Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>CN(C)C=O>[Si:20]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5]1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Into a 50-mL round-bottom flask was placed benzyl 3-hydroxyazetidine-1-carboxylate (2.15 g, 10.38 mmol, 1.00 equiv), TBSCl (2.34 g, 15.60 mmol, 1.50 equiv), imidazole (1.27 g, 18.68 mmol, 1.80 equiv) and N,N-dimethylformamide (15 mL). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 30 mL of water. The mixture was extracted with 3×40 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of sodium chloride (sat.). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). Purification afforded 3.0 g (90%) of benzyl 3-[(tert-butyldimethylsilyl)oxy]azetidine-1-carboxylate (50.3) as a light yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[C:4]([C:21](=[O:24])[CH2:22][CH3:23])[CH:3]=1>C(O)C.C(O)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[C:4]([C:21](=[O:24])[CH2:22][CH3:23])[CH:3]=1
Reactant: CCOC(=O)N1C2C=C(c3ccc(Cl)cc3C(=O)CC)CC1CC2
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)N1C2CCC1CC(c1ccc(Cl)cc1C(=O)CC)C2

Procedure:
A solution of ethyl 3-(4-chloro-2-propionylphenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (2-6) (1.50 g, 4.31 mmol,) in 10 mL of ethanol and 10 mL acetic acid was shaken under hydrogen at 1 atmospheric pressure with platinum oxide (980 mg, 0.431 mmol, added in portions) for 60 h at room temperature. Solid was filtered through a pad of Celite and rinsed with ethanol. The ethanol solution was concentrated to give (2-7) as colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH:13]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[N:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:14]1>>[CH:13]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[N:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[N:2]([CH3:1])[CH3:12])[CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: CN(C)c1ccccc1C(=O)O
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: CN(C)c1ccccc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-dimethylaminobenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (61% yield). 1H NMR (300 MHz, CDCl3) δ 8.04, 7.96, 7.36-7.25, 7.05-6.94, 4.17-3.40, 2.80, 1.51, 0.80-0.73, 0.47-0.42, 0.12-0.07.
Reaction SMILES: BrC1C=CC([C@@H]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23](=[O:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])C)=CC=1.[CH3:27][Mg]Br>C1COCC1>[OH:25][C:23]([CH3:24])([CH3:27])[CH2:22][C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:12][C:11](=[O:26])[NH:10][CH2:15][CH2:14]1
Reactant: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)CC1(c2ccccc2)CCNC(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl -1,3-oxazinan-2-one (12 g, 28.8 mmol) in anhydrous THF (100 mL) was added dropwise methylmagnesium bromide (48 mL, 144 mmol) at −78° C. under nitrogen. The mixture was stirred at rt for 1 h. The reaction mixture was quenched with aqueous NH4Cl solution (50 mL) in ice water bath. The layers were separated and the aqueous layer was extracted with EtOAc (150 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC and chiral HPLC to afford (S)-3-(S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (6.6 g, 53%).
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:4].[C:19]([O-])([O-])=O.[K+].[K+].CI.O>C(#N)C>[CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH3:19])[N:14]=[CH:15][C:16]=2[CH:17]=[O:18])=[CH:8][CH:7]=1)([CH3:2])[CH3:4]
Reactant: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1ccc(-c2c(C=O)cnn2C)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A mixture of 3-[4-(propan-2-yloxy)phenyl]-1H-pyrazole-4-carbaldehyde hydrochloride (400 mg, 1.5 mmol) and K2CO3 (624 mg, 4.5 mmol) in acetonitrile (6 ml) was stirred at 0-5° C. for 1 h. Methyl iodide (310 mg, 2.2 mmol) was added and stirred at ambient temperature for 48 h. The reaction was poured into water (200 mL), extracted with EtOAc (50 mL×3). The combined extracts were washed with brine (100 mL), dried, and concentrated under vacuum. The residue was purified by prep-TLC using Hexane:EtOAc (21:9) as eluent to afford 5-(4-isopropoxyphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (88 mg, Yield 21%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.63 (s, 1H), 8.05 (s, 1H), 7.36-7.32 (m, 2H), 7.06-7.02 (m, 2H), 4.69-4.64 (m, 1H), 3.84 (s, 3H), 1.0 (d, J=6 Hz, 6H) ppm. LCMS (method C): RT=2.11 min, m/z=245.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[CH3:11])=[O:5])[CH3:2].S(Cl)([Cl:15])(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([Cl:15])[O:8][C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccoc1C
Reactant: O=S(=O)(Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Cl)oc1C
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-3-furancarboxylic acid ethyl ester (10.5 g) was dissolved in acetonitrile (50 ml), and sulfuryl chloride (5.6 ml) was added under ice-cooling. The mixture was stirred at 10° C. for 30 minutes, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours, and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-2-methyl-3-furancarboxylic acid ethyl ester (10 g) as oil. 5-Chloro-2-methyl-3-furancarboxylic acid ethyl ester (10 g) was dissolved in ethanol (100 ml), and 1N aqueous sodium hydroxide (60 ml) was added. The mixture was stirred under reflux for 30 minutes and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were recrystallized from acetone-hexane to give 5-chloro-2-methyl-3-furancarboxylic acid (5.5 g) as crystals.
Reaction SMILES: [OH:1][C:2]([C:35]([F:38])([F:37])[F:36])([CH2:18][C:19]([C:22]1[C:30]2[O:29][CH2:28][CH2:27][C:26]=2[CH:25]=[C:24]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:23]=1)([CH3:21])[CH3:20])[CH2:3][C:4]#[C:5][C:6]1[C:13]([N+:14]([O-])=O)=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH3:17].C(O)(=O)C>C(O)C.ClCCl.[Fe]>[NH2:14][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([CH3:17])[C:6]=1[C:5]#[C:4][CH2:3][C:2]([OH:1])([C:35]([F:37])([F:38])[F:36])[CH2:18][C:19]([C:22]1[C:30]2[O:29][CH2:28][CH2:27][C:26]=2[CH:25]=[C:24]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:23]=1)([CH3:21])[CH3:20])[C:10]#[N:11]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Agent: [Fe]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C#N)cc(N)c1C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Temperature: 90 °C
Yield: 90 %

Procedure:
A stirred solution of 4-[4-hydroxy-6-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-6-methyl-4-trifluoromethylhept-1-ynyl]-3-methyl-5-nitrobenzonitrile. (165 mg, 0.3 mmol) in 6 mL of absolute ethanol was treated with 4 mL of glacial acetic acid and iron powder (335 mg, 6 mmol). The resulting mixture was heated at 90° C. for 30 minutes, cooled to room temperature, diluted with 200 mL of dichloromethane, and filtered through a pad of CELITE® filter aid. The filtrate was washed with three 50 mL portions of saturated aqueous sodium carbonate solution and two 25 mL portions of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 140 mg of 3-amino-4-[4-hydroxy-6-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-6-methyl-4-trifluoromethylhept-1-ynyl]-5-methylbenzonitrile as a light brownish oil (90% yield).
Reaction SMILES: O[CH:2]([C:23]1[N:27]([CH3:28])[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[N:24]=1)[C:3]1[S:18][C:6]2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[S:19][CH:20]([CH3:22])[CH3:21].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH3:12][N:9]1[C:10](=[O:11])[C:5]2[C:4]([S:19][CH:20]([CH3:21])[CH3:22])=[C:3]([CH2:2][C:23]3[N:27]([CH3:28])[C:26]4[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=4[N:24]=3)[S:18][C:6]=2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]1=[O:13]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(C(O)c3nc4ccccc4n3C)sc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(Cc3nc4ccccc4n3C)sc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.1 %

Procedure:
Prepared according to the method described in Example 39 from 6-[hydroxy(1-methyl-1H-benzimidazol-2-yl)methyl]-3-methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.48 g, Example 44), trifluoroacetic acid (6 ml) and triethylsilane (3 ml) with stirring at room temperature for 24 hours. After work up, the residue was absorbed onto silica and purified by flash silica chromatography eluting with acetone:isohexane (1:5) to give the title compound as a white foam (0.135 g).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=1.C(N(CC)CC)C.CN1CCCC1=O>[Cu]I>[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=4)[CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1
Reactant: COc1cccc(Br)n1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCNC2
Agent: [Cu]I
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1cccc(N2CCCC3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)n1

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (35 mg, 0.00012 mol), 2-bromo-6-methoxypyridine (34 mg, 0.00018 mol), triethylamine (200 μL, 0.001 mol), and copper(I) iodide (28 mg, 0.00014 mol) in N-methylpyrrolidinone (1.0 mL, 0.010 mol) was microwave irradiated at 180° C. for 20 min. After allowing the reaction mixture to cool to rt the crude mixture was purified by prep.-HPLC to afford 8.3 mg of the desired product. LC-MS: 360.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].I[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>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].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C.CC(O)(C)C>[C:37]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([NH:1][C:2]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[CH:11][C:3]=2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:31][CH:32]=1)(=[O:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: CC(=O)Nc1ccc(I)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Nc2cc(CCc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 2-methyl-2-propanol 2.5 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.12 g were added cesium carbonate 0.26 g, N-(4-iodophenyl)acetamide 0.16 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 10 mg, tris(dibenzylideneacetone)dipalladium(0) 4.0 mg and palladium acetate 2.0 mg at room temperature, and it was stirred at 80° C. for 4 hours. Tris(dibenzylideneacetone)dipalladium(0) 4.0 mg, palladium acetate 2.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 10 mg were added to it, and it was stirred at 80° C. for 12 hours. Cesium carbonate 0.26 g, N-(4-iodophenyl)acetamide 0.16 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 1 mg, tris(dibenzylideneacetone)dipalladium(0) 4.0 mg and palladium acetate 2.0 mg were added to it, and it was stirred at 80° C. for 5 hours and 30 minutes. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 10 mg, tris(dibenzylideneacetone)dipalladium(0) 4.0 mg and palladium acetate 2.0 mg were added to it, and it was stirred at 80° C. for 12 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=1:1] to give tert-butyl 2-((4-(acetamido)phenyl)amino)-4-phenethylbenzoate.
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1>O>[N:5]1([CH2:4][C:3]([OH:10])=[O:2])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: COC(=O)Cn1ccnc1
Solvent: O
Product: O=C(O)Cn1ccnc1
Yield: 88.9 %

Procedure:
Under nitrogen, refluxed 300 mg of imidazol-1-yl-acetic acid methyl ester in 12 ml of H2O for 6 hours. Evaporated in vacuo after cooling to yield 240 mg of white solid (97%) 1H NMR (400 MHz, CD3OD) δ 4.79 (2H, s), 7.41 (1H, s), 7.48 (1H, s), 8.70 (1H, s).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[NH2:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[CH2:32]([O:31][C:29]([CH2:28][C:24]1[CH:23]=[C:22]([NH:21]/[C:4](=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:27]=[CH:26][CH:25]=1)=[O:30])[CH3:33]
Reactant: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Reactant: CCOC(=O)Cc1cccc(N)c1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 1c from 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and ethyl 3-aminophenylacetate in DMF.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].CO>[Ni].O>[C:11]([CH:9]([OH:10])[CH:7]([OH:8])[CH:5]([OH:6])[CH:3]([OH:4])[CH2:2][NH:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:13])=[O:12]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: [Ni]
Solvent: CO
Solvent: O
Product: O=C(O)CC[C@H](NCC(O)C(O)C(O)C(O)C(=O)O)C(=O)O

Procedure:
As starting material D-glucuronic acid and L-(+)-glutamic acid were used. The reductive amination was carried out using Raney nickel as a catalyst and heating for 2 hours to 50° C. and for 4 hours to 70° C. The product obtained had a melting point of 90° C. (with sintering) an RF -value of 0.70 (determined on DC-finished plates of silica gel G (Merck) with a transporting liquid made up of 70 parts by volume of methanol and 30 parts by volume of water).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:21]>O.[Cu]Br>[Br:21][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: N#Cc1cnccc1-c1cc(N)ccc1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1cnccc1-c1cc(Br)ccc1F
Temperature: 3 °C
Reaction time: 2 h

Procedure:
4-(5-Amino-2-fluorophenyl)nicotinonitrile (0.65 g, 3.05 mmol) was treated with 48% hydrobromic acid (25 ml) and the resulting suspension stirred and cooled to 3° C. (internal temperature). A solution of sodium nitrite (0.24 g, 3.5 mmol) in water (1 ml) was then added dropwise over 20 min keeping the internal temperature <5° C. Stirring at <5° C. was continued for 2 h before pouring the reaction into a cooled (5° C.) solution of freshly purified copper(I) bromide (1.53 g, 10.7 mmol) in 48% hydrobromic acid (10 ml). The resulting purple reaction mixture was stirred at 5° C. for 10 min then warmed to 50° C. for 20 min. The reaction was diluted with ice-cold water (50 ml) and extracted with ethyl acetate (2×25 ml). The organic extracts were combined, washed with 5% aqueous sodium sulfite and saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography (silica gel, CH2Cl2) afforded 4-(5-bromo-2-fluorophenyl)-nicotinonitrile as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.17 (1H, t, J 9 Hz), 7.44-7.46 (1H, m), 7.57 (1H, dd, J 6, 2 Hz), 7.61-7.66 (1H, m), 8.87 (1H, d, J 5), 9.00 (1H, d, J 1 Hz).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH2:5]1)=[O:3].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH:6]1[CH2:7][N:4]([C:2]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:3])[CH2:5]1
Reactant: C=CCN
Reactant: O=C(Cl)N1CC(Oc2cccc(Cl)c2)C1
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2cccc(Cl)c2)C1
Reaction time: 2 h
Yield: 37.5 %

Procedure:
A solution of 5.4 g (0.017 mole) of 1-chlorocarbonyl-3-(3-chlorophenoxy)azetidine in 20 ml of tetrahydrofuran was treated with 2.3 g (0.04 mole) of 2-propenylamine and stirred for 2 hr. The reaction solution was concentrated in vacuo to a rose beige solid. Trituration of the solid with water gave, after filtering, 4.4 g of crude product. After drying, the solid was recrystallized with charcoal treatment from 2% acetone/isopropyl ether to yield 1.7 g (37.5%) of pale beige crystals, m.p. 87°-89° C.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].Cl.[NH:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:27]([O:29][CH3:30])=[O:28]>ClCCl>[N+:8]([C:11]1[CH:12]=[C:13]([S:17]([N:22]2[CH2:26][CH2:25][CH2:24][C@@H:23]2[C:27]([O:29][CH3:30])=[O:28])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CCCN1S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.38 ml of triethylamine were added dropwise, over the course of 30 minutes, to a solution of 2.56 g of 3-nitrobenzenesulfonyl chloride and 1.91 g of methyl (R)-pyrrolidine-2-carboxylate hydrochloride in 30 ml of dichloromethane (30 ml) cooled to 0° C. The reaction medium was left at ambient temperature and stirred for 1 hour. The reaction medium was diluted with 50 ml of dichloromethane, and washed with a 1 M sodium hydrogen phosphate solution (2×50 ml) and a saturated sodium hydrogen carbonate solution (50 ml). The organic phase was dried over magnesium sulfate and evaporated 3.00 g of methyl (R)-1-(3-nitrobenzenesulfonyl)pyrrolidine-2-carboxylate were obtained and used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17]C)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2Cc1ccc(Br)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2Cc1ccc(Br)cc1
Reaction time: 8 h
Yield: 10.1 %

Procedure:
To a solution of 1-(4-bromobenzyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.10 g, 0.25 mmol) in CH2Cl2 (15 mL) at 0° C. under nitrogen was added boron tribromide (1.47 mL, 1.47 mmol). The reaction was allowed to reach RT. After 8 hours, the reaction was poured into water (10 mL) and neutralized with saturated sodium bicarbonate. Additional CH2Cl2 (25 mL) was added, the organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was then chromatographed (SiO2, 2:1, hexanes/ethyl acetate) to provide the title compound (0.010 g, 10% yield): 1H NMR (CDCl3) 7.33 (d, 2H), 7.24 (dd, 2H), 6.97 (d, 1H), 6.88 (d, 2H), 6.80 (d, 2H), 6.75 (dd, 2H), 6.66 (m, 1H), 6.27 (s, 1H), 4.78 (t, 1H), 3.53 (m 2H), 3.13 (dd, 1H), 2.96 (m, 2H), 2.62 (m, 1H); ES-MS (m/z) 392 [M−H]−.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([I:20])[CH:11]=1>C1COCC1>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([I:20])[CH:11]=1
Reactant: COC(=O)c1ccc(NC(C)=O)c(I)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CO)cc1I
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Lithium aluminium hydride (2.43 g, 64.1 mmol) was taken in a dry, three-necked, round bottom flask. Anhydrous THF (80 mL) was added and cooled to −10° C. A solution of 4-acetylamino-3-iodo-benzoic acid methyl ester (10.2 g, 32.0 mmol) in anhydrous THF (60 mL) was added dropwise at −10° C. over a period of 45 minutes under nitrogen. Stirring was continued at −10° C. for 1 hour. The reaction mixture was quenched with saturated sodium sulfate aqueous solution. The reaction mixture was then filtered, and the filtrate was concentrated. The solid was washed with methanol. The combined organic phases were dried over anhydrous Na2SO4. The solvent was evaporated. The crude compound was purified by the Simpliflash system (5% methanol in CH2Cl2 as eluent), to give N-(4-hydroxymethyl-2-iodo-phenyl)-acetamide as a white solid. Yield: 6.36 g (68%).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH2:20]([Mg]Br)[CH:21]([CH3:23])[CH3:22].O1CCCC1>>[CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]([OH:9])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:2]
Reactant: CC(C)C[Mg]Br
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Solvent: C1CCOC1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(O)CC(C)C
Yield: 83 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde (805 mg) and 1N isobutylmagnesium bromide-tetrahydrofuran solution (6.0 mL) to give the title compound (819 mg, 83%) as an oil.