Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.C([C:10]1[CH:25]=[CH:24][C:13]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:12][CH:11]=1)=O.N1CCCCC1.C(=O)=O>N1C=CC=CC=1.O>[CH2:17]([O:16][C:14]([C:13]1[CH:24]=[CH:25][C:10]([CH:3]=[CH:2][C:1]([OH:7])=[O:6])=[CH:11][CH:12]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)C=Cc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
245 g (2.4 mol) of malonic acid were dissolved in 360 ml of pyridine (exothermic, temperature raised to about 50° C.). Then 503 g of the crude benzyl 4-formylbenzoate obtained in step a) and 20 ml of piperidine were added, and the mixture was heated to reflux until the production of carbon dioxide had ceased (about 7 h). The mixture was cooled to room temperature, then 2 l of water were added and the product was precipitated by acidification of the stirred mixture with ca. 600 ml of concentrated hydrochloric acid to pH 1.8 at 10° C. The precipitated product was filtered off, washed with water and dried at 50° C. under reduced pressure. Combined yield of step a) and step b): 529.1 g (97%).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.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]>[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:2]=1[C:21]1[CH:22]=[CH:23][C:18]([C:16]([O:15][CH3:14])=[O:17])=[CH:19][CH:20]=1)=[O:5]
Reactant: O=Cc1ccc(C(F)(F)F)cc1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C=O)cc1
Temperature: 25 °C

Procedure:
2-bromo-4-(trifluoromethyl)benzaldehyde (1.0 g, 4.0 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (854 mg, 4.7 mmol), Pd(dppf)Cl2 (324 mg, 0.4 mmol), and K2CO3 (1.1 g, 7.9 mmol) were dissolved in 1,4-dioxane (24 mL) and water (6 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [Mg].[C:2]1([CH2:8][CH2:9][C:10]2[CH:11]=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](O)(=[O:19])[CH3:18]>O1CCCC1>[C:2]1([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(CCc2ccccc2)c1
Reactant: CC(=O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(CCc2ccccc2)c1
Reaction time: 1 h
Yield: 92 %

Procedure:
A Grignard compound synthesized from 1.0 g of magnesium and 10.0 g of 3-(2-phenylethyl)-bromobenzene in 30 ml of tetrahydrofuran was dropped at -60° C. under stirring for 3 min into 7.6 g of anhydrous acetic acid dissolved in 20 ml of tetrahydrofuran in a nitrogen atmosphere and stirred for further one hour. Then, the reaction solution was poured into a mixture of ice and an aqueous saturated solution of ammonium chloride and extracted with toluene. After separating the solution, it was washed with an aqueous 2N-solution of sodium hydroxide and saturated saline solution successively, dried over anhydrous sodium sulfate and then concentrated to solid. The residue was purified by silica gel column chromatography, using benzene/n-hexane (1:1) as an elute, to obtain 7.9 g of 1-(3-(2-phenylethyl)-phenyl)-ethanone as an oily product. Then, by using 5.0 g of the thus obtained acetophenone compound, 3.8 g of (Z)-2-(4-methylpiperazin-1-yl)-1-(3-(2-phenylethyl)-phenyl)-ethanone oxime hydrochloride with the melting point of from 185° to 188° C. (decomposition) and 0.5 g of (E)-2-(4-methylpiperazin-1-yl)-1-(3-(2-phenylethyl)-phenyl)-ethanone oxime with the melting point from 133° to 134° C. were obtained in the same manner as in Example 33.
Reaction SMILES: [C:1]([Cl:10])(=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CCOCC>[CH3:18][S:19]([O:9][N:8]=[C:1]([Cl:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: ON=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C(Cl)c1ccccc1
Reaction time: 1 h
Yield: 36.8 %

Procedure:
The 9.4 g of recovered benzohydroximoyl chloride was dissolved in 100 ml of anhydrous ether and the solution was cooled to -20°. To the cold solution was rapidly added 12.3 g of triethylamine. To this mixture was slowly added (during 45 minutes) a solution of 6.95 g of methanesulfonyl chloride in 50 ml of anhydrous ether. The mixture was stirred at -30° for 1 hour, then at ambient temperature for about 16 hours. The mixture was filtered and the filtrate was conconcentrated under reduced pressure to give a yellow solid. The solid was recrystallized from a benzene-hexane mixture to give 5.2 g of N-(methanesulfonyloxy)benzimidoyl chloride, m.p. 106°-108°.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[CH:12][C:10]=3[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc2oc(-c3ccccc3)cc2c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Nc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of 2-phenylbenzofuran-5-amine (210 mg, 1.00 mmol) in pyridine (5 mL) at room temperature was added isobutyryl chloride (120 μL, 1.10 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed with saturated aqueous copper sulfate solution followed by saturated aqueous potassium carbonate solution. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting material was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:3 v/v to ethyl acetate/hexanes 1:2 v/v) to afford 134 mg (48%) of the title compound (LCMS RT=6.81 min, MH+ 280.1)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)#[N:2].Cl.[NH2:34][OH:35].CC(C)([O-])C.[Na+]>C(O)C>[NH2:2]/[C:1](=[N:34]\[OH:35])/[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1
Reactant: NO
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(C#N)cc23)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(/C(N)=N/O)cc23)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 77.2 %

Procedure:
To a mixture of tert-butyl [6-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (3.0 g, 7.0 mmol), hydroxylamine hydrochloride (0.73 g, 11 mmol) and ethanol (75 ml) was added sodium tert-butoxide (1.2 g, 11 mmol), and the mixture was stirred at 70° C. for 6 hrs. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate-tetrahydrofuran and water and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give tert-butyl [6-[(Z)-amino(hydroxyimino)methyl]-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (2.5 g, yield 79%) as a white powder.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:20][S:21]([O:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:3]1)(=[O:23])=[O:22]
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H](C2)N1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](OS(C)(=O)=O)C2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (185 mg) in pyridine (2 mL), was added methanesulfonyl chloride (117 mg). The mixture was stirred at room temperature for 2 hrs. The resulting mixture was evaporated in vacuo. To the residue, water was added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound (237 mg).
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[NH:8]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[OH:20][C@@H:21]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34](O)[CH:33]=1)[CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[OH:20][C@@H:21]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([O:5][CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[NH:8]2)[CH:37]=1)[CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: CS(=O)(=O)OCC1CCCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCCC(=O)N2)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of (6-oxopiperidin-2-yl)methyl methanesulfonate (0.44 g, 2.2 mmol) in DMF (15 ml) was added Cs2CO3 (3.5 g, 11 mmol) and phenol (Intermediate I) (0.88 g, 3.3 mmol). The reaction mixture was stirred at room temperature for 40 hours and partitioned between water and ethyl acetate. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (20% MeOH-EtOAc) gave tert-butyl ((3R)-3-hydroxy-3-(3-((6-oxopiperidin-2-yl)methoxy)phenyl)propyl)carbamate as a yellow oil. Yield (0.17 g, 20%); 1H NMR (400 MHz, CD3OD) δ 7.24 (t, J=8.0 Hz, 1H), 6.97-6.93 (m, 2H), 6.84 (d, J=8.0 Hz, 1H), 4.64 (t, J=7.2 Hz, 1H), 4.06-4.02 (m, 1H), 3.94-3.90 (m, 1H), 3.86-3.76 (m, 1H), 3.15-3.06 (m, 2H), 2.37-2.30 (m, 2H), 2.05-1.92 (m, 3H), 1.86-1.75 (m, 3H), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([CH:12]=[CH:13][C:14]#[N:15])[CH:5]=[CH:4][C:3]1=2.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([NH:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:29][C:30](O)=[O:31])(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:14]([CH:13]=[CH:12][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH:28]([NH:27][S:24]([C:19]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=1)(=[O:26])=[O:25])[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[CH2:11][CH2:10][CH2:9]2)#[N:15]
Reactant: N#CC=Cc1ccc2c(c1)CCCC2N
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC=Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-acrylonitrile (100 mg, 0.504 mmol) in CH2Cl2 (10 mL) was added 3-(3,4-dichlorobenzene-sulfonylamino)-3-(4-fluoro-phenyl)-propionic acid (210 mg, 0.554 mmol), HATU (96 mg, 0.252 mmol), EDC (106 mg, 0.55 mmol), and DIEA (0.17 mL, 1.008 mmol). The resulting mixture was stirred at RT for 18 h. Solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with Hex:Acetone mixture (75:25) gave final compound. MS m/z: 573.12 (M+H). Calc'd. for C28H24Cl2FN3O3S-572.48.
Reaction SMILES: [CH3:1][CH:2]1[O:23][C:22]2[C:5](=[CH:6][C:7]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9][C:8]=3[CH:21]=2)[NH:4][CH2:3]1.CI.[C:26](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][CH:2]1[O:23][C:22]2[C:5](=[CH:6][C:7]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9][C:8]=3[CH:21]=2)[N:4]([CH3:26])[CH2:3]1
Reactant: CC1CNc2cc3c(cc2O1)CCN(C(=O)OC(C)(C)C)CC3
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CC1CN(C)c2cc3c(cc2O1)CCN(C(=O)OC(C)(C)C)CC3
Reaction time: 13 h
Yield: 43.9 %

Procedure:
To a solution of 120 mg of t-butyl 2-methyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 4 ml of DMF were added 0.026 ml of methyl iodide and 104 mg of potassium carbonate at room temperature, followed by stirring for 13 hours. To the reaction mixture were added 0.012 ml of methyl iodide and 26 mg of potassium carbonate, followed by further stirring for 3 hours. To the reaction mixture was added water, followed by extraction with EtOAc twice. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 55 mg of t-butyl 2,4-dimethyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH2:12][CH2:13][OH:14])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].[CH3:19][S:20][CH2:21]Cl.[Na+].[I-]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].COCCOC.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH2:12][CH2:13][O:14][CH2:19][S:20][CH3:21])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCO
Reactant: CSCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: COCCOC
Product: COC(=O)c1ccc2c(c1)ncn2CCOCSC
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A solution of 1-(2-hydroxyethyl)-1H-benzimidazole-5-carboxylic acid methyl ester (0.5 g. 2.27 mmol) in a mixture of dry THF:DME (25 mL:15 mL) was cooled to 5° C. NaH (0.081 g, 3.4 mmol) was added and stirred for 30 min at the same temperature. A mixture of chloromethyl methyl sulphide (0.285 g, 2.95 mmol) and NaI (0.408 g, 2.95 mmol) was then added slowly followed by TBAI (0.087 g, 0.22 mmol). The reaction was allowed to stir for overnight at ambient temperature. It was then quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic layer was evaporated to give 0.53 g (83%) of 1-(2-methylsulfanylmethoxyethyl)-1H-benzimidazole-5-carboxylic acid methyl ester. 1H NMR (300 MHz, CDCl3) δ 1.9 (s, 3H), 3.9 (t, 2H), 3.95 (s, 3H), 4.4 (t, 2H), 4.6 (s, 2H), 7.45 (d, 1H), 8.05 (m, 2H), 8.5 (d, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[I:18]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([I:18])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3cccc(Cl)c3n2)cc1
Solvent: ClCCl
Product: Fc1ccc(-c2nc3c(Cl)cccn3c2I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
8-Chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine (2 g, 8.1 mmol) was dissolved in dichloromethane (30 mL). To this solution was added N-iodosuccinimide (2.7 g, 12.1 mmol) and the resulting mixture stirred at room temperature overnight. Additional dichloromethane was added to the reaction mixture and this solution was extracted with 1 M sodium hydroxide (2×60 mL) and water, dried (magnesium sulfate), filtered and concentrated to a solid. Recrystallization from acetonitrile gave 8-chloro-2-(4-fluorophenyl)-3-iodoimidazo[1,2-α]pyridine (2.4 g, 80%) as a white solid. 1H NMR (CDCl3): δ 8.22 (d, 1H), 8.11 (q, 2H), 7.41 (d, 1H), 7.20 (t, 2H), 6.94 (t, 1H); 19F NMR (CDCl3) δ −113.2; MS m/z 373 (M+1).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:27])[CH:16]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][O:18]2)=[CH:13][CH:12]=1.IC.[NH4+].[Cl-]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:27])[C:16]([CH3:2])([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][O:18]2)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)OCC(c1ccncc1)C2=O
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)OCC(C)(c1ccncc1)C2=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of LDA (2.0 mol/l, 0.863 ml, 1.73 mmol) in tetrahydrofuran (1.5 ml) was added at −78° C. a solution of 7-methoxy-3-(4-pyridyl)chroman-4-one (220 mg, 0.863 mmol) in tetrahydrofuran (2 ml), which was then stirred for 30 minutes. Iodomethane (0.537 ml, 8.63 mmol) was added to -the reaclion solution, which was warmed to −10° C. and stirred for 3 hours. After the reaction was completed, the reaction solution was neutralized under ice-cooling using saturated aqueous NH4Cl solution, extracted with ethyl acetate, and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=1:2) to give 7-methoxy-3-methyl-3-(4-pyridyl)chroman-4-one (131 mg, yield 56%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][C@H:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[CH3:20]>>[CH3:28][O:27][C:25]([C:24]1[CH:29]=[CH:30][C:21]([C@@H:19]([NH:18][C:14]([C@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH3:20])=[CH:22][CH:23]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2C(=O)OC(C)(C)C)cc1
Yield: 95.2 %

Procedure:
The title compound (D5) (405 mg) was prepared according to the general procedure for amides preparation starting from (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (250 mg, available from Sigma Aldrich #516341), and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (235 mg). Reaction time: 18 hrs.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[N:7][S:8][C:9]=1[NH:10]C(OC(C)(C)C)=O)=[O:4].Cl>O1CCOCC1>[CH3:1][NH:2][C:3]([C:5]1[N:6]=[N:7][S:8][C:9]=1[NH2:10])=[O:4]
Reactant: CNC(=O)c1nnsc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1nnsc1N
Reaction time: 72 h
Yield: 491.7 %

Procedure:
A solution of 5-tert-butoxycarbonylamino-[1,2,3]thiadiazole-4-carboxylic acid methylamide (0.23 g, 0.9 mmol) in dioxane (4 ml) was treated with HCl (6 ml, 4M dioxane solution) at ambient temperature and stirred for 3 days. The solvent was evaporated, and the residue was suspended in diethylether, mixed and sucked off. The remaining solid material was dissolved in dichloromethane and extracted with NaOH (10 ml, 1M aqueous solution). The aqueous phase was extracted with dichloromethane, and the combined organic layers were dried and the solvent was evaporated to yield the product as colorless solid (0.7 g, 48%) which was used without any further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:13]Br>[Fe].C(Cl)(Cl)(Cl)Cl>[Br:13][C:9]1[CH:8]=[C:7]([CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)c1ccc(C(C)C)cc1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1ccc(C(C)C)c(Br)c1

Procedure:
To a one-liter flask containing 243 parts of p-diisopropylbenzene, 300 parts of carbon tetrachloride and 2.5 parts of iron powder is added dropwise 240 parts of bromine and sufficient carbon tetrachloride to make 180 parts of solution during seven hours at a temperature of -5°C. The solution is decanted from the residual ferric bromide and washed twice with 3N HCl. The carbon tetrachloride is removed under reduced pressure. A solution of 40 parts potassium hydroxide in two hundred parts of ethyl alcohol is added and refluxed 0.5 hr. The solution is poured into water, separated, washed with dilute hydrochloric acid, dilute sodium bisulfite solution and water, and dried. The solvent is removed and the 2-bromo-1,4-diisopropylbenzene distilled, bp 142°C at 25 mm, nD25 1.5292.
Reaction SMILES: C(N)C.[N+:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[C-:5].[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCC.C(OCC)(=O)C>ClCCl.N#N>[CH3:10][O:9][C:7]([C@H:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:18][CH:5]=[N:4]1)=[O:8]
Reactant: O=Cc1ccccc1
Reactant: [C-]#[N+]CC(=O)OC
Agent: CCN
Agent: N#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)[C@@H]1N=CO[C@H]1c1ccccc1
Yield: 0.1 %

Procedure:
27.5 mg (0.055 mmol) of bis(cyclohexylisocyanide)-gold tetrafluoroborate, 39.7 mg (0.056 mmol) of (R)-N-methyl-N-[2-(diethylamino)-ethyl]-1-[(S)-1',2bis(-ethylamine and 0.549 g (5.54 mmol) of methyl isocyano-acetate were dissolved in 5.5 ml of dry dichloromethane, and 0.642 g (6.05 mmol) of benzaldehyde was added thereto. The reaction mixture was reacted for 20 hours at 25° C in N2 atmosphere. After the solvent was concentrated, the residue formed was subjected to silica-gel column chromatography (solvent: hexane/ethyl acetate =1/2) to obtain 0.96 mg (84.6%) of trans-4-methoxycarbonyl-5- phenyl-2-oxazoline and 0.12 g (10.4%) of the corresponding cis-form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:13][C:12]=3[CH:24]=2)=[CH:4][C:3]=1[N+:25]([O-])=O.[Sn](Cl)Cl.[OH-].[Na+].[Sn].S([O-])([O-])(=O)=O.[Na+].[Na+]>CC(OC)(C)C.C(O)(=O)C>[NH2:25][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:13][C:12]=3[CH:24]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: C=CCOC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Agent: Cl[Sn]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: C=CCOC(=O)N1CCOc2ccc(-c3ccc(N)c(N)c3)cc2C1
Temperature: 45 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
Prop-2-en-1-yl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (4.2 g, 11.2 mmol) was taken into glacial acetic acid (25 mL) and the solution was warmed to 45° C. Tin (II) chloride (8.51 g, 44.8 mmol) was added in portions over 5 minutes and the mixture was allowed to stir at this temperature for 6 h. The mixture was then cooled to room temperature and diluted with MTBE (100 mL). 50% aqueous sodium hydroxide was then added in small portions with stirring until complete precipitation of tin salts occurred. Anhydrous sodium sulfate was then added in portions until the precipitated salts formed a fine granular solid and the mixture was filtered. The filter cake was washed with additional MTBE and the combined organic filtrate was concentrated. The residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate. 50% aqueous sodium hydroxide was added to the biphasic mixture in portions until the aqueous pH was 9-10. The layers were then separated and the organic solution washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to provide prop-2-en-1-yl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (2.7 g, 71% yield) as a yellow solid. MS (EI) for C19H21N3O3: 340 (MH+).