Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=O)=[CH:6][C:5]=1[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])([O-:3])=[O:2].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][CH:10]2[C:11]3[C:7](=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Reactant: Nc1ccc(F)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCOC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(Nc1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of ethyl 6-nitro-1-oxo-2,3-dihydro-1H-inden-5-ylcarbamate (0.47 g, 1.8 mmol), 4-fluoroaniline (0.24 g, 2.2 mmol), and decaborane (200 mg) in 20 ml of anhydrous methanol was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by column (hexane/EtOAc, 5:1) to give a pure product (0.51 g, 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17])[CH:6]=[CH:5]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:35][Si](C)(C)C)(C)C.[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH2:35])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: CN1CCC[C@H]1Cn1ccc2cc(Br)ccc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CN1CCC[C@H]1Cn1ccc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
compound 102 (106 mg, 0.362 mmol), tris(dibenzylideneacetone)dipalladium (0) (33.1 mg, 0.0362 mmol) and anhydrous tetrahydrofuran (10 mL) were charged to a dry argon purged flask fitted with magnetic stir bar and condenser. A solution of tri-tert-butylphosphine (146.3 mg, 222 ul, 0.0723 mmol, 10 wt % in hexane) is added followed by dropwise addition of a 1M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1.084 ml, 1.084 mmol) and mixture refluxed for a period of 90 minutes. The mixture was cooled to room temperature then to 0° C., quenched with 1M HCl (10 mL) and stirred for 10 minutes. The solution was diluted with ethyl acetate and 5M NH4OH added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (MeOH:CH2Cl2, 1:9) to yield compound 103 (67 mg, 80.8%)as a pale yellow solid. 1H NMR (DMSO-d6) δ 1.40-1.70 (2×m, 4H), 2.08-2.20 (m, 1H), 2.18 (s, 3H), 2.89-2.99 (m, 1H), 3.89 (dd, 1H, J=14.1, 6.9 Hz), 4.12 (dd, 1H, J=14.2, 5.1 Hz), 4.46 (brs, 2H), 6.10 (d, 1H, J=3.0 Hz), 6.51 (dd, 1H, J=8.7, 2.0 Hz), 6.66 (d, 1H, J=2.0 Hz), 7.12-7.15 (m, 2H); ESI-MS (m/z, %): 230 (MH+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[Na+]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:11]3[C:16]([CH:9]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(-c2cc3ccccc3[nH]2)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To 47.2 g of polyphosphoric acid was added 13.62 g (0.10 mol) of 4′-hydroxyacetophenone and 10.0 mL (0.10 mol) of phenylhydrazine at room temperature. The mixture was heated at 150° C. (oil bath temp) for 1 h. After cooling to room temperature an ice-cold H2O (250 mL) was added and the dark brown mixture was stirred overnight. This was then neutralized with 5.0 N NaOH (100 mL) and extracted with EtOAc (1 L×4) which was washed with saturated aqueous NaHCO3 and brine (500 mL each). Organic layers were dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated to ca. 200-300 mL. This was treated with charcoal, filtered and concentrated. The crude 2-(4-hydroxyphenyl)indole 12.02 g (57%) was obtained. The crude phenolic indole (10.7 g; 51 mmol) was treated with 33.32 g (0.10 mol) of Cs2CO3 and 6.7 mL (56 mmol) of benzyl bromide in ca. 250 mL of DMF at room temperature overnight. The mixture was filtered through a pad of diatomaceous earth with thorough EtOAc rinse. The filtrate was taken up in to 1 L of EtOAc and washed with H2O (500 mL×2) and brine (500 mL) which were back-extracted with EtOAc (1 L×3). Combined organic layers were dried over MgSO4, concentrated and purified by PrepLC with 10:90 benzene-hexanes and 10:10:80 benzene-Et2O-hexanes to obtain 5.34 g (27%) of N,O-dibenzylated product and 1.94 g (13%) of the named benzyl ether.
Reaction SMILES: [CH2:1](OC1C=CC(C2C=CC(=O)NN=2)=CC=1OC)C(C)C.[CH2:21]([O:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:35]=[CH:36][C:37](=[O:40])[NH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:22](C)C.C(OC1C=C(C2C=CC(=O)NN=2)C=CC=1OC)C.COC1C=C(C2C=CC(=O)NN=2)C=CC=1OCCC>>[CH:21]([O:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:35]=[CH:36][C:37](=[O:40])[NH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])([CH3:22])[CH3:1]
Reactant: COc1cc(-c2ccc(=O)[nH]n2)ccc1OCC(C)C
Reactant: COc1ccc(-c2ccc(=O)[nH]n2)cc1OCC(C)C
Agent: CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Agent: CCOc1cc(-c2ccc(=O)[nH]n2)ccc1OC
Product: COc1ccc(-c2ccc(=O)[nH]n2)cc1OC(C)C

Procedure:
The following are obtained analogously: 6-(4-isobutoxy-3-methoxyphenyl)-3[2H ]pyridazinone, m.p. 184°, 42.2% of theory, 6-(3-isobutoxy-4-methoxyphenyl)-3[2H]pyridazinone, m.p. 186°, 58.4% of theory, 6-(3-ethoxy-4-methoxyphenyl )-3[2H]pyridazinone, m.p. 171°, 73.1% of theory and 6-(3-methoxy-4-n-propoxyphenyl)-3[2H ]pyridazinone, m.p. 173°, 66.3% of theory.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]([OH:17])=O)[C:11]=3[CH:18]=2)=[N:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:17])[C:11]=3[CH:18]=2)=[N:4][N:3]=1
Reactant: C1COCCN1
Reactant: Cc1nnc(-c2ccc3occ(C(=O)O)c3c2)o1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc3occ(C(=O)N4CCOCC4)c3c2)o1
Reaction time: 0.25 h
Yield: 27 %

Procedure:
To a suspension of 5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-carboxylic acid (97.7 mg, 0.400 mmol) and N,N-dimethylformamide (1 drop) in tetrahydrofuran (5 mL) was added oxalyl chloride (0.0698 mL, 0.800 mmol) at room temperature, and the resulting mixture was stirred for 15 min. The reaction mixture was added dropwise to a mixture of morpholine (0.105 mL, 1.20 mmol) and saturated aqueous sodium hydrogen carbonate solution (5 mL) at room temperature, and the resulting mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and recrystallized from methanol/water to give the title compound (33.8 mg, yield 27%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CC([O-])=O.[K+].Cl[C:53]1[CH:58]=[CH:57][N:56]=[CH:55][C:54]=1[N+:59]([O-:61])=[O:60]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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].C(Cl)Cl.O.CCOC(C)=O>[CH3:8][C:6]1[N:5]=[C:4]([NH2:9])[CH:3]=[C:2]([C:53]2[CH:58]=[CH:57][N:56]=[CH:55][C:54]=2[N+:59]([O-:61])=[O:60])[CH:7]=1
Reactant: Cc1cc(Cl)cc(N)n1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccncc2[N+](=O)[O-])cc(N)n1
Temperature: 110 °C
Yield: 35 %

Procedure:
To a solution of 4-chloro-6-methylpyridin-2-amine (1.0 equiv.) in dioxane was added bis(pinacolato)diboron (2.0 equiv.), Pd2(dba)3 (0.05 equiv.), PCy3 (0.075 equiv.), and KOAc (3.0 equiv.). The reaction was heated for 3 hrs at 110° C., then filtered, and concentrated. The crude material was dried under vacuo, then dissolved in DME/2M Na2CO3 (3:1), 4-chloro-3-nitropyridine (2.0 equiv.) was added, followed by Pd(dppf)Cl2-DCM (0.1 equiv.). The mixture was heated to 120° C. for 1 hr, then EtOAc and H2O were added, the organic phase was removed, dried with Na2SO4, and concentrated. Purification via SiO2 column chromatography eluting with EtOAc yielded 6-methyl-3′-nitro-4,4′-bipyridin-2-amine in 35% yield. LCMS (m/z): 231.1 (MH+) LC Rt=1.47 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]([CH:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:24][CH:25]([F:49])[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]2[CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:36]=[C:35]([CH3:48])[CH:34]=2)[N:27]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:49][CH:25]([F:24])[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]2[CH:38]=[C:37]([C:2]3[CH:3]=[N:4][C:5]([CH:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[C@H:9]4[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]4)=[N:6][CH:7]=3)[CH:36]=[C:35]([CH3:48])[CH:34]=2)[N:27]=1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)[C@H]1CC[C@H](C(OS(C)(=O)=O)c2ncc(Cl)cn2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CC[C@H](C(OS(C)(=O)=O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)F)n4)c3)cn2)CC1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
A mixture of methyl trans-4-{(5-chloropyrimidin-2-yl)[(methylsulfonyl)oxy]methyl}cyclohexanecarboxylate (48 mg, 0.13 mmol), 4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (48 mg, 0.13 mmol), tris(dibenzylideneacetone)-dipalladium(0) (6.1 mg, 0.006 mmol), XPhos (6.2 mg, 0.012 mmol), and potassium phosphate tribasic trihydrate (0.11 g, 0.4 mmol) in 1,4-dioxane/water (2 mL/0.5 mL) was stirred at 90° C. under a nitrogen atmosphere for 12 hours. After cooling to 20° C., the mixture was diluted with brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to afford methyl trans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl][(methylsulfonyl)oxy]methyl}cyclohexanecarboxylate. MS ESI calc'd. for C26H30F2N5O5S[M+H]+ 562. found 562. 1H NMR: (400 MHz, CD3OD) δ 9.12 (s, 2H), 8.66 (d, J=4.8 Hz, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.26 (s, 1H), 7.06 (d, J=4.8 Hz, 1H), 6.61 (t, J=54.4 Hz, 1H), 5.47 (d, J=7.0 Hz, 1H), 3.66 (s, 3H), 3.08 (s, 3H), 2.46 (s, 3H), 2.34 (s, 1H), 2.10-2.00 (m, 4H), 1.52-1.31 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.C(OC(C1C(=O)N(CC2C=CC(F)=CC=2)C2C=CSC=2C=1N1CCN(C(C2OC=CC=2)=O)CC1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=2)[C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2[nH]c1=O
Reactant: Fc1cccc(CBr)c1
Agent: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2n(Cc2ccc(F)cc2)c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 7-[4-(furan-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (10) and 3-fluoro benzyl bromide by applying a similar method as described for 4-(4-fluoro-benzyl)-7-[4-(furan-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (11). Yield 210 mg, (22%). 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.82 (m, 4H), 4.26 (q, J=7.2 Hz, 2H), 5.38 (s, 2H), 6.65 (m, 1H), 7.07 (m, 4H), 7.34 (d, J=5.6 Hz, 1H), 7.37 (m, 1H), 7.88 (m, 1H), 8.03 (d, J=5.6 Hz, 1H); EIMS m/z 510 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]O)[C:5]([C:10]([OH:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][O:13][C:10]([CH3:11])([CH3:12])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc(Cl)nc1CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OCc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-[6-Chloro-2-(hydroxymethyl)pyridin-3-yl]propan-2-ol (200 mg, 0.99 mmol) was taken up in tetrahydrofuran (5 mL) and cooled to −78° C. n-Butyllithium (1.24 mL 011.6 M in hexanes, 1.98 mmol) was added dropwise and the mixture was allowed to stir for 30 minutes. p-Toluenesulfonylchloride (190 mg, 0.99 mmol) was then added in one portion and the mixture was allowed to warm to room temperature warm slowly to 0° C. over two hours and then left to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride and the biphasic mixture was extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified via flash chromatography (silica, 0-50% ethyl acetate/hexanes) to afford the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:24]1[O:33][C:32]2[C:26](=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[O:25]1.CC(O)CCC.Cl>C(O)(C)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:32]2[O:33][CH2:24][O:25][C:26]=12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Nc1cccc2c1OCO2
Agent: Cl
Solvent: CCCC(C)O
Solvent: CC(C)O
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Yield: 106.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (0.1 g), 2,3-methylenedioxyaniline (0.048 g), pentan-2-ol (5 ml) and a solution of hydrogen chloride in isopropanol (6M, 4 drops) was stirred and heated to 100° C. for 5 hours. The resultant mixture was cooled to ambient temperature and the precipitate was isolated by filtration, washed with pentan-2-ol and dried under vacuum. There was thus obtained the title compound (0.138 g) as a dihydrochloride salt; NMR Spectrum: (DMSOd6 and CF3COOD) 2.35 (m, 2H), 2.5 (m, 2H), 3.15 (m, 2H), 3.3 (m, 2H), 3.55 (d, 2H), 3.8 (t, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 6.1 (s, 2H), 7.0 (m, 3H), 7.4 (s, 1H), 8.2 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 439; Elemental Analysis: Found C, 52.8; H, 5.56; N, 10.68. C23H26N4O5 2HCl 0.5H2O requires C, 53.08; H, 5.62; N, 10.77%.
Reaction SMILES: [Br:1]Br.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11]2)[N:6]=[CH:5]1.O.[OH-].[NH4+]>C(O)(=O)C>[Br:1][C:15]1[CH:14]=[C:13]2[C:18]([CH:10]([CH2:9][C:7]3[N:6]=[CH:5][NH:4][CH:8]=3)[CH2:11][CH2:12]2)=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc2c(c1)C(Cc1c[nH]cn1)CC2
Reactant: BrBr
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Oc1cc2c(cc1Br)CCC2Cc1c[nH]cn1
Temperature: 21.5 °C
Reaction time: 3 h

Procedure:
Bromine (130 mg, 1 eq.) is added dropwise to a stirred suspension of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol hydrochloride (130 mg) in acetic acid (6 ml). The mixture is stirred at 20-23° C. for 3 hours. The reaction mixture is then poured into water and is made alkaline with ammonium hydroxide solution. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated to dryness. The product is purified by flash chromatography using methylene chloride-methanol as eluent and is then converted to the hydrochloride salt in ethyl acetate-ethanol solution.
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:15]=[CH:16][CH2:17][CH2:18][CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:14])[NH:8]1)=[CH:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCC=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-(1-pentenyl)-6-methylpiperidine (2.5 g, 9.35 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-(1-pentenyl)-6-methylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid that was homogeneous by TLC analysis. mp 150.4-150.9° C.; 1H NMR (250 MHz) δ 9.5-9.3 (br. d, 2H), 5.74-5.62 (m, 2H), 4.19 (s, 1H), 3.55 (s, 1H), 2.1-1.3 (m, 13H), 0.87 (t, 3H); 13C NMR (62.7 MHz) δ 136.8 (s), 123.0 (s), 48.3 (s), 47.9 (s), 29.9 (s), 28.8 (s), 28.4 (s), 22.3 (s), 17.6 (s), 17.1 (s), 13.8 (s). FT-IR (neat): 3424, 3171, 2939, 1635, 1597, 1582, 1459, 1432, 1384, 1287, 1123, 1075, 895. Elemental Analysis for C11H22NCl: C, 64.83%; H, 10.9%; N, 6.87%. Found: C, 64.77%; H, 10.82%; N, 6.85%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH:12](OCC)(OCC)OCC>>[O:11]1[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=[CH:12]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(C(=O)O)ccc1O
Product: O=C(O)c1ccc2ocnc2c1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 3-amino-4-hydroxybenzoic acid (8.0 g, 1.0 eq) and 60 mL CH(OEt)3 was heated to reflux for 3 h, and then cooled to rt. The remaining CH(OEt)3 was removed under reduced pressure to give the desired product (7.8 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 13.00 (brs, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:12]([F:20])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21]N(Cl)C(OCC)=O>>[C:1]([C:5]1[O:6][C:7]2[C:13]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:12]([F:20])[CH:11]=[C:10]([Cl:21])[C:8]=2[N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)N(Cl)Cl
Reactant: CCOC(=O)Nc1c(F)ccc2nc(C(C)(C)C)oc12
Product: CCOC(=O)Nc1c(F)cc(Cl)c2nc(C(C)(C)C)oc12

Procedure:
The second starting material used to prepared those compounds in which the benzoxazole ring is formed first is a substituted-3-chloroaniline (STM2). The aniline (STM2) is reacted with the appropriate alkyl anhydride, for example trimethylacetic anhydride, under acidic conditions, yielding the corresponding N-(substituted-3-chlorophenyl)alkylamide (B-1). The aniline (STM2) can also be reacted with the appropriate propanoic acid (A-2), for example 2-methoxy-2-methylpropanoic acid, under basic conditions to form the appropriate N-(substituted-3-chlorophenyl)-substituted-alkylpropion-amide (B-2), for example N-(3-chloro-4-fluorophenyl)-2-methoxy-2-methyl-propionamide. The amides (B-1 or B-2) are in turn treated with n-butyl-lithium and cyclized with solid carbon dioxide, affording the corresponding [2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]carboxylic acid (C), for example, (2-t-butyl-6-fluorobenzoxazol-7-yl)carboxylic acid. The so-prepared carboxylic acid (C) is then reacted with ethyl chloroformate, 4-methylmorpholine, and sodium azide, yielding the corresponding [2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]carbonyl azide (C-1), which is treated with ethanol to form the corresponding ethyl N-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]carbamate (D). Additional substituents may optionally be added to the benzoxazole ring at this point. For example, ethyl N-(2-t-butyl-6-fluorobenzoxazol-7-yl)carbamate (D) is treated with N,N-dichlorourethane under acidic conditions, affording ethyl N-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)carbamate (E). The carbamates D and E are then reacted with ethyl 3-amino-4,4,4-trifluorocrotonate, sodium methoxide, and DBU to form the corresponding 3-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]-6-trifluoromethyl-2,4-(1H,3H)-pyrimidine-dione (F). The pyrimidinedione (F) is further reacted under basic conditions with an alkyl halide, for example methyl iodide, or O-(2,4-dinitrophenyl)hydroxylamine, or 1-aminooxysulfonyl-2,4,6-trimethylbenzene, affording the targeted 3-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]-1-alkyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (I) or 3-[2-alkyl- or 2-(substituted-alkyl)-substituted-benzoxazol-7-yl]-1-amino-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (II). Examples 1, 2, 4, and 5 provide the detailed procedures for this route.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH3:22].[CH:23](N1CCCCC1)=[O:24]>CCCCCC.O1CCCC1.O.C(O)(=O)C>[Br:13][C:14]1[C:15]([O:21][CH3:22])=[C:16]([C:17]([F:20])=[CH:18][CH:19]=1)[CH:23]=[O:24]
Reactant: O=CN1CCCCC1
Reactant: COc1cc(F)ccc1Br
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Br)ccc(F)c1C=O
Reaction time: 0.17 h

Procedure:
In an atmosphere of nitrogen gas, 18.7 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 5 g of N,N-diisopropylamine in 89 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 1 hour and 10 minutes, 9.27 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a was added dropwise. After stirring at the same temperature for 1.5 hours, 5.52 ml of N-formylpiperidine was added dropwise. After stirring at the same temperature for 25 minutes, 9 ml of acetic acid was added at the same temperature, water was added at room temperature, and the mixture was extracted with diethyl ether for three times. The extract was sequentially washed with 0.2 N hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 5.65 g of the title compound as pale yellow crystals.