Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:31])[C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22](OC(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH:67][C:68](=[O:75])[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:62]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:9](=[CH:4][CH:3]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:31])[C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22]([N:61]3[CH2:66][CH2:65][CH2:64][CH:63]([NH:67][C:68](=[O:75])[C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)[CH2:62]3)=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@H](C(=O)OC(C)(C)C)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: O=C(NC1CCCNC1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@H](C(=O)N1CCCC(NC(=O)c2ccccc2)C1)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
A solution of tert-butyl (2R)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoate (0.017 g) in DCM (0.5 ml) was treated with trifluoroacetic acid (0.5 ml) and stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to give an oil which was subsequently treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.01 g), HOBT (0.007 g) and triethylamine (0.020 ml). After stirring at room temperature for 1 h, N-piperidin-3-ylbenzamide (0.010 g) was added and stirring was continued for 16 h. The reaction mixture was partitioned between DCM and water. The organic extract was concentrated under reduced pressure and the residue purified using SPE (silica, eluting with cyclohexane:ethyl acetate 3:1, 1:1, 1:3, ethyl acetate) to give the title compound (0.012 g) as a pale yellow gum.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]=2[CH:6]=1)=[N+]=[N-].[H][H]>CN(C)C=O>[NH2:1][CH2:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]=2[CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc2sc3ccccc3c(=O)c2c1
Reactant: [H][H]
Solvent: CN(C)C=O
Product: NCc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 60 °C
Yield: 95.3 %

Procedure:
5 g of 2-azidomethylthioxanthone are dissolved in 50 ml of N,N-dimethylformamide, and 0.5 g of Pd-on-charcoal is added, in an autoclave. Hydrogen is then passed in. The reaction is monitored by means of IR spectroscopy. It has ended when the band at 2,100 cm-1 has disappeared. The reaction mixture is diluted with N,N-dimethylformamide, heated to 60° C. and filtered, the filtrate is cooled and water is added. The crystals which have precipitated are separated off by filtration and dried. 4.3 g (95.3% of theory) of 2-aminomethylthioxanthone are obtained. Melting point: 134°-136° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O[C:14]1C=C(O)C=CC=1C(O)=O.CI.C(=O)([O-])[O-].[K+].[K+]>S1(CCCC1)(=O)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1ccc(OC)cc1O
Reaction time: 8 h

Procedure:
Methyl 2,4-dihydroxybenzoate (prepared from 2,4-dihydroxybenzoic acid by the general method of Brunner (Monatsh. 1913, 34, 916) (12 g) was treated with methyl iodide (12.2 g) and anhydrous potassium carbonate (4.95 g) in dry sulpholane (140 ml) at 60°-70° C. After 8 hours, further methyl iodide (12.2 g) was added and heating was continued for 14 hours. The excess of methyl iodide was evaporated and the mixture was poured into a mixture of ice and water (1 liter) and the mixture was acidified with aqueous acetic acid (2N). The separated solid was filtered off and washed with water to give methyl 2-hydroxy-4-methoxybenzoate (10.8 g), m.p. 47°-50° C. [a sample of which, purified by chromatography on silica gel (eluting with chloroform), had the melting point 49°-51° C⟧ The said crude methyl 2-hydroxy-4-methoxybenzoate (2.0 g) was heated with benzyl chloride (1.88 g) and anhydrous potassium carbonate (0.76 g) in dry sulpholane (15 ml) at 100° C. for 16 hours and was then poured into a mixture of ice and water (300 ml). The mixture was extracted with diethyl ether and the extract was washed with several portions of aqueous sodium hydroxide solution (0.5N) at 0° C., and was then dried and evaporated to give crude methyl 2-benzyloxy-4-methoxybenzoate (2.5 g) in the form of an oil. This material was heated at reflux with a mixture of aqueous sodium hydroxide solution (2N; 100 ml) and ethanol (20 ml) for 3 hours. The mixture was then treated with water (100 ml) and then cooled and extracted with diethyl ether (2 × 50 ml). The aqueous layer was cooled to 10° C. and acidified to pH 2 by treatment with concentrated hydrochloric acid to give 2-benzyloxy-4-methoxybenzoic acid (1.6 g), m.p. 99°-101° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[SH:11].[Br-].[Na+]>[O-]CC.[Na+]>[CH2:2]([S:11][C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Sc1cccs1
Reactant: CCCCBr
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Product: CCCCSc1cccs1
Temperature: 80 °C

Procedure:
1-Bromobutane (32.76 g, 0.239 mol) was added dropwise to a stirred solution of compound 5 (13.87 g, 0.120 mol) in sodium ethoxide (2.75 g of sodium metal in 100 ml of super-dry ethanol) at room temperature. The solution was heated at 80° C. for 2 h (glc and tlc analysis revealed a complete reaction) and the sodium bromide was filtered off. The solvent was removed in vacuo and the residue was distilled to give a colourless liquid.
Reaction SMILES: C(C1C=C(S[C:12]([S:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([O:26][CH2:27][C@H:28]3[C@H:32]([CH2:33][O:34][CH3:35])[O:31]C(OCC)[O:29]3)=[C:18]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:17]=2)([CH3:14])[CH3:13])C=C(C(C)(C)C)C=1O)(C)(C)C.[C:48]([OH:51])(=O)[CH3:49]>CO.O>[C:39]([C:18]1[CH:17]=[C:16]([SH:15]([CH:12]([CH3:13])[CH3:14])[S:15][C:16]2[CH:21]=[C:49]([C:22]([CH3:20])([CH3:23])[CH3:24])[C:48]([OH:51])=[C:18]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:17]=2)[CH:21]=[C:20]([C:22]([CH3:24])([CH3:25])[CH3:23])[C:19]=1[O:26][CH2:27][C@H:28]([OH:29])[C@@H:32]([OH:31])[CH2:33][O:34][CH3:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(=O)O
Reactant: CCOC1O[C@@H](COC)[C@H](COc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1
Solvent: O
Solvent: CO
Product: COC[C@H](O)[C@@H](O)COc1c(C(C)(C)C)cc([SH](Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
2,6-Di-tert-butyl-4-{1-[3,5-di-tert-butyl-4-(2-ethoxy-5(s)-methoxymethyl-[1,3]dioxolan-4(S)-ylmethoxy)-phenylsulfanyl]-1-methyl-ethylsulfanyl}-phenol (Ex-15A, 0.72 g, 1.1 mmol) was dissolved in methanol (3 mL). Acetic acid (0.14 mL) and water (0.14 mL) were added and the resultant mixture was stirred at reflux for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate and concentrated to an off-white foam. The residue was dissolved in methanol (3 mL) and potassium carbonate (0.085 g) was added. The mixture was stirred at room temperature for 30 min and diluted with water (10 mL). The solution was extracted with dichloromethane (3×10 mL), dried over sodium sulfate, and concentrated to a white foam. Silica gel chromatography (3:1 ethyl acetate: hexanes) gave 0.18 g (99%) of 1-{2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxyphenylsulfanyl)-1-methylethylsulfanyl]phenoxy}-4-methoxybutane-2(S),3(S)-diol as a white solid, mp 62–64° C. 1H-NMR (CDCl3) δ 7.55 (s, 2H), 7.45 (s, 2H), 5.36 (s, 1H), 4.25–4.26 (m, 1H), 3.86–3.90 (m, 3H), 3.59–3.61 (m, 2H), 3.41 (s, 3H), 2.79 (d, 1H, J=4.8 Hz), 2.63 (d, 1H, J=4.8 Hz), 1.42–1.45 (m, 42H). HRMS (ESI) calcd for C36H58O5S2 (M+Na), 657.3624; Found, 657.3630. Anal. calcd. for C36H58O5S2: C, 68.10, H, 9.21, S, 10.10; Found: C, 68.47, H, 9.38, S, 9.85.
Reaction SMILES: [BrH:1].C1C2C(=CC=CC=2)CCC1.BrBr.[CH3:14][C:15]([CH3:22])([CH:20]=[CH2:21])[CH2:16][C:17]([OH:19])=[O:18].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:1][CH2:21][CH2:20][C:15]([CH3:22])([CH3:14])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: Br
Reactant: C=CC(C)(C)CC(=O)O
Agent: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccc2c(c1)CCCC2
Product: CC(C)(CCBr)CC(=O)O
Temperature: -10 °C

Procedure:
A stream of dry hydrogen bromide gas (made from 83.3 m) of tetralin and 71 ml of bromine) was bubbled through a stirred solution of 3,3-dimethylpent-4-enoic acid (80 g, 0.625 mol) in dry light petroleum b.p. 40°-60° C. (940 ml) together with benzoyl peroxide (6.4 g, 0.025 mol) until it was saturated (about 2 hours) whilst the reaction mixture was maintained at the temperature between 10°-20° C. by occasional cooling. After completion of the reaction, the mixture was cooled down to -10° C. and the solid product was collected (near quantitative yield). The product was sufficiently pure by NMR spectroscopy to be used directly in the next step synthesis. However, a pure product was obtained after recrystallised from light petroleum spirit m.p. 53°-55° C. 1H NMR δ3.43 (2H, t), 2.27 (2H, s), 2.10 (2H, t), and 1.08 (6H, s).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=O)[CH2:14]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Agent: CN(C)c1ccncc1
Agent: NC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)CCC21CCNCC1
Reaction time: 3 h

Procedure:
To a solution of 1.0 g (3.21 mmol) of the intermediate obtained in Step B in 3.0 ml of dichloromethane was added 0.945 ml (6.74 mmol) of triethylamine and 50 mg of DMAP and finally 0.501 ml (3.53 mmol) of trifluroacetic acid anhydride. The reaction mixture was stirred for 3 hours and then diluted with 20 ml of dichloromethane. The solution was washed with water, dried over magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, hexane/ethyl acetate 2:1) gave 568 mg(1.91 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:12][O:13][CH:14]([O:22][CH3:23])[C:15](=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:16]([C:15]([CH:14]([O:13][CH3:12])[O:22][CH3:23])=[O:21])[C:17]([O:19][CH3:20])=[O:18])([O-:3])=[O:2]
Reactant: COC(=O)CC(=O)C(OC)OC
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)C(OC)OC
Yield: 105.8 %

Procedure:
To a solution of 2-nitrobenzaldehyde (6.80 g), methyl 4,4-dimethoxyacetoacetate (8.72 g) and acetic acid (0.54 g) in benzene (30 ml), was added piperidine (0.46 g), in a similar manner to aforementioned examples 1-i) and 2-i), and the mixture was heated to reflux for 2 hours under azeotropic dehydration. The reaction mixture, after cooling, was diluted with benzene (100 ml), washed three times with water, and in turn with diluted aqueous sodium bicarbonate solution and water, dried over magnesium sulfated and evaporated to dryness under reduce pressure to give oily methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (14.73 g). A mixture of the above obtained oil (14.70 g) and isopropyl 3-aminocrotonate (7.09 g) was heated at 60° to 63° C. for 2 hours and at 85° to 90° C. for about 10 hours. The reaction mixture was treated with ethyl acetate to give yellowish crystals which were collected by filtration and washed with methanol. The filtrate was concentrated and the residue was treated with methanol to give additional crystals. The combined crystals (11.10 g) were recrystallized from methanol to give pure crystals of isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 143°-145° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[CH:22].C1(C)C=CC(S(O)(=O)=[O:30])=CC=1.O.CCOCC>C(#N)C>[C:21]([C:3]1[C:4]([C:19]#[N:20])=[N:5][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[C:2]=1[NH2:1])(=[O:30])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethynylpyrazole (0.345 g) in acetonitrile (5 ml) was added p-toluenesulphonic acid (0.5 g) and the mixture was stirred at room temperature for 2 hours and then poured into water (100 ml) and ether (100 ml). The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution (50 ml), brine (50 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluted with dichloromethane:hexane (10:1). Combination and evaporation of suitable fractions gave the title compound as a white crystalline solid, m.p. 200-1° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:34][C@H:35]1[CH2:40][NH:39][CH2:38][CH2:37][NH:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:39]5[CH2:38][CH2:37][NH:36][C@@H:35]([CH3:34])[CH2:40]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: C[C@H]1CNCCN1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H]1CN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (250 mg) in tetrahydrofuran (10 mL) was added (2S)-2-methylpiperazine (270 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (230 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (111 mg, yield 38%) as a colorless amorphous solid. MS: 549 (MH+).
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[F:22][C:23]1[CH:24]=[C:25]([NH:26][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[N+:19]([O-:21])=[O:20])[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(F)c1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Product: O=[N+]([O-])c1c(Nc2cccc(F)c2)ccc2ccccc12

Procedure:
1-Nitro-2-naphthyl triflate and 3-fluoroaniline were used in a process similar to Example 1(1) to give the titled compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:9][CH:10]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24]>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])=[CH:6][CH:7]=1
Reactant: Fc1ccccc1-c1ccc(CCCBr)cn1
Reactant: O=C1CCCCN1
Product: O=C1CCCCN1CCCc1ccc(-c2ccccc2F)nc1

Procedure:
50 mg (0.17 mmol) of 5-(3-bromopropyl)-2-(2-fluorophenyl)pyridine were reacted with 18.5 mg (0.18 mmol) of piperidin-2-one analogously to example 1d). Yield: 16 mg (31%).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[CH2:23][S:24][C@@H:25]2[C@H:37]([NH:38][C:39](=[O:47])[CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:36](=[O:48])[N:26]2[C:27]=1[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29]>C(OCC)(=O)C>[Br-:20].[C:41]1([CH2:40][C:39]([NH:38][C@@H:37]2[C:36](=[O:48])[N:26]3[C:27]([C:28]([O:30][CH2:31][C:32]([Cl:33])([Cl:34])[Cl:35])=[O:29])=[C:22]([CH2:21][P+:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:23][S:24][C@H:25]23)=[O:47])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CBr)CS[C@H]12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Product: [Br-]
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A solution of triphenylphosphine (4.98 g, 2 equiv.) in ethyl acetate (30 ml) was added over a period of 15 minutes to a stirred solution of 2,2,2-trichloroethyl 3-bromomethyl-7β-phenylacetamidoceph-3-em-4-carboxylate (5.2 g, ca. 9.5 mmole) in ethyl acetate. The mixture was stirred in the absence of light for 2 hours when the precipitated solid was filtered off, washed with ethyl acetate and dried to give the title phosphonium salt (6.17 g, 81%), λmax. (EtOH) 268.5 nm (ε 10,450) and 275.5 nm(ε 10,050), λmax. (CHBr3) 3412 (NH), 1784 (azetidin-2-one), 1722 (CO2R), 1678 and 1498 (CONH) and 1440 cm-1 (P+ --C6H5).
Reaction SMILES: [C:1]([C:5]1C=CC(C)=CC=1)(C)([CH3:3])[CH3:2].ON1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2C1=O.[O:24]=O>C(O)(=O)C>[C:1]([C:21]1[CH:22]=[CH:15][C:16]([C:17]([OH:18])=[O:24])=[CH:19][CH:20]=1)([CH3:5])([CH3:3])[CH3:2]
Reactant: O=O
Reactant: Cc1ccc(C(C)(C)C)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C(=O)O)cc1
Yield: 88 %

Procedure:
To 25 milliliters of acetic acid were added 1.49 grams (10 millimoles) of 4-t-butyl-1-methylbenzene, 0.16 gram (1 millimole) of N-hydroxyphthalimide and 0.018 gram (0.05 millimole) of acetylacetonatocobalt(III) Co(AA)3, and the resultant mixture was stirred in an oxygen atmosphere at 100° C. for 6 hours. With a transformation rate of 95%, 4-t-butyl-1-methylbenzene was transformed into 4-t-butylbenzoic acid (yield 88%).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(C1C(O[SiH](C)C)=C(Br)C(OC)=CC=1CC1C(=O)C=CCC1(C)C)(C)(C)C>>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:9]2[C:2](=[O:1])[CH:3]=[C:4]([CH3:10])[CH2:5][C:6]2([CH3:8])[CH3:7])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: COc1cc(CC2C(=O)C=CCC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Product: CC1=CC(=O)C(Cc2ccc([N+](=O)[O-])cc2)C(C)(C)C1

Procedure:
This compound was prepared from isophorone (2.065 g, 14.94 mmol) and p-nitrobenzyl bromide (4.06 g, 18.80 mmol, 1.25 equiv) in the manner previously described for the synthesis of enone 13, affording 1.891 g (46%), of the nitro-enone as a pale yellow oil. 1H NMR (400MHz, CDCl3) δ0.98 and 1.13 (2s, 2×3H, geminal-CH3 's), 1.92 (s, 3H, 3-CH3), 2.17 and 2.31 (ABq, 2H, JAB =18.5 Hz, 4-H), 2.38 (dd, 1H, J=9.0, 3.3 Hz, 6-H), 2.75 and 3.05 (d of ABq, 2H, JAB =14.0 Hz, JA =3.2 Hz, JB =8.9 Hz, benzylic-CH2), 5.84 (s, 1H), 7.33 (d, 2H, J=8.2 Hz, Ar--H) and 7.53 ppm (d, 2H, J=8.2 Hz, Ar--H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][O:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
To a solution of 4-phenoxyphenol (200 mg, 1.07 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (75 mg, 1.875 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (382 mg, 1.074 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (256 mg, 64%); MS; m/z 370 (M+H) LCMS (UV)>90%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].[OH-:13].[Na+]>CS(C)=O.O>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([OH:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(O)cc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,4,6-trifluoronitrobenzene (10 g) in dimethyl sulphoxide(50 mL) was treated with 10N sodium hydroxide(12 mL) and the mixture was stirred at room temperature for 18 h. The mixture was diluted with water and washed with ether. The aqueous phase was then acidified and extracted with ether. The extract was washed with brine, dried and evaporated to dryness and the residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product(8.3 g) [m/e 174, MH−].
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][O:19][C:20]([F:23])([F:22])[F:21])[O:12]1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:12][C@H:13]([CH2:18][O:19][C:20]([F:23])([F:22])[F:21])[C@@H:14]([OH:17])[C@H:15]2[OH:16])=[CH:26][CH:25]=1
Reactant: NCCc1ccncc1
Reactant: O[C@@H]1[C@H](O)[C@@H](COC(F)(F)F)O[C@H]1n1cnc2c(Cl)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O[C@@H]1[C@H](O)[C@@H](COC(F)(F)F)O[C@H]1n1cnc2c(NCCc3ccncc3)ncnc21
Yield: 30.7 %

Procedure:
(2R,3R,4S,5R)-2-(6-Chloro-purin-9-yl)-5-trifluoromethoxymethyl-tetrahydro-furan-3,4-diol (42 mg), 2-pyridin-4-yl-ethylamine (58 mg), and diisopropylethylamine (0.124 ml) were heated at 80° C. in isopropanol (5 ml) in a reactivial for 17 h. The solution was evaporated under a stream of nitrogen and purified by autoprep HPLC to afford the title compound as a colourless solid (16 mg).