Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[Cl:8].[CH:10](O)(C)[CH3:11].ClCC=O>O>[Cl:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[N:4]=1
Reactant: Nc1nnc(Cl)cc1Cl
Reactant: CC(C)O
Agent: O=CCCl
Solvent: O
Product: Clc1cc(Cl)c2nccn2n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
A mixture of 3-amino-4,6-dichloropyridazine (0.315 g, 1.92 mmol), 3 mL of isopropanol and 0.5 mL of a 50% chloroacetaldehyde in water solution was stirred at 80° C. for 20 h, then concentrated to remove isopropanol. The resulting yellow mixture was treated with 10 mL of a saturated aq. NaHCO3 solution and extracted with two 10 mL portions of dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to a yellow oil. Column chromatography (0->33% EtOAc/hexanes) afforded 0.313 g (87%) of 6,8-dichloro-imidazo[1,2-b]pyridazine as a light yellow solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:3]1.Cl.[CH3:23][O:24][C:25]12[CH2:32][CH2:31][C:28]([NH2:33])([CH2:29][CH2:30]1)[CH2:27][CH2:26]2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:33][C:28]34[CH2:31][CH2:32][C:25]([O:24][CH3:23])([CH2:26][CH2:27]3)[CH2:30][CH2:29]4)[N:10]=2)[CH2:3]1
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(N[C@@H]2CCC[C@H](O)C2)n1
Reactant: COC12CCC(N)(CC1)CC2
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC12CCC(Nc3ncc(C(N)=O)c(N[C@@H]4CCC[C@H](O)C4)n3)(CC1)CC2
Temperature: 130 °C
Reaction time: 3 h
Yield: 15.5 %

Procedure:
To a solution of 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (1.2 g, 3.8 mmol; synthesis described herein) and 4-methoxybicyclo[2.2.2]octan-1-amine hydrochloride (600 mg, 3.1 mmol) in NMP (12 mL) was added DIEA (1.03 g, 8 mmol). The resulting mixture was stirred at 130° C. under microwave irradiation for 3 h. The resulting mixture was purified by reverse phase column chromatography to give the desired product (230 mg, 0.6 mmol, 15.5% yield). 1H-NMR (400 MHz, CDCl3) δ ppm 8.70 (brs, 1H), 8.08 (s, 1H), 5.40 (brs, 2H), 5.01 (br. s, 1H), 3.99-3.96 (m, 1H), 3.75-3.70 (m, 1H), 3.19 (s, 3H), 2.37-2.34 (m, 1H), 2.15-2.11 (m, 6H), 1.99-1.97 (m, 2H), 1.90-1.86 (m, 1H), 1.80-1.76 (m, 6H), 1.38-1.22 (m, 4H). MS (ESI) m/z=390.2[M+1]+.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([CH3:18])=[C:16]([NH2:19])[S:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:20][C@@H:21]1[CH2:23][C@H:22]1[C:24](OCC1C=CC=CC=1)=[O:25]>ClCCl>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17]([CH3:18])=[C:16]([NH:19][C:24]([C@@H:22]3[CH2:23][C@H:21]3[CH3:20])=[O:25])[S:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: C[C@@H]1C[C@H]1C(=O)OCc1ccccc1
Reactant: COc1ccc(-c2nsc(N)c2C)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2C)cc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
Add trimethylaluminum (2 M in toluene, 3.59 g, 45.5 mmol) to a 0° C. solution of 3-(4-methoxyphenyl)-4-methylisothiazol-5-ylamine (10.0 g, 45.5 mmol) in dichloromethane (455 mL). Stir 5 min and add benzyl (R,R)-2-methylcyclopropane-carboxylate (8.64 g, 45.5 mmol). Heat to 50° C. with nitrogen flow to remove solvent. The resulting oil is heated at 50° C. for 3 h. Quench with water and dilute with EtOAc (300 mL). Wash with 0.1 N HCl, dry (K2CO3), evaporate, and crystallize from hexane/EtOAc to afford (R,R)—N-[3-(4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide. Yield: 80.4%. ES-MS: m/e 303.0 (m+1). (The mother liquor may be used for further recrystallizations.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O-:15])([O-])=[O:13].[K+].[K+].CN([CH:21]=[O:22])C>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:22][C:21]2[CH:4]=[C:3]([CH:2]=[CH:7][CH:6]=2)[C:12]([OH:15])=[O:13])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Product: O=C(O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of DMF (50 mL) was added 1-bromo-2-nitro-4-chloro-benzene (10.0 g, 42.2 mmol), 3-hydxoxybenzoic acid (5.8 g, 42.0 mmol), and K2CO3 (17.5 g, 0.13 mol). The solution was heated to 85° C. and stirred overnight. The reaction was poured into distill water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine, and dried over Na2SO4, filtered and concentrated under vacuum giving a crude oil. This oil was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (90:10) to give the title compound (7.4 gm, 60
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:10][O:11][CH2:12][CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][O:11][CH2:12][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COCCCl
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1cnc2ccccc21
Temperature: 100 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
In a nitrogen atmosphere, a mixture of 118 g of benzimidazole, 94.5 g of 2-chloroethyl methyl ether, 138 g of potassium carbonate, and 400 g of N,N-dimethylformamide was heated and stirred at 100° C. for 20 hours. The reaction mixture was subjected to conventional aqueous work-up and distillation under reduced pressure for purification, to give 154 g of 1-(2-methoxyethyl)-1H-benzimidazole (boiling point 125° C./33 Pa, yield 87%).
Reaction SMILES: C(O[C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18]C=1)C=C.[NH2:23][C:24]1[CH:44]=[CH:43][C:27]([C:28]([NH:30][CH:31]([CH3:42])[C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH:35]2C(O)=O)=[O:33])=[O:29])=[CH:26][C:25]=1[Cl:45].O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([CH:35]2[CH2:36][CH2:37][CH2:38][N:34]2[C:32](=[O:33])[CH:31]([NH:30][C:28](=[O:29])[C:27]2[CH:43]=[CH:44][C:24]([NH2:23])=[C:25]([Cl:45])[CH:26]=2)[CH3:42])=[O:22])[CH2:11][C:10](=[O:12])[O:9]1)[C:15]1[CH:16]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1

Procedure:
Was prepared from the syn diastereomer of (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester (40) and 97a following the method used for 98a. The title compound was isolated as a pale yellow solid (720 mg, 51% yield). 1H-NMR (500 MHz, CD3OD) δ 1.16 (d, 0.5H), 1.40 (d, 2.5H), 1.64-2.25 (m, 4H), 2.61 (dd, 1H), 2.79 (dd, 1H), 3.37-3.59 (m, 1H), 3.59-3.74 (m, 1H), 3.77-3.92 (m, 1H), 4.29-4.47 (m, 1H), 4.47-5.02 (m, 4H), 5.48 (s, 0.5H), 5.66 (d, 1H), 5.68 (d, 0.5H), 6.79 (d, 1H), 7.17-7.52 (m, 5H), 7.48-7.62 (m, 1H), 7.68-7.83 (m, 1H). Analytical HPLC 15.98 min. LC-MS (ES+) m/e=529.2 (MH+).
Reaction SMILES: C1(CO[C:9]([N:11]2[CH2:20][CH2:19][N:18]3[CH:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]5=[O:35])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])C=CC=CC=1.C(N(CC)CC)C.[CH2:43]([O:50][CH2:51]C(Cl)=O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CO.C(Cl)Cl.[Pd]>[C:44]1([CH2:43][O:50][CH2:51][C:9]([N:11]2[CH2:20][CH2:19][N:18]3[CH:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]5=[O:35])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)OCC2CN(C(=O)OCc4ccccc4)CCN32)C(=O)O1
Reactant: O=C(Cl)COCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)OCC2CN(C(=O)COCc4ccccc4)CCN32)C(=O)O1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a flask containing 8-[5-(S)-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-1,2,4a, 5-tetrahydropyrazino[2,1-c][1,4]benzoxazine-3(4H)-carboxylic acid phenylmethyl ester (EXAMPLE 1, 150 mg, 0.31 mmol) in methanol (5 mL) and methylene chloride (5 mL) is introduced 10% palladium on carbon (70 mg). The mixture is placed under a hydrogen balloon for 17 hours, filtered through celite, and concentrated in vacuo. The residue is dissolved in methylene chloride (10 mL) and triethylamine (0.09 mL, 0.62 mmol) and benzyloxyacetyl chloride (0.06 mL, 0.40 mmol) are added at 0° C. under an inert atmosphere. The reaction is warmed to ambient temperature, stirred for 15 hours, washed with water (10 mL) and saline, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (96/4). The appropriate fractions are combined (Rf= 0.46, TLC, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.36-7.29, 6.96-6.94, 6.85, 6.70, 4.69, 4.60, 4.50, 4.23-4.15, 3.97-3.91, 3.70-3.52, 3.27, 2.99, 2.82, 2.65, 2.44, 1.98.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](=[O:41])(=[O:40])[NH:38][CH3:39])=[CH:33][CH:32]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([S:37](=[O:41])(=[O:40])[NH:38][CH3:39])=[CH:35][CH:36]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: CNS(=O)(=O)c1ccc(NC(=O)c2c(N)ncnc2Cl)cc1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1ccc(NC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 23 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.33 mmol), 4-amino-6-chloro-N-(4-(N-methylsulfamoyl)phenyl)pyrimidine-5-carboxamide (123 mg, 0.36 mmol), DIEA (344 μl, 1.97 mmol) and cesium fluoride (150 mg, 0.99 mmol) were suspended in tert-butanol (10 ml) and the mixture was heated at 80° C. in a sealed tube for 24 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by reverse phase chromatography using SP1® Purification System to give 47 mg (23% yield) as a solid. Purity 94%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>C(#N)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[S:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1S
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: CC#N
Product: COc1cc2nccc(Sc3ccc(F)cc3C(=O)O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
5-Fluoro-2-mercaptobenzoic acid (278 mg) and 4-chloro-6,7-dimethoxyquinoline (300 mg) were suspended in acetonitrile (6 ml), and the suspension was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, the mixture was neutralized with sodium hydrogencarbonate and was then extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give 2-(6,7-dimethoxy-quinolin-4-ylsulfanyl)-5-fluoro-benzoic acid (152 mg, yield 31%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[Na].[Na].[C:35]([C:37]1[C:41](=[C:42]([C:45]#[N:46])[C:43]#[N:44])[NH:40][C:39](=[O:47])[C:38]=1O)#[N:36].O=P(Cl)(Cl)Cl>CN(C)C=O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:13]=[CH:14][C:15]([C:38]2[C:39](=[O:47])[NH:40][C:41](=[C:42]([C:45]#[N:46])[C:43]#[N:44])[C:37]=2[C:35]#[N:36])=[CH:16][CH:17]=1)[CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:3])[CH3:2]
Reactant: N#CC(C#N)=C1NC(=O)C(O)=C1C#N
Reactant: CCCCC(CC)CN(CCCCCCOC(C)=O)c1ccccc1
Agent: [Na]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(CC)CN(CCCCCCOC(C)=O)c1ccc(C2=C(C#N)C(=C(C#N)C#N)NC2=O)cc1
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
In a three-neck flask, 6-((2-ethylhexyl)(phenyl)amino)hexyl acetate (7.0 g, 0.020 mol) was dissolved in dimethylformamide (100 ml), stirred, and added with acetic anhydride (2.9 g, 0.028 mol) and 4-cyano-5-dicyanomethylene-3-hydroxy-2-oxo-3-pyrroline disodium salt (5.6 g, 0.024 mol). The temperature was decreased to 0° C., after which POCl3 was slowly added thereto for 30 min, and the mixture was allowed to react at room temperature for 6 hours with stirring. A solid product was precipitated with water, filtered, and then dried, thus obtaining 4.0 g of a dark blue solid.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:15]C1C=C(C=CC=1)CBr.COP(OC)OC>>[CH3:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:2]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Reactant: Cc1cccc(CBr)c1
Agent: COP(OC)OC
Product: COP(=O)(Cc1cccc(C)c1)OC

Procedure:
Following the procedure of Compound 11, 3-methylbenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[CH:17][C:18]([C:22]#[N:23])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:32])[F:31])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C([OH:37])(C)(C)C>O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[CH:17][C:18]([C:22]([NH2:23])=[O:37])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:31])[F:32])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: Cc1nc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Solvent: O
Product: Cc1nc(C(N)=O)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridine-2-carbonitrile (47.2 mg, 0.100 mmol) in tert-butyl alcohol (2 mL) potassium hydroxide (22.4 mg, 0.400 mmol). The reaction mixture was stirred at 80° C. for 5 min. After cooling, the reaction mixture was diluted with water 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 30-80% ethyl acetate/n-hexane gradient mixture to give a title compound as a colorless amorphous (16.6 mg, 0.0399 mmol, 34%).
Reaction SMILES: Cl[CH:2]([CH3:9])[C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[OH:10][C:11]1[C:16]2[C:17]3[CH2:18][NH:19][CH2:20][CH2:21][C:22]=3[C:23]([CH3:26])([CH3:25])[O:24][C:15]=2[CH:14]=[C:13]([CH:27]([CH3:35])[CH:28]([CH3:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[OH:10][C:11]1[C:16]2[C:17]3[CH2:18][N:19]([CH:2]([CH3:9])[C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4])[CH2:20][CH2:21][C:22]=3[C:23]([CH3:25])([CH3:26])[O:24][C:15]=2[CH:14]=[C:13]([CH:27]([CH3:35])[CH:28]([CH3:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: CC(Cl)C(=O)NC(N)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C(C)C(=O)NC(N)=O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.66 g. (0.011 mole) of 2-chloropropionylurea in 20 ml. of dimethylformamide was added dropwise to a stirred solution of 3.57 g. (0.01 mole) of 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine in 20 ml. of dimethylformamide and 1.11 g. (0.011 mole) of triethylamine. The reaction mixture was stirred at room temperature for 72 hours, diluted with 60 ml. of water, and extracted with ether. The ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by chromatography on a 100-200 mesh Florisil activated magnesium silicate column and chloroform; m.p. 95°-100°.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:25]1([C@@H:31]([NH2:33])[CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH:25]1([C@@H:31]([NH:33][C:2]2[S:3][C:4]3[CH:10]=[C:9]([CH2:11][N:12]4[C:16]5[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=5[N:14]=[CH:13]4)[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Reactant: C[C@H](N)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc2ncn(Cc3ccc4nc(N[C@@H](C)C5CCCCC5)sc4c3)c2cc1OC
Temperature: 100 °C
Yield: 53.8 %

Procedure:
A stirred mixture of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole from Example 2 (80 mg, 0.198 mmol), (S)-(+)-1-cyclohexylethylamine (50 mg, 0.396 mmol) and DIEA (77 mg, 0.594 mmol) in anhydrous DMA (2 mL) was heated at 100° C. for 72 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (S)—N-(1-cyclohexylethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine (48 mg, 54%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.62 (s, 1H), 7.29 (m, 1H), 7.12-7.23 (m, 3H), 5.40 (s, 2H), 3.76 (2×s, 6H), 1.55-1.79 (m, 6H), 1.32 (m, 1H), 0.93-1.22 (m, 8H). LCMS (ESI) m/z 451 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][CH2:28]O)[CH:22]=[CH:23][C:24]=1[Cl:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][CH2:28][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: OCCCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 3-(3,4-dichlorophenyl)propanol (129 mg, 0.630 mmol) synthesized in (11A) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (130 mg, yield: 73%).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].CS([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])(=O)=O.O>CS(C)=O>[CH2:30]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[CH2:19]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCCCCCCCCCS(C)(=O)=O
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a suspension of sodium theobromine (6.00 g, 30.0 mmol) in dimethylsulfoxide (60 mL) was added 12-methanesulfonyl-1-dodecene and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (120 mL) and extracted with diethyl ether (2×100 mL). The organic portions were combined, dried using magnesium sulfate and evaporated to give a cream solid. Recrystallization from ethyl acetate/hexane 1:1 yields 6.97 g (67% yield) 1-(11-dodecenyl)-3,7-dimethylxanthine (inventive compound no. 2516) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[C:10]1[C:11](=[O:22])[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18](=[O:21])[C:19]=1[Br:20]>C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[C:11](=[O:22])[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:18](=[O:21])[C:19]=2[Br:20])=[CH:4][CH:3]=1
Reactant: O=C1C(Br)=C(Br)C(=O)c2ncccc21
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: O=C1C(Nc2ccc(Cl)cc2)=C(Br)C(=O)c2ncccc21

Procedure:
CeCl3 (0.1 mmol) as a catalyst and 4 equivalents of 4-chloroaniline (10 mmol) were added to 6,7-dibromo-5,8-quinolindion (10 mmol) dissolved in ethanol (100 ml). The reaction mixture was heated at reflux for 8 hrs. After reading the completion of reaction by TLC, it was cooled, filtered, and recrystallized with ethanol to give redish powder of 6-[(N-4-chlorophenyl)amino]-7-bromo-5,8-quinolidione.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:13]=O.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[ClH:21]>CC(C)=O.C(O)C>[ClH:21].[OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10](=[O:12])[CH2:11][CH2:13][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CC(=O)C=Cc1ccc(O)cc1
Reactant: C=O
Reactant: C1COCCN1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Product: O=C(/C=C/c1ccc(O)cc1)CCN1CCOCC1
Temperature: 25 °C

Procedure:
4.86 g (0.03 mole) of 4-(4-hydroxyphenyl)-3-buten-2-one, 1.2 g (0.04 mole) of paraformaldehyde and 2.6 g (0.03 mole) of morpholine is added to 60 ml of ethanol and 6 ml of concentrated HCl is added thereto. The mixture is heated at reflux temperature for 18 hours and then cooled to room temperature. The resultant mixture is diluted with acetone to a volume of 250 ml and subsequently chilled overnight. The insoluble material is filtered and recrystallized from a mixture of ethyl and methyl alcohols. The crystals are filtered and vacuum dried overnight, yielding (E)-1-(4-hydroxyphenyl)-5-(4-morpholinyl)-1-penten-3-one hydrochloride; m.p. 195°-196° C.