Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[C:13]2[CH:20]3[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:22][CH:14]2[CH2:15]4)[CH2:19]3)[O:9][CH2:10][CH2:11]I)[CH:5]=[CH:6][CH:7]=1.C1COCC1.[NH3:28]>C(=O)=O>[NH2:28][CH2:11][CH2:10][O:9][C:8](=[C:13]1[CH:20]2[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: N
Reactant: Oc1cccc(C(OCCI)=C2C3CC4CC(C3)CC2C4)c1
Agent: O=C=O
Solvent: C1CCOC1
Product: NCCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(O)c1
Temperature: 40 °C
Yield: 90 %

Procedure:
A solution of [(3-hydroxyphenyl)(2-iodoethoxy)methylene]adamantane (3.0 g, 0.01 mol)in a minimum amount of THF was added into 10 mL of liquid ammonia in a sealed tube which was kept in dry ice. After sealing the tube this was heated at 40° C. in an oil bath for 17 h. The reaction mixture was cooled down and solvent evaporated to obtain a white solid. This material was extracted with methylene chloride. The combined organic layers were washed with water, dried over MgSO4, and concentrated to give 2.0 g (90%) of the product as a white solid: mp 55° C.; 1H NMR (CDCl3) δ1.77-1.96 (m, 12H), 2.68 (bs, 1H), 2.85 (t, 2H, J=4.8 MHz), 3.23 (bs, 1H), 3.48 (t, 2H, J=4.8 MHz), 4.46 (bs, 2H), 6.70-7.17 (m, 4 H); 13C NMR (CDCl3) δ28.16, 30.28, 32.19, 36.99, 38.88, 39.04, 41.33, 70.45, 114.97, 116.17, 120.63, 129.02, 131.89, 136.69, 141.79, 156.86; MS m/e (rel intensity) 299 (10), 256 (100), 239 (5), 199 (6), 135 (12), 121 (27), 93 (12), 77(5). Exact mass: calcd 299.1885, found: 299.1891. ##STR31##
Reaction SMILES: CC1C=NC(C)=CN=1.CN([CH2:12][CH2:13][C:14]1[CH:19]=[N:18][C:17]([CH2:20][CH2:21]N(C)C)=[CH:16][N:15]=1)C>>[CH:13]([C:14]1[CH:19]=[N:18][C:17]([CH:20]=[CH2:21])=[CH:16][N:15]=1)=[CH2:12]
Reactant: CN(C)CCc1cnc(CCN(C)C)cn1
Agent: Cc1cnc(C)cn1
Product: C=Cc1cnc(C=C)cn1
Yield: 47 %

Procedure:
The procedure of Example 1 was followed using 2,5-dimethylpyrazine as the starting material. The intermediate, 2,5-bis(N,N-dimethylaminoethyl)pyrazine, was prepared at a yield of 47% (118°-130° C./1.2 mm Hg). The product 2,5-divinylpyrazine was collected at 46°-50° C./1.2 mm Hg (36%, nD =1.595). It was found to be slightly soluble in water. 1H NMR (CDCl3) δ 5.57 (2H, dd, J=9.0, 1.2 Hz), 6.31 (2H, dd, J=17.7, 1.2 Hz), 6.80 (2H, dd, J=17.7, 9.0 Hz), 8.51 (2H, s); 13C NMR (CDCl3) δ 120.18, 133.27, 142.31, 149.38.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]3[C:9]2=[O:14])[CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccnc(N)c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1
Reaction time: 12 h
Yield: 42.5 %

Procedure:
To a stirring solution of 4-methyl-2-aminopyridine (50 g, 460 mmol) in acetic acid (1 L) was added phthalic anhydride (68 g, 460 mmol) and the reaction was heated to reflux. After 12 h, acetic anhydride (43 mL, 460 mmol) was added and the solution continued to stir at reflux for an additional 48 h. The solvent was then removed in vacuo and the solid residue was suspended in toluene and concentrated in vacuo twice. The solid was then suspended in ethyl acetate with vigorous stirring and filtered. After repeating this ethyl acetate washing procedure the solid was dried overnight in vacuo to give 46.6 g (42%) of a white solid.
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:11])[C:9]#[CH:10]>C1(C)C=CC=CC=1>[CH2:8]([NH:11][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[C:9]#[CH:10]
Reactant: COCC(Cl)C=O
Reactant: C#CCN
Solvent: Cc1ccccc1
Product: C#CCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Propargylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-propargylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:4][N:3]=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>N1C=CC=CC=1>[OH:14][C:10]1[CH:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:16](=[O:17])[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cnc(-c2cccc(O)c2)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cnc(-c2cccc(O)c2)cn1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-(3-hydroxyphenyl)pyrazine (89 mg) in pyridine (10 mL) was added under ice-cooling phenyl chloroformate (63 μL). The mixture was stirred for 1 hour and then poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The extract was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with ethyl ether (10 mL) to give the subject compound (51 mg).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][NH:15][CH2:16][CH3:17])([OH:13])[CH2:9]1)C1C=CC=CC=1.[CH2:18]=O>C(O)=O>[CH2:16]([N:15]([CH2:14][C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:18])[CH3:17]
Reactant: CCNCC1(O)CCN(Cc2ccccc2)C1
Reactant: C=O
Solvent: O=CO
Product: CCN(C)CC1(O)CCNC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1.8 g (93 mmol) 1-benzyl-3-ethylaminomethyl-3-hydroxy-pyrrolidine (according to example Ca) are dissolved in a mixture of 9.5 g formic acid and 8.5 g 37% proof aqueous formaldehyde solution. The mixture is stirred at 80° C. for 4 hours. The solvents are removed in vacuo, the residue is taken up in water, and the pH is adjusted alkaline with potassium carbonate. The reaction mixture is then extracted with chloroforme, and the organic phase is dried with potassium carbonate. After filtration the organic solvent is removed in vacuo and the residue is destilled.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[NH:24]([C:25]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:3][CH2:2]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)c1ccc(NC2CCNCC2)nc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC2CCN(C(=O)Nc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
A mixture of methyl 6-(4-piperidylamino)nicotinate (0.73 g) and phenyl isocyanate (388 mg) in THF (30 ml) was stirred at ambient temperature for 12 hours. IPE (30 ml) was added to a reaction mixture and the precipitate was collected by filtration to give methyl 6-{[1-(anilinocarbonyl)-4-piperidyl]amino}nicotinate (0.72 g)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH:10]([NH:12][C:13]1[NH:17][N:16]=[C:15]([S:18](Cl)(=[O:20])=[O:19])[N:14]=1)=[O:11].S(Cl)(Cl)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:18]([C:15]2[N:14]=[C:13]([NH:12][CH:10]=[O:11])[NH:17][N:16]=2)(=[O:19])=[O:20])=[CH:4][C:3]=1[CH3:9]
Reactant: O=CNc1nc(S(=O)(=O)Cl)n[nH]1
Reactant: Cc1cc(N)ccc1Br
Solvent: CC#N
Solvent: O=S(=O)(Cl)Cl
Product: Cc1cc(NS(=O)(=O)c2n[nH]c(NC=O)n2)ccc1Br

Procedure:
A mixture of 4-bromo-3-methylaniline (3.72 g, 20 mmol) and 5-formamido-1,2,4-triazole-3-sulfonyl chloride (2.10 g, 10 mmol) in 50 mL of acetonitrile was refluxed under nitrogen until all of the sulfonyl chloride has been consumed (approximately 1 hr). The mixture was cooled and filtered. The precipitate was dispersed in 200 mL of 1% aqueous HCl solution and filtered again to yield the title compound as a white solid, 3.0 g (84%) m.p. 282°-284° C., M+ -Br at 280.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[NH:12][CH:13]=2)=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21].C(N(C(C)C)C(C)C)C.[CH2:33]([O:40][C:41](ON1C(=O)CCC1=O)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:41]([O:40][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:42])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)=[CH:5][C:4]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Fc1ccc(-c2c[nH]c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
To 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine hydrochloride salt (1510.00 mg; 3.91 mmol; 1.00 eq.) in DCM was added Ethyldiisopropylamine (2.81 ml; 15.64 mmol; 4.00 eq.) and stirred for 5 mins. N-(Benzyloxycarbonyloxy) succinimide (1169.26 mg; 4.69 mmol; 1.20 eq.) was then added. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM, washed with water, 5% NaHCO3 aq and brine. The organic layer was dried and concentrated. The residue was subjected to SNAP column (100 g), eluted with 20-80% EA in hexane to afford the title compound (1310 mg, yield 74.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17](=[O:25])(=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1ccccc1S(=O)CC2
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1ccccc1S(=O)(=O)CC2
Temperature: 25 °C

Procedure:
To a solution of 14 g of 2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one 7-oxide prepared in Example 14 in 200 ml of acetic acid is added 15 ml of hydrogen peroxide with stirring at room temperature. The mixture is stirred at 50°-55° C. for 2 hours, poured into 1 liter of water and the precipitated crystals are collected by filtration. The crude products obtained are purified by column chromatography on silica gel and recrystallized from chloroform-methanol to give 9.8 g of 2-(4-chlorophenyl-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one 7,7-dioxide, melting at above 310° C.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([NH2:23])=O)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:33]2)=CC=1.CCOC(C)=O.Cl>COCCOC>[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21](=[S:33])[NH2:23])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=S)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a suspension of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxamide (340 mg, 1.0 mmol) obtained above in DME (10 mL) was added 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (485 mg, 1.2 mmol), and the mixture was stirred at 80° C. for 1 h. The reaction mixture was allowed to cool to rt, and then were added EtOAc (15 mL) and 1N hydrochloric acid (15 mL) and then the resulting suspension was filtered. The residue was washed with water (5 mL) and EtOAc (5 mL) to give the title compound (172 mg, 48%) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:23]([O:30][C:31]([N:4]1[C@H:3]([CH2:2][OH:1])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1Cc2[nH]c3ccccc3c2C[C@H]1CO
Reaction time: 3 h
Yield: 86 %

Procedure:
2.02 g of (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline are dissolved in 24 ml of methanol, and 1.5 ml of triethylamine and 1.8 ml of benzyloxycarbonyl chloride are added dropwise to the mixture. The mixture is stirred at 5°-10° C. for 3 hours, and the mixture is evaporated to remove the solvent. The residue is dissolved in ethyl acetate. The solution is washed with water, a 0.5M citric acid solution and water, dried and then evaporated to remove the solvent. 2.90 g of (3S)-2-benzyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline are obtained as colorless oil. Yield: 86%
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.C1(C)C=CC(S([N:26]=[N+:27]=[N-])(=O)=O)=CC=1>CC#N>[CH3:6][O:5][C:3](=[O:4])[C:2](=[N+:26]=[N-:27])[C:1]([O:8][CH3:9])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(=O)CC(=O)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 39 °C
Reaction time: 0.25 h

Procedure:
9.9 g. (0.075 mole) of dimethyl malonate, 50 ml of anhydrous acetonitrile, and 7.6 g (0.075 mole) of triethylamine (b.p. 88.5-90.5° C.) were added to a 300 ml double-jacketed flask with a dropping funnel, reflux condenser and mechanical stirrer (Rushton). The temperature of the mixture was adjusted to 20° C., and 14.8 g (0.075 mole) of p-toluenesulfonyl azide in 50 ml of CH3CN is added dropwise with vigorous stirring over 15 minutes. The addition caused the reaction mixture to warm to 38-40° C. and assume a yellow colour. After the mixture had been stirred at room temperature for 2.5 hours, the solvent was evaporated at 35° C. (12 mm). The partially crystalline residue was triturated with 100 ml of ether, and the mixture, including the insoluble residue, was placed in a 500 ml separatory funnel. The mixture was washed successively with a 50 ml solution of potassium hydroxide (2N) and a 50 ml solution of potassium hydroxide (0.5N) solution. The yellow-orange ethereal phase was dried over anhydrous sodium sulfate, and the solvent evaporated at 35° (15 mm) until the residue had attained a constant weight. The yellow-orange diazo ester weighed 5 g. The product was checked by 1HNMR spectroscopy and found to be ca. 90% pure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14])([O-:3])=[O:2].[CH2:15](O)[CH2:16][CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]12[O:18][CH2:17][CH2:16][CH2:15][O:14]1)([O-:3])=[O:2]
Reactant: OCCCO
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C12OCCCO2

Procedure:
A mixture of 5-nitroisatin (5.00 g, 26.0 mmol), 1,3 propandiol (4.76 mL , 65 mmol, 2.5 eq) and p-toluenesulfonic acid mono-hydrate (0.989 g, 5.2 mmol, 0.2 mol %)) in benzene (500 mL) was refluxed with a Dean Stark Trap for 23 hr. The benzene was decanted off and concentrated. The crude product was purified on Biotage KP silica gel eluting with 50/50 petroleum ether/EtOAc to give the title compound as an off white solid (1.78 g, 27% yield). NMR (300 Mz, DMSO-d6): consistent.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].[C:32]1([C:37](Cl)=[O:38])[S:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:37]([C:32]3[S:36][CH:35]=[CH:34][CH:33]=3)=[O:38])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.47 g, 5.50 mmol) (obtained as described in Reference Example 62(1)) in methanol (120 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide (2.47 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (115 ml). To the mixture were added thenoyl chloride (0.71 ml, 6.60 mmol) and triethylamine (0.92 ml, 6.60 mmol), and the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(thiophene-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (1.88 g, yield 64%) as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[C:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.C([O-])(=O)C.[Na+].[I:22]Cl>C(Cl)(Cl)Cl.CO.O=[Pt]=O>[I:22][C:5]1[CH:6]=[C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:15]=[CH:16][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc(C=C2CCOCC2)cc1
Reactant: ClI
Agent: O=[Pt]=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1ccc(CC2CCOCC2)cc1I
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 34 %

Procedure:
A mixture of 4-(4-nitrobenzylidene)tetrahydro-2H-pyran (2.0 g) and PtO2 (0.2 g) is hydrogenated at 40 p.s.i. H2 for 3.5 h. The mixture is filtered through celite and the filtrate condensed. The crude residue is dissolved in a mixture of 40 mL CHCl3 and 4 mL MeOH. To this is added sodium acetate (2.24 g), followed by the dropwise addition of a solution of ICl (0.69 mL) in MeOH (10 mL). The reaction is stirred at room temperature for 1 h then quenched by pouring into an iced saturated solution of aqueous sodium bisulfite (200 mL). The mixture is stirred for 30 minutes then concentrated until all of the organics are gone. The aqueous solution is extracted with CH2Cl2 (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed (Biotage flash 40M, eluent CH2Cl2) to yield 1.0 g (34%) of the desired product as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]([NH:18][C:19](=[O:21])[CH3:20])=[C:6]([Br:22])[CH:5]=1)(=[O:3])[CH3:2].[Li+].[CH3:24][CH:25]([N-]C(C)C)[CH3:26].C(Br)C=C>C1COCC1>[C:1]([C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]([N:18]([CH2:26][CH:25]=[CH2:24])[C:19](=[O:21])[CH3:20])=[C:6]([Br:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCN(C(C)=O)c1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Temperature: -78 °C
Yield: 57.7 %

Procedure:
A solution of N-(4-acetyl-5-benzyloxy-2-bromo-phenyl)-acetamide (1.03 g, 2.85 mmol) in anhydrous THF (20 ml) under nitrogen was cooled to −78° C. followed by the dropwise addition of LDA (2.1 ml, 2M solution, 4.3 mmol). The reaction was continued to stir for an hour at −78° C. and then quenched with allyl bromide (0.44 ml, 2.85 mmol). The reaction was allowed to warm to room temperature and continued to stir overnight. The solution was partitioned between EtOAc and water. The organics were collected and washed with water, brine and then dried (MgSO4). Purification by column chromatography in hexane/EtOAc (1:1) afforded a white solid (0.662 g, 58%). LC/MS: RT=2.703 min. 402/404 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Br[C:19]([CH2:21][CH3:22])=[CH2:20].O>CC(=O)CC>[F:7][C:8]([F:16])([F:17])[C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:20][CH:19]=[CH:21][CH3:22]
Reactant: C=C(Br)CC
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC=CCOc1cccc(C(F)(F)F)c1

Procedure:
18 g of potassium carbonate were added to 15 ml of 3-trifluoromethylphenol and 25 ml of 2-butanone with stirring and then 15.1 ml of 2-bromobutene in 70 ml of 2-butanone were added. The mixture was refluxed for 90 minutes, then stirred for 72 hours at ambient temperature. 300 ml of water were then added, followed by extraction with methylene chloride. The extracts were dried and concentrated to dryness to obtain 21.73 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([NH2:33])=[N:31][OH:32])[CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C@@H:14]([CH3:15])[CH2:13][CH2:12][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22].[CH:34](OCC)(OCC)OCC>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[N:33]=[CH:34][O:32][N:31]=3)[CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C@@H:14]([CH3:15])[CH2:13][CH2:12][CH:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:10]1(=[O:22])=[O:23]
Reactant: CCOC(OCC)OCC
Reactant: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(N2CCC(C(N)=NO)CC2)cc1F
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(N2CCC(c3ncon3)CC2)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of 1-[3-fluoro-4-[[(3S)-3-methyl-1,1-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N′-hydroxy-piperidine-4-carboxamidine Stereoisomer A (150 mg, 0.32 mmol) in triethyl orthoformate (2 mL) was heated to 100° C. for 1 hour. 2 drops of trifluoroacetic acid were then added and the reaction was stirred at 100° C. for 1 hour. The solution was then concentrated and purified by preparative HPLC to give (3S)-2-[[2-fluoro-4-[4-(1,2,4-oxadiazol-3-yl)-1-piperidyl]phenyl]methyl]-3-methyl-6-phenyl-thiazinane 1,1-dioxide Stereoisomer A (31.8 mg, 21% yield). 1H NMR (400 MHz, DMSO) δ 9.53-9.49 (s, 1H), 7.49-7.43 (m, 2H), 7.43-7.35 (m, 3H), 7.35-7.29 (m, 1H), 6.85-6.79 (m, 1H), 6.77-6.69 (m, 1H), 4.50-4.36 (m, 2H), 4.32-4.23 (m, 1H), 4.15-4.02 (m, 1H), 3.81-3.69 (m, 2H), 3.13-3.01 (m, 1H), 2.97-2.83 (m, 2H), 2.46-2.37 (m, 1H), 2.14-1.97 (m, 3H), 1.89-1.70 (m, 3H), 1.70-1.59 (m, 1H), 1.13-1.05 (d, J=6.8 Hz, 3H); LCMS [M+1]+=485.2.