Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC3CCCC3)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cccc(OCC3CCCC3)c2c(N)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a solution of ethyl 4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylate (Example 18a, 16.8 g, 51.2 mmol) in EtOH (100 mL) was added NaOH (2 N, 64 mL) at room temperature. The reaction mixture was refluxed for 4 h. After it was cooled down to room temperature, the reaction solution was filtered to remove any possible solid residue. The filtrate was carefully neutralized with 2N HCl to pH 7 at 0° C. The resultant precipitate was collected by filtration, washed with water, re-dissolved in EtOH (500 mL) and water (30 mL), and treated with activated charcoal (650 mg) at 70° C. for 0.5 h. The charcoal was removed by filtration, and the filtrate was concentrated and stored at 4° C. overnight. The resulting precipitate was collected by filtration, washed with cold 25% EtOH in H2O, and dried under vacuum at 60° C. overnight to give the title compound as an off-white solid (7.5 g, 49%). 1H NR (400 MHz, DMSO-d6) δ 1.31-1.37 (m, 2H), 1.53-1.64 (m, 4H), 1.79-1.85 (m, 2H), 2.47-2.50 (m, 1H), 2.75 (s, 3H), 4.11 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 8.77 (brs, 1H), 12.26 (brs, 1H), 12.75 (brs, 1H). 1H NR (400 MHz, CD3OD) δ 1.39-1.49 (m, 2H), 1.63-1.77 (m, 4H), 1.91-1.98 (m, 2H), 2.51-2.61 (m, 1H), 2.78 (s, 3H), 4.16 (d, J=8.0 Hz, 2H), 7.08 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H). MS 301 (MH+).
Reaction SMILES: [OH-].[NH4+].[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C:5]([CH3:8])([CH3:7])[CH3:6]>CC(C)=O>[NH2:3][CH:4]([C:9]([OH:11])=[O:10])[C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)(C)C(N)C(=O)O
Temperature: 85 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
Ammonium hydroxide (50 mL, 30%) solution was placed in an autoclave and D-tert-leucine (5 g) was added. Autoclave was closed and the contents were heated to 85° C. under stirring for 12 hours. After cooling the solution was transferred and concentrated under vacuum at 55° C. The solid residue obtained was stirred with acetone (20 mL), filtered and dried to obtain DL-tert-leucine (4.6 g, 92% yield, L-isomer: 42%, D-isomer: 58%)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[NH:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: O[C@H]1CCCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1
Temperature: 65 °C

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.106 g, 0.301 mmol, from Example 47, Step 2), (3S)-piperidin-3-ol hydrochloride (0.0498 g, 0.362 mmol), palladium acetate (1 mg, 0.006 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6 mg, 0.009 mmol), and cesium carbonate (0.274 g, 0.843 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over sodium sulfate and evaporated to dryness. The resulting residue was purified on silica gel, eluting with 0 to 100% ethyl acetate in hexane, to give the desired product. LCMS calculated for C16H18ClN2O2 (M+H)+: m/z=305.1; Found: 305.0.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:37][CH:36]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22]CC)=[O:21])[CH:13]=[CH:12][C:11]1=2)C.[OH-].[K+].C(O)(=O)C.Cl>O1CCOCC1.O>[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:37][CH:36]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([OH:22])=[O:21])[CH:13]=[CH:12][C:11]1=2)([OH:49])=[O:3]
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(CCc2ccccc2)cc1)C1CCCc2nc(C(=O)OCC)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)CCCCN(CCc1ccccc1OCc1ccc(CCc2ccccc2)cc1)C1CCCc2nc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
259 mg (0.39 mmol) of ethyl 5-{(5-ethoxy-5-oxopentyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}-phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 50A) were taken up in 4 ml of dioxane, 2 ml of a 2 M solution of potassium hydroxide in water were added and the mixture was stirred at room temperature overnight. After the reaction had gone to completio, the reaction mixture was acidified slightly using 0.75 ml of acetic acid and 1 N of hydrochloric acid and then concentrated to dryness. The residue obtained was purified by preparative HPLC. This gave 183 mg (0.30 mmol, 77% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(Cl)(Cl)Cl.O>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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:8][C:6]1[CH:7]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Brc1cncc(N2CCOCC2)c1
Yield: 64.8 %

Procedure:
To a solution of 3,5-dibromopyridine (XL) (1.68 g, 7.1 mmol) in dioxane (14 mL) was added morpholine (682 mg, 7.8 mmol), CsCO3 (3.24 g, 9.93 mmol) and xantphos (123 mg, 0.21 mmol). The solution was degassed before adding Pd2(dba)3 (195 mg, 0.21 mmol). The reaction was microwaved at 90° C. for 4 h. The reaction was poured into a mixture of CHCl3/H2O; the aqueous layer was separated, washed with water, then brine and concentrated under vacuum. The crude product was purified on a silica gel column (100% hexane→1:3 EtOAc:hexane) to give 4-(5-bromopyridin-3-yl)morpholine (XLI) as a yellow solid (1.12 g, 4.6 mmol, 65% yield). ESIMS found C9H11BrN2O m/z 244 (M+H).
Reaction SMILES: [CH2:1]([NH:8]/[CH:9]=[CH:10]/[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1(C)C=CC=CC=1>[CH2:1]([N:8](/[CH:9]=[CH:10]/[CH2:11][CH3:12])[C:20](=[O:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC/C=C/NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC/C=C/N(Cc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 62a (3.22 g, 20 mmol) in 10 mL of toluene, was added triethylamine (2.79 mL, 20 mmol). The mixture was cooled to 0° C. and acetic anhydride (1.89 mL, 20 mmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. It was then concentrated on high vacuum to give crude 62b.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=O>C1COCC1>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
A solution of 2,2-dimethyl-1-[4(4-nitro-phenyl)-piperazin-1-yl]-propan-1-one (8.0 g, 27.5 mmol) in THF (100 mL) was added dropwise to a solution of borane-dimethylsulfide complex (16 mL, 166 mmol) in THF (100 mL) over 30 minutes and stirred for 3 h at room temperature. The mixture was quenched with saturated ammonium chloride solution (200 mL) and concentrated to remove organic solvents under reduced pressure (<45° C.). The aqueous layer was extracted with ethyl acetate (3×100 mL) then the combined extracts were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated to dryness to afford 1-(2,2-dimethyl-propyl)-4-(4-nitro-phenyl)-piperazine (6 g, 79%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O.N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:18][C:14]1[NH:13][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc[nH]1
Agent: COc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2c(c1)C(=Cc1ccc[nH]1)C(=O)N2
Temperature: 85 °C

Procedure:
5-Methoxyindolin-2-one was prepared by the method of Crestini, C.; Saladino, R. Synth. Commun. (1994), Vol. 24, NO. 20, p. 2835. A solution of 5-methoxyindolin-2-one (0.41 g, 2.5 mmol) and 2-pyrrolecarboxaldehyde (0.25 g, 2.6 mmol) in ethanol (5 mL) was treated with piperidine (0.05 g, 0.65 mmol). The reaction mixture was then heated to 85° C. for 3 hours. The reaction was then cooled to ambient temperature and the reaction mixture was chromatographed on SiO2 (12 g) using 3:1 hexane/ethyl acetate to afford 5-methoxy-3-[(pyrrol-2-yl)methylene]indolin-2-one; (0.48 g); 1H NMR (400 MHz, DMSO-d6) δ 3.74 (s, 3H), 6.30 (m, 1H), 6.60–6.80 (m, 3H), 7.30 (m, 1H), 7.35 (m, 1H), 7.76 (m, 1H), 10.80 (s, 1H) ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[NH:9])=[CH:5][C:4]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1.[CH3:22]N.O>CO>[NH:9]=[C:8]([NH:10][CH3:22])[C:6]1[S:7][C:3]([S:2][CH3:1])=[C:4]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH:5]=1
Reactant: CSc1sc(C(=N)N)cc1-c1nc(-c2ccccc2)cs1
Reactant: CN
Solvent: O
Solvent: CO
Product: CNC(=N)c1cc(-c2nc(-c3ccccc3)cs2)c(SC)s1
Yield: 72 %

Procedure:
5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine (20 mg, 0.06 mmol) as prepared in Example 10 step (b) was dissolved in MeOH, and to this solution methylamine (0.6 mL, 2M solution in tetrahydrofuran) was added. This solution was refluxed for 6h, at which time the solvents were removed under vacuum to give a solid. This solid was dissolved in a small amount of MeOH. H2O was added dropwise to the methanolic solution until a precipitate was formed. This solid was isolated, washed with a small amount of water and dried under vacuum to give 15 mg (72%) of {imino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))(2-thienyl)]methyl}methylamine. 1H-NMR (DMSO-d6; 300 MHz) δ 2.77 (s, 3H), 3.00 (s, 3H), 7.36-7.42 (m, 1H), 7.47-7.52 (m, 2H), 8.07-8.10 (m, 2H), 8.23 (s, 1H), 8.55 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C16H15N3S3, 346.5 (M+H), found 346.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:19]1[CH2:24][C@@H:23]([C:25](=[O:30])N(OC)C)[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:20]1)=[O:17].[CH2:42]([Mg]Br)[CH3:43].C1COCC1.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:40])[CH3:41])[C@H:19]1[CH2:24][C@@H:23]([C:25](=[O:30])[CH2:42][CH3:43])[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:20]1)=[O:17]
Reactant: CC[Mg]Br
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N(C)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCCCOC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (22.7 g) in THF (20 ml) was added 1M-ethylmagnesium bromide-THF solution (119 ml) at room temperature, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-3:2) was concentrated under reduced pressure to give the object product (14.96 g).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]1([N:33]2[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]3[O:46][N:45]=[C:44]4[C:47]5[C:52]([CH2:53][CH2:54][C:43]=34)=[CH:51][C:50]([CH:55]=[CH2:56])=[CH:49][CH:48]=5)[CH:35]=[N:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O>[C:1]1([C:7](=[N:14][CH:15]([CH2:56][CH2:55][C:50]2[CH:51]=[C:52]3[C:47](=[CH:48][CH:49]=2)[C:44]2=[N:45][O:46][C:42]([C:36]4[CH:35]=[N:34][N:33]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:37]=4[C:38]([F:40])([F:41])[F:39])=[C:43]2[CH2:54][CH2:53]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A solution of ethyl 2-(diphenylmethyleneamino)acetate (315 mg, 1.178 mmol) in anhydrous dimethylsulfoxide (1 mL) was purged with nitrogen for 10 min before cesium carbonate (192 mg, 0.589 mmol) was added. The mixture was purged with nitrogen for 5 min. and stirred at room temperature for 30 min. Next, 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 50A, 100 mg, 0.245 mmol) was added, the mixture was purged with nitrogen for 5 min and then stirred at 40° C. for 5 hr. The reaction mixture was cooled, diluted with water (10 mL), and extracted with ethyl acetate (3×5 mL). The ethyl acetate extracts were dried over sodium sulfate and concentrated under reduced pressure. Flash chromatography purification using an ISCO setup (4 g silica gel column, 10→100% ethyl acetate in hexanes) afforded ethyl 2-(diphenylmethyleneamino)-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (160 mg, 0.237 mmol, 97% yield) as a glassy solid. LC/MS M+1=675.4.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([CH2:10][C:11]([OH:13])=O)[CH2:9][CH2:8]1.C1(CC(Cl)=O)CC1.[CH3:21][NH:22][O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].Cl.CNOC>ClCCl.O>[CH3:24][O:23][N:22]([CH3:21])[C:11](=[O:13])[CH2:10][CH:7]1[CH2:9][CH2:8]1
Reactant: O=C(O)CC1CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)CC1CC1
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)CC1CC1
Temperature: 0 °C
Reaction time: 42 h

Procedure:
Oxalyl chloride (9.6 ml) was added dropwise at 0° C. under nitrogen to a stirred solution of cyclopropaneacetic acid (10 g) in dichloromethane (250 ml), then the mixture was stirred at 0° C. for 1 hour and at ambient temperature for 42 hours. The resulting solution of cyclopropaneacetyl chloride was added dropwise at 0-5° C. to a stirred aqueous solution of N,O-dimethylhydroxylamine prepared by addition of potassium carbonate (24.8 g) in portions at 0-5° C. over 30 minutes to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (10.2 g) in water (110 ml). When the addition of the acid chloride solution was complete, the mixture was stirred at 0° C. for 20 minutes and at ambient temperature for 4 hours. The organic phase was separated, washed with saturated aqueous sodium chloride solution (50 ml) and dried (MgSO4), then the solvent was removed in vacuo to leave N-methoxy-N-methylcyclopropaneacetamide (13.6 g) as a colourless oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:5]([I:13])=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl[CH2:24][C:25]1[C:26]2[C:31]([CH:32]=[C:33]3[C:38]=1[CH:37]=[CH:36][CH:35]=[CH:34]3)=[CH:30][CH:29]=[CH:28][CH:27]=2.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CN(C=O)C>[CH:27]1[C:26]2[C:31](=[CH:32][C:33]3[C:38]([C:25]=2[CH2:24][O:1][C:2]2[C:3]4[O:16][N:15]=[C:14]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:4]=4[C:5]([I:13])=[N:6][C:7]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccccc3)noc2c1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(I)c2c(-c3ccccc3)noc2c1OCc1c2ccccc2cc2ccccc12
Temperature: 55 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (300 mg, 0.73 mmol), 9-chloromethylanthracene (249 mg, 1.10 mmol), 18-crown-6 (29 mg, 0.11 mmol) and K2CO3 (152 mg, 1.10 mmol) were added to DMF, and the mixture was stirred at 55° C. for 3 h. EtOAc (50 mL) was added and the organic layer was washed with brine and dried over MgSO4. Solvent was removed in vacuo and the crude product was purified twice by flash chromatography (0-30% EtOAc/hexanes) to give 200 mg of the title compound. 1H NMR (CDCl3, 200 MHz): δ=8.65-8.80 (m, 2H), 8.18 (s, 1H), 7.70-7.80 (m, 2H), 7.40-7.55 (m, 3H), 7.18-7.30 (m, 6H), 6.30 (s, 2H), 3.95 (q, 2H, J=7.0 Hz), 0.72 (t, 3H, J=7.2 Hz).
Reaction SMILES: I(C1C=CC=CC=1)=O.B(F)(F)F.C[Si](C)(C)[O:15][C:16]([C:18]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)=[CH2:17].[CH3:30][OH:31]>>[CH3:30][O:31][CH2:15][C:16]([C:18]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: CO
Reactant: C=C(O[Si](C)(C)C)c1ccnc2ncccc12
Agent: FB(F)F
Agent: O=Ic1ccccc1
Product: COCC(=O)c1ccnc2ncccc12
Temperature: 25 °C

Procedure:
To a suspension of iodosobenzene (347 mg, 1.57 mmol), in MeOH (7.2 ml) in an ice bath was added borontrifluoride diethyletherate (0.200 ml, 1.57 mmol) followed by 4-(1-trimethylsilanyloxy-vinyl)-[1,8]-naphthyridine from Step 1 (350 mg, 1.43 mmol) in minimum amount of MeOH. The reaction mixture was warmed to RT overnight and then quenched with solid NaHCO3 and diluted with water. Iodobenzene was extracted with EtOAc and the desired material re-extracted with DCM 2×. The organic layers were dried over Na2SO4 and concentrated to an orange oil (110 mg), which consisted of a 2:3 mixture of starting material and desired title compound. MS (ESI+) for m/z 203 (M+H)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].ClC(Cl)C.[C:9](Cl)(=[O:12])[CH2:10][CH3:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([O:22][CH3:23])[C:18]([CH3:21])=[CH:19][C:20]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)Cl
Reactant: COc1cc(Cl)ccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCC(=O)c1cc(C)c(OC)cc1Cl
Temperature: 0 °C

Procedure:
In a three neck round bottom flask equipped with a reflux condenser and stir bar under N2 atmosphere was added finely pulverized aluminum trichloride (8.7 g, 65.2 mmol) to dichloroethane (22 mL). The solution was chilled to 0° C. Propionyl chloride was added dropwise 4.9 mL (57 mmol)and the mixture was stirred vigorously for 10 min. 4-Chloro-2-methoxy-1-methyl-benzene (8.5 g, 54.3 mmol) was then added dropwise with cooling to maintain internal solution temperature below 20° C. For less reactive aromatic rings the arene itself was used as solvent. The mixture was stirred for one hour with gradual warming to room temperature, then heated to 50° C. overnight. When starting material was not visible by TLC the reaction was cooled to room temperature. The reaction was quenched by pouring into ice and the layers separated in a separatory funnel. The aqueous phase was extracted once with chloroform. The combined organic layers were washed with 10 N HCl, water, aqueous NaHCO3 (saturated) then dried (sodium sulfate), and concentrated in vacuo. The product was then purified by chromatography on silica using an ethyl acetate/hexane gradient. Yield: 5.41 g white crystalls (51%). 1H NMR (300 MHz, CDCl3) •1.28 (t, CH3, 3H, J=7.0 Hz), 2.27 (s, CH3, 3H), 3.06 (q, CH2, 2H, J=7.0 Hz) 3.95 (s, —OCH3, 3 H), 6.91 (s, Ar, 1H, ), 6.95 (s, Ar, 1H), 7.50 (s, Ar, 1H).
Reaction SMILES: [OH:1][CH:2]([C:28]([F:31])([F:30])[F:29])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:7][CH:6]=1.[C:32](Cl)(=[O:36])[CH2:33][CH2:34][CH3:35]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:32]([O:1][CH:2]([C:28]([F:30])([F:31])[F:29])[CH:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC(=O)Cl
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(O)C(F)(F)F)cc2)nc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(OC(=O)CCC)C(F)(F)F)cc2)nc1
Reaction time: 4 h
Yield: 93.1 %

Procedure:
1.0 g of (-)-2-(4-(3-hydroxy-4,4,4-trifluoro-1-butenyl)phenyl)-5-decyloxypyrimidine was dissolved in 20 ml of pyridine. The solution was added with 0.5 g of butyryl chloride and stirred at 25°-30° C. for 4 hours. The reaction mixture was diluted with 100 ml of toluene and washed with 4N hydrochloric acid, water, a 5% sodium bicarbonate solution and water successively in that order, and then the toluene layer was concentrated under reduced pressure. The residue was purified by subjecting it to silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 1.08 g of (+)-2-(4-(3-butyryloxy-4,4,4-trifluoro-1-butenyl)phenyl)-5-decyloxypyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)[CH:19]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Reactant: OB(O)c1ccncc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3ccncc3)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.5) (0.185 g, 0.5 mmol) and commercially available 4-pyridineboronic acid (0.08 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.06 g, 29%). MS (ISP) 413.0 [(M+H)+]; mp 193° C.