Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=C)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:27].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=[O:27])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:2])[CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-vinyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.300 g, 0.000894 mol) was dissolved in THF (20 mL) and H2O (10 mL). Osmium tetroxide (0.550 mL, 0.0716 mmol, 4% wt in water) was added followed by Sodium metaperiodate (0.383 g, 0.00179 mol). The reaction was stirred overnight at room temperature. The reaction was quenched using saturated sodium thiosulfate. 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carbaldehyde (0.302 g, 95.1% yield) was isolated using an aqueous workup and carried on without further purification
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:18][C:19]([CH3:35])=[C:20]([C:22]([NH:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:23])[N:21]=4)=[C:13]([NH:36][CH:37]([CH3:39])[CH3:38])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CCOCC.Cl>C(Cl)Cl>[NH2:27][CH2:26][CH2:25][NH:24][C:22]([C:20]1[N:21]=[C:17]([C:14]2[CH:15]=[N:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[CH:12][C:13]=2[NH:36][CH:37]([CH3:38])[CH3:39])[O:18][C:19]=1[CH3:35])=[O:23]
Reactant: Cc1oc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1C(=O)NCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1oc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1C(=O)NCCN
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamido)ethyl)carbamate in DCM (5 mL) was treated with ether.HCl (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction temperature was raised to room temperature and stirred for 30 min. The reaction mixture was concentrated to dryness. The material obtained was purified by prep. HPLC to afford N-(2-aminoethyl)-2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamide 1H NMR: 400 MHz, DMSO-d6: δ 1.35 (d, J=6.40 Hz, 6H), 2.64 (s, 3H), 2.70-2.80 (m, 2H), 3.70-3.74 (m, 1H), 6.17 (s, 1H), 7.60 (dd, J=2.00, 9.00 Hz, 1H), 7.79 (d, J=7.20 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.02 (bs, 1H), 8.53 (s, 1H), 8.67 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.35 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min; retention time: 1.646 min; LCMS (ES-API), m/z 452.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 30 min (36 min run time); Flow rate: 1.0 μL/min; Retention time: 8.956 min; Purity: 91.1%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([F:15])[C:3]=1[C:16]1[N:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][C:17]=1[F:26].C1COCC1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([F:15])[C:3]=1[C:16]1[N:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:17]=1[F:26]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(OC3CCCOC3)cc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(F)c(-c2c(F)cc(OC3CCCOC3)cc2F)n1

Procedure:
The methyl 6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylate was treated with THF (2 mL), MeOH (2 mL) and 1.0 M aq. NaOH (2 mL, 2 mmol) at room temperature for 1 h. The volatile organic solvents were removed and the residue was neutralized to pH-5-6 with 1 M HCl. The solid that precipitated was filtered, rinsed with water, and dried to give sub-title compound as a white solid. LCMS calc. for C17H15F3NO4 (M+H)+ m/z=354.1. found: 353.9.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[N:11][C:12]=1[F:13].C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>CCCCCC.C1COCC1>[F:13][C:12]1[N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:9]=[CH:8][C:7]=1[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CN(C)CCCOc1ccc(Br)c(F)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
A solution of n-butyllithium (0.693 g, 10.83 mmol) in n-hexane (4.33 mL) was added to a stirred mixture of 3-(5-bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (2 g, 7.22 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.014 g, 10.83 mmol) in THF (20 mL) at −78° C. over a period of 20 minutes under an inert atmosphere. The resulting mixture was allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was quenched with sat. NaHCO3 solution and concentrated in vacuo. The crude product was purified by FCC, elution gradient 0 to 10% MeOH in DCM, to afford the desired material (2.50 g, 1.07%). Mass Spectrum: m/z (ES+)[M+H]+=325.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: NCC1CCOCC1
Solvent: CS(C)=O
Product: c1ccc2c(c1)ncn2-c1nc(NCC2CCOCC2)nc2[nH]cnc12
Temperature: 120 °C

Procedure:
250 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 531 mg μl of 4-aminomethyl-tetrahydropyran, and the mixture is then heated at 120° C. for approximately 2 days. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. 142 mg of expected product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1ccc(OC)cc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc(OC)cc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(4-methoxyphenyl)acetate hydrochloride (prepared by the Bucherer Modification of the Strecker procedure as described in J. P. Greenstein et al., “The Chemistry of Amino Acids”, Vol. 1, p. 698, Wiley, New York (1961)), the title compound was prepared as a solid (mp=170-174° C.). The reaction was monitored by tlc (Rf=0.1 in 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 98:2 CHCS3/MeOH as the eluent.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]=[C:14]([OH:16])[NH:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[F:22][C:23]([S:26][CH2:27][C:28](Cl)=[O:29])([F:25])[F:24].[OH-].[Na+]>CC(C)=O.C([O-])(O)=O.[Na+]>[F:22][C:23]([S:26][CH2:27][C:28]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]=[C:14]([OH:16])[NH:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:29])([F:25])[F:24]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3n[nH]c(O)n3)CS[C@H]12
Reactant: O=C(Cl)CSC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(CSC(F)(F)F)NC1C(=O)N2C(C(=O)O)=C(CSc3n[nH]c(O)n3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cold solution (-20°) of 7-amino-3-(5-hydroxy-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid (3.39 g., 0.01 mole) in a mixture of acetone (62.5 ml.) and 3% NaHCO3 (62.5 ml.) is added dropwise over a 30 minute period a solution of trifluoromethylmercaptoacetyl chloride (2.24 g., 0.012 mol.) in acetone (20 ml.) The solution is maintained at pH 8 by adding 10% sodium hydroxide as needed. The reaction is stirred for 20 minutes at -15° to -20° and then allowed to warm to room temperature. The solution is washed with ether, covered with ethyl acetate and acidified to pH 2. The aqueous phase is separated and extracted with ethyl acetate. The combined ethyl acetate phases are combined, washed with water, dried, and evaporated to give the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH:47]([CH2:50]OS(C)(=O)=O)[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH:47]([CH2:50][N:19]2[C:20]3[C:25](=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[CH:22][CH:21]=3)[C:17]([C:14]3[N:15]=[C:16]4[C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:9][N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:11]4=[N:12][CH:13]=3)=[N:18]2)[CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CCN(C(=O)OC(C)(C)C)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A round-bottomed flask was charged with 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (120 mg, 0.23 mmol), 3-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (crude from Step 1, 215 mg, 0.54 mmol), cesium carbonate (258 mg, 0.79 mmol) and DMF (1 ml). The reaction mixture was stirred at 110° C. for 1.5 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/hexanes (gradient: 0-40% EtOAc). The appropriate fractions were combined and concentrated and the residue was triturated with petroleum ether to afford 138 mg (86%) of 3-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-ylmethyl}-pyrrolidine-1-carboxylic acid tert-butyl ester as a light yellow powder.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)=[O:4].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[CH:6][C:7]=1[CH2:12][OH:13]
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Reactant: c1ccc(CNCCCCCCOCCCc2ccccn2)cc1
Solvent: C1CCOC1
Product: O=C(CN(CCCCCCOCCCc1ccccn1)Cc1ccccc1)c1ccc(O)c(CO)c1
Yield: 67.8 %

Procedure:
A solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (2.45 g), N-[6-[3-(2-pyridinyl)propoxy]hexyl]benzenemethanamine (3.26 g) and DEA (2.6 g) in THF (25 ml) was left at room temperature for 48 h. The precipitate was removed by filtration, the solvent was evaporated and the residual red oil was purified by FCC eluting with System B (95:5:1→90:10:1) to give the title compound as a pale yellow oil (3.32 g), t.l.c. (System A 80:20:1) Rf 0.21.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:14]1[C:15](=[O:30])O[C:17](=[O:29])[C:18]=1[C:19]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=1)=[C:4]1[CH2:13][CH2:12][CH2:11][CH2:10][N:5]12.C[N:32](C)C=O>N>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:14]1[C:15](=[O:30])[NH:32][C:17](=[O:29])[C:18]=1[C:19]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=1)=[C:4]1[CH2:13][CH2:12][CH2:11][CH2:10][N:5]12
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCCC4)C(=O)OC2=O)c2ccccc21
Agent: N
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCCC4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 72 mg of 3-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)-4-(1-methyl-3-indolyl)furan-2,5-dione in 5 ml of dimethylformamide and 5 ml of 33% aqueous ammonia was heated to 140° C. for 4 hours. The resulting crystals were filtered off and dried to give 50 mg of 3-(6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 286°-289° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([CH3:29])[CH2:12][C:13]2(O)[CH2:18][CH2:17][C:16]([N:25]([CH3:27])[CH3:26])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:2]1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.ClCCl>ClCCCl>[CH3:26][N:25]([CH3:27])[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:18][C:13]2([C:2]3[NH:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]=3[CH2:10][C@@H:11]([CH3:29])[CH2:12]2)[CH2:14][CH2:15]1
Reactant: C[C@H](Cc1c[nH]c2ccccc12)CC1(O)CCC(c2ccccc2)(N(C)C)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H]1Cc2c([nH]c3ccccc23)C2(CCC(c3ccccc3)(N(C)C)CC2)C1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of (R)-1-(3-(1H-indol-3-yl)-2-methylpropyl)-4-(dimethylamino)-4-phenylcyclohexanol (100 mg, 0.25 mmol) in anhydrous 1,2-dichloroethane (10 mL) was mixed with trifluoromethane sulphonic acid trimethylsilyl ester (222 mg, 181 μL, 1 mmol) and stirred for 4 h at 50° C. After adding dichloromethane (10 mL) the solution was washed with 1 M potassium carbonate solution (2×10 mL), water (10 mL) and saturated sodium chloride solution (10 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. The residue (90 mg) was taken up in methanol (10 mL) and stirred for 16 h at room temperature. The precipitated solid was separated from the solution by decanting, the remaining solid once again mixed with methanol, stirred and decanted, as a result of which Example No. 15 was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(Cl)(Cl)Cl>[CH3:13][C:11]1([CH3:12])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:8][C:9](=[O:14])[CH2:10]1
Reactant: CC(C)=CC(=O)Nc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
9.4 g (48.7 mmol) of 3-methyl-2-butenoic acid-(4-fluorophenyl)amide is heated to 130–140° C. and mixed in portions with 9.6 g (73.5 mmol) of aluminum trichloride. After the addition is completed, the temperature is kept at 80° C. for 30 more minutes. It is allowed to cool to room temperature and carefully treated with 60 ml of ice water. After 150 ml of chloroform is added, the batch is stirred for 15 minutes, acidified with dilute hydrochloric acid and extracted with chloroform (3×150 ml). The combined organic extracts are washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 6.0 g.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH2:25][F:26])(=[O:22])=[O:21])=[CH:13][CH:14]=2)[CH:9]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:7][CH:8]1[CH:9]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]2[CH:11]=[C:12]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH2:25][F:26])(=[O:22])=[O:21])[CH:13]=[CH:14][C:15]=2[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)CCCF)cc2C1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCc2ccc(CNS(=O)(=O)CCCF)cc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl[1-benzyl-7-({[(3-fluoropropyl)sulfonyl]amino}methyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (9.3 mg, 0.019 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (excess) was added. The reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (silica gel, dichloromethane, methanol).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=O)=[CH:11][CH:10]=1.S(Cl)(Cl)=O>CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]2[O:18][CH2:17][CH2:16][N:15]=2)=[CH:11][CH:10]=1
Reactant: O=C(NCCO)c1ccc(OCCCCCCBr)cc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: BrCCCCCCOc1ccc(C2=NCCO2)cc1
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To 100 g of 4-(6-bromohexyloxy)-N-(2-hydroxyethyl)benzamide was added dropwise 112 g (75 ml) of thionyl chloride over a 20 minute period. The mixture was stirred for 45 minutes and then diluted with several volumes of ether. A solid product separated which was collected and rinsed with ether to give 90 g of 2-[4-(6-bromohexyloxy)phenyl]-4,5-dihydro-oxazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C@H:11]1[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]1)[N:17]=[C:18]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc(S(C)(=O)=O)cc2)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(S(C)(=O)=O)cc1

Procedure:
8.0 g of (−)-cis-N-[2-(3,4-dimethoxyphenyl)cyclohexyl]-4-methanesulfonylbenzamide are suspended in 150 ml of toluene, treated with 4 ml of phosphorus oxychloride and heated under reflux for 5.5 h. The reaction solution is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is extracted with satd sodium hydrogencarbonate solution and water. After chromatography on silica gel using petroleum etherlethyl acetate/triethylamine in the ratio 6/3/1, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:10])=[C:4]([CH3:13])[CH:3]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Cc1cc(Cl)ccc1OCC(=O)O
Product: Cc1cc(Cl)ccc1OCC(=O)N1CCCc2ccccc21
Yield: 46 %

Procedure:
The title compound was synthesized according to General Procedure D using 2-(4-chloro-2-methylphenoxy)acetic acid and compound 3 to yield compound 56 (365 mg, 46%): MS (APCI): m/z 316 [M+H]+. Anal. Calcd. for C18H18ClNO2: C, 68.46; H, 5.75; N, 4.44. Found: C, 68.41; H, 5.92; N, 4.51.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:5]2[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]2=[O:9])=[O:24])=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)[C@@H]1COC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[C@@H]1COC(=O)N1C(=O)Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
To a solution of (4R)-4-isopropyl-1,3-oxazolidin-2-one (5.2 g, 40.3 mmol) in dry THF (100 mL) at −78° C. under argon, was added dropwise a 2.5M solution of n-BuLi in hexanes (17.0 mL, 42.5 mmol). After stirring at −78° C. for 15 min, (4-fluorophenyl)acetyl chloride (6.34 mL, 46.4 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 30 min and 0° C. for 15 min, quenched with saturated NH4Cl (15 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated Na2CO3 following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%–15% EtOAc/hexane) to give 8.35 g (31.5 mmol, 78%) of (4R)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.30–7.25 (m, 2H), 7.10 (t, 2H, J=8.5 Hz), 4.46–4.41 (m, 1H), 4.36–4.15 (m, 4H), 2.40–2.28 (m, 1H), 0.88 (d, 3H, J=7.6 Hz), 0.79 (d, 3H, J=7.6 Hz); ESMS m/e: 266.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:6]([F:12])[CH:5]=1)=[O:3].[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16].[H-].[Na+]>>[Cl:10][C:9]1[CH:8]=[C:7]([Cl:11])[C:6]([F:12])=[CH:5][C:4]=1[C:2]([CH2:1][C:13]([O:14][CH2:15][CH3:16])=[O:17])=[O:3]
Reactant: CC(=O)c1cc(F)c(Cl)cc1Cl
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1cc(F)c(Cl)cc1Cl

Procedure:
Condensation of 2,4-dichloro-5-fluoroacetophenone 2 with diethyl carbonate in the presence of NaH yielded ethyl 2,4-dichloro-5-fluorobenzoylacetate 3. Treatment of the latter with triethyl orthoformate in acetic anhydride gave the carbon homologue enol ether intermediate 4 which was allowed to react with a slight excess of cyclopropylamine in methylene chloride at room temperature to give the enaminoketoester 5. Cyclization of the latter with 1 molar equivalent of NaH in refluxing dioxane yielded ethyl 1,4-dihydro-4-oxo-quinoline-3-carboxylate 6 which was then hydrolysed with aqueous NaOH to give 1-cyclopropyl-6-chloro-7-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (IM) 7. See also Scheme 1 below (Maurer, F. and Grohe, K., DE 3 435 392 through Chem. Abst., Vol. 105, No.5, 1984, pp. 97158e). Compound data:
Reaction SMILES: [N:1]([C:4]1[C:9](Cl)=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=[O:12])=[N+:2]=[N-:3].[Br:13]C1C(Cl)=C(C=O)C=NC=1.[N-]=[N+]=[N-].[Na+]>>[N:1]([C:4]1[C:9]([Br:13])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=[O:12])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(Cl)cncc1C=O
Reactant: O=Cc1cncc(Br)c1Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1c(Br)cncc1C=O
Yield: 83 %

Procedure:
Following the procedure described for 4-azido-5-chloro-pyridine-3-carbaldehyde, 5-bromo-4-chloropyridine-3-carbaldehyde and sodium azide were reacted to afford the title compound as a pale yellow solid (3.18 g, 83% yield). 1H NMR (400 MHz, CDCl3): δ 10.30 (s, 1H), 8.85 (s, 1H), 8.79 (s, 1H).