Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N:12]([CH3:19])[N:13]=[C:14]([OH:18])[C:15](=[O:17])[N:16]=3)[CH2:7][S:8][C@H:3]12.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH:25](=[N:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N:12]([CH3:19])[N:13]=[C:14]([OH:18])[C:15](=[O:17])[N:16]=3)[CH2:7][S:8][C@H:3]12)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1nc(O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1nc(O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N=Cc3ccccc3)[C@H]2SC1
Yield: 93.2 %

Procedure:
A suspension of 7β-amino-3-[(2,5-dihydro-6- hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl]ceph-3-em-4-carboxylic acid (see EP 65748) (3.71 g) in dimethylformamide (50 ml) was treated with benzaldehyde (4.24 g) and the mixture was sonicated in an ultrasound bath at 25° for 0.5 hours, by which time a clear solution had resulted. After evaporation to dryness in vacuo the residue was triturated with ether to give the title compound, (4.28 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[C:5]([CH3:25])[N:4]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C.Cl.[CH2:44]([O:46][C:47](=[O:57])[C@H:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[NH2:49])[CH3:45]>CN(C)C=O>[CH2:44]([O:46][C:47](=[O:57])[C@H:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[NH:49][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:6]3[C:7]([NH2:9])=[N:8][C:3]([NH2:2])=[N:4][C:5]=3[CH3:25])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1)[CH3:45]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N2CCN(c3c(C)nc(N)nc3N)CC2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.8 %

Procedure:
A mixture of 4.27 g (0.01137 mole) of 4-[4-(2,4-diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]benzoic acid hydrochloride, 6.12 g (0.0375 mole) of diethyl phosphorocyanidate and 7.0 ml (0.050 mole) of triethylamine in 300 ml of previously dried dimethylformamide was stirred at room temperature for five hours and then at 80° C. for five minutes. The solution was cooled to room temperature, and a solution of 3.00 g (0.0125 mole) of L-glutamic acid diethyl ester hydrochloride and 1.74 ml (0.0125 mole) of triethylamine was added. The resulting mixture was stirred for two hours at room temperature. The solvent was removed under high vacuum at 40° C. and the gummy residue partitioned between 500 ml of dichloromethane and 500 ml of 5% sodium bicarbonate solution. The organic layer was separated, washed with water and then with saturated sodium chloride solution and dried over magnesium sulfate. The dried solution was concentrated in vacuo to give a yellow solid. Recrystallization from acetonitrile gave 3.9 g of the product as a tan solid, mp 224° C. (dec.).
Reaction SMILES: [N:1]1([C@@H:5]([CH3:8])[CH2:6][OH:7])[CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])[CH3:11]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Si:13]([O:7][CH2:6][C@@H:5]([N:1]1[CH2:4][CH2:3][CH2:2]1)[CH3:8])([C:10]([CH3:12])([CH3:11])[CH3:9])([CH3:15])[CH3:14]
Reactant: C[C@@H](CO)N1CCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
A mixture of (S)-2-(azetidin-1-yl)propan-1-ol (99.7 mmol), TBSCl (15.8 g, 105 mmol), DMAP (1.22 g, 10 mmol), and TEA (30.3 g, 0.30 mol) in toluene (150 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified on a silica gel column eluted with a 1:5 ethyl acetate/petroleum ether then a 1:10 MeOH/DCM, to afford the title compound (2.92 g). 1H NMR (CDCl3): δ 3.54-3.49 (m, 1H), 3.29-3.16 (m, 5H), 2.33-2.27 (m, 1H), 2.07-1.98 (m, 2H), 0.88 (s, 9H), 0.87 (d, 3H), 0.03 (s, 6H); LCMS: 230 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:28])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1.CC(O)=O>CO.[Pd]>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:28])[S:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CN(C)CCCC#Cc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)CCCCCc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h
Yield: 67 %

Procedure:
A solution of 40 mg (0.094 mmol) of N-[4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 3 ml MeOH/0.3 ml dioxane was treated with 0.094 ml 1N AcOH in MeOH followed by 4 mg Pd/C10%, type EION (under argon) and then hydrogenated (1 atm) for 3 h. The reaction mixture was filtered (Celite) and extracted with aqueous sat. NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl solution, dried (Na2SO4) and evaporated to yield 27 mg (66%) of N-[4-(5-Dimethylamino-pentyl)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 429 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CC(C)=O>[Cl:15][CH2:16][CH2:17][C:18]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:19]
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)CCCl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(CCCl)Nc1cccc(F)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 3-fluoroaniline (10 g, 90.00 mmol) in acetone (40 ml) was added pyridine (18 g, 227.56 mmol) and 3-chloropropanoyl chloride (13.73 g, 108.14 mmol) and the reaction was stirred for 3 h at 55° C. The resulting solution was extracted with ethyl acetate (3×50 ml) and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 3-chloro-N-(3-fluorophenyl)propanamide as a yellow solid (13.21 g, 73%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1c(C)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 77.5 °C
Yield: 52.2 %

Procedure:
To a mixture of 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid, ethyl ester (0.76 g, 3.47 mmol) and potassium carbonate (0.92 g, 6.67 mmol) in acetonitrile (10 ml) was added benzyl bromide (1.0 ml, 1.4 g, 8.4 mmol). The mixture was heated at 75-80° C. for 18 h. The reaction was cooled to room temperature, quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes) to yield 5-benzyloxy-2-methyl-1H-indole-3-carboxylic acid, ethyl ester (Compound 53) as a yellow solid (0.56 g, 52%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]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]>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]([NH:11][C:10](=[O:23])[O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)([CH3:14])[CH3:13])=[CH:16][C:17]=1[C:26]1[CH:27]=[CH:28][O:24][CH:25]=1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Reactant: OB(O)c1ccoc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2ccoc2)c1
Yield: 42.6 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (110 mg, 0.296 mmol), furan-3-boronic acid (47.9 mg, 0.428 mmol) and tris(dibenzylideneacetone)dipalladium(0) gave the title compound as a white solid (47 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 7.88 (ddd, J=0.9, 1.5, 2.5 Hz, 1H), 7.53 (dd, J=2.5, 7.1 Hz, 1H), 7.50 (t, J=1.7 Hz, 1H), 7.31-7.23 (m, 1H), 7.08 (dd, J=8.6, 10.6 Hz, 1H), 6.76 (dt, J=0.8, 1.7 Hz, 1H), 5.22 (s, 1H), 4.62 (s, 1H), 3.40-2.11 (m, 6H), 2.02-0.87 (m, 5H), 1.59 (dd, J=11.6, 70.3 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.0, 157.5, 150.2, 143.9, 127.44, 127.36, 127.0, 126.1, 123.8, 116.6, 116.4, 71.5, 55.9, 55.0, 47.6, 46.7, 30.1, 29.9, 25.6, 24.8, 19.8 ppm. Purity: 96% UPLCMS (210 nm); retention time 0.85 min; (M+1) 372.9.
Reaction SMILES: [BH3-]C#N.[Na+].C(O)(=O)C.[C:9]([O:13][C:14]([NH:16][N:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:15])([CH3:12])([CH3:11])[CH3:10]>C1COCC1>[C:9]([O:13][C:14]([NH:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCCCC=NNC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCNNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
6.65 g of NaBH3CN are solubilized in acetic acid (10.5 g; 175 mmoles). The solution is cooled at 0° C. and a solution in anhydrous THF (35 mL; 0.15 M) of t-butyl-2-pentylidenhydrazincarboxylate (7.00 g; 35 mmoles) prepared in example 11a is dropwise added. The reaction mixture is then let to warm to room temperature under stirring for 24 hours. The organic phase is washed with a 10% NaHCO3 solution and then extracted with chloroform. The organic phase is recovered and the solvent removed under vacuum. The obtained residue is purified by chromatography on silica gel using as eluent a chloroform/methanol 90:1 volume/volume mixture. 6.3 g of t-butyl-2-pentylhydrazincarboxylate are obtained (white solid; yield 90%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)[CH:25]=[O:26]>>[C:17]1([CH2:16][N:13]2[CH2:12][CH2:11][CH:10]([N:9]3[CH2:8][C:7]4[CH:6]=[CH:5][CH:4]=[N:3][C:2]=4[NH:1][C:25]3=[O:26])[CH2:15][CH2:14]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)C=O
Reactant: Nc1ncccc1CNC1CCN(Cc2ccccc2)CC1
Product: O=C1Nc2ncccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4.2 g (0.0142 mol) of 2-amino-3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-pyridine, 2.4 g (0.0148 mol) of N,N′-carbonyldiimidazole and 50 ml of dimethylformamide was heated to 100° C. for 30 minutes. The still warm mixture was stirred into 300 ml of ice water, the precipitate formed was suction filtered and recrystallised from acetonitrile. After drying in vacuo 4.5 g (98.3% of theory) of colourless crystals of melting point 187° C. were obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:15][C:16]1[C:17]([F:23])=[N:18][CH:19]=[C:20](O)[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:15][C:16]1[CH:21]=[C:20]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:19]=[N:18][C:17]=1[F:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1cnc(F)c(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(F)c(Br)c1

Procedure:
A sample of 1-BOC-2-(S)-pyrrolidinemethanol, prepared as described above, and of 3-bromo-2-fluoro-5-hydroxypyridine, prepared as in step b above, are reacted with triphenylphosphine and DEAD in THF at room temperature for 16 hours, to give the title compound.
Reaction SMILES: [Br-].[C:2](O[K])([CH3:5])([CH3:4])[CH3:3].O=C1C[CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11]C1>O1CCCC1>[CH2:3]=[C:2]1[CH2:5][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH2:4]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)O[K]
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 159.7 %

Procedure:
51.1 g of methyltoluphenylphosphonium bromide was added to a mixture of 16.1 g tert-butoxy potassium and 500 ml tetrahydrofuran, and then stirred for 1 hr and 20 min at room temperature. 16.1 g of benzyl 4-oxo-1-piperidinecarboxylate was added thereto, and the mixture was stirred for 2 hr and 40 min at room temperature. The reaction solution was evaporated, diethyl ether was added thereto, and then filtered through Celite. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated, and the resulting residue was subjected to silica gel column chromatography to give 25.5 g of benzyl 4-methylene-1-piperidinecarboxylate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][OH:32])=[CH:26][CH:25]=2)=[N:21][CH:22]=1>CN(C=O)C>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:32][CH2:31][CH2:30][C:27]3[CH:26]=[CH:25][C:24]([O:23][C:20]4[CH:19]=[CH:18][C:17]([C:16]([F:34])([F:15])[F:33])=[CH:22][N:21]=4)=[CH:29][CH:28]=3)[CH:3]=2)[CH2:9][CH2:10]1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCCc1ccc(Oc3ccc(C(F)(F)F)cn3)cc1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.269 mmol), sodium hydride (21.55 mg, 0.539 mmol) and 2-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)ethanol (76 mg, 0.269 mmol) in DMF (1 mL).
Reaction SMILES: [F:1][C:2]([F:18])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])[C:3]([F:6])([F:5])[F:4].[CH3:19][N:20]=[C:21]=[O:22].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:21]([NH:20][CH3:19])=[O:22])(=[O:16])=[O:15])[C:3]([F:6])([F:5])[F:4]
Reactant: CN=C=O
Reactant: NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F

Procedure:
The 2-pentafluoroethoxyphenylsulfonamide obtained in Example 4b is suspended in 400 ml of methylene chloride. Then 16.3 g of methyl isocyanate are added and 28.2 g of triethylamine are subsequently added dropwise over 15 minutes to form a clear solution. The solution is evaporated to dryness, and the residue is dissolved in 5% sodium carbonate solution. N-(2-pentafluoroethoxyphenylsulfonyl)-N'-methylurea with a melting point of 177°-179° C., is precipitated from the solution by acidification with 10% hydrochloric acid. Yield: 74.6 g.
Reaction SMILES: CS(O)(=O)=O.[CH:6]([O:19][C:20]([C:22]1[N:23]2[CH:26]([S:27][CH2:28][C:29]=1[C:30]1[S:34][C:33]([CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=1)[CH:25]([NH:42]C(OC(C)(C)C)=O)[C:24]2=[O:50])=[O:21])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[NH2:42][CH:25]1[C:24](=[O:50])[N:23]2[CH:26]1[S:27][CH2:28][C:29]([C:30]1[S:34][C:33]([CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=1)=[C:22]2[C:20]([O:19][CH:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CSC12
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CSC12
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
A solution of methanesulphonic acid (10 cc) is added to a solution of 2-benzhydroxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-[2-(pyrid-3-ylmethyl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (10 g) in acetonitrile (100 cc). The mixture is stirred for 5 minutes and is poured into a 50:50 (by volume) mixture (500 cc) of saturated sodium bicarbonate solution and ethyl acetate. The organic phase is decanted and then washed successively with distilled water (200 cc) and saturated sodium chloride solution (200 cc). It is dried over anhydrous magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. 7-Amino-2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyrid-3-yl-methyl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (6.36 g) is obtained in the form of a chestnut-coloured froth.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:27])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:27])=[CH:6][CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)ccn2c1=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(C)=O)cc3)ccn2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
50 mg of ethyl 8-(4-aminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 2) was dissolved in 2 ml of pyridine. 17 mg of acetic anhydride was added to the obtained solution, and they were stirred at room temperature for 16 hours. Water was added to the reaction mixture. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduce pressure, and the obtained residue was purified by the silica gel column chromatography (eluent: chloroform/ethyl acetate=4/1) to obtain 55 mg of ethyl 8-(4-acetylaminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.[CH3:9][C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH2:21][CH2:22][C:23]1[S:24][C:25]([C:28](O)=[O:29])=[CH:26][N:27]=1>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:28]([C:25]1[S:24][C:23]([CH2:22][CH2:21][C:11]2[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][O:14][C:10]=2[CH3:9])=[N:27][CH:26]=1)=[O:29])([CH3:3])[CH3:2]
Reactant: Cc1onc(-c2ccccc2)c1CCc1ncc(C(=O)O)s1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1CCc1ncc(C(=O)NC(C)C)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a stirred solution of isopropylamine (75 mg, 1.27 mmol) in dioxane (5 mL) under argon and at room temperature was added trimethylaluminium (0.6 mL of a 2M solution in toluene, 1.2 ml). After 1 h, a solution of 2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (100 mg, 0.32 mmol) in dioxane (5 mL) was added and the reaction mixture warmed to 90° C. After 3 h, the reaction mixture was cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 3% methanol in dichloromethane) gave the title compound (78 mg, 69%) as a pale yellow oil. MS: m/e=356.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[N:16]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1ccccc1F
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1N1CCCCC1
Yield: 95.1 %

Procedure:
A mixture of o-fluorobenzaldehyde (1.24 gm, 10 mmol), potassium carbonate (2.76 gm, 20 mmol), and piperidine (1.7 gm, 20 mmol) was refluxed in dry DMF for 6 hrs. After the completion of reaction DMF was distilled out at vaccum and 5 ml of water was added to the residue and extracted the product with ethyl acetate (10 ml×2). Organic layer was dried over sodium sulphate and evaporated the solvent to afford 1.8 gm of product (8) (90.5%) 1HNMR CDCl3 (Spectrum 9): 1.68(m, 6H), 3.05(m, 4H), 7.05(m, 2H), 7.45(dd, 1H), 7.75(dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[C:12]([NH:16][C:17](=[O:31])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:19]=1)([CH3:15])([CH3:14])[CH3:13].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([NH:16][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:31])[CH2:30][CH2:29]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: Nc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(Cl)c3)CC2)c1
Yield: 94.1 %

Procedure:
4-Amino-3-chlorobenzoic acid (1.04 g, 6.06 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)-benzamide (888 mg, 3.22 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydro-chloride (1.742 g, 9.09 mmol) and triethylamine (1.23 g, 1.69 mL, 12.12 mmol) were combined and stirred in acetonitrile (20 mL) at room temperature overnight (under nitrogen). The reaction was concentrated under reduced pressure and the residue was diluted with dichloromethane (30 mL) and water. The organic layer was separated, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 4% methanol/dichloromethane) to afford the title compound (1.3 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=1.[Cl-].[CH:23]1([NH:26][C:27](=[O:39])[CH:28]([OH:38])[CH:29]([NH3+:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:25][CH2:24]1.ClCCl>CCCCC>[CH:23]1([NH:26][C:27](=[O:39])[CH:28]([OH:38])[CH:29]([NH:37][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[N:15][C:7]=2[N:5]2[CH:6]=[C:2]([F:1])[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4]2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:24][CH2:25]1
Reactant: [NH3+]C(Cc1ccccc1)C(O)C(=O)NC1CC1
Reactant: O=C(O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCC
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-n1cc(F)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting 2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinic acid and 4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-a minium chloride. The obtained crude product was treated with a mixture of dichloromethane and n-pentane gave 148 mg of the desired product; ESI-MS [M+H]+: 500.2.