Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[C:54]([C:57]1[N:58]=[N:59][NH:60][CH:61]=1)(O)=[O:55]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:54]([C:57]2[N:58]=[N:59][NH:60][CH:61]=2)=[O:55])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1c[nH]nn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2c[nH]nn2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 87 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 4-carboxy-1,2,3-triazole as the starting materials in 87% yield. LCMS for C26H26ClN10O2 (M+H)+: m/z=545.0.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1[C:6](=[O:10])[N:7]=[CH:8][CH:9]=1>O1CCCC1>[C:1]([N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10])(=[O:3])[CH3:2]
Reactant: O=C1N=CC=N1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N1CCNC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
23.6 parts by weight of acetyl chloride in 100 parts by volume of tetrahydrofurane were added dropwise over the course of 60 minutes to a suspension of 25.8 parts by weight of imidazol-2-one in 350 parts by volume of dry tetrahydrofurane at 0° C. The mixture was stirred for 3 hours at room temperature, dry air was subsequently blown through the solution for some time, the solvent was then removed in vacuo and the residue was recrystallized from boiling nitromethane.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[Na+].[Na+].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: CCCNC1Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(C(=O)CC)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of N-indan-2-yl-propylamine (9.5 g, 54.3 mmol) in methylene chloride was added aq. Na2CO3 (150 mL, 3%) followed by propionyl chloride (7.5 mL, 86.3 mmol). The mixture was stirred at ambient temperature for 1 h. The layers were separated and the organic layer was washed with water, separated and dried (MgSO4). Evaporation of the solvent yielded 7 g (56%) of N-indan-2-yl-N-propyl-propionamide. MS m/e 231 (1, M+), 116 (100), 117 (23), 57 (11), 146 (9).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:19]4[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=4[N:13]([CH3:21])[CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([N:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]4[C:19]5[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=5[N:13]([CH3:21])[CH:12]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(Cl)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine HCl (70.6 mg, 0.234 mmol), (3-chlorophenyl)acetic acid (39.9 mg, 0.234 mmol), HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added Hunig's base (0.163 mL, 0.936 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water (100 mL), purple solid formed. EtOAc (100 mL) was used to extract the product. The Organic phase was separated from the water phase, dried by MgSO4, evaporated to dryness, to give purple solid which still had some starting material. The solid was sonicated in water (10 mL), then filtered and dried to afford 5-{1-[(3-chlorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a purple solid.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[O:6][CH3:7])[CH2:2][CH2:3][CH3:4].OC[C:18]1[CH:31]=[CH:30][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1>ClCCCl>[CH2:8]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:12][CH2:13][CH2:14][CH3:15])[O:6][CH2:7][C:27]1[CH:28]=[CH:29][C:24]([C:22]([C:21]2[CH:30]=[CH:31][CH:18]=[CH:19][CH:20]=2)=[O:23])=[CH:25][CH:26]=1)[CH2:9][CH2:10][CH3:11]
Reactant: O=C(c1ccccc1)c1ccc(CO)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)OC
Solvent: ClCCCl
Product: CCCC[Sn](CCCC)(CCCC)OCc1ccc(C(=O)c2ccccc2)cc1
Yield: 56.2 %

Procedure:
In a 50 ml dry three-neck-flask, 2.5 g (7.8 mmol) of tri-n-butylmethoxy tin are added to 1.5 g (7.1 mmol) of 4-(hydroxymethyl)-benzophenone in 15 ml of 1,2-dichlorethane at room temperature in the course of 0.5 h under argon. 1H-NMR-spectrum confirms the complete conversion. The solution is concentrated and the crude product, 3.6 g of a yellow oil, is distilled in a bulb-to-bulb distillation apparatus in vacuum (0.016 mbar) at 160-170° C. The resulting colorless oil (2.8 g) is distilled a second time in a bulb-to-bulb distillation apparatus (0.020 mbar). 2.0 g of the title product are obtained as a colorless oil (boiling area 294-308° C.). The structure is further confirmed by 1H-NMR and 13C-NMR-spectra.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[N:20]=[C:19]([CH3:21])[N:18]([CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25](Cl)[CH:24]=4)[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CS(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[N:20]=[C:19]([CH3:21])[N:18]([CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH:24]=4)[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2nc(-c3ccc(C(C)(C)C)cc3)no2)nn1Cc1ccnc(Cl)c1
Solvent: CS(C)=O
Product: Cc1nc(-c2nc(-c3ccc(C(C)(C)C)cc3)no2)nn1Cc1ccnc(N2CCN(C)CC2)c1
Temperature: 140 °C
Yield: 22 %

Procedure:
3-(4-(tert-Butyl)phenyl)-5-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole (90 mg, 0.221 mmol) and 1-methylpiperazine (265 mg, 2.65 mmol) were dissolved in DMSO (3 mL) in a sealed tube reaction vessel. The reaction was heated at 140° C. overnight and then cooled to RT and partitioned between H2O (25 mL) and EtOAc (25 mL). The organic layer was separated, washed with H2O (2×25 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product which was purified by prep-HPLC (MeCN/H2O 20%-60% MeCN, containing 0.1% TFA). The product was taken up in EtOAc (10 mL), washed with sat. NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated to afford 3-(4-(tert-butyl)phenyl)-5-(5-methyl-1-((2-(4-methylpiperazin-1-yl)pyridin-4-yl)methyl)-1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole as a yellow foam (23 mg, 22%). MS (ES+) C26H32N8O requires: 472. found 473 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.19-8.15 (m, 3H), 7.51 (d, J=8.4 Hz, 2H), 6.42 (d, J=4.9 Hz, 1H), 6.39 (s, 1H), 5.36 (s, 2H), 3.70-3.50 (m, 4H), 2.69-2.46 (bs, 3H), 2.54 (s, 3H), 2.46-2.30 (m, 4H), 1.37 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:14])[CH:5]=[C:6]([Cl:13])[C:7]=1[C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:13])[C:7]=1[C:8]([Cl:12])=[C:9]([Cl:10])[Cl:11])[CH2:14][Br:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(C(Cl)=C(Cl)Cl)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClC(Cl)=C(Cl)c1c(Cl)cc(CBr)cc1Cl

Procedure:
From the reaction of 3,5-dichloro-4-(trichlorovinyl)toluene (2.15 g), dibenzoyl peroxide (0.33 g), and N-bromosuccinimide (2.05 g) in 85 ml of benzene at reflux as in Example 30, 3,5-dichloro-4-(trichlorovinyl)benzyl bromide is obtained. This material (2.7 g) and sodium azide (0.8 g) in ethanol (25 ml) is heated for 2 hours. The crude product is chromatographed on silica gel to give pure 3,5-dichloro-4-(trichlorovinyl)benzyl azide.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.CCCCCC.[Cl:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([C:42]([C:41]2[CH:45]=[CH:46][C:38]([Cl:37])=[CH:39][CH:40]=2)=[O:43])=[C:12]([Cl:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
A stirred -55° C. solution of 3,5-dichlorobenzyl t-butyldimethylsilyl ether (1.46 g, 5.00 mmol) and tetramethylethylenediamine (0.755 mL, 0.581 g, 5.01 mmol) in tetrahydrofuran (5 mL) under nitrogen atmosphere was treated dropwise over 10 minutes with a 1.6 M solution of n-butyllithium in hexane (3.3 mL, 5.25 mmol). After 30 minutes at -55° C., a solution of p-chlorobenzoyl chloride (0.875 g, 5.00 mmol) in tetrahydrofuran (1.0 mL) was added over 15 minutes. The resulting mixture was stirred 2 hours at -55° to -30° C. and 1.5 hours at ambient temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride (1.1 mL) and stirred 30 minutes. The mixture was treated with sodium sulfate (1.1 g), stirred 1 hour, and decanted. The residual solid was washed well with diethyl ether. The combined solution and washes were extracted twice with water, once with 10% aqueous citric acid, and once with brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to provide 1.93 g of crude brown oil. A total of 585 mg of oil was chromatographed on eight 1000μ 20 cm×20 cm silica gel preparative thick layer chromatography plates developed with 5:1 (v/v) hexane-ethyl acetate to provide 356 mg (60%) 4-(t-butyldimethylsilyloxymethyl)-2,4',6-trichlorobenzophenone; NMR (CDCl3): 0.14 s (6H), 0.95 s (9H), 4.72 s (2H), 7.27 s (2H), 7.35 d (J=9Hz, 2H), 7.70 d (J=9Hz, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([CH3:15])[NH:10]2.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:33][C@H:32]2[NH:34][CH2:35][C@@H:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2.C([O-])([O-])=O.[K+].[K+].C(#N)C>O.C(OCC)(=O)C>[CH3:15][C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]1[CH2:35][CH:27]3[N:26]([C:17]4[CH:18]=[CH:19][C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:16]=4)[CH2:33][CH:32]1[CH2:31][CH:30]=[CH:29][CH2:28]3)[CH:14]=[CH:13][CH:12]=2
Reactant: Cc1cc2c(OCCCCl)cccc2[nH]1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc2c(OCCCN3CC4CC=CCC3CN4c3ccc4ccccc4c3)cccc2[nH]1

Procedure:
4-(3-Chloro-propoxy)-2-methyl-1H-indole (0.16 g, 0.72 mmol), Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (0.1 g, 0.38 mmol), K2CO3 (72 mg, 0.52 mmol), acetonitrile (30 mL) were placed in a round bottom flask and refluxed overnight. To the reaction mixture were then added ethyl acetate (100 mL) and water (100 mL) and the resulting mixture stirred for 30 minutes. The organic layer was separated and dried with magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield a crude solid. The crude solid was purified with flash chromatography gradient [20% Ethyl acetate/heptane to 100% Ethyl acetate] to yield the title compound as a residue.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].CC(C)([O-])C.[K+].Cl[C:17]1[N:18]=[N+:19]([O-:24])[C:20]([Cl:23])=[CH:21][CH:22]=1.O>O1CCOCC1.CS(C)=O>[Cl:23][C:20]1[N+:19]([O-:24])=[N:18][C:17]([O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[S:2][CH3:1])=[CH:22][CH:21]=1
Reactant: [O-][n+]1nc(Cl)ccc1Cl
Reactant: CSc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CSc1ccccc1Oc1ccc(Cl)[n+]([O-])n1
Reaction time: 0.58 h
Yield: 56.8 %

Procedure:
In a mixed solvent of 1,4-dioxane (5 mL) and dimethylsulfoxide (5 mL) was dissolved 454 mg (3.24 mmol) of 2-(methylsulfanyl)phenol, to the solution was added 519 mg (4.63 mmol) of potassium tert-butoxide and the mixture was stirred for 35 minutes. To the mixture was added 424 mg (2.57 mmol) of 3,6-dichloropyridazine 1-oxide and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, eluted with hexane:ethyl acetate=3:1) to obtain 391 mg (1.46 mmol, Yield: 56.8%) of 6-chloro-3-[2-(methylsulfanyl)phenoxy]pyridazine 1-oxide.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:17]=3[C:18]#[N:19])=[CH:13][C:12]=2[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][C:17]=3[C:18]#[N:19])=[CH:13][C:12]=2[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(CO)ccc1-c1cc2cc(Cc3ccccc3)ccc2o1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Product: N#Cc1cc(C=O)ccc1-c1cc2cc(Cc3ccccc3)ccc2o1
Reaction time: 1 h
Yield: 93 %

Procedure:
A suspension of 2-(5-Benzylbenzofuran-2-yl)-5-(hydroxymethyl)benzonitrile (0.03 g, 0.09 mmol), Molecular sieves 4A (0.2 g), TPAP (0.0016 mg, 0.004 mmol) and N-morpholino oxide (0.02 g, 0.18 mmol) in acetonitrile was stirred for 1 hour and then filtered through celite to obtain title compound in 93% yield (step 4, Scheme 5): 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.25 (s, 1H), 8.24 (d, 1H), 8.14 (d, 1H), 7.84 (s, 1H), 7.45 (m, 2H), 7.38-7.18 (m, 6H), 4.06 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[NH:13][CH2:12][CH2:11][S:10]1.[CH3:20][CH2:21]CCCC.C([Li])CCC.C(I)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[N:13]([CH2:20][CH3:21])[CH2:12][CH2:11][S:10]1
Reactant: Clc1ccc(C2(Cn3cncn3)NCCS2)c(Cl)c1
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCN1CCSC1(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
2.0 g of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-yl methyl) thiazolidine used in Working Example 7 was dissolved in anhydrous tetrahydrofuran. After cooling the solution to -50° C., 4.5 ml of a n-hexane solution containing 15% of n-butyl lithium was added and the mixture was stirred for 30 minutes at the same temperature. Then, 2.2 g of ethyl iodide was added and the mixture was reacted for 1 hour at the same temperature. Then, the temperature was gradually raised to room temperature. After distilling off tetrahydrofuran under reduced pressure, the reaction product was purified by silica gel column chromatography using a solvent mixture of chloroform and ethyl acetate as the developer, whereby 1.0 g of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-yl methyl)-3-ethyl thiazolidine (Compound No. 56 in Table 1) was obtained.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH2:13][CH2:12][N:11]([C@@:14]2([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[S:20][C@H:19]3[N:16]([C:17](=[O:31])[C@H:18]3[NH:21]C(=O)CC3C=CC=CC=3)[CH2:15]2)[C:10]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>C(Cl)Cl.O>[NH2:21][C@@H:18]1[C:17](=[O:31])[N:16]2[C@@H:19]1[S:20][C@@:14]([N:11]1[CH2:12][CH2:13][N:9]([N:8]=[CH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]1=[O:45])([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)=[O:33])[CH2:15]2
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Temperature: -60 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
In 132 ml of methylene chloride was dissolved 6.6 g of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0]heptane. The solution was cooled to -60° C. Thereto were added 4.66 ml of N,N-dimethylaniline and 3.3 g of phosphorus pentachloride. The mixture was stirred at -40° to -20° C. for 1 hour and cooled to -60° C. To the reaction mixture was added 13.8 ml of anhydrous methanol. The temperature of the mixture was elevated to 0° C. in 30 minutes and mixed with 66 ml of water. The resulting mixture was stirred for 15 minutes with ice cooling. The resulting crystals were collected by filtration and suspended in a mixed solvent consisting of 50 ml of water and 100 ml of methylene chloride. The suspension was adjusted to pH 7.5 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 4.5 g (yield: 84.0%) of (3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[C:12]([C:28]#[N:29])=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[CH3:26][N:25]([CH3:27])[C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:18]=[C:13]3[C:12]([C:28]#[N:29])=[CH:11][NH:10][C:14]3=[N:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(-c2cnc3c(c2)c(C#N)cn3S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1ccc(-c2cnc3[nH]cc(C#N)c3c2)cc1
Temperature: 110 °C
Yield: 55.1 %

Procedure:
A mixture of 2 (41.5 mg, 0.103 mmol) and 10% aqueous NaOH (2.0 mL) in EtOH (4.0 mL) was heated at 110° C. for 40 min. It was then poured onto water (5 mL), extracted with ethyl acetate (4×10 mL) and the combined organic extracts dried (MgSO4) and concentrated. The residue was purified by preparative TLC (PTLC) using 5% ethyl acetate in dichloromethane as eluent to give 3 as a light orange solid (14.9 mg, 36%); 1H NMR (400 MHz, CDCl3) δ 3.06 (s, 6H), 6.86 (d, J=8.9 Hz, 2H), 7.55 (d, J=8.9 Hz, 2H), 7.89 (s, 1H), 8.25 (d, J=2.0 Hz, 1H), 8.64 (bs, 1H); MS (CI) m/z 304.0 (MH+MeCN).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[OH:12])=[O:4].[C:13](OCC)(=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(O)C>[OH:11][C:9]1[CH:10]=[C:5]2[C:6](=[CH:7][CH:8]=1)[O:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2][C:3]2=[O:4]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2cc(O)ccc2o1
Temperature: 25 °C

Procedure:
1.1 3.8 g of sodium are dissolved in portions in 300 ml of ethanol with stirring. A solution of 5.0 g of 2,5-dihydroxyacetophenone and 17.8 ml of diethyl oxalate in 25 ml of ethanol is subsequently added dropwise. The reaction mixture is then heated at 80° for 3 hours and cooled to room temperature, and 10 ml of 32% HCl are added dropwise. The mixture is heated at 90° for 30 minutes and cooled, and the solvent is removed. Conventional work-up gives 5.6 g of 6-hydroxy-2-ethoxycarbonylchromen-4-one (“AA”).
Reaction SMILES: C([SiH2]O[C:7](C)(C)[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)([OH:27])[CH2:17][C:18]2[O:23][C:22]([CH3:25])([CH3:24])[O:21][C:20](=[O:26])[CH:19]=2)=[CH:10][C:9]=1[CH2:33][CH3:34])(C)(C)C>CCO.[OH-].[OH-].[Pd+2]>[CH:28]1([C:16]([OH:27])([CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([CH3:7])=[C:9]([CH2:33][CH3:34])[CH:10]=2)[CH2:17][C:18]2[O:23][C:22]([CH3:24])([CH3:25])[O:21][C:20](=[O:26])[CH:19]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCc1cc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)ccc1C(C)(C)O[SiH2]C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(CCC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)ccc1C
Reaction time: 15 h

Procedure:
To a solution of 6-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-phenyl]-2-cyclopentyl-2-hydroxy-but-3-ynyl}-2,2-dimethyl-[1,3]dioxin-4-one (1.0 g) in EtOH (50 mL) was added Pd(OH)2 (20 wt %, 100 mg). The reaction was stirred under H2 atmosphere for 15 hours. The reaction was filtered through a pad of celite and the solvent was removed under reduced pressure to afford the desired product. 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 3 H), 1.43-1.69 (m, 8 H), 1.71 (s, 6 H), 1.79-1.85 (m, 2 H), 2.05-2.16 (m, 1 H), 2.27 (s, 3 H), 2.44-2.66 (m, 6 H), 5.37 (s, 1 H), 6.89-6.95 (m, 2 H), 7.04-7.08 (m, 1 H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Cl>>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccc4ccccc4c3)cc2)C(O)C1
Reactant: COc1ccccc1CCl
Product: COc1ccccc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCc2ccc3ccccc3c2)cc1

Procedure:
In analogy to the procedure described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(naphthalen-2-ylmethoxy)-phenyl]-piperidine-1-carboxylate with 2-methoxybenzyl chloride there was obtained tert-butyl (3RS,4RS)-3-(2-methoxy-benzyloxy)-4-[4-(naphthalen-2-ylmethoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 554 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([S:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])C>CO.[OH-].[Na+]>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([S:11][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:20])=[O:3])=[CH:17][CH:16]=1
Reactant: CCCCCC(Sc1ccc(OC)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(Sc1ccc(OC)cc1)C(=O)O

Procedure:
2-(4-Methoxy-phenylsulfanyl)-heptanoic acid was prepared starting with 2-(4-methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (4 g, 13.5 mmol) dissolved in methanol (300 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 1. Yield 3 g (83%). yellow oil. MS: 267.1 (m−H)−.