Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.Cl.[NH2:26][C:27]1([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:34][C:32](=[O:33])[C:27]4([CH2:31][CH2:30][CH2:29][CH2:28]4)[N:26]=3)[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NC(=O)C1(N)CCCC1
Agent: Cl
Product: Cc1c(C2=NC3(CCCC3)C(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 25 was synthesized from 4a (251 mg, 0.66 mmol) and 5j (140 mg, 0.98 mmol) as a white solid (140 mg, 45%) in a manner similar to that described in Example 53. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, 1H), 7.32˜7.26 (m, 3H), 7.12 (s, 1H), 7.02 (d, 2H), 2.49 (m, 2H), 2.36 (s, 3H), 2.17 (m, 2H), 1.86 (m, 4H); ESMS m/z: 473.1 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[C:27]([C:35]([O:37][CH3:38])=[O:36])=[CH:28][C:29]2[N:30]([N:32]=[CH:33][N:34]=2)[N:31]=1.C(N(C(C)C)C(C)C)C.[Cl-].[Na+]>CN(C)C=O.O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[C:27]([C:35]([O:37][CH3:38])=[O:36])=[CH:28][C:29]4[N:30]([N:32]=[CH:33][N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: COC(=O)c1cc2ncnn2nc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ncnn2nc1NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 41.4 %

Procedure:
1.42 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 929 mg of methyl (6-chloro[1,2,4]triazolo[1,5-b]pyridazin-7-yl)carboxylate were dissolved in 20 ml of N,N-dimethylformamide; 1.51 ml of N-ethyldiisopropylamine was added, followed by stirring at 70° C. for 6 hours. After cooling, water was added; the mixture was saturated with sodium chloride and extracted with ethyl acetate-tetrahydrofuran (1:1); the extract was dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated; the residue was crystallized by the addition of ethyl acetate-ethyl ether-hexane (1:2:1), collected by filtration, washed with hexane and dried to yield 905 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH:10](I)[CH3:11])=[O:4].[BH4-].[Na+].Cl>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: COC(=O)c1sccc1C(C)I
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1ccsc1C(=O)OC
Reaction time: 1 h

Procedure:
3-Acetyl-2-thiophenecarboxylic acid methyl ester (3.87 g) synthesized in this manner was dissolved in methanol (50 ml), and sodium borohydride (0.95 g) was added under ice-cooling. The mixture was stirred at room temperature for 1 hour, and 1N hydrochloric acid (50 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-(1-hydroxyethyl)-2-thiophenecarboxylic acid methyl ester (3.77 g). This product was dissolved in ethyl acetate (100 ml), and methanesulfonyl chloride (2.86 g), triethylamine (3.5 g) and dimethylaminopyridine (0.2 g) were added. The mixture was stirred at room temperature for 2 hours, and 1N hydrochloric acid (50 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (100 ml), and sodium iodide (10 g) was added. The mixture was stirred at room temperature for 2 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The desired fractions were concentrated under reduced pressure to give 3-(1-iodoethyl)-2-thiophenecarboxylic acid methyl ester (3.0 g). 3-(1-iodoethyl)-2-thiophenecarboxylic acid methyl ester was dissolved in dimethylsulfoxide (10 ml), and sodium borohydride (0.4 g) was added at room temperature. The mixture was stirred for 1 hour, and 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g). A mixture of 3-ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g), 1N aqueous sodium hydroxide (15 ml), tetrahydrofuran (30 ml) and methanol (10 ml) was stirred at room temperature for 1 hour. The mixture was washed with diethyl ether, and the aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-ethyl-2-thiophenecarboxylic acid (0.9 g) as crystals.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([N:16]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:17]([O:19][CH3:20])=[O:18])[C:13]2[C:8](=[CH:9][C:10]([O:38][CH3:39])=[C:11]([O:36][CH3:37])[CH:12]=2)[N:7]1[C:40](OC(CC)C)=[O:41])=O)C.[BH4-].[Na+].O>CO>[CH3:20][O:19][C:17](=[O:18])[N:16]([CH2:21][C:22]1[CH:23]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH:14]1[C:13]2[C:8](=[CH:9][C:10]([O:38][CH3:39])=[C:11]([O:36][CH3:37])[CH:12]=2)[N:7]2[C:40](=[O:41])[O:3][CH2:4][CH:6]2[CH2:15]1
Reactant: CCOC(=O)[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CC2COC(=O)N2c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of cis 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester (Example 5) (100 mg, 0.15 mmol) in 8.5 mL methanol at 0° C. was added sodium borohydride (57 mg, 1.5 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed using 80% ethyl acetate/hexanes to afford the title product (70 mg). 1H NMR (CDCl3) δ 1.8 (br, 1H), 2.4 (br, I H), 3.6 (s, 3H), 6.5 (br, 1H), 7.6 (br, 2H), 7.9 (s, 1H).
Reaction SMILES: C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.[Li].Cl[CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]1.[CH2:32]([Si:34]([CH2:42][CH3:43])([CH2:40][CH3:41])[C:35]([F:39])=[C:36](F)[F:37])[CH3:33]>C1COCC1.O>[F:39]/[C:35](/[Si:34]([CH2:40][CH3:41])([CH2:42][CH3:43])[CH2:32][CH3:33])=[C:36](/[F:37])\[CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]1
Reactant: CCCC1CCC(Cl)CC1
Reactant: CC[Si](CC)(CC)C(F)=C(F)F
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCC(/C(F)=C(\F)[Si](CC)(CC)CC)CC1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
74.1 g (0.28 mol) of 4,4′-di-tert-butylbiphenyl are initially introduced in 1000 ml of THF in an argon atmosphere, and 1.6 g (0.23 mol) of lithium (granules) are added at 0° C. After 5 h, the blue solution is cooled to −78° C., and 40.6 g (0.25 mol) of 1-chloro-4-propylcyclohexane are added. After 30 min at this temperature, 49.6 g (0.25 mol) of triethyltrifluorovinylsilane are metered in. The mixture is warmed slowly and stirred at room temperature for 16 h. Water is added, and the batch is extracted with MTBE. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water and saturated sodium chloride solution. The solution is dried using sodium sulfate and concentrated under reduced pressure. The residue is digested with methanol, and insoluble material is filtered off. The filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography (SiO2, pentane), giving [(Z)-1,2-difluoro-2-(4-propylcyclohexyl)vinyl]triethylsilane as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[O:14]([NH2:16])[CH3:15]>>[CH3:15][O:14][N:16]=[CH:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=CCCc1ccc(Cl)c(Cl)c1
Reactant: CON
Agent: Cl
Product: CON=CCCc1ccc(Cl)c(Cl)c1
Yield: 91 %

Procedure:
Reaction of 3-(3,4-dichlorophenyl)-propionaldehyde (Heck, J. Amer. Chem. Soc., 90, 1968, 5526) with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (91% yield), bp 80-90° C./0.5 torr (bulb to bulb distillation, air bath temperature). 1HNMR indicated a 55:45 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.63 and 2.76 (2H, 2 m, CH2), 2.9 (2H, m, CH2), 3.96 and 4.01 (3H, 2 s, OCH3), 6.77 (t, J=5.5 Hz, CH), 7.16-7.5 (3H, m, aromatics and CH).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:25])(=[N:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:18])[CH:12]=2)=[CH:5][C:4]=1[N:26]=[CH:27][N:28](C)[CH3:29])#N.[NH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1.ClCCl.CO>CO>[CH2:23]([O:22][C:20]([N:19]=[S:17]([CH3:25])([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][C:6]2[CH:5]=[C:4]3[C:3]([C:29]([NH:31][C:32]4[S:33][CH:34]=[CH:35][N:36]=4)=[N:28][CH:27]=[N:26]3)=[CH:8][CH:7]=2)[CH:12]=1)=[O:18])=[O:21])[CH3:24]
Reactant: Nc1nccs1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(CNc2ccc(C#N)c(N=CN(C)C)c2)c1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1cccc(CNc2ccc3c(Nc4nccs4)ncnc3c2)c1
Yield: 43 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylamino}phenyl)-N,N-dimethylformimidamide (90 mg, 0.21 mmol) with 2-aminothiazole (26 mg, 0.25 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 43% yield (43 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]([OH:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)=[C:4]([N+:18]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:18][C:4]1[CH:3]=[C:2]([Cl:1])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:13]([OH:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CC(O)c1cccc(Oc2ccc(Cl)cc2N)c1
Yield: 70.1 %

Procedure:
The product from Example 170b (0.98 g, 3.3 mmol) was reduced with SnCl2 as described in Example 1f to give the title compound (0.61 g, 70%).
Reaction SMILES: N([O-])=O.[Na+].[BrH:5].[CH3:6][C:7]1[CH:8]=[C:9]([CH:11]=[C:12]([CH3:14])[CH:13]=1)N.CCCCCC>O.[Cu]Br>[Br:5][C:9]1[CH:8]=[C:7]([CH3:6])[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(C)cc(Br)c1
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 42 g of sodium nitrite in 150 ml of water is added to a mixture, cooled to −5° C., of 200 ml of 48% HBr and 50 g of 3,5-dimethylaniline. The reaction mixture is stirred for 1 hour at from −5° C. to 0° C. Finally, this reaction mixture is slowly added to a mixture, heated to 80° C., of 88.3 g of copper(I) bromide and 150 ml of 48% HBr. The reaction mixture is stirred for 2 hours at 80° C. and observed by TLC monitoring (silica; hexane). When the reaction is complete, the product is obtained by water-vapour distillation and is purified by column chromatography (silica; hexane). In this manner, 1-bromo-3,5-dimethylbenzene was obtained in a yield of 60% (30 g).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[C:11]([N+:12]([O-])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[H][H]>[Pt].CN1CCOCC1>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[C:11]([NH:12][OH:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: [H][H]
Reactant: Cc1ccccc1OCc1ncccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CN1CCOCC1
Product: Cc1ccccc1OCc1ncccc1NO
Yield: 161.3 %

Procedure:
A mixture of 5.0 g (21 mmol) of 2-(2-methylphenoxymethyl)-3-nitropyridine (Example 3.d) and 100 ml of N-methylmorpholine was hydrogenated at room temperature (approximately 25° C.) and an H2 pressure of approximately 1.1 bar in the presence of 1 g of 5% platinum/charcoal (51% water; manufactured by Degussa). The hydrogen uptake ceased after approximately 90 minutes. The catalyst was removed by filtration through active charcoal. The resulting solution was freed from solvent under reduced pressure, and the residue obtained was treated with approximately 50 ml of petroleum ether. This gave 7.8 g (90%) of the title compound as a white solid. The solvent was removed under reduced pressure ("high vacuum"), and the residue obtained was washed using hexane. This gave 4.5 g (94%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[O+][O-].[C:4]([O:8][C:9]([N:11]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12]1[CH:17]=[C:16]([CH:18]=C)[N:15]=[C:14]([C:20]([O:22][CH3:23])=[O:21])[C:13]=1[O:24][CH3:25])=[O:10])([CH3:7])([CH3:6])[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:4]([O:8][C:9]([N:11]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12]1[CH:17]=[C:16]([CH:18]=[O:1])[N:15]=[C:14]([C:20]([O:22][CH3:23])=[O:21])[C:13]=1[O:24][CH3:25])=[O:10])([CH3:5])([CH3:7])[CH3:6]
Reactant: O=[O+][O-]
Reactant: C=Cc1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(OC)c(C(=O)OC)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1nc(C=O)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
Ozone was bubbled through a solution of methyl 4-[bis(tert-butoxycarbonyl)amino]6-ethenyl-3-methoxypyridine-2-carboxylate (0.382 g, 0.935 mmol) in CH2Cl2 (9.35 ml) at −78° C. until the solution turned blue. Oxygen was bubbled through the reaction mixture until the solution turned yellow and triphenylphosphine (0.294 g, 1.122 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was then adsorbed onto celite and the residue was purified by flash column chromatography (ISCO, SiO2 24 g, hexanes/EtOAc 100:0 to 0:100 gradient) to afford methyl 4-[bis(tert-butoxycarbonyl)amino]-6-formyl-3-methoxypyridine-2-carboxylate (279 mg, 0.680 mmol, 72.7% yield) as a light yellow oil. ESIMS m/z 411 ([M−H]+); 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.88 (s, 1H), 4.05 (s, 3H), 3.95 (s, 3H), 1.43 (s, 18H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:5]=[CH:6][C:7]=1[C:8]1[C:9](OC)=N[C:11]([O:14][C@@H:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[N:12][CH:13]=1.Br[C:41]1C=C(C)C(O[C@@H]2COC3=NC([N+]([O-])=O)=CN3C2)=N[CH:46]=1>>[F:1][C:2]1[CH:3]=[C:4]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[N:12][C:11]([O:14][C@@H:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[C:41]([CH3:46])[CH:9]=1
Reactant: COc1nc(O[C@@H]2COc3nc([N+](=O)[O-])cn3C2)ncc1-c1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Reactant: Cc1cc(Br)cnc1O[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3cnc(O[C@@H]4COc5nc([N+](=O)[O-])cn5C4)c(C)c3)c(F)c2)C(=O)O1

Procedure:
N-(3-{3-Fluoro-4-[4-methoxy-2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6(S)-yloxy)-pyrimidin-5-yl]-phenyl}-2-oxo-oxazolidin-5(S)-ylmethyl)-acetamide. The title compound was prepared by following the same procedure as described in the preparation of Example 7, except 6(S)-(5-bromo-3-methyl-pyridin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine was used in place of 6(S)-(5-bromo-pyridin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine. ESI MS m/z 527.3 (M+H+); 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.56 (s, 1H), 7.49 (dd, J=12.8, 2.0 Hz, 1H), 7.38 (s, 1H), 7.32 (t, J=8.4 Hz, 1H), 7.24-7.21 (m, 1H), 5.89 (t, J=6.0 Hz, 1H), 5.73 (s, 1H), 4.78-4.75 (m, 2H), 4.48 (d, J=12.8 Hz, 1H), 4.36 (d, J=2.4 Hz, 2H), 3.76 (dd, J=9.2, 6.8 Hz, 1H), 3.66-3.59 (m, 2H), 2.10 (s, 3H), 1.97 (s, 3H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]1(/[C:19](/[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CI.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][CH:24]([CH2:23][CH2:22][CH2:21]/[CH:20]=[C:19](\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)CCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
A solution of diisopropylamine (0.21 ml, 1.46 mmole) in tetrahydrofurane (3 ml) was cooled at -60° C. under argon, and a hexane solution of n-butyl lithium (1.6M, 0.92 ml, 1.46 mmole) was added dropwise to the solution. After stirring for 10 minutes, a solution of methyl (E)-7-phenyl-7-(3-pyridyl)-6-heptenoate (360 mg, 1.22 mmole) in tetrahydrofuran (2 ml) was added dropwise to the solution, followed by stirring at -60° to -70° C. for 20 minutes. Subsequently, methyl iodide (0.12 ml, 1.83 mmole) was added, and the reaction was allowed to proceed at the same temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel, and development was effected with isopropyl ether:ethyl acetate (7:3) to yield methyl (E)-2-methyl-7-phenyl- 7-(3-pyridyl)-6-heptenoate (3-a) (270 mg, 71.6 %).
Reaction SMILES: [C:1]1([N:7]2[CH2:13][C:11](=[O:12])[NH:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([O:16][CH2:17][CH2:18]Cl)=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([N:7]2[CH2:13][C:11](=[O:12])[N:10]([CH2:18][CH2:17][O:16][CH:14]=[CH2:15])[C:8]2=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Reactant: C=COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=COCCN1C(=O)CN(c2ccccc2)C1=O

Procedure:
16.12 g (0.1 mol) of 1-phenylhydantoin, 12.25 g (0.1 mol+15% excess) of 2-chloroethyl vinyl ether, 7.25 g (0.05 mol+5% excess) of potassium carbonate and 50 ml of dimethylformamide are reacted for 1 hour at 120°-125° C. The reaction mixture is worked up analogously to Example 1 and 20.3 g (82.4% of theory) of a brownish, crystalline crude product melting at 119°-120° C. are obtained. 5 g of crude product are recrystallised from 25 ml of chloroform and 3.9 g of the pure compound are isolated. The melting point is 120°-121° C.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>ClCCl>[CH:17]1([CH2:16][N:3]2[CH2:2][CH2:1][C@@H:10]3[C@H:5]([CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)[CH2:4]2)[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Solvent: ClCCl
Product: c1ccc2c(c1)CC[C@@H]1CN(CC3CC3)CC[C@@H]21
Reaction time: 24 h
Yield: 62 %

Procedure:
To a solution of 0.200 g (1.07 mmol) of trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in anhydrous dichloromethane (20 ml) was added 0.200 g (1.48 mmol) of (bromomethyl)cyclopropane and the reaction mixture was left to stand for 24 h. The solvent was removed in vacuo and the residue was chromatographed on flash silica, eluting with 10% methanol/dichloromethane to give 0.160 g (62%) of the title product as an oil. The hydrochloride salt was made using etheral hydrogen chloride. Upon evaporation of the solvent, washing with ether and recrystallisation from ethanol/ethyl acetate/petroleum ether, the title product hydrochloride was obtained as a white sold, m.p. 255°-257° C. NMR δ(D2O) 0.43 (2H, m), 0.78 (2H, m), 1.17 (1H, m), 1.58 (1H, m), 1.80-1.94 (2H, m), 2.67-2.77 (2H, m), 2.90-2.97 (3H, m), 3.09 (2H, d, J=7.4 Hz), 3.20 (1H, t of d, J=13.1 and 3.0 Hz), 3.74 (1H, m), 3.87 (1H, m), 7.22-7.31 (3H, m), 7.36-7.38 (1H, m). m/z (CI+, NH3) 242 (M+H)+, 182, 165.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH:9]1([CH2:12][CH:13](OS(C)(=O)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:10]1.[H-].[Na+].[Br-].[Li+]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:13]([CH2:12][CH:9]2[CH2:11][CH2:10]2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: CCOC(=O)C(CC1CC1)OS(C)(=O)=O
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Product: CCOC(=O)C(CC1CC1)n1ccc(Br)cc1=O
Temperature: 65 °C
Reaction time: 8 h

Procedure:
1.02 g (5.87 mmol) of 4-bromopyridin-2(1H)-one and 2.23 g (purity 56%, 5.28 mmol) of ethyl 3-cyclopropyl-2-[(methylsulphonyl)oxy]propanoate (racemate) in the presence of 1.15 eq. of sodium hydride and 2.3 eq. of lithium bromide were reacted according to General Method 4C (stirred at 65° C. overnight). Yield: 246 mg (13% of theory)
Reaction SMILES: C(O)(=O)C(O)=O.C([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[CH:21]([CH2:28][C:29]1[CH:34]=[C:33]([Br:35])[C:32]([O:36][CH3:37])=[C:31]([Br:38])[CH:30]=1)[NH:20][CH2:19][CH2:18]2)C1C=CC=CC=1.[ClH:39]>C(O)(=O)C>[ClH:39].[Br:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([Br:38])[C:32]=1[O:36][CH3:37])[CH2:28][CH:21]1[C:22]2[C:17](=[CH:16][C:15]([OH:14])=[C:24]([N+:25]([O-:27])=[O:26])[CH:23]=2)[CH2:18][CH2:19][NH:20]1
Reactant: COc1c(Br)cc(CC2NCCc3cc(OCc4ccccc4)c([N+](=O)[O-])cc32)cc1Br
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: COc1c(Br)cc(CC2NCCc3cc(O)c([N+](=O)[O-])cc32)cc1Br

Procedure:
A solution of 6-benzyloxy-1-(3,5-dibromo-4-methoxybenzyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline oxalate (13.05 g, 0.02 mol) in 250 mL of acetic acid and 250 mL of conc. HCl was refluxed for 1 h, solvents evaporated to dryness and the residue was recrystallized from MeOH-ether (first dissolved in 500 mL of MeOH and concentrated in a stream of argon). Yield 9.04 g (89%).