Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[N:17][CH:18](Br)[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:25]>CCOCC>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[N:17][CH:18]([NH2:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)C(Br)N=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(N)N=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.1 parts of ethyl (2-benzoyl-4-chlorophenylazo)bromoacetate in 16 volume parts of ether is added 160 volume parts of concentrated aqueous ammonia. After stirring the mixture for 1 hour at room temperature, the ether layer is separated, washed with water and evaporated to remove the solvent. The crystalline residue is collected by filtration, washed with ethanol and dried. The procedure gives ethyl (2-benzoyl-4-chlorophenylazo)-aminoacetate. Recrystallization from ethanol gives yellowish orange needles melting at 126°-127°C.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18]>CCOCC>[OH:9][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:11][C:10]([NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18]
Reactant: O=C1Cc2ccccc2O1
Reactant: NNc1ccccc1
Solvent: CCOCC
Product: O=C(Cc1ccccc1O)NNc1ccccc1
Reaction time: 3 h

Procedure:
Phenyl hydrazine (0.73 ml) was added to a solution of 2-Coumaranone (1 g) in ether (25 ml) and the mixture stirred for 3 hours. The product was collected by filtration, washed with ether and dried.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH2:26][CH2:27][C:28]5[N:29]([C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=5)[N:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:38](O)(=O)[CH2:39][CH2:40]CC>>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH2:26][CH2:27][C:28]5[N:29]([C:31]([C:34]([F:36])([F:35])[F:37])=[N:32][N:33]=5)[N:30]=4)[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[CH2:8][CH2:9]1)(=[O:3])[CH2:2][CH2:38][CH2:39][CH3:40]
Reactant: CC(=O)N1CCN(CCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Reactant: CCCCC(=O)O
Product: CCCCC(=O)N1CCN(CCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 77 %

Procedure:
Obtained in 77% yield by an analogous method to Example 4.1, starting from 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 32, preparation of starting materials) and pentanoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH2:9][CH2:10][O:11][CH3:12])([CH3:4])(C)C.C(O)[C:15]1[CH:20]=[CH:19]C=[CH:17][CH:16]=1.O.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>C1C=CC=CC=1>[C:23]1([CH3:33])[CH:24]=[CH:25][C:26]([S:29]([OH:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1.[CH2:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH2:9][CH2:10][O:11][CH3:12])[C:4]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: COCCNCC(=O)OC(C)(C)C
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCCNCC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in 200 ml of benzene was added 63.8 g of benzyl alcohol and 72.9 g of p-toluenesulfonic acid monohydrate. The mixture was heated at reflux for 10 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solution was concentrated in vacuo, and to the residue was added 300 ml of dry ethyl ether. After 2 hours at room temperature, the formed precipitate was filtered, washed with dry ethyl ether and then recrystallized from ethyl acetate to yield 99.2 g (85 percent) of N-(2-methoxyethyl)glycine benzyl ester p-toluenesulfonate, M.P. 95°-6° C. The following amino acid benzyl ester p-toluenesulfonate not previously reported in the chemical literature were synthesized by the aforementioned procedure.
Reaction SMILES: [Cl:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.C([O:40]C(NOC(OC(C)(C)C)=O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]([OH:40])[C:20]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCN(O)C(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (Example 96, 100 mg, 0.3 mmol), N,O-Bis-tert-butoxycarbonylhydroxylamine (Baillie, L. C.; Batsanov, A.; Bearder, J. R.; Whiting, D. A. J. Chem. Soc. Perkin Trans. 1, 1998, 20, 3471., 140 mg, 0.6 mmol) and triphenylphosphine (158 mg, 0.6 mmol) in THF (10 mL) was added diethyl azodicarboxylate (DEAD) (0.1 mL, 0.6 mmol). The mixture was stirred under nitrogen atmosphere at room temperature for 2.5 h. The solvent was removed and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 174 mg (quant.) of the title compound as yellow amorphous: 1H-NMR (CDCl3) δ 7.84 (1H, s), 7.46 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.16 (1H, s), 3.92 (2H, t, J=6.7 Hz), 3.05 (2H, t, J=6.7 Hz), 2.76 (2H, q, J=7.6 Hz), 1.56 (9H, s), 1.46 (9H, s), 1.33 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:48])[CH2:11][NH:12][CH2:13][C@@H:14]1[C@H:17]([NH:18][C:19](=[O:46])/[C:20](=[N:34]\[O:35][C:36]([CH3:45])([CH3:44])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])/[C:21]2[N:22]=[C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[S:24][CH:25]=2)[C:16](=[O:47])[NH:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:54](N2C=NC=C2)=[O:55])C=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:48][C:54](=[O:55])[N:12]([CH2:13][C@@H:14]2[C@H:17]([NH:18][C:19](=[O:46])/[C:20](=[N:34]\[O:35][C:36]([CH3:45])([CH3:44])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])/[C:21]3[N:22]=[C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[S:24][CH:25]=3)[C:16](=[O:47])[NH:15]2)[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNC[C@@H](O)COCc2ccccc2)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2C[C@H](COCc3ccccc3)OC2=O)cs1
Yield: 58.3 %

Procedure:
Prepared in analogous manner to example 63 step 2, using tert-butyl 2-(((Z)-(2-(((2R,3S)-2-((((R)-3-(benzyloxy)-2-hydroxypropyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (126 mg, 0.182 mmol), CDI (53 mg, 0.33 mmol), DCM (5 mL). The crude residue was purified via silica gel chromatography (MeOH-DCM, 3-5%) to afford the title compound (76 mg, 58%). LCMS: m/z=715.3 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][C:9]([Br:13])=[C:10]([C:11]#[N:12])[C:3]=12.C(O[CH:18]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:24]([CH3:37])[C@H:19]1[O:20][C:21](=[O:23])[CH3:22])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[C:9]([Br:13])[N:8]([C@@H:18]3[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@@H:24]([CH3:37])[C@H:19]3[O:20][C:21](=[O:23])[CH3:22])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](C)[C@H]1OC(C)=O
Reactant: N#Cc1c(Br)nc2[nH]cnc(N)c1-2
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@H](C)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(Br)c(C#N)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
BSA (0.29 mL, 2.0 mmol) was added into a stirred suspension of 4-amino-6-bromo-5-cyano-1H-pyrrolo[2,3-d]pyrimidine (0.24 g, 1 mmol; prepared according to Nucleic Acid Chemistry, Part IV, Townsend, L. B. and Tipson, R. S.; Ed.; Wiley-Interscience: New York, 1991, pp. 16–17 and Synthetic Commun. 1998, 28, 3835) in dry acetonitrile (10 mL) at room temperature under argon. After 15 min, 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-3-methyl-D-ribofuranose (J. Med. Chem. (1976), 19, 1265) (0.36 g, 1.0 mmol) was added along with TMSOTf (0.54 g, 3 mmol). The mixture was stirred at room temperature for 5 min and then at 80° C. for 0.5 h. The solution was cooled, diluted with ethyl acetate (50 mL) and poured into ice-cold saturated aqueous NaHCO3 (15 mL). The layers were separated. The organic layer was washed with brine (15 mL), dried (Na2SO4) and then evaporated. The residue was purified on silica gel column using a solvent system of hexanes/EtOAc: 3/1. Appropriate fractions were collected and evaporated to provide the title compound as colorless foam (0.21 g).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:16][O-:17].[Na+]>>[CH3:16][O:17][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc2ccccc2c2c1ncn2C

Procedure:
Using the method of Example 157, 4-chloro-1-methyl-1H-imidazo[4,5-c]quinoline (from Example 114) was reacted with sodium methoxide to provide 4-methoxy-1-methyl-1H-imidazo[4,5-c]quinoline, melting point after recrystallization from ethyl acetate 160°-162° C. Analysis: Calculated for C12H11N3O: %C, 67.6; %H, 5.2; N, 19.7; Found: %C, 67.3; %H, 5.0; %N, 19.8.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Br[CH2:11][CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:11][CH:12]=[O:13]
Reactant: Cc1cccc(C)c1N
Reactant: O=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Dimethylaniline (100 grams), the diethyl acetal of 2-bromoacetaldehyde (59.1 grams) and sodium carbonate (31.8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture was heated at a temperature of about 150°C for a period of about 30 hours. After this time the reaction mixture was cooled to room temperature and was filtered. The filtrate was then distilled under vacuum to yield the desired product the diethyl acetal of 2-(2,6-dimethylanilino)acetaldehyde as the residue.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:30](O)[CH2:31][CH:32]([CH3:34])[CH3:33])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:36])[C:13]1=[O:37])(C(C)(C)C)(C)C.[CH:38](O)=[O:39]>CC(=O)OCC.O.[Zn]>[CH:38]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:36])[C:13]1=[O:37])=[O:39]
Reactant: O=CO
Reactant: CC(C)CC(O)c1c(-c2cccc(Cl)c2)ncc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(-c2cccc(Cl)c2)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 50 °C
Yield: 70 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-(3-chlorophenyl)-5-(1-hydroxy-3-methylbutyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.055 mmol) in HCOOH (1 mL) was added Zn dust (35.6 mg, 0.55 mmol). The reaction was heated at 50° C. for 1 h, cooled to RT and diluted with EA (5 mL) and water (1 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4 and concentrated to give 3-(6-(3-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate. LCMS MH+ 444 and TR=1.738 min and 3-(6-(3-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate. LCMS: MH+ 446 and TR=1.956 min, (21 mg, 70% yield) as a solid. Used without further purification.
Reaction SMILES: [Na].[C:2]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)(=[O:4])[CH3:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14]C)=[O:12].OS(O)(=O)=O>CO>[O:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:2](=[O:4])[CH2:3][C:10](=[O:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccco1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccco1
Temperature: 0 °C
Yield: 35.4 %

Procedure:
(see, e.g., Ghosh, A. K., et al., J Med Chem 2005, 48, 6767-71). To a stirred solution of MeOH (150 mL) at room temperature under nitrogen, freshly cut Na (1.81 g, 78.7 mmol) was added in pieces and with care. After all the sodium dissolved, a mixture of 2-acetylfuran (6 mL, 59.8 mmol) and diethyl oxalate (8.14 mL, 59.9 mmol) was added dropwise over a period of 3 min at room temperature. The resulting mixture was continued to stir. Brown precipitates formed after 20 min stir. The mixture was stirred for a total of 1 h. The reaction mixture was cooled to 0° C., and a mixture of concentrated H2SO4 and ice was added. Some solid precipitated at this point which was filtered off but was not the desired product by 1H NMR. The filterate was extracted with CH2Cl2 (50 mL×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was recrystallized from hot iPrOH to give the title compound (4.15 g, 35%) as a dark brown solid. 1H NMR (400 MHz, CDCl3) δ 7.67-7.65 (m, 1H), 7.33 (d, J=3.6 Hz, 1H), 6.93 (s, 1H), 6.60 (dd, J=3.5, 1.5 Hz, 1H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 181.01, 165.39, 162.43, 150.82, 147.73, 118.58, 113.14, 99.17, 53.18.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:15][C:14]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:13]=3[CH2:12]2)=[N:8][CH:7]=1)=[O:5])C.O.[OH-].[Li+].O>C1COCC1>[C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:15][C:14]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:13]=3[CH2:12]2)=[N:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc(N2CC3=C(CN(C(=O)OC(C)(C)C)C3)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2=C(C1)CN(c1ncc(C(=O)O)s1)C2
Reaction time: 8 h

Procedure:
tert-Butyl 5-(5-ethoxycarbonylthiazol-2-yl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carboxylate (1.34 g, 3.66 mmol) and lithium hydroxide hydrate (385 mg, 9.17 mmol) were stirred in 150 ml of THF and 50 ml of water at 50° C. for 2 h and at 80° C. for 8 h. THF was concentrated under reduced pressure and the water phase was extracted with ethyl acetate. The water phase was acidified and extracted again with ethyl acetate. The organic phase was concentrated. Yield: 662 mg (53%), M+H+: 338.10.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C.O.[NH2:14][NH2:15]>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH:14][NH2:15])=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc(Br)cc1

Procedure:
Ethyl-4-bromobenzoate is treated with hydrazine monohydrate in methanol under reflux conditions to obtain product X, 4-bromobenzoic hydrazide. Reaction of compound X with bromobenzoic acid in pyridine at 120° C. gives product XI, bis-(4-bromophenyl) hydrazine. Compound XI is then treated with sulfonyl chloride to afford 2,5-bis-(4-bromophenyl)-1,3,4-oxadiazole (Compound XII), which is further reacted 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane under conditions similar to step-3 in Example 1. The resulting product thus obtained is subjected to Suzuki coupling conditions similar to step-5 in Example 1 to obtain the desired product XIII. Other alligator clips which can be introduced are CN, SCN, NH2, pyridine.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[N:5][NH:4][CH2:3]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(#N)C>[CH3:1][CH:2]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:12][CH:13]=2)=[N:5][N:4]([C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=2)=[O:29])[CH2:3]1
Reactant: CC1CNN=C(c2ccc(OC(F)(F)F)cc2)O1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: CC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C(c2ccc(OC(F)(F)F)cc2)O1
Yield: 87.3 %

Procedure:
1 g of the 5,6-dihydro-6-methyl-2-(4-trifluoromethoxyphenyl)-4H-1,3,4-oxadiazine prepared above was dissolved in 10 ml of acetonitrile. 1 g of 4-(trifluoromethyl)phenyl isocyanate was added dropwise and then the resulting reaction mixture was refluxed for two hours. Evaporation of the solvent at reduced pressure afforded 1.5 g of 5,6-dihydro-6-methyl-2-(4-trifluoromethoxy-phenyl)-N-(4-trifluoromethylphenyl)-4H-1,3,4-oxadiazine-4-carboxamide as a solid which was washed with a few milliliters of acetonitrile. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13]>C(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][S:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[F:6]
Reactant: Fc1ccccc1S
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: Fc1ccccc1SSc1ccccc1F
Reaction time: 0.5 h

Procedure:
Sulfuryl chloride (0.7 ml) was added dropwise to a solution of 2-fluorobenzenethiol (1.5 ml) in DCM (20 ml) at 0° C. The reaction mixture was stirred for 30 min, then concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane to give the sub-title compound as an oil, yield 1.7 g.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]2[O:34][CH2:35][O:36][C:17]2=[CH:16][CH:15]=1.O[CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:38][CH2:39][N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]2[O:34][CH2:35][O:36][C:17]2=[CH:16][CH:15]=1
Reactant: OCCN1CCCC1
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.9 %

Procedure:
Diethyl azodicarboxylate (0.182 ml) was added dropwise to a stirred mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-6-methoxyquinazoline (0.2 g), N-(2-hydroxyethyl)pyrrolidine (0.086 g), triphenylphosphine (0.303 g) and methylene chloride (3 ml) and the reaction mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using a 45:4:1 mixture of methylene chloride, methanol and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.033 g) as a white solid; NMR Spectrum: (DMSOd6 and CF3CO2D) 1.9 (m, 2H), 2.1 (m, 2H), 3.2 (m, 2H), 3.7 (m, 2H), 3.8 (m, 2H), 4.05 (s, 3H), 4.6 (m, 2H),6.2 (s, 2H), 7.1 (d, 1H), 7.5 (s, 1H), 8.2 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M−H− 441 and 443.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[OH-].[Na+].[CH2:7]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[C:23]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)[CH2:19]2)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:2]([NH:4][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([C:23](=[C:18]2[CH2:17][CH:16]3[N:15]([CH2:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:32][CH:31]=1)[CH3:3]
Reactant: CCN
Reactant: O=C(Cl)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCNC(=O)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
A mixture of 11.4 g (0.14 mole) of ethylamine hydrochloride and 150 mL of 3N NaOH and 100 mL of CH2Cl2 were cooled in an ice bath. A solution of 4.7 g (0.015 mole) of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzoyl chloride prepared using Procedure E in 60 mL of CH2Cl2 was added. After the addition was complete, the ice bath was removed and the reaction stirred at room temperature for 2 h. The organics were separated off and washed with water, brine and dried (K2CO3). The solvent was evaporated in vacuo and converted to the HCl salt with Et2O/HCl to give 1.86 g of N-ethyl-4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzamide; mp 296-298° C. (Decomp). MS m/z (MH+) 451. 1H NMR (DMSO-d6) δ 8.5 (ar, 1H); 7.8 (d, 2H); 7.4-7.1 (ar, 12H); 4.05 (bs, 2H); 3.4-3.2 (m, 3H); 3.1 (s, 3H); 2.9 (d, 2H); 2.4 -2.1 (m, 4H); 1.8 (m, 2H); 1.1 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].Cl[CH2:16][C:17]([NH2:19])=[O:18].O1CCOCCOCCOCCOCCOCC1>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([O:6][CH2:16][C:17]([NH2:19])=[O:18])=[O:5]
Reactant: NC(=O)CCl
Reactant: O=C(O)c1c(Cl)ccc(Cl)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)COC(=O)c1c(Cl)ccc(Cl)c1Cl

Procedure:
This compound was prepared in the manner of Example I, using 15.0 grams (0.066 mole) of 2,3,6-trichlorobenzoic acid, 4.4 grams (0.066 mole) of potassium hydroxide, 6.2 grams (0.066 mole) of 2-chloroacetamide, and 1.8 grams of 1,4,7,10,13,16-hexaoxacyclooctadecane in 300 ml of dry toluene and 200 ml of dimethylformamide. The crude product was purified by liquid chromatography, followed by recrystallization from ethyl acetate. The yield was 0.9 gram of (aminocarbonyl)methyl 2,3,6-trichlorobenzoate; mp 158°-160°. The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: C([C@@H]1COC(=O)[N:9]1[C:14]([C@@H:16]([S:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][C:30]=1[N+]([O-])=O)[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:15])C1C=CC=CC=1.C(O)C>[Pd].C(O)(=O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][C@H:16]2[C:14](=[O:15])[NH:9][C:30]3[CH:31]=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:38]=[CH:39][C:29]=3[S:28]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccc(S[C@@H](CCCc2ccc(OC)cc2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)NC(=O)[C@H](CCCc1ccc(OC)cc1)S2
Temperature: 25 °C
Reaction time: 3 h
Yield: 471.7 %

Procedure:
Ethyl 4-{[(1S)-1-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-4-(4-methoxyphenyl)butyl]thio}-3-3-nitrobenzoate (Reference Example 22) (0.62 g, 0.11 mmol), ethanol (10 ml), acetic acid (5 ml) and 10% Pd—C (1.5 g) were mixed, and the mixture was stirred for 3 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by a silica gel chromatography (40 g, ethyl acetate:hexane=1:3) to obtain ethyl (2S)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (0.2 g, 98.3% e.e.), i.e., the compound described in Example 7.