Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:13][N:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:23]=[O:24]>>[Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[C:13]([CH2:23][OH:24])[N:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1ncc(Sc2cccc(Cl)c2)[nH]1
Product: CC(C)(C)[Si](C)(C)OCc1nc(CO)c(Sc2cccc(Cl)c2)[nH]1
Yield: 33 %

Procedure:
An aqueous solution of 2.0 g (5.6 mmol) of 2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazole (45') in 37% formaline (10 ml) was heated at 120° C. for 10 hours in a sealed tube. The reaction mixture was washed out with methanol from the tube, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:1), the crude product was washed with n-hexane, and filtered to give 716 mg of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazol-4-yl]methanol (46) (yield 33%). mp 136-137° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([O:11]CC)=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[NH3:14]>>[N+:1]([C:4]1[C:5]([C:9]([NH2:14])=[O:11])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: N
Product: NC(=O)c1n[nH]cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
Ethyl 4-nitro-1H-pyrazole-3-carboxylate (741 mg, 4 mmol) was heated at 90° C. with a concentrated solution of aqueous ammonia (28%, 20 ml) in a sealed vessel for 3 hours. The mixture was evaporated and the residue was triturated with diethyl ether to give 4-nitro-1H-pyrazole-3-carboxamide (0.54 g, 86% yield) as a white solid:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C@@H:7]([OH:8])[C@H:6]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:5]2[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:4]=2[O:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:26])[C@@H:7]([OH:8])[C@H:6]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:5]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:4]=2[O:3]1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])ccc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: CC1(C)Oc2cc(N)ccc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Reaction time: 4 h

Procedure:
A mixture of 1.01 g (2.85 mmol) of trans-2-(3,4-dihydro-2,2-dimethyl-3-hydroxy-7-nitro-2H-1-benzopyran-4-yl)-2,3-dihydro-1H-isoindol-1-one and 250 mg of 10% Pd/C in methanol (30 mL) was hydrogenated at atmospheric pressure for 4 hours. Filtration through Solka Floc® using a methanol rinse and concentration gave crude title compound which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:54]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:54])[C:8]=2[N:17]=1
Reactant: COCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCC(=O)N1CCOCC1

Procedure:
2-(2-Methoxyethyl)-1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinoline (4.55 g, 11.1 mmol) was treated with mCPBA (4.97 g, 21.6 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (3.69 g, 19.4 mmol) according to the method described in Part D of Example 8. The crude product was recrystallized twice from ethyl acetate to provide 1.17 g of 2-(2-methoxyethyl)-1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinolin-4-amine as brown needles, mp 131-132° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[CH2:14][CH2:13][C:12]=3[C:11]([CH3:22])=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl.C([O-])(O)=O.[Na+]>[CH3:22][C:11]1[C:12]2[CH2:13][CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[C:17]=2[N:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[N:10]=1
Reactant: COc1ccc(-n2nc(C)c3c2-c2ccccc2CC3)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nn(-c2ccc(O)cc2)c2c1CCc1ccccc1-2
Temperature: -40 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
1-(4-Methoxyphenyl)-3-methyl-4,5-dihydro-1H-benzo[g]indazole (200 mg, 0.69 mmol) was dissolved in dichloromethane (2 mL) under N2 and cooled to −40° C. Boron tribromide (2.07 mL, 1 M in dichloromethane, 2.07 mmol) was added dropwise and the solution was stirred for 4 hours, warming to room temperature. The reaction mixture was carefully diluted with saturated NaHCO3 solution. The mixture was extracted with dichloromethane, and the extracts were dried over MgSO4 and concentrated. SiO2 chromatography with 20-80% ethyl acetate/hexanes gave 144 mg of the desired product (76% yield). LC-MS (C18H16N2O calculated 276) m/z 277 (M+H).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:14]([O:25][CH2:26]C)(=[O:24])[C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1>CN(C)C=O>[CH3:26][O:25][C:14](=[O:24])[C:15]1[CH:23]=[CH:22][C:20]([O:21][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])=[C:17]([O:18][CH3:19])[CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.5 %

Procedure:
Imidazole (3.47 g, 51.0 mmol) and t-butyldimethylsilyl chloride (3.84 g, 25.5 mmol) were added to a solution of ethyl vanillate (5.0 g, 25.5 mmol) in N,N-dimethylformamide (50 mL) at room temperature, and the mixture was stirred at room temperature for three hours. The reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=10:1) to give the title compound (7.90 g, 100%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.ClC1C(Cl)=CC=CC=1CC1N2CCN(C(C)C)C(=O)C2=C(O)C(=O)N=1>>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12
Reactant: CC(C)N1CCn2c(Cc3ccccc3-c3ccncc3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CC(C)N1CCn2c(Cc3cccc(Cl)c3Cl)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccncc3)nc(=O)c(O)c2C1=O
Yield: 14.8 %

Procedure:
9-Hydroxy-2-isopropyl-6-(2-pyridin-4-yl-benzyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (154) (30 mg, 14.77%) as a light yellow solid was synthesized from 9-benzyloxy-2-isopropyl-6-(2-pyridin-4-yl-benzyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (153) (250 mg, 0.52 mmol) following the procedure as described for 6-(2,3-dichlorobenzyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (135).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH:13](OC)(OC)OC.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>C(Cl)Cl>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=[CH:13]1.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: COC(OC)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of diamine 248 (1.14 g, 6.80 mmol) in CH2Cl2 (10 mL) was added trimethyl orthoformate (5 mL, 46 mmol, 6.7 eq) (or any other acylating agent of choice, 6 eq) followed by TFA (0.43 mL, 5.6 mmol, 0.8 eq) and the mixture was stirred at room temperature for 2 h. Precipitate was collected by filtration, washed with CH2Cl2 and dried to afford the title compound 249 as TFA salt (1.23 g, 62% yield). 1H NMR: (CDCl3) δ (ppm): 8.57 (d, J=1.8 Hz, 1H), 8.20 (dd, J=1.8, 9.2 Hz, 1H), 8.18 (s, 1H), 7.54 (d, J=9.2 Hz, 1H), 3.94 (s, 3H). LRMS: (calc.) 177.2; (obt.) 178.1 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[CH:10]([O:26][CH2:27][CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[O:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][C:32]=1[CH2:42][C:43](O)=[O:44].C(Cl)Cl.Cl>CCCCCCC.CCOC(C)=O.C(Cl)CCl>[CH2:1]([O:8][C:9](=[O:29])[CH:10]([O:26][CH2:27][CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:43](=[O:44])[CH2:42][C:32]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:35][C:31]=2[CH3:30])=[C:14]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid benzyl ester (45 mg, 0.11 mol) and (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (25 mg, 0.11 mmol) in dry DCM (2.0 mL) first DMAP (2.8 mg, 0.02 mmol) and then EDC×HCl (26.5 mg, 0.13 mmol) was added and the mixture was stirred under nitrogen atmosphere at room temperature for 17 h. The solvent was removed under vacuo and the product was isolated out of the remaining oil by column chromatography using n-heptane/EtOAc (4:1) as the eluent. The title compound was obtained as an oil (56.1 mg, 82.6%). 1H NMR (400 MHz, CDCl3): δ 7.95 (m, 2H), 7.40 (m, 2H), 7.32 (m, 2H), 7.25 (m, 2H), 6.98-67.20 (m, 10H), 5.08, (d, 2H), 3.97 (t, 1H), 3.85 (s, 2H), 3.70 (s, 2H), 3.55 (m, 1H), 3.28 (m, 1H), 2.93 (d, 2H), 2.32 (s, 3H), 1.1 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].C(OCC)(=O)C>ClCCl.O1CCCC1>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:19](=[O:22])[CH:20]=[CH2:21])=[CH:3][CH:4]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
p-Aminobenzyl alcohol (12.31 g, 100 mmol) was dissolved in a mixture of dichloromethane (200 mL) and tetrahydrofuran (20 mL) containing N,N-diisopropylethylamine (35 mL, 200 mmol). The resulting homogeneous solution was then cooled to 0° C. and acryloyl chloride (8.2 mL, 100 mmol) was added drop-wise over a 30-minute period while keeping the internal temperature of the reaction mixture below 20° C. The reaction mixture was stirred at 0° C. for about 60 minutes. The reaction mixture was poured into ice-cold 1M hydrochloric acid (0.6 L) and the organic layer was separated and evaporated to dryness to give a crude material (5 g) consisting primarily of the bis-acylated side product. The acidic aqueous layer was then extracted with ethyl acetate (2×200 mL) and the combined ethyl acetate layers were dried with sodium sulfate, filtered and concentrated under reduced pressure to provide a residue. Trituration of the residue with ethyl acetate yielded the title compound (10.5 g, 98.5% pure). An additional 2 g of the title compound were obtained by trituration of the crude material obtained from the dichloromethane layer.
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH:10]1([NH2:14])[CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>>[CH:10]1([NH:14][CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCC1
Reactant: CCOC(CBr)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOC(CNC1CCC1)OCC

Procedure:
A solution of 1.75 ml (11.65 mmol) of 1-bromo-2,2-diethoxyethane and 2 ml (23.3 mmol) of cyclobutylamine was heated at 80° C. in a closed vessel overnight. The reaction mixture was mixed with 40% NaOH (in H2O) and extracted, with ether. The organic phase was isolated, dried (MgSO4) and concentrated in vacuo. 2.39 g of substance were obtained as an orange liquid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Li][CH2:14][CH2:15][CH2:16][CH3:17].BrCCCC>C1COCC1>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1
Reactant: [Li]CCCC
Reactant: Cc1cc(C)c2c(n1)N(C)CC2
Solvent: CCCCBr
Solvent: C1CCOC1
Product: CCCCCc1cc(C)c2c(n1)N(C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 225 mg (1.39 mmol) of 1,4,6-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 4 mL of THF was added 1.39 mL (2.22 mmol, 1.6 M in hexanes) of n-BuLi followed by 157 μL (1.46 mmol) of 1-bromobutane at −78° C. The reaction mixture was slowly warmed to room temperature and stirred for another 16 h. The reaction mixture was quenched by the addition of 10 mL of sat aq NH4Cl at 0° C. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (25 3.2 cm). Elution with 10:1 hexanes/ethyl acetate gave the product as a yellow oil: yield 0.20 g (66%); silica gel TLC Rf 0.15 (8:1:1 hexanes/ethyl acetate/MeOH); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.30-1.36 (m, 4H), 1.66 (quint, 2H, J=7.6 Hz), 2.08 (s, 3H), 2.55 (t, 2H, J=8.0 Hz), 2.81 (t, 2H, J=8.0 Hz), 2.88 (s, 3H), 3.38 (t, 2H, J=8.0 Hz) and 6.13 (s, 1H); 13C NMR (CDCl3) δ 14.1, 18.0, 22.6, 24.4, 29.6, 31.8, 33.3, 38.0, 52.5, 112.4, 118.2, 141.1, 159.1 and 163.7; mass spectrum, m/z 218.2 (M+) (theoretical 218.3); mass spectrum (APCI), m/z 219.1864 (M+H)+ (C14H23N2 requires 219.1861).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.Cl[C:38]1[CH:39]=[C:40]([C:44](=[O:46])[CH3:45])[CH:41]=[CH:42][CH:43]=1.[CH3:47][C@@H:48]1[CH2:53][NH:52][CH2:51][C@H:50]([CH3:54])[NH:49]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[CH3:47][C@H:48]1[NH:49][C@@H:50]([CH3:54])[CH2:51][N:52]([C:38]2[CH:39]=[C:40]([C:44](=[O:46])[CH3:45])[CH:41]=[CH:42][CH:43]=2)[CH2:53]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CC(=O)c1cccc(N2C[C@@H](C)N[C@@H](C)C2)c1
Temperature: 100 °C
Yield: 15 %

Procedure:
An oven-dried MW tube was charged with Pd2(dba)3 (592 mg, 0.65 mmol), K3PO4 (1.92 g, 9.06 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (127 mg, 0.32 mmol). The tube was purged and backfilled with N2 and then 1-(3-chloro-phenyl)-ethanone (1 g, 6.47 mmol), (2R,6S)-2,6-dimethyl-piperazine (886 mg, 7.76 mmol) and DME (10 ml) were added. The mixture was heated in a MW apparatus for 4 h at 100° C. and then further Pd2(dba)3 (592 mg, 0.65 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (127 mg, 0.32 mmol) were added. The reaction mixture was heated to 100° C. for additional 10 h and then the solid was filtered off over a Celite pad. The filtrate was diluted with AcOEt and extracted with 1 M HCl. The aqueous phase was brought to basic conditions with NH4OH and extracted with AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: AcOEt/MeOH 8:2) to give 226 mg of 1-[3-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-phenyl]-ethanone.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:23]([C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH2:26][CH3:27].C1CCC(N=C=NC2CCCCC2)CC1.C1(C)C=CC=CC=1.CCCCCCC>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[C@H:14]2[CH2:15][CH2:16][C@H:17]([C:20]([O:22][C:31]3[CH:30]=[CH:29][C:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:33][CH:32]=3)=[O:21])[CH2:18][CH2:19]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](/C=C/[C@H]2CC[C@H](C(=O)O)CC2)CC1
Reactant: CCCCCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(OC(=O)[C@H]2CC[C@H](/C=C/[C@H]3CC[C@H](CCCCC)CC3)CC2)cc1
Reaction time: 12 h

Procedure:
(E)-trans-4-(2-(trans-4-pentylcyclohexyl)vinyl)cyclohexane carboxylic acid in an amount of 1.1 g (3.6 mmol), 0.7 g (4.3 mmol) of 4-pentylphenol, 0.1 g (1.1 mmol) of DMAP, and 20 ml of dichloromethane were mixed. To this mixture was added dropwise 4 ml of solution of 1.0 g (4.7 mmol) of DCC in dichloromethane while being cooled with ice in 5 min, and stirred as it was for 12 hours. Separated crystals were filtered off. To the filtrate was added 70 ml of toluene, washed with 2N-NaOH five times and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure. The residue thus obtained was subjected to silica gel column chromatography (eluent: toluene/heptane=1/1) to obtain 1.5 g of a crude (E)-4-pentylphenyl trans-4-(2-(trans-4-pentylcyclohexyl)vinyl)cyclohexanecarboxylate. This crude product was recrystallized from a mixed solvent of heptane/diethyl ether to obtain 1.2 g of the subjective compound (yield 74.7%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O-:11])=[O:10])=[CH:7][C:6]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][NH2:19])(=[O:3])[CH3:2]>[OH-].[Na+]>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][NH2:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)[O-])cc1NC(=O)CCCN
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(C(=O)O)cc1NC(=O)CCCN
Temperature: 0 °C
Reaction time: 1 h
Yield: 286.4 %

Procedure:
Compound 22 (60 mg, 0.17 mmol) was dissolved in cold 0.1N NaOH (1.5 mL) and stirred at 0° C. for one hour. The solution was adjusted to pH 7 and the aqueous layer was concentrated to dryness on a rotary evaporator. The residue was dried under vacuum to give 112 (136 mg) as a white solid mixture containing inorganic salts: mp 215°-240° C. (dec). This solid was dissolved in water (5 mL), the insoluble material was filtered, and the filtrate was concentrated to provide 112 (130 mg, 100%): mp 240°-245° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[Cl:37][CH2:38][CH2:39][CH2:40][C:41](Cl)=[O:42]>O.C(OCC)(=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:9]([C:41](=[O:42])[CH2:40][CH2:39][CH2:38][Cl:37])[CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:21][CH:22]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Reactant: O=C(Cl)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCCl)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1 g (2.3 mmol) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [compound (A)] is dissolved in 100 ml of abs. DMF under argon. 110 mg (4.6 mmol) of sodium hydride (98% strength) are added, and the mixture is stirred at RT for 20 min. Then 4.37 g (30.97 mmol) of chlorobutanoyl chloride are added, keeping the reaction temperature at RT. The reaction mixture is stirred at RT for 16 h and is then admixed with 25 ml of water added gradually with cooling. Subsequently, 300 ml of ethyl acetate are added and a further 50 ml of water. The phases are separated and the ethyl acetate phase is concentrated in vacuo. The residue is stirred up with ethyl acetate and filtered. The mother liquor is concentrated and the residue is purified by flash chromatography on silica gel with toluene/ethanol 5:1 as eluent. The appropriate fractions which contain the target compound and also those which contain a bis-acylated compound formed after enolization are combined and the solvent is removed. The residue is admixed with a saturated solution of hydrogen chloride in dichloromethane and stirred at RT overnight. This is followed by concentrating in vacuo and the residue is again purified by flash chromatography on silica gel with toluene/ethanol 6:1 as eluent. The appropriate fractions are concentrated and the residue is lyophilized from dioxane to obtain 94 mg (7.5% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2([CH3:22])[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:21])[N:4]=1.CN1C=CN=C1.[F:29][CH:30]([F:35])[S:31](Cl)(=[O:33])=[O:32]>ClCCl>[F:29][CH:30]([F:35])[S:31]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)([CH3:22])[C:12]1=[O:21])(=[O:33])=[O:32]
Reactant: COc1nc(OC)nc(C2(C)C(=O)Nc3c(F)cccc32)n1
Reactant: O=S(=O)(Cl)C(F)F
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1nc(OC)nc(C2(C)C(=O)N(S(=O)(=O)C(F)F)c3c(F)cccc32)n1
Temperature: -20 °C
Yield: 25 %

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-7-fluoro-3-methyl-1,3-dihydro-2H-indol-2-one (0.50 g) and 1-methyl-1H-imidazole (0.37 g) are introduced as initial charge in 5 ml of dichloromethane and cooled to −20° C. With stirring, difluoromethanesulfonyl chloride (0.58 g) is added dropwise and the mixture is slowly warmed to room temperature. The mixture is stirred for 3 hours at room temperature. HPLC analysis detects starting material (67%), the desired product (25%) and further components. The mixture is added to 10 ml of water, the phases are separated and the organic phase is concentrated by evaporation in vacuo. The residue is purified by chromatography and the product is separated off from the unreacted starting material. This gives the title compound in an HPLC purity of 86% (0.16 g, 22% of theory). By means of 2D-NMR, it is possible to confirm the structure as N-sulfonylated compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]1([CH3:25])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21](Cl)(=[O:23])=[O:22]>>[C:13]1([CH3:25])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:23]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2c(C)cc(C)cc2C)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-mesitylenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (7.5 mg) with purity >90%. LCMS (pos) m/z 369.0.