Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:37])[CH2:9][NH:10][C:11]2[C:16]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH:24]=[C:25]([CH3:26])[C:19]=4[N:18]=3)=[C:15]([O:33]C)[N:14]=[C:13]([O:35]C)[N:12]=2)[CH:5]=[CH:6][CH:7]=1>CC(O)=O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:37])[CH2:9][NH:10][C:11]2[NH:12][C:13](=[O:35])[NH:14][C:15](=[O:33])[C:16]=2[C:17]2[NH:21][C:20]3[CH:22]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:24]=[C:25]([CH3:26])[C:19]=3[N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(NCC(O)c2cccc(Cl)c2)c(-c2nc3c(C)cc(N4CCOCC4)cc3[nH]2)c(OC)n1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(N2CCOCC2)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)[nH]c(=O)[nH]c3=O)nc12
Temperature: 55 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
A solution of 1-(3-chloro-phenyl)-2-[2,6-dimethoxy-5-(4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-pyrimidin-4-ylamino]-ethanol (0.041 g, 0.078 mmol) in a mixture of AcOH (17.4 M) and HCl (11.6 M: (1.3 mL: 1.0 mL) was stirred in a sealed tube at 55° C. for 18 hours. Then solvents were evaporated in vacuo and the crude material was purified by preparative HPLC (see method below) to give the title compound as a beige solid (29 mg, 77%), HPLC 99%. LCMS (+ESI, M+H+) m/z 497. IR (KBr, cm−1) 3420, 2961, 2856, 1717, 1635, 1559; 1H NMR (400 MHz DMSO) δ 11.88 (s, 2H), 10.84 (s, 1H), 7.58 (s, 1H), 7.46-7.30 (m, 3H), 6.97 (d, J=2 Hz, 1H), 6.68 (s, 1H), 6.10 (br s, 1H), 4.90 (m, 1H), 3.89 (m, 1H), 3.76 (m, 4H), 3.61 (m, 1H), 3.04 (m, 4H), 2.49 (3H, s); HRMS calcd for C24H25ClN6O4:497.1704; found 497.1698.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH3:12])[C:5]([C:24]#[C:25][CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:24]=[C:25]([CH:26]([O:27][CH2:28][CH3:29])[O:30][CH2:31][CH3:32])[N:8]([CH2:9][CH:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH3:12])[C:6]=2[N:7]=1
Reactant: CCOC(C#Cc1cnc(Cl)nc1NCC(CC)NC(=O)OCc1ccccc1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCOC(OCC)c1cc2cnc(Cl)nc2n1CC(CC)NC(=O)OCc1ccccc1

Procedure:
benzyl N-[1-[[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]propyl]carbamate is synthesized by treating benzyl N-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]propyl]carbamate with TBAF using similar experimental conditions as described for the synthesis tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) (M+H) 461
Reaction SMILES: C(O[C:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:7][C:6](=[O:23])[CH:5]=1)C.[CH2:24]([Li])[CH3:25].O>C1C=CC=CC=1>[CH2:24]([C:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:7][C:6](=[O:23])[CH:5]=1)[CH3:25]
Reactant: [Li]CC
Reactant: CCOC1=CC(=O)CC(c2ccccc2OCOCCOC)C1
Solvent: c1ccccc1
Solvent: O
Product: CCC1=CC(=O)CC(c2ccccc2OCOCCOC)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 3-ethoxy-5-(2-methoxyethoxymethoxyphenyl)-2-cyclohexenone (2.0 g) in benzene (60 ml) was added dropwise with stirring in an atmosphere of dry nitrogen to an ice-cooled 1.5 M solution of ethyllithium in benzene (20.8 ml). When the addition was complete, water was added and the mixture was allowed to stand overnight at room temperature. The benzene layer was separated and the aqueous layer was extracted with ether. The organic solutions were combined, dried and the solvents were evaporated under reduced pressure. The residue was purified by preparative-layer chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (b.p. 60°-80°) for elution to afford the title compound (0.65 g) as a pale yellow oil. (Found: C, 70.9; H, 7.7. C18H24O4 requires C, 71.0; H, 7.9%.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[C:12]([CH3:23])[C:11]([C:24]([O:26]CC)=[O:25])=[N:10]1.[OH-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=2)=[C:12]([CH3:23])[C:11]([C:24]([OH:26])=[O:25])=[N:10]1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(N(C)C)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(N(C)C)cc1
Yield: 39.1 %

Procedure:
Ethyl 1-(2,4-dichlorophenyl)-5-[4-(dimethylamino)phenyl]-4-methyl-1H-pyrazole-3-carboxylate (1 eq, 39 mg, 0.072 mmol) and lithium hydroxide (3 eq, 5.2 mg, 0.215 mmol) was heated at 65° C. in tetrahydrofuran (3 mL) and water (3 mL) for 16 h. The reaction was quenched with a small amount of 10% HCl. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-10% methanol/dichloromethane with 1% acetic acid to yield 1-(2,4-dichlorophenyl)-5-[4-(dimethylamino)phenyl]-4-methyl-1H-pyrazole-3-carboxylic acid (11 mg, 39%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.36 (s, 3H) 2.84-3.05 (m, 6H) 6.60 (d, J=7.35 Hz, 2H) 6.97 (d, J=7.44 Hz, 2H) 7.20-7.37 (m, 2H) 7.42 (br. s., 1H)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH:12]([CH3:14])[CH3:13])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1
Reactant: CC(C)N
Reactant: Clc1nc(Cl)c2cscc2n1
Solvent: CCO
Product: CC(C)Nc1nc(Cl)nc2cscc12
Yield: 97.8 %

Procedure:
45 g (0.22 moles) of 2,4-dichloro-thieno[3,4-d]pyrimidine are suspended in 1800 ml of absolute ethyl alcohol. To the cooled mixture 28.5 g (0.48 moles) of isopropylamine are added drop by drop whilst agitating vigorously and maintaining the temperature at between 0° and 5°C. A clear solution is obtained which is agitated for a further hour at ambient temperature. The solution is concentrated, making sure that the temperature of the bath does not exceed 30°C. The syrupy residue is poured into iced water whilst agitating well. A yellow solid is formed which is drained off, washed with water and dried. 49 g of 2-chloro-4-isopropylamino-thieno[3,4-d]pyrimidine are obtained with a yield reaching 98% of theory. M.P. : 189°-191°C.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:28]([F:34])([F:33])[F:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)CC(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (92 mg, 84%), MS (ISP) m/z=439.4 [(M+H)+], mp 197° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3,3,3-trifluoropropanoic acid.
Reaction SMILES: Cl.[CH:2]([N:5]([C@@H:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)[C:6]([C:8]1[C:9]([C:28]([F:31])([F:30])[F:29])=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]=2[CH:27]=1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[C:46]([O:48][CH:49]([Cl:51])[CH3:50])=[O:47]>C(Cl)(Cl)Cl>[CH3:18][C:15]1([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]2[CH:27]=[C:8]([C:6]([N:5]([CH:2]([CH3:3])[CH3:4])[C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:46]([O:48][CH:49]([Cl:51])[CH3:50])=[O:47])[CH2:33]3)=[O:7])[C:9]([C:28]([F:30])([F:29])[F:31])=[CH:10][C:11]=2[O:16]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCNC3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)Cl)C3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-isopropyl-2,2-dimethyl-3-oxo-N-[(3R)-piperidin-3-yl]-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide hydrochloride (3.0 g) in chloroform (25 ml) were added successively triethylamine (0.98 ml) and 1-chloroethyl chloroformate (0.63 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was concentrated to give the title compound (3.55 g) as white amorphous. The obtained title compound was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:12])=O)[CH2:7][C:6]=2[CH:13]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:46]3[CH2:45][CH2:44][N:43]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47]3)=[O:12])[CH2:7][C:6]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)C1Cc2cc(Cl)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2Cc3cc(Cl)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of 5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid (1 g, 5 mmol) in N,N-dimethylformamide (10 ml) was added EDAC.HCl (1.45 g, 7.56 mmol, 1.5 eq), HOBt (1.02 g, 7.55 mmol, 1.5 eq), triethylamine (1.52 g, 15.0 mmol, 3 eq) and tert-butyl piperazine-1-carboxylate (935 mg, 5.02 mmol, 1 eq). The resulting solution was stirred overnight at room temperature, quenched with water (200 ml), and then extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (3×100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 10%-20% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford tert-butyl 4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine-1-carboxylate as a off-white solid (1.2 g, 65%). (ES, m/z): [M+H]+ 367; 1H NMR (300 MHz, CDCl3): δ 7.05-7.22 (m, 2H), 6.72 (d, J=8.4 Hz, 1H), 5.38-5.45 (m, 1H), 3.75-3.90 (m, 3H), 3.25-3.70 (m, 7H), 1.50 (s, 9H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]([NH2:12])([CH2:10][CH3:11])[CH3:9]>C(OCC)C>[CH:8]([NH:12][C:1]([CH:2]=[CH:3][C:4]([OH:6])=[O:5])=[O:7])([CH2:10][CH3:11])[CH3:9]
Reactant: CCC(C)N
Reactant: O=C1C=CC(=O)O1
Solvent: CCOCC
Product: CCC(C)NC(=O)C=CC(=O)O

Procedure:
To a stirred solution of maleic anhydride, 95% (42.1 g, 0.4 mol) in 500 mL diethyl ether at 0° C. was added drop wise sec-butyl amine (29.25 g, 0.4 mol) in 50 mL diethyl ether. The resulting mixture was stirred while a solid formed, which was recovered by filtration. The residue was washed with 2×100 mL diethyl ether and dried to yield 51.76 g of the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10]>>[OH:8][C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Oc1cccc(Br)c1
Product: O=Cc1ccc(-c2cccc(O)c2)cc1
Yield: 65.8 %

Procedure:
In a manner similar to that of Example 1(e), starting with 20 g (115 mmol) of 3-bromophenol and 26 g (173 mmol) of 4-formylbenzene boronic acid, 15 g (65%) of the expected product are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2.[OH-].[Na+]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(-c2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1
Temperature: 25 °C

Procedure:
To a 100-mL, round-bottomed flask containing 4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.15 g, 0.61 mmol) and 5-hydroxyindole (0.24 g, 1.8 mmol, Aldrich) in 1,4-dioxane (12 mL), was added NaOH (8.0 mL, 8.0 mmol, 1.0 N). The mixture was heated at reflux for 4 h, and after cooling to room temperature, the solvent was removed in vacuum. EtOAc (15 mL) was added to the residue, and the organic layer was washed with 1 N NaOH (10 mL), water (10 mL), dried over Na2SO4, filtered, and concentrated in vacuum. After purifying the crude product by silica gel chromatography (4:1 hexanes/EtOAc), the resulting solid was dissolved in acetone (3 mL). Water (5 mL) was added dropwise to this mixture, and a white precipitate fell out of solution, which was collected by filtration, washed with water (0.5 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound. Mp: 143–145° C. MS (ESI, pos. ion) m/z: 344 (M+1). Anal. Calcd for C22H21N3O.(H2O)1/8: C, 76.44; H, 6.20; N, 12.16. Found: C, 76.63; H, 6.20; N, 12.12.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:13][C:14]([OH:16])=O)=[C:8]([CH:12]=1)[C:9](O)=[O:10])([O-:3])=[O:2].O.[NH3:18]>>[N+:1]([C:4]1[CH:12]=[C:8]2[C:7]([CH2:13][C:14](=[O:16])[NH:18][C:9]2=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: O
Product: O=C1Cc2ccc([N+](=O)[O-])cc2C(=O)N1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
230 mg of 5-nitro-2-carboxymethyl-benzoic acid was placed in a 10 ml flask followed by adding 1 mL of ammonia water. The resulting mixture was heated and fluxed for 30 min to evaporate the solvent. Then the system was heated to 150° C. under reduced pressure by oil pump, after progressed for 20 min the reaction was processed as follows: the solid is dissolved with acetone and applied on silica gel column (petroleum ether: acetic ether=1:1) to obtain 7-nitro-4H-isoquinoline-1,3-dione.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=1)[O:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23]C)=[O:22].[OH-].[Na+].Cl>C1COCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=1)[O:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1cccc(COc2cccc(OCc3ccc4ccccc4n3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(COc2cccc(OCc3ccc4ccccc4n3)c2)c1
Temperature: 50 °C

Procedure:
A mixture of 1.6 g of methyl 3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoate and 0.5 g of NaOH in 20 ml of THF and 5 ml of H2O is heated at 50° C. overnight. The reaction mixture is acidified to pH 4 by 1N HCl solution, filtered and dried to give 3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid. (M.P. 149-151° C.)
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=O>>[NH2:13][C:14]1[CH:15]=[C:16]([C:17]2[O:12][C:3]3[CH:4]=[C:5]4[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]4)=[CH:11][C:2]=3[N:1]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cc2ccccc2cc1O
Reactant: Nc1cccc(C(=O)O)c1
Product: Nc1cccc(-c2nc3cc4ccccc4cc3o2)c1

Procedure:
Prepared by the method of Example 1a), from 3-amino-2-naphthol (579 mg, 3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitle compound was obtained, 58 mg (6%). 1H NMR (CDCl3) δ 8.12(s, 1H), 7.90(m, 3H), 7.65(dt, J=1.5, 7.5 Hz, 1H), 7.60(t, J=2.3 Hz, 1H), 7.42(m, 2H), 7.27(t, J=7.9 Hz), 6.82(dd, J=2.3, 7.9 Hz). MS 261 m/z (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3C(=CC=C[CH:18]=3)C[C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[C@@H]2C[O:37]C[C@H]2O)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[CH2:12][O:20][CH2:18][C@H:19]2[OH:37])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(N[C@@H]2COC[C@H]2O)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(N[C@@H]2COC[C@H]2O)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting trans-(+/−)-4-[(3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow solid. IR (diffuse reflectance) 3398, 2971, 2938, 1569, 1539, 1490, 1466, 1447, 1413, 1397, 1251, 1232, 1054, 969, 891 cm−1; OAMS supporting ions at: ESI+ 315.9 & ESI− 313.9; MS (EI) m/z 315 (M+); HRMS (FAB) calcd for C12H18BRN3O2+H1 316.0661, found 316.0656; Anal. Calcd for C12H18BrN3O2: C, 45.58; H, 5.74; N, 13.29. Found: C, 45.49; H, 5.84; N, 13.14.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([OH:38])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[N+:53]([C:56]1[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[CH:58][CH:57]=1)([O-:55])=[O:54].O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([O:38][S:62]([C:59]5[CH:58]=[CH:57][C:56]([N+:53]([O-:55])=[O:54])=[CH:61][CH:60]=5)(=[O:63])=[O:64])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](OS(=O)(=O)c3ccc([N+](=O)[O-])cc3)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
To a solution of Compound (48a) (200 mg, 0.34 mmol) in 15 ml of dichloromethane were added 83 mg (0.68 mmol) of dimethylaminopyridine and 112 mg (0.51 mmol) of p-nitrobenzenesulfonyl chloride under ice-cooling, and the mixture stirred for 6 hours at the same temperature. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed sequentially with 1N HCl, water, an aqueous saturated sodium hydrogen carbonate solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size B; toluene:ethyl acetate=4:1) to give 184 mg (70%) of Compound (48f).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[C:16]([C:21]#[C:22][Si](C)(C)C)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[OH:27]S(O)(=O)=O.O>CC(C)=O>[C:21]([C:16]1[C:17]([F:20])=[C:18]([F:19])[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:27])[CH3:22]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1F
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F

Procedure:
A mixture of methyl 2-(2-fluorophenylamino)-3,4-difluoro-5-((trimethylsilyl)ethynyl)benzoate (9 mmol, 3.5 g), HgSO4 (9 mmol, 2.67 g), and cone. H2SO4 (18 mmol, 0.96 ml) in acetone:H2O (70:12 ml) was refluxed at 65° C. overnight. The mixture was concentrated, diluted with EtOAc, and washed with water and brine. The organic fractions are combined, dried over MgSO4 and concentrated under reduced pressure. The crude material (brown solid) was triturated with MeOH and the precipitate was filtered, washed with additional MeOH and dried to yield the desired product in 60% (1.78 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:17](Cl)=[N:16][C:15]2[C:10](=[CH:11][C:12]([Cl:20])=[C:13]([Cl:19])[CH:14]=2)[N:9]=1>CCO>[N:1]1([C:17]2[C:8]([Cl:7])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([Cl:19])=[C:12]([Cl:20])[CH:11]=3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1cc2nc(Cl)c(Cl)nc2cc1Cl
Solvent: CCO
Product: Clc1cc2nc(Cl)c(N3CCNCC3)nc2cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Piperazine (0.69 g, 8.06 mmol) was added to a stirred suspension of 2,3,6,7-tetrachloroquinoxaline (1.08 g, 4.03 mmol) in EtOH (125 mL) at room temperature. The mixture was stirred at room temperature for 8 h and filtered to give the product as a pale yellow solid: yield 0.88 g (69%), mp>300° C. MS m/z 316/318 (M)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)([CH3:15])[CH3:14])=[C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH:6]=1)(=[O:3])[CH3:2].[CH3:39][Si](C)(C)[N-][Si](C)(C)C.[K+].CI>O1CCCC1>[C:1]([N:4]([CH3:39])[C:5]1[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=2)([CH3:15])[CH3:14])=[C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(=O)N(C)c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 60 mg (0.11 mmol) N-(6-acetylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 2 ml tetrahydrofuran at room temperature under argon were added dropwise 0.13 ml (0.12 mmol) of a 1 M solution of potassium hexamethyldisilazide in tetrahydrofuran. Stirring was continued for 1 h at room temperature and 17 mg (0.12 mmol) methyl iodide were added. After stirring overnight, the solvent was evaporated and the residue was purified by flash-chromatography to give 40 mg (65%) of the title compound as white foam. MS m/e (%): 574 (M+Na+, 17), 552 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[OH-].[K+].[CH3:23]I>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:23])[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([NH2:20])=[O:19])[C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc3cccc(C(N)=O)c3[nH]2)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(-c2nc3c(C(N)=O)cccc3n2C)cc1

Procedure:
2-(4'-Methoxyphenyl)benzimidazole-4-carboxamide (NU1076 from Example 5) (105.3 mg, 0.394 mmol) and powdered potassium hydroxide (22 mg, 0.394 mmol) were suspended in acetone (4 ml) and stirred until all the solids had dissolved. Methyl iodide (24.6 μl1, 0.394 mnol) was added and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure and the white solid residue purified by column chromatography with dichloromethane/methanol 95:5 to give fine white crystals of the title compound. (33.2 mg, 30%)