Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].BrCC>>[CH2:9]([O:8][P:1]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O:2][CH2:3][CH3:4])=[O:5])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)CBr
Solvent: CCBr
Product: CCOC(=O)CP(=O)(OCC)OCC
Temperature: 100 °C
Yield: 95 %

Procedure:
100 parts by weight of triethyl phosphite and 100 parts by weight of ethyl bromoacetate were put into a reactor equipped with a distillation tube, and the inside of the reactor was substituted by nitrogen. Subsequently, the reactor was heated at 100° C. to start a reaction. Since bromoethane as a by-product began to distill out immediately, the reaction was maintained until the distillation-out of bromoethane slowed down. When the distillation-out of bromoethane became moderate, the reactor was further heated at 150° C. to continue the reaction for 3 hours. The reaction mixture was distilled at 180° C. under a normal pressure to obtain an achromatic transparent liquid (yield of 95%, boiling point of 177° C./760 mmHg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:35][C@H:36]1[CH2:53][C@@:51]2([CH3:52])[C@@H:47]([CH2:48][CH2:49][C@@H:50]2O)[C@H:46]2[C@@:37]1([F:57])[C@:38]1([CH3:56])[C:43]([CH2:44][CH2:45]2)=[CH:42][C:41](=[O:55])[CH:40]=[CH:39]1)(=[O:34])[CH3:33].[C:58]1([SH:64])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>O1CCCC1.C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:32]([O:35][C@H:36]1[CH2:53][C@@:51]2([CH3:52])[C@@H:47]([CH2:48][CH2:49][C@H:50]2[S:64][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C@H:46]2[C@@:37]1([F:57])[C@:38]1([CH3:56])[C:43]([CH2:44][CH2:45]2)=[CH:42][C:41](=[O:55])[CH:40]=[CH:39]1)(=[O:34])[CH3:33]
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Reactant: Sc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H]1C[C@]2(C)[C@H](Sc3ccccc3)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
To a magnetically stirred solution of triphenylphosphine (1.05 g) in dry tetrahydrofuran (15.0 ml) maintained at 0° C. was added diethylazodicarboxylate (0.488 ml) and the mixture was stirred at 0° C. for thirty minutes. To this stirred solution at 0° C. was added dropwise, a mixture of (11β,17β)-11-(acetyloxy)-9-fluoro-17-hydroxyandrosta-1,4-dien-3-one (362 mg, 1 mmole) and thiophenol (0.276 ml) dissolved in 5.0 ml of tetrahydrofuran. The solution was added over a ten minute period and then the reaction mixture stirred for 1 hour at 0° C., followed by 5.5 hours at room temperature. TLC (silica gel, 7:3 chloroform:ethyl acetate) indicated very little reaction taking place so the mixture was refluxed under nitrogen for 48.0 hours, followed by quenching in water and extraction with chloroform (4×50 ml). The combined chloroform extracts were dried over anhydrous magnesium sulfate and evaporated to a yellow oil. This was dissolved in a mixture of chloroform and hexane (8:2) and preadsorbed on silica gel. Flash chromatography was performed and the desired product was successfully eluted with (9:1) chloroform:hexane. The product-containing fractions were pooled, evaporated to an oil, taken up in hot ethyl acetate and evaporated to a yellow crystalline material which was vacuum dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:26])[C:10]([C:16]1[CH:23]=[C:22]([CH3:24])[C:19]([C:20]#[N:21])=[C:18]([CH3:25])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:26])[C:10]([C:16]3[CH:17]=[C:18]([CH3:25])[C:19]([C:20]#[N:21])=[C:22]([CH3:24])[CH:23]=3)([OH:15])[C:11]([F:14])([F:12])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[CH:29][C:28]=1[Cl:27]
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cc(C)c1C#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3cc(C)c(C#N)c(C)c3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 5, 4-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-2,6-dimethyl-benzonitrile (Example 141, step 5) was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=550.1 [M−H+].
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:7])=[CH:4][C:3]=1[N+:26]([O-])=O.C([O-])=O.[NH4+]>O1CCCC1.O.[Fe]>[NH2:26][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:2]=1[NH2:1])[C:6]([C:8]1[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7]
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1N
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 977.4 %

Procedure:
A 1 L three-neck flask equipped with a mechanical stirrer was charged with a mixture of benzyl 2-(4-amino-3-nitrobenzoyl)benzoate (50 g, 133 mmole), iron powder (74 g, 1.30 mol), and ammonium formate (167 g, 2.60 mol) in tetrahydrofuran (300 mL) and water (200 mL). The mixture was stirred vigorously at 80° C. for 90 minutes, cooled to room temperature and filtered through celite. The celite was washed with ethyl acetate (500 mL), and the filtrate was partitioned. The organic portion was washed with 2N sodium hydroxide (2×100 mL), water, brine, dried over sodium sulfate and concentrated in-vacuo to afford benzyl 2-(3,4-diaminobenzoyl)benzoate (47 g, 1.30 mol) as a brown oil. 1H NMR (400 MHz, d6-DMSO): 7.94 (d, 1H), 7.70-7.66 (m, 1H), 7.61-7.58 (m, 1H), 7.37-7.21 (m, 6H), 6.98 (s, 1H), 6.70 (d, 1H), 6.47 (d, 1H), 5.54 (s, 2H), 5.09 (s, 2H), 4.72 (s, 2H); MS (EI) for C21H18N2O3: 349 (MNa+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].S(C1C=CC(C)=CC=1)(O[CH2:14][C:15]([F:18])([F:17])[F:16])(=O)=O>>[F:16][C:15]([F:18])([F:17])[CH2:14][NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1N
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Product: Cc1ccc(O)cc1NCC(F)(F)F
Reaction time: 5 h

Procedure:
3-Amino-4-methylphenol (9.84 g; 0.08 mole) and trifluoroethyl tosylate (20.32 g; 0.08 mole) were mixed in a 500 ml round-bottomed flask and the flask purged with nitrogen. A short air condenser was added, the nitrogen stream was slowed and located towards the top of the condenser, and the flask was immersed in an oil bath at 200° C. A temperature in the range of 150°-250° C. is acceptable. After the molten reagents had been swirled to complete mixing, the heating was continued for five hours. The flask was allowed to cool and before the mixture had solidified, it was dispersed and dissolved in 200 ml of chloroform. Over four days a light brown precipitate of the tosylate salt of 3-amino-4-methylphenol appeared which was filtered off and recovered. The chloroform was extracted with 10% aqueous sodium hydroxide and the dark brown aqueous phase was extracted with chloroform 50 ml. Ice and concentrated hydrochloric acid (21 ml) were added to the aqueous phase and the brown oil was extracted into chloroform 100 ml plus 50 ml. The chloroform solution was washed with 1N hydrochloric and the chloroform layer was separated, dried with sodium sulfate, filtered and evaporated to give a brown gum that crystallized over a day 8.0 g (49%). Recrystallization from petroleum ether 60/80 gave white, fluffy needles mp. 64°-65°. NMR (deuterodimethylsulfoxide): δ8.86 (s, 1H, OH); 6.8-5.9 (m, 3H, ring protons) resolved as AB quartet at 6.74 (C-5 CH) and 6.01 (C-6 CH), J=8.0 Hz together with 6.13 (d, 1H, J=1.0 Hz, C-2 CH) which in turn coupled with the high-field half of the AB quartet; 5.33 (t, 1H, J=6.8 Hz, N-H); 4.0-3.7 (m, 2H, CH2) resolved as two quadruplets, JCF3, CH2 =9.6 Hz, JCH2, NH =6.8 Hz; 1.99 (s, 3H, CH3). Anal. calc. for C9H10F3NO: C, 52.68; H, 4.91; N, 6.83. Found: C, 52.58; H, 4.99; N, 6.80.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH3:43][N:44]([CH2:46][CH2:47][NH2:48])[CH3:45].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:48][CH2:47][CH2:46][N:44]([CH3:45])[CH3:43])=[O:25]
Reactant: CN(C)CCN
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(C)CCNC(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and dimethylaminoethylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: C[C:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1([CH2:23][CH3:24])[O:22][CH2:21][CH2:20][O:19]1)([C:10]([O-:12])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Li+].[OH-]>C1COCC1.O>[C:6]([O:5][C:3]([CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1([CH2:23][CH3:24])[O:19][CH2:20][CH2:21][O:22]1)[C:10]([OH:12])=[O:11])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCC1(CCCCCC(C)(C(=O)[O-])C(=O)OC(C)(C)C)OCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CCCCCC(C(=O)O)C(=O)OC(C)(C)C)OCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of A1 (1 eq.) in THF/H2O (2:1, 0.09 M solution) was treated with LiOH (1.1 eq) and the solution was stirred for 3 hr at RT. The reaction was quenched with 6N HCl and the product was extracted with EtOAc. The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure to yield a white solid which was used without any further purification. 1H NMR (400 MHz, CDCl3) δ: 3.86 (4H, s), 3.16 (1H, t, J=7.3 Hz), 1.90-1.68 (2H, m), 1.63-1.46 (4H, m), 1.39 (9H, s), 1.33-1.15 (6H, m), 0.84 (3H, t, J=7.5 Hz). MS (ES) C17H30O6 requires: 330, found: 331 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=O)[CH:6]=[CH:7][CH:8]=1.[CH2:18]([O:20][C:21]1[C:22]([OH:32])=[C:23]([CH:27]=[C:28]([CH:30]=O)[CH:29]=1)[C:24]([OH:26])=[O:25])[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[CH2:18]([O:20][C:21]1[C:22]([OH:32])=[C:23]([CH:27]=[C:28]([CH:30]2[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:36][C:34](=[O:35])[NH:33]2)[CH:29]=1)[C:24]([OH:26])=[O:25])[CH3:19]
Reactant: CCOc1cc(C=O)cc(C(=O)O)c1O
Reactant: NC(N)=O
Reactant: COc1cccc(CC(=O)c2cccnc2)c1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccnc3)=C2c2cccc(OC)c2)cc(C(=O)O)c1O
Yield: 17.5 %

Procedure:
To a solution of 2-(3-methoxyphenyl)-1-(pyridin-3-yl)ethanone (Intermediate 69) (70 mg, 0.31 mmol), 3-ethoxy-5-formyl-2-hydroxy-benzoic acid (Intermediate 62) (65 mg, 0.31 mmol) and urea (60 mg, 1.0 mmol) in 3 mL of ethanol was added 0.2 mL of concentrated HCl, then the mixture was refluxed for 2 days. The solvent was removed and the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 135 (25 mg, yield 16.9%). 1H NMR (CD3OD 400 MHz): δ 8.73 (d, J=6.8 Hz, 1H), 8.72 (s, 1H), 8.52 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.08 (t, J=8.0 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 7.17 (m, 3H), 6.98 (d, J=2.4 Hz, 1H), 6.74 (dd, J1=2.4 Hz, J2=8.4 Hz, 1H), 6.50 (dd, J1=2.4 Hz, J2=12.0 Hz, 2H), 5.41 (s, 1H); 4.00 (m, 2H). 3.63 (s, 3H), 1.36 (t, J=6.8 Hz, 3H); MS (ESI): m/z 462.1 [M+1]+.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[Na+].[Na+].C[C:8]1[O:12][C:11](CCCOC2C(C)=CC(C3N=NN(C)N=3)=CC=2C)=[CH:10][CH:9]=1.BrBr.[CH3:33]O>[Cl-].[Na+].O>[CH3:33][O:3][CH:1]1[CH:9]=[CH:10][CH:11]([O:12][CH3:8])[O:4]1
Reactant: Cc1ccc(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)o1
Reactant: O=C([O-])[O-]
Reactant: CO
Agent: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC1C=CC(OC)O1

Procedure:
Sodium carbonate (1.2 g) was added to a cooled (-10° C.) solution of 5-methyl 2-[3-[2,6-dimethyl-4-(2-methyl-tetrazol-5-yl)phenoxy]-propyl]furan from example 9d (780 mg, 2.4 mmol) in 18 mL of methanol with stirring, and then bromine (0.135 g, 14 mmol) in 8 mL of methanol was added dropwise until the brown color persisted, and the resulting reaction mixture was allowed to stir at -10° C. for 45 min. To the mixture was added brine, extracted with ether (3×25 mL), and the organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo to yield an oil which was purified by MPLC chromatography (ethyl acetate/hexane 3:7) to afford 820 mg (76.3%) of 5-methyl-2-[3-[2,6-dimethyl-4-]2-methyl-tetrazol-5-yl)phenoxy]-propyl]-2,5-dimethoxy-2,5-dihydrofuran.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:22])[NH:10][CH:11]([CH2:20][OH:21])[C:12](=[O:19])[NH:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>ClCCl.CN(C)C=O>[C:1]1([CH2:7][O:8][C:9](=[O:22])[NH:10][CH:11]([CH2:20][O:21][C:23](=[O:25])[CH3:24])[C:12](=[O:19])[NH:13][N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CO)C(=O)Nn1cccc1)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(NC(=O)OCc1ccccc1)C(=O)Nn1cccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a stirred solution of (±)-phenylmethyl-[1-(hydroxymethyl)-2-oxo-2-(1H-pyrrol-1-ylamino)ethyl]carbamate (4.26 g) in 100 ml of dichloromethane and 20 ml of dimethylformamide were added acetic anhydride (3.0 ml) and pyridine (2.5 ml). The reaction mixture was stirred overnight at room temperature and then combined with the product from a 5.41 mmol scale reaction which was performed under the same conditions. The reaction mixture was washed with 5% citric acid and water, and dried over magnesium sulfate. After evaporation, the crude product was purified by flash column chromatography (silica gel, DCM/methanol, 30:1). Recrystallization from ethyl acetate/n-hexane afforded the product as a powder (2.96 g, 44%), m.p. 154°-155° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24]OS(C)(=O)=O)=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:30])[CH2:4][CH3:5])[CH3:2].[NH3:31]>CO>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:31])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:30])[CH2:4][CH3:5])[CH3:2]
Reactant: N
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCOS(C)(=O)=O)cc3)no2)cc1C
Solvent: CO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCN)cc3)no2)cc1C

Procedure:
To a cooled (0° C.) solution of 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethanol (196 mg, 488 μmol) and DIPEA (84 mg, 732 μmol) in THF (5 mL), methanesulfonyl chloride (126 mg, 976 μmol) is added as a solution in THF (2.5 mL). The reaction mixture is stirred at 0° C. for 1 h, then at rt for 1 h. The mixture is diluted with DCM (100 mL) and washed with brine (3×50 mL). The organic extract is dried over MgSO4, filtered, concentrated and dried to give crude methanesulfonic acid 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl ester (295 mg); LC-MS: tR=0.59 min; [M+1]+=449.71. b) A solution of methanesulfonic acid 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl ester (295 mg, 658 μmol) in 7 N NH3 in methanol (10 mL) is stirred in a sealed vessel at 80° C. for 16 h. The reaction mixture is concentrated and dried to give the title compound (255 mg) as a pale yellow oil; LC-MS: tR=0.64 min; [M+1]+=370.97.
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=O)[CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][CH:12]=1>CO>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CCN1CCCC1)Nc1cccc(Br)c1
Solvent: CO
Solvent: C1CCOC1
Product: Brc1cccc(NCCCN2CCCC2)c1
Reaction time: 8 h

Procedure:
A 1M solution of BH3 in tetrahydrofuran (10 ml, 10 mmol) was added dropwise to N-(3-bromo-phenyl)-3-pyrrolidin-1-yl-propionamide (0.3 g, 1 mmol) and the solution was stirred overnight at reflux then subsequently hydrolysed by slow addition of excess of methanol and refluxing for a further 2 hours. The solvent was removed under reduced pressure and aqueous ammonium chloride was added. The aqueous phase was extracted twice with ethyl acetate and the organics were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in methanol and loaded onto an SCX cartridge, which was washed with methanol and the product subsequently eluted with 2M ammonia in methanol. Removal of all solvents under rotary evaporation gave the desired product. Yield 0.23 g, 82%. LCMS method: 2, RT: 2.71 min; MI: 283-285 [M+1].
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1.[CH3:19][N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH2:21]1>C(O)C>[Br-:1].[Br-:1].[CH3:19][N+:20]1([CH:16]([CH3:17])[CH2:15][CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][CH:7]=[CH:12][CH:11]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[CH3:19][N+:20]1([CH:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CN1C=CC=CC1
Reactant: BrCCCCCc1ccc(CCCCCBr)cc1
Solvent: CCO
Product: CC(CCCc1ccccc1)[N+]1(C)CCCCC1
Product: [Br-]
Reaction time: 8 h

Procedure:
To a solution of 376 mg of 1,4-bis(5-bromopentyl)benzene in 2 ml of absolute ethanol, 365 μl of N-methylpyridine was added, and the mixture was refluxed for 5 hours. After concentration under a reduced pressure and addition of acetone, and the mixture was allowed to stand overnight. The product was filtered and recrystallized from ethanol (0.5 ml)--acetone (2 ml) to obtain 455 mg of the title compound as a colorless crystal.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH2:26][CH2:27][CH3:28])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CCCOC(=O)c1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCCOC(=O)c1ccccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg), n-propyl salicylate (360 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight and at 140° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (104 mg, yield 57%).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16](S(O)(=O)=O)=[CH:15][CH:14]=1.[CH2:24]=C(C)C>C1(C)C=CC=CC=1>[CH3:24][CH:23]([C:4]1[CH:5]=[CH:6][C:1]([NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11])=[CH:2][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=C(C)C
Reactant: CCOC(=O)Nc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1ccc(C(C)c2ccccc2)cc1
Temperature: 100 °C
Yield: 72 %

Procedure:
A mixture of 165 parts of ethyl N-phenylcarbamate and 10 grams of p-toluenesulfonic acid is heated, in a stirred autoclave, to 100° C. whilst stirring, and 112 parts of isobutene are pumped in over two hours. After completion of the addition of isobutene, the mixture is stirred for a further two hours at 100° C. It is then diluted with 100 parts of toluene and extracted with aqueous sodium carbonate solution, and the end product is distilled under reduced pressure. 169 parts (72% of theory, based on carbamic acid ester II) of ethyl N-(4-tert.-butylphenyl)-carbamate, of boiling point 125°-127° C./0.2 mbar, are obtained. The conversion is 76 percent.
Reaction SMILES: O=C1C2(CCNCC2)C(=O)CC1.O1[C:17]2([CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]4=[O:39])=[CH:25][C:24]=3[F:40])[CH2:19][CH2:18]2)[O:16]CC1.CC(C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[F:40][C:24]1[CH:25]=[C:26]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][C:17](=[O:16])[CH2:18][CH2:19]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)C12CCNCC2
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
Using a commercially available 1,4-dioxo-8-aza-spiro[4.5]decane, (S)-N-{3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}- acetamide is synthesized by the same method as in Step 1. To an acetone solution (70 ml) of this compound (3.79 g), water (20 ml) and p-toluenesulfonic acid monohydrate (3.66 g) are added successively and the mixture is heated under reflux for 3 hours. After the reaction mixture is cooled to room temperature, acetone is distilled off and the aqueous layer is neutralized with triethylamine. The solution is extracted with methylene chloride and the organic layer is washed with brine, dried over anhydrous sodium sulfate. The solvent is evaporated and the residue is purified by silica gel column chromatography (solvent: chloroform/methanol=50/1-25/1) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=[O:15])[O:12][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C1(C)C(C)=CC=CC=1.CS(O)(=O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:12])[N:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:13](=[O:15])[CH2:14]2)=[CH:6][CH:7]=1
Reactant: Nc1ccncc1
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CC(c2ccc(Cl)cc2)CC(=O)N1c1ccncc1
Reaction time: 96 h

Procedure:
The starting material is prepared as follows: The mixture of 22.4 g of 3-(p-chlorophenyl)-glutaric anhydride, 10.3 g of 4-aminopyridine, 350 ml of xylene and 1.5 g of methane sulfonic acid is refluxed on a water separator while stirring for 4 days. After the first day an additional 0.5 g of methane sulfonic acid is added and the hot solution is finally decanted from some gummy material. The crystals formed on cooling are filtered off, triturated with hot ethanol, cooled, filtered off again and dried to yield the 4-(p-chlorophenyl)-1-(4-pyridyl)-piperidin-2,6-dione melting at 204°-206°.