CH:25]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(OCC)OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][N:13]1[CH:25]=[N:24][C:15]2[C:14]1=[N:19][C:18]([NH:20][CH:21]=[O:22])=[N:17][C:16]=2[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(NOCCCOCc2ccccc2)n1
Agent: CCOC(OCC)OC(C)=O
Product: O=CNc1nc(Cl)c2ncn(OCCCOCc3ccccc3)c2n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
6-(3-Benzyloxyprop-1-oxyamino)-4-chloro-2,5-diformamido pyrimidine (4.3 g, 11.3 mmol) in diethoxymethyl acetate (40 ml) was heated at 120° C. for 2.5 hours. The mixture was then cooled and evaporated to a syrup. The residue was dissolved in methanol (40 ml) and concentrated aqueous ammonia (5 ml). The solution was then stirred for 30 minutes at 20° C., evaporated under reduced pressure and the residue co-evaporated with methanol. Column chromatography on silica gel (eluted with chloroform-methanol, 50:1) gave the title compound (3.93 g, 95%) IR: υmax 3120, 3080, 1700, 1615, 1580, 1500, 1435 cm-1. 1H NMR: δH (CDC3) 2.15 (2H, quintet, J=6 Hz, CH2CH2CH2), 3.75 (2H, t, J=6 Hz, CH2OCH2Ph), 4.55 (4H, m, CH2ON, CH2Ph), 7.40 (5H, m, Ph), 8.10 (1H, s, H-8), 8.40 (1H, d, J=10 Hz, D2O exchangeable, NHCHO), 9.60 (1H, d, J=10 Hz, NHCHO).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][C:12]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.P(Br)(Br)(Br)=O.[CH3:29][Sn:30](Cl)([CH3:32])[CH3:31]>>[CH3:23][C:18]1[CH:17]=[C:16]([C:12]2[CH:13]=[CH:14][C:15]3[C:10]([CH:11]=2)=[N:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]=3[Sn:30]([CH3:32])([CH3:31])[CH3:29])[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1cc(C)cc(-c2ccc3c(Br)c4ccccc4nc3c2)c1
Agent: O=P(Br)(Br)Br
Product: Cc1cc(C)cc(-c2ccc3c([Sn](C)(C)C)c4ccccc4nc3c2)c1

Procedure:
FIG. 38 depicts the synthesis of 1,8-bis(3,3′-(3,5-dimethylphenyl)-9,9′-diacridyl)naphthalene (32). Suzuki coupling of commercially available 3-bromoaniline, 25, and 3,5-dimethylboronic acid afforded 3-(3,5-dimethyl-phenyl)aniline, 26, in high yields. Treatment of 26 with 2-chlorobenzoic acid 27 gave N-3-(3,5-dimethylphenyl)anthranilic acid, 28, which was converted to 9-bromo-3-(3,5-dimethylphenyl)acridine, 29, using phosphorous oxybromide. Lithiation of 29 at −78° C. followed by stannylation with trimethylstannyl chloride resulted in the formation of 3-(3,5-dimethylphenyl)-9-trimethylstannylacridine, 30, in high yields. Employing stannane 30 and 1,8-dibromonaphthalene 31 in a CuO-promoted Stille coupling yielded 1,8-bis(3,3′-(3,5-dimethylphenyl)-9,9′-diacridyl)naphthalene, 32. We were pleased to find that the anti-isomers of 32 can be separated on a WhelkO-1 column. The CD spectra of the enantiomers of 32 are shown in FIG. 39.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.Cl.[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][C@H:20]([NH2:23])[CH2:21][F:22].CN(C)C.C1(N=C=NC2CCCCC2)CCCCC1>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:23][C@H:20]([CH2:21][F:22])[CH2:19][CH2:18][C:17]([O:16][CH3:15])=[O:24])=[O:8]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: COC(=O)CC[C@H](N)CF
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)CC[C@@H](CF)NC(=O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.70 g of 2,4-dichlorophenoxyacetic acid, 0.59 g of 4 and 0.44 ml of trimethylamine were mixed with 75 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes. Then, 0.65 g of N,N'-dicyclohexylcarbodiimide was added and the mixture was stirred at room temperature overnight. Several drops of glacial acetic acid were added and the mixture was filtered. The filtrate was washed successively with water, 1N hydrochloric acid, and half-saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and stripped of solvent. The residue was triturated with ethyl acetate, the mixture was filtered and the solvent was evaporated from the filtrate under reduced pressure. The solid residue was triturated with hexane, the mixture was filtered and the solvent was evaporated from the filtrate. The solid residue was chromatographed over silica gel, first with a 1:3 v:v mixture of ethyl acetate and hexane as eluent, then with a 1:1 v:v mixture of ethyl acetate and hexane as eluent. On workup, 16 was obtained, as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH:19]1([N:22]2[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23]2)[CH2:21][CH2:20]1>C(#N)C>[CH:19]1([NH:22][CH2:23][CH:24]2[CH2:25][CH2:26][N:28]([C:2]3[N:11]=[C:10]4[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]4[CH2:12][CH3:13])=[CH:4][C:3]=3[F:18])[CH2:27]2)[CH2:20][CH2:21]1
Reactant: NCC1CCN(C2CC2)C1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNC4CC4)C3)nc21
Yield: 53.4 %

Procedure:
A near solution of 0.82 g (3.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 1.4 g (10 mmole) of cyclopropyl-3-pyrrolidinemethanamine in 50 ml of acetonitrile was heated at reflux for two hours. The solvent was removed in vacuo, the residue dissolved in water, filtered through a fiber glass pad to clarify and the filtrate adjusted to pH 2.0 with 6M hydrochloric acid. The resulting clear solution was lyophilized and the residue recrystallized from ethanol to give 600 mg of 7-[3-[(cyclopropylamino)methyl]-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 271°-274° C. as the hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:17]=[CH:16][CH:15]=1
Reactant: Brc1cccc2cccnc12
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2cccc3cccnc23)c1
Temperature: 120 °C
Yield: 90 %

Procedure:
To a solution of 8-bromoquinoline (208.05 mg, 1.0 mmol) in dioxane/H2O (10 mL) was added (3-methoxyphenyl)boronic acid (182.3 mg, 1.2 mmol), Pd(dppf)Cl2 (100 mg) and K2CO3 (276 mg, 2 mmol). The reaction mixture was heated at 120° C. under microwave conditions for 30 minutes before cooling and being concentrated to remove the solvents. The residue was dissolved in ethyl acetate, washed with water and the separated organic layer concentrated to yield a crude product which was used in next step without further purification. (312 mg, Yield 90%). LCMS (m/z): 236.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([OH:30])([CH3:29])[CH2:4][NH:5][C:6]([C:8]1[C:13]([N:14]2C(C)=CC=C2C)=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=1)=[O:7].Cl.NO.CCN(CC)CC>CCO.O>[F:32][C:2]([F:1])([F:31])[C:3]([OH:30])([CH3:29])[CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[C:10]([C:25]([F:27])([F:26])[F:28])[N:9]=1)=[O:7]
Reactant: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(C(F)(F)F)nc1C(=O)NCC(C)(O)C(F)(F)F
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(O)(CNC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)cc1N)C(F)(F)F
Temperature: 98 °C

Procedure:
To a stirred solution of 3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (985 mg, 2.064 mmol) in 2:1 EtOH/H2O (7.5 ml) was added hydroxylamine hydrochloride (1.43 g, 20.64 mmol) followed by NEt3 (575 ml, 4.13 mmol). The reaction mixture was heated to reflux (˜98° C.) for 11.5 hours and then allowed to cool to RT. The solvent was removed in vacuo and the resulting residue was partitioned between EtOAc (25 ml) and water (25 ml). The aqueous layer was separated and extracted with EtOAc (2×25 ml) and the combined organic extracts were washed with brine (50 ml), dried (MgSO4) and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 0-25% EtOAc in iso-hexane to afford the title product as a pale yellow solid; LC-MS: Rt 1.24 min; MS m/z 400.0 [M+H]+; Method 2 minLC_v003.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:23])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:9]=2)=[O:4].[NH2:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].C[O-].[Na+]>COCCO>[CH:17]1([O:16][C:10]2[CH:9]=[C:8]3[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:24][C@@H:25]([CH3:26])[C:27]([OH:29])=[O:28])=[O:4])[C:6](=[O:23])[O:7]3)=[CH:12][CH:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1c(O)c2ccc(OC3CCCCC3)cc2oc1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2ccc(OC3CCCCC3)cc2oc1=O)C(=O)O
Yield: 72.5 %

Procedure:
A mixture of 7-cyclohexyloxy-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (80 mg, 0.25 mmol), L-alanine (224 mg, 2.5 mmol) and sodium methoxide (108 mg, 2 mmol) in 2-methoxyethanol (3.5 mL) was microwaved at 150° C. for 2 h and then concentrated. Residue was dissolved in water (70 mL) and extracted with (1/1) EtOAc/hexanes which was discarded. The aqueous layer was acidified using 1 N HCl to pH=3-4 and extracted with EtOAc (2×). Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (68 mg). MS ESI(−) m/e: 374.07 (M−1).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43](O)=[O:44])=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][N:48]=1>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:44])[N:46]([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][N:48]=3)[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:36]([F:42])=[CH:37][CH:38]=[CH:39][C:40]=3[F:41])[C:13]=2[S:14][C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:20][CH:21]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cn1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccc(F)cn2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 31.5 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-(N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (10.0 g, 15.65 mmol) and 2-amino-5-fluoropyridine (3.51 g, 31.30 mmol) gave N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(5-fluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (3.39 g, 32%) as white solids. The similar reaction as described in Reference Example 18 by using the compound (1.0 g, 1.46 mmol) gave the title compound (560 mg, 64%) as white solids.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH2:9][NH2:10])=[N:7][CH:8]=1.CCN(CC)CC.[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C1(C)C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH2:9][N:10]2[C:22](=[O:23])[C:21]3[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:24])=[N:7][CH:8]=1
Reactant: NCc1ncc(Br)cc1Cl
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1ncc(Br)cc1Cl
Yield: 50.8 %

Procedure:
To a stirred solution of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added Et3N (0.41 g, 4.08 mmol) and phthalic anhydride (0.24 g, 1.63 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a white solid (0.25 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.74 (m, 2H), 4.56 (m, 2H); ESIMS m/z 349 ([M−H]−); IR (thin film) 3307, 1665, 1114, 813 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18](Cl)=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:32][C:33]([CH3:35])=[O:34]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:33]([OH:34])([CH3:35])[CH3:32])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(C)(C)O)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (300.0 mg, 0.659 mmol) in tetrahydrofuran (6.0 mL) was added n-butyllithium (1.60 M solution in n-hexane, 1.03 mL, 1.65 mmol) at −78° C., and the mixture was stirred for 30 min. To the mixture was added acetone (0.24 mL, 3.30 mmol) at −78° C. The mixture was stirred at room temperature for 4.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (80.0 mg, 0.185 mmol, 28%).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1)([O-])=O.C([Cl:15])(=O)C.C([O-])([O-])=O.[K+].[K+]>>[Cl:15][C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Cl)cc[n+]1[O-]
Temperature: 25 °C

Procedure:
15.4 g (0.1 mol) of 4-nitro-2-picoline-N-oxide are added in portions at 0° C. to 75 ml of acetyl chloride. On warming to room temperature, a clear solution results which is added dropwise to ice with stirring. After adding K2CO3, the mixture is extracted several times using dichloromethane and ethyl acetate. After evaporating, the product is purified chromatographically on silica gel. The oil obtained crystallizes on standing, m.p. 37° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].CO[C:13]1[C:14](=O)[C:15](=[O:19])[C:16]=1[O:17]C>CO>[CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:13]2[C:16](=[O:17])[C:15](=[O:19])[C:14]=2[N:7]2[CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1CCCNCC1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: CCCN1CCCN(c2c(N3CCCN(CCC)CC3)c(=O)c2=O)CC1

Procedure:
A solution of 3.1 grams of 1-propylhomopiperazine in 20 ml. of methanol is mixed with a solution of 1.6 grams of 3,4-dimethoxy-3-cyclobutene-1,2-dione in 50 ml. of methanol and refluxed under nitrogen for 5 hours. The methanol solvent is evaporated by heating on a steam bath and the residual solid is dissolved in 70 ml. of anhydrous benzene at room temperature, treated with charcoal, and filtered. The resulting filtrate is diluted with 250 ml. of hexane and the precipitate which forms is separated by filtration and dried and then recrystallized from 1000 ml. of refluxing hexane to give 3,4-bis(4-propyl-1-homopiperazinyl)-3-cyclobutene-1,2-dione as white crystals melting at about 90°-92° C.