Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH:20]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)#[N:2].[C:28]([Si](Cl)(C)C)(C)(C)C.N1C=CN=C1.CN(C)C=O>O>[C:1]([C:3]1[CH:4]=[C:5]([N:16]([CH3:28])[C:17]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH:20]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)#[N:2]
Reactant: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1cc2ccccc2s1)c1ccc(N2CCC(O)CC2)c(C#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
N-[3-Cyano-4-(4-hydroxypiperidin-1-yl)phenyl]benzo[b]thiophene-2-carboxamide (2.0 g) obtained in Example 12, tertiary butyldimethylsilyl chloride (0.9 g) and imidazole (0.4 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 12 hr. Then the reaction mixture was treated with water and the organic layer was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in dimethylformamide. Under ice-cooling, sodium hydride (60% contained, 0.2 g) (was added and the mixture was stirred for 1 hr and methyl iodide (0.6 g) was added. The mixture was further stirred for 1 hr. The reaction mixture was treated with water and the organic layer was extracted with toluene. The extract was washed with water and the solvent was evaporated under reduced pressure. To the residue were added tetrabutylammonium fluoride (0.93 g) and tetrahydrofuran(15 ml) and the mixture was stirred at 60° C. for 4.5 hr. Then the solvent was evaporated and the residue was separated and purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (0.8 g). melting point: 211-212° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:32][C:27]1[CH:26]=[C:25]([C:19]2([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=[C:16]([C:14]3[CH:13]=[CH:12][C:3]([C:4]([NH:6][CH2:7][C:8]([F:10])([F:9])[F:11])=[O:5])=[C:2]([NH:1][CH3:35])[CH:15]=3)[CH2:20]2)[CH:30]=[C:29]([Cl:31])[CH:28]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
In a solution of 0.25 g of 2-amino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-(2,2,2-trifluoroethyl)benzoic acid amide (Compound of the present invention No. 5-329) synthesized in Synthetic Example 12 and 0.06 g of 36% formaldehyde aqueous solution in 7 ml of 1,2-dichloroethane, 1.00 g of sodium triacetoxy borohydride was added with stirring at room temperature in three portions at 1 hour-interval, and continued to stir at the same temperature for further 2 hours. After the completion of the reaction, the reaction mixture was poured to 5 ml of ice water, the organic phase was collected, and the solvent was distilled under reduced pressure. The residue was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (0:1 to 1:3 gradient), and 0.13 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylamino-N-(2,2,2-trifluoroethyl)benzoic acid amide was obtained as pale yellow crystal, and 0.13 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-dimethylamino-N-(2,2,2-trifluoroethyl)benzoic acid amide was obtained as pale yellow resinous substance.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=[O:10])([CH3:3])[CH3:2].S(=O)(=O)([OH:16])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[C:9]([OH:16])=[O:10])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1C=O
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Isopropyl-2-methoxybenzaldehyde (2.8 g, 15.7 mmol) was dissolved in acetone (40 mL). To this solution was added sulfamic acid (2.29 g, 23.57 mmol) and sodium chlorite (1.71 g, 18.85 mmol) in water (40 mL). The mixture was stirred at rt in an open flask for 12 hrs. The acetone was removed and the mixture was extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated to afford the title compound. MS (DCI/NH4+) m/z 212 (M+NH4)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[OH:33][C:27]([C:29]([F:32])([F:31])[F:30])=[O:28].[NH2:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccn1)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To (S)-benzyl 2-((tert-butoxycarbonyl)amino)-3-(pyridin-2-yl)propanoate (0.558 g, 1.57 mmol) was added DCM (2 mL) followed by TFA (2 mL). The reaction mixture was allowed to stand for 1 h at which time it was concentrated to provide (S)-benzyl 2-amino-3-(pyridin-2-yl)propanoate TFA salt (quant. yield) as a yellow oil. MS (EI) for C17H16F3N2O3, found 257.2 [M-TFA]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31]C(OC)=O)=[CH:26][C:25]=1[OH:36]>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:36][C:25]3[CH:26]=[C:27]([OH:31])[C:28]([CH3:30])=[CH:29][C:24]=3[F:23])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: COC(=O)Oc1cc(O)c(F)cc1C
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(Oc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccccc1
Yield: 73.8 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (132 mg, 0.4 mmol), (prepared as described for the starting material in Example 1), and 2-fluoro-5-methoxycarbonyloxy-4-methylphenol (96 mg, 0.48 mmol) in pyridine (2 ml) was heated at reflux for 3 hours. The mixture was allowed to cool, the solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ether (70/30). The resulting solid was crystallised from methylene chloride and-methanol to give 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxyquinazoline (120 mg, 64%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:14][C:13]([O:15][C@@H:16]4[CH:23]5[CH2:24][N:19]6[CH2:20][CH:21]([CH2:25][CH:17]4[CH2:18]6)[CH2:22]5)=[N:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:34])C=1>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:14][C:13]([O:15][C@@H:16]4[CH:17]5[CH2:18][N+:19]6([O-:34])[CH2:20][CH:21]([CH2:22][CH:23]4[CH2:24]6)[CH2:25]5)=[N:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cc2cc(-c3cnc(OC4C5CC6CC4CN(C6)C5)s3)ccc2[nH]1
Solvent: CO
Product: [O-][N+]12CC3CC(C1)C(Oc1ncc(-c4ccc5[nH]ccc5c4)s1)C(C3)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the product of Example 28A (105 mg, 0.30 mmol) in methanol (4 mL) was treated with 3-chloroperbenzoic acid (mCPBA; 70-75%; 71.0 mg, 0.30 mmol; Aldrich) and stirred at ambient temperature for 4 hours. The resulting material was purified by preparative HPLC [Waters® XTerra RP18 column, 5μ, 30×100 mm, flow rate 40 mL/minutes, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide] to afford the title compound: 1H NMR (300 MHz, methanol-D4) δ ppm 1.70-2.02 (m, 2H), 2.10-2.29 (m, 1H), 2.29-2.47 (m, 1H), 2.58-2.78 (m, 2H), 3.57-3.67 (m, 5H), 5.32 (t, J=3.3 Hz, 1H), 6.46 (d, J=3.0 Hz, 1H), 7.26 (d, J=3.3 Hz, 1H), 7.27-7.31 (m, 2H), 7.36-7.42 (m, 1H), 7.66 (d, J=1.3 Hz, 1H). MS (DCI/NH3) m/z=368 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4](I)[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[CH:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([C:19]#[C:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])[CH:3]=1
Reactant: Cc1cc(Cl)cc(I)c1N
Reactant: C#Cc1ccccc1Cl
Product: Cc1cc(Cl)cc(C#Cc2ccccc2Cl)c1N
Yield: 68.4 %

Procedure:
The title compound was prepared in analogy to example 10 step A from 4-chloro-2-iodo-6-methyl-phenylamine (1.5 g, 5.61 mmol) and 1-chloro-2-ethynyl-benzene (920 mg, 6.73 mmol) to afford 4-chloro-2-(2-chloro-phenylethynyl)-6-methyl-phenylamine (1.06 g, 68%) as an off white solid. LC-MS (ESI): 276 (M+H)+.
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[CH2:8][N:9]([CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([OH:36])=[O:35])[CH:29]=3)[CH:24]=2)[O:19]1)C(OC(C)(C)C)=O)(C)C.Cl>O1CCOCC1>[OH:6][C@H:7]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[CH2:8][NH:9][CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([OH:36])=[O:35])[CH:29]=3)[CH:24]=2)[O:19]1
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(-c3ccnc(C(=O)O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)ccn1

Procedure:
4-{(2R)-2-[([(2R)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}-2-pyridinecarboxylic acid (Example 70, 29 mg, 0.05 mmol) was stirred in an excess of 4M HCl in dioxane at room temperature for 18 hours. The volatile components were removed by rotary evaporation, and the residue was washed with dichloromethane. After drying under vacuum, the title compound was collected as the tri-hydrochloride salt (23 mg, 93%): 1H NMR (300 MHz, CD3OD) δ 9.07 (broad s, 1 H), 8.90 (d, 1 H), 8.83-8.78 (m, 3 H), 8.49 (d, 1 H), 8.18 (t, 1 H), 7.94-7.89 (m, 2 H), 7.20 (d, 1 H), 5.52-5.46 (m, 1 H), 4.67-4.61 (m, 1 H), 3.76-3.57 (m, 2 H), 3.51-3.39 (m, 2 H), 3.10-3.05 (m, 2 H), 2.29-2.20 (m, 1 H), 1.95-1.83 (m, 1 H); MS m/z 406.2 (MH+ of the free base).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:38]([O:39][CH3:40])=[CH:37][C:15]2[NH:16][C:17](=[O:36])[C:18]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([O:34][CH3:35])[CH:26]=4)=[CH:21][C:19]=3[NH:20][C:14]=2[CH:13]=1)(C)(C)C.[N+](CC)(CC)(CC)CC.[F-].O>C1COCC1>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:38]([O:39][CH3:40])=[CH:37][C:15]2[NH:16][C:17](=[O:36])[C:18]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([O:34][CH3:35])[CH:26]=4)=[CH:21][C:19]=3[NH:20][C:14]=2[CH:13]=1
Reactant: COc1cc2c(cc1OCCCCO[Si](C)(C)C(C)(C)C)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCCCCO)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Yield: 28 %

Procedure:
A mixture of Example 500A, Et4NF.H2O (10 equiv.) and THF was heated overnight at 65° C., concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by preparative HPLC to provide 50 mg (28%) of the desired product. MS (ESI) m/e 480 (M+H)+; 1H NMR (400 MHz, DMSO-d6) □ 9.63 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=1.2 Hz, 1H), 7.35 (dd, J=1.5, 8.6 Hz, 1H), 7.28-7.30 (m, 2H), 6.70 (s, 1H), 6.65 (s, 1H), 4.03 (s, 3H), 3.89 (t, J=6.6 Hz, 2H), 3.67 (s, 3H), 3.44 (t, J=6.4 Hz, 2H), 1.69-1.76 (m, 2H), 1.51-1.58 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].N#N.[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C.O>[CH2:31]([N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:11]=[C:2]([CH3:1])[C:3]([B:12]3[O:13][C:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[O:16]3)=[CH:4][C:5]1=2)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: Cc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)NCCO2
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCOc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: 70 °C
Yield: 52.9 %

Procedure:
A solution of 7-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.488 g, 1.774 mmol, prepared according to the procedures outlined for related compounds in Ref. WO20100130034) and K2CO3 (0.490 g, 3.55 mmol) in dry DMF (5 mL) was sparged with N2 for 5 min, treated with allyl bromide (0.773 mL, 8.87 mmol), then heated (70° C.) for 22 h. The reaction was diluted with water (50 mL) and extracted into EtOAc (50 mL) and washed with water, brine and then dried (Na2SO4), filtered, and concentrated. The crude was purified by biotage column chromatography (12 g SiO2, 0% (3 CV), 0-40% (10 CV), 40% (2 CV), EtOAc in hexanes). Product rich fractions were re-purified by biotage (0% (3 CV), 0-40% (15 CV), 40% (2 CV), EtOAc in hexanes) to afford the desired product (0.345 g, 0.938 mmol, 52.9% yield), as a colorless viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.20 (s, 1H), 6.62 (d, J=0.5 Hz, 1H), 5.92 (ddt, J=16.9, 10.4, 5.9 Hz, 1H), 5.29 (dq, J=17.2, 1.6 Hz, 1H), 5.23 (dq, J=10.2, 1.4 Hz, 1H), 4.30-4.24 (m, 2H), 3.89 (dt, J=5.9, 1.3 Hz, 2H), 3.27-3.18 (m, 2H), 2.43 (s, 3H), 1.33 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1>N.CO.[Ni].C(Cl)Cl>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][C:4]=1[C:10]([F:11])([F:12])[F:13]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: [Ni]
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NCc1ccc(N)cc1C(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of 4-amino-2-(trifluoromethyl)benzonitrile (5.0 g, 26.7 mmol) in 7.0 M ammonia in MeOH (20.0 mL) was added Raney Nickel 2800 (50% slurry in water, 320 mg). The mixture was allowed to stir under an atmosphere of hydrogen for 18 h, then at 50 psi for 18 h. The mixture was diluted with DCM and filtered through Celite. The filtrate was evaporated and the residue was purified by column chromatography on silica to 4-(aminomethyl)-3-(trifluoro-methyl)aniline as an orange solid (3.43 g, 67%). LCMS: (FA) ES+ 187.1 ES− 185.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=1)[CH2:5][CH3:6].C(N(CCN[C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([I:45])[CH:41]=2)[N:36]=1)=[O:34])CCOC1C(F)=NC=CC=1)C>>[Br:16][C:12]1[N:11]=[C:10]([NH:9][CH2:8][CH2:7][N:4]([CH2:3][CH2:2][NH:1][C:33]([C:35]2[CH:44]=[N:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([I:45])[CH:41]=3)[N:36]=2)=[O:34])[CH2:5][CH3:6])[CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Reactant: CCN(CCN)CCNc1cccc(Br)n1
Product: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCNc1cccc(Br)n1
Yield: 70 %

Procedure:
This compound was prepared, starting from compound 62 (120 mg, 0.42 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 7 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 63 (166 mg, 0.33 mmol) as a yellow solid. Yield 70%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.34; mp 49-51° C.; IR (KBr) ν 1160, 1594, 1671, 2750-3000, 3200-3400 cm−1: 1H NMR (400 MHz, CDCl3) δ 1.04 (t, 3H, J=7.1 Hz), 2.64 (q, 2H, J=7.1 Hz), 2.74 (m, 4H), 3.27 (q, 2H, J=5.3 Hz), 3.57 (q, 2H, J=5.8 Hz), 5.32 (m, 1H), 6.16 (d, 1H, J=8.1 Hz), 6.56 (d, 1H, J=7.4 Hz), 7.05 (t, 1H, J=7.8 Hz), 7.81 (d, 1H, J=8.8 Hz), 8.05 (dd, 1H, J=1.9, 8.8 Hz), 8.25 (m, 1H), 8.55 (d, 1H, J=1.9 Hz), 9.58 (s, 1H); ESI-MS m/z 568.9 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]#[N:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].C[Si]([N:18]=[N+:19]=[N-:20])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][C:12]2[NH:20][N:19]=[N:18][N:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CCSc1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(SCc2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To 2-[(4-nitrophenyl)sulfanyl]acetonitrile (6.8 g) was added toluene (70 ml), and to this solution was added trimethylsilylazide (8.1 g) and then, dibutyl tin oxide (VI) (0.87 g), and the mixture was heated to reflux for 6 hours. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and azeotropically distilled with methanol. To the obtained residue was added 10% aqueous solution (50 ml) of sodium carbonate, and the mixture was washed with ethyl acetate. The pH was adjusted to about pH 3 with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was washed with hexane/ethyl acetate to give 5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole (6.7 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:18])[C@H:10]2[NH:14][C:15]([NH2:17])=[S:16])[C:7]=1[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].Br[CH2:36][C:37](=O)[C:38]([O:40][Si](C)(C)C)=[O:39].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:18])[C@H:10]2[NH:14][C:15]2[S:16][CH:36]=[C:37]([C:38]([OH:40])=[O:39])[N:17]=2)[C:7]=1[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(N)=S)[C@H]2SC1
Reactant: C[Si](C)(C)OC(=O)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(C(=O)O)cs3)[C@H]2SC1
Yield: 92.5 %

Procedure:
A mixture of 770 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(aminothioxomethyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 425 mg of 3-bromo-2-oxopropanoic acid, trimethylsilyl ester, 110 mg of potassium carbonate and 15 ml of acetonitrile was reacted as described in Example 1, giving 810 mg of the desired compound.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:10][C:11](=[O:23])[CH:12]=[C:13]([CH2:21][CH3:22])[CH:14]([CH3:20])[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:7][CH2:8][CH3:9]>C(O)=O>[CH2:6]([O:10][C:11]([CH:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]([CH3:20])=[C:13]1[CH2:21][CH3:22])=[O:23])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC(=O)C=C(CC)C(C)CC=C(C)C
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: CCCCOC(=O)C1C(CC)=C(C)CCC1(C)C
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A mixture of 81 ml of concentrated formic acid and 9 ml of concentrated sulphuric acid is cooled to 5°-10° C and there are cautiously added at this temperature 10 g (39.7 mmol) of 3-ethyl-4,7-dimethyl-2,6-octadienoic acid n-butyl ester. The mixture is left to come to room temperature and then stirred at room temperature for ca 1 hour. The mixture is then poured on to ice extracted three times with hexane. The combined hexane solutions are washed once with water, twice with sodium bicarbonate solution and three times with water, dried over sodium sulphate and concentrated. The crude product (9.1 g) is fractionally distilled. There are obtained 6.9 g (69%) of pure 2-ethyl-3,6,6-trimethyl-2-cyclohexene-1-carboxylic acid n-butyl ester of boiling point 73°-74° C/0.03 mm Hg; nD20 = 1.4663. The ester has a powerful balsamic and spicy odor with a slight buttery undertone.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][OH:20].C(=O)([O-])O.[K+]>O1CCCC1>[OH:20][CH2:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][CH:1]=[O:3]
Reactant: O=CO
Reactant: Nc1ccccc1CCO
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNc1ccccc1CCO
Temperature: 60 °C
Reaction time: 2 h

Procedure:
12.6 ml of formic acid were added dropwise at 0° C. to 15 ml of acetic anhydride, and the mixture was then stirred for 2 hours at 60° C. After cooling to 20° C., the mixture was diluted with 140 ml of tetrahydrofuran, cooled to −4° C., and at this temperature a solution of 18.4 g of 2-(2-aminophenyl)ethanol in 185 ml of tetrahydrofuran was added dropwise. After stirring for 3 hours at −6° C. the mixture was neutralised with aqueous potassium hydrogen carbonate solution (25% KHCO3) and extracted four times with 300 ml of ethyl acetate each time. The combined extracts were dried over sodium sulfate and concentrated by evaporation in vacuo. 18.4 g (94% of theory) of the title compound were thereby obtained in the form of yellowish crystals that melted at 49–54° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:18]Br>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[S:7][C:8]([Br:18])=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1sccc1C
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1sc(Br)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 62.3 (0.61 g, 3.58 mmol) and pyridine (0.29 mL, 3.58 mmol) in DCM (24 mL) was added bromine (3.58 mL, 1.0 M solution in DCM) dropwise at 0° C. The mixture was stirred for 30 minutes at 0° C. and warmed to room temperature over 1 hour. Upon completion, the reaction was diluted with DCM, washed with saturated Na2S2O3 and brine, dried (Na2SO4), and concentrated to afford 62.4. The crude product was used without further purification.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:9]([O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(OCc2ccccc2)CCC1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a round bottomed flask equipped with Dean-Stark apparatus was added 1,3-cyclohexanedione (60.0 g), toluene (450 ml), p-toluenesulfonic acid monohydrate (1.35 g) and benzyl alcohol (52.6 g, 487). The resulting solution was heated to reflux temperature for 12 hr. The reaction mixture was cooled to room temperature and then washed with saturated aqueous sodium carbonate solution (2×100 ml). The organic layer was then washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, affording a brown oil (94.9 g) which crystallised upon standing for 17 hr. The crude crystalline material was slurried in isopropyl ether (20 ml). The mixture was filtered and the crystalline material was washed with ice cold isopropyl ether (3×30 ml), then with cold petroleum ether (2×20 ml). The resulting peach-colored crystalline solid was dried overnight under reduced pressure, furnishing the title compound (74.4 g, 76%). m/z (ES+) 203 (M+H+).