Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:2]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21].O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([NH:12][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[N:9][N:8]=2)[CH:2]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1nnc(-c2cccnc2)o1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nnc(-c2cccnc2)o1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 5-pyridin-3-yl-1,3,4-oxadiazol-2-ylamine (1.00 g, 6.17 mmol) and pyridine (1.47 ml, 18.5 mmol) in tetrahydrofuran (20 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.70 ml, 12.3 mmol), and the mixture was stirred at room temperature for 1.5 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.13 g (54.5%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:18]([OH:20])=O)=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH3:22])([CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:39]1(OC(N(C)C)=[N+](C)C)[C:43]2[N:44]=CC=C[C:42]=2N=N1.ONC(=N)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:18]3[O:20][N:44]=[C:43]([CH3:42])[N:39]=3)=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH3:21])([CH3:22])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cc(C(=O)O)c(Cl)cc21
Agent: CC(=N)NO
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(-c2cc3c(cc2Cl)N(C(=O)OC(C)(C)C)CC3(C)C)n1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 47.1 %

Procedure:
To 6-chloro-3,3-dimethyl-2,3-dihydro-indole-1,5-dicarboxylic acid 1-tert-butyl ester (0.067 g, 0.21 mmol) in DMF (1.03 mL) was added N,N-diisopropylethylamine (0.126 μL, 0.72 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.08 g, 0.21 mmol) at room temperature. After stirring for 10 minutes, N-hydroxyacetamidine (0.015 g, 0.41 mmol) was added and the reaction stirred for 18 h. DMF (3.44 mL) was added and the reaction heated to 120° C. for 3 h. Water was added and the mixture extracted with diethyl ether (3×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-60%, EtOAc in petrol 40-60) gave the title compound (36 mg). MS: [M+H]+=364.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C:12]2[C:7](=[C:8]([O:14]C)[C:9]([CH3:13])=[CH:10][CH:11]=2)[CH2:6][C@@H:5]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH3:25])[CH2:18][CH2:17]2)[O:4]1.B(Cl)(Cl)[Cl:37]>ClCCl>[ClH:34].[ClH:37].[NH2:1][CH2:2][C@H:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([CH3:13])=[CH:10][CH:11]=2)[CH2:6][C@@H:5]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH3:25])[CH2:18][CH2:17]2)[O:4]1
Reactant: ClB(Cl)Cl
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCN(CCC(C)NC(=O)c3ccc(Cl)cc3)CC1)O[C@H]2CN
Solvent: ClCCl
Product: Cc1ccc2c(c1O)C[C@@H](C1CCN(CCC(C)NC(=O)c3ccc(Cl)cc3)CC1)O[C@H]2CN
Product: Cl
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Cool a solution of N-{3-[4-((1R,3S)-1-aminomethyl-5-methoxy-6-methyl-isochroman-3-yl)-piperidin-1-yl]-1-methyl-propyl}-4-chloro-benzamide in anhydrous dichloromethane (4 mL) to −20° C., and add 6 equivalents of BCl3 (using 1M BCl3 in dichloromethane) slowly into the solution. Following complete addition, stir the reaction mixture at −20° C. for 2 hours and 0° C. for 1 hour. Cool again to −20° C. and quench with anhydrous CH3OH (0.5 mL). Allow the resulting solution to warm to room temperature and concentrate. Purify the crude product on a 2 g SCX column and then by chromatography on a 1 g silica gel column (eluted by 7N NH3 in methanol:ethyl acetate=1:10). Collect the appropriate fractions, concentrate and convert to the title compound with 2M HCl in diethyl ether. CIMS 486.2, tR (min)=2.30.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[C:12](OC(=O)CC)(=O)[CH2:13][CH3:14]>C(OCC)C>[CH2:13]([C:14]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1)[CH3:12]
Reactant: Nc1ccncc1S(N)(=O)=O
Reactant: CCC(=O)OC(=O)CC
Solvent: CCOCC
Product: CCC1=NS(=O)(=O)c2cnccc2N1
Temperature: 150 °C

Procedure:
A mixture of 1 g of 4-aminopyridine-3-sulfonamide (Preparation 2) and 10 cm3 of propionic anhydride is heated at 150° C. for 8 hours. After cooling, an equal volume of diethyl ether is added and the precipitate obtained is collected on a filter, washed with diethyl ether and dried. It is recrystallized from hot water.
Reaction SMILES: [I:1]([O-])(=O)=O.[K+].[C:6]([N:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[I-:27].[K+]>C(O)(=O)C>[I:27][C:18]1[CH:17]=[CH:16][C:15]2[N:14]([C:6](=[O:13])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:26]3[C:21]([C:20]=2[CH:19]=1)=[CH:22][C:23]([I:1])=[CH:24][CH:25]=3
Reactant: [I-]
Reactant: O=C(c1ccccc1)n1c2ccccc2c2ccccc21
Reactant: [O-][I+2]([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(c1ccccc1)n1c2ccc(I)cc2c2cc(I)ccc21

Procedure:
Potassium iodate (16.05 g, 75 mmol, available from Aldrich) is added in one portion to a stirred mixture of 9-benzoyl-9H-carbazole (34 mmol, available from Aldrich), potassium iodide (10.96 g, 66 mmol), and acetic acid (100 ml) at 80° C. The reaction mixture is stirred and heated for 1 hour. After the reaction was completed, the acetic acid is removed by distillation. The residue is dissolved in ethyl acetate and washed several times with water and sodium bicarbonate solution. The organic layer is dried over anhydrous magnesium sulfate, filtered, concentrated, and dried. The product is isolated and purified by conventional purification techniques such as recrystallization and chromatography.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][CH:35]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:36][CH:37]=O>>[CH3:34][CH:35]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:36][CH:37]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)CCCC(C)CC=O
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)CCCC(C)CC=CCc1ccccc1
Yield: 55.1 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.85 g, 8.61 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 5.4 mL, 8.61 mmol, 1.0 equiv.) and 3,7-dimethyloctanal (2.02 g, 12.9 mmol, 1.5 equiv.), 1.16 g (55%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>>[O:30]=[C:25]1[NH:26][C:27](=[O:29])[C:28](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:10]=3)=[CH:7][CH:8]=2)[S:24]1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(C=O)cc2)c1
Reactant: O=C1CSC(=O)N1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 91.4 %

Procedure:
In a manner similar to that of Example 1(f) by reacting 7.4 g (24 mmol) of tert-butyl (4′-formyl-biphenyl-3-ylmethyl)carbamate (prepared as in Example 1(e) from tert-butyl (3-bromo benzyl)carbamate)with 2.8 g (24 mmol) of 2,4-thiazolidine dione, 9 g (95%) of the expected product are obtained.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.O.Cl>C1COCC1.O>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:19])=[O:4])=[CH:7][CH:8]=2)[CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
LiOH (67 mg, 1.6 mmol) was added to a stirred solution 4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (124 mg, 0.73 mmol) in THF:H2O (1:1, 4 mL), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added and acidified it with 10% aqueous HCl and concentrated under reduced pressure to afford 116 mg (85.13% yield) of 4-(4-methyl-piperazin-1-yl)-benzoic acid. 1H NMR (DMSO-D2O): δ 7.8 (d, 2H), 7.0 (d, 2H), 3.4 (s, 4H), 2.8 (s, 4H), 2.4 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([N:5]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)[C:6](=[O:8])[O-:7])([CH3:4])[CH3:3].[Li][C:18]([CH3:21])([CH3:20])[CH3:19].CCCCC.[CH3:27][O:28][C:29](Cl)=[O:30].[Cl-].[NH4+]>O1CCCC1>[Cl:16][C:11]1[CH:12]=[C:13]([F:15])[C:14]([C:29]([O:28][CH3:27])=[O:30])=[C:9]([NH:5][C:6]([O:7][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:8])[CH:10]=1.[CH3:4][C:2]([N:5]([C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([F:15])[C:14]=1[C:29](=[O:30])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:6](=[O:7])[O-:8])([CH3:1])[CH3:3]
Reactant: CC(C)(C)N(C(=O)[O-])c1cc(F)cc(Cl)c1
Reactant: [Li]C(C)(C)C
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)C(=O)c1c(F)cc(Cl)cc1N(C(=O)[O-])C(C)(C)C
Product: COC(=O)c1c(F)cc(Cl)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 1,1-dimethylethyl(3-chloro-5-fluorophenyl)carbamate (7.34 g, 30 mmol) in tetrahydrofuran (200 mL, Aldrich) at −78° C. was slowly added tBuLi as a 1.7M solution in pentane (46 mL, 78 mmol, 2.6 equiv.). The resulting bright yellow solution was maintained at −78° C. for 3 hours, at which time methylchloroformate (3.02 mL, 39 mmol, Fluka) was added dropwise. After 45 minutes aqueous ammonium chloride (100 mL) was added and the reaction was warmed to room temperature. The organic layer was washed with brine, taken to a residue under reduced pressure, and purified by chromatography on SiO2 (10 to 30% ethyl acetate/hexanes) to afford methyl 4-chloro-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-fluorobenzoate as a pale yellow oil (6.4, 70% yield) as a roughly 5:1 mixture with 1,1-dimethylethyl[5-chloro-2-(2,2-dimethylpropanoyl)-3-fluorophenyl]carbamate which was removed in the subsequent step. 1H NMR (400 MHz, CDCl3) δ ppm 1.52 (s, 9 H), 3.95 (s, 3 H), 6.76 (d, J=2.20 Hz, 1 H), 6.78 (d, J=4 Hz, 1H) 8.31-8.34 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:16]O>>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:16])=[O:9]
Reactant: Nc1ccncc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnccc1N

Procedure:
A mixture of compound 4-aminopyridine-3-carboxylic acid (100 g, 0.7 mol) and concentrated sulfuric acid (400 g, 4.0 mol) in absolute methanol (1.5 L) was stirred under reflux for 24 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with ice-water (800 mL), basified with 2 N of aqueous solution of sodium hydroxide to about pH 10 and then extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with water (500 mL), dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]=[O:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].Br[C:37]1[CH:42]=[CH:41][C:40]([CH:43]([F:45])[F:44])=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]([C:37]1[CH:42]=[CH:41][C:40]([CH:43]([F:45])[F:44])=[CH:39][CH:38]=1)[OH:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: FC(F)c1ccc(Br)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(C(F)F)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole-3-carboxaldehyde obtained in Example 29-(1) and 1-bromo-4-difluoromethylbenzene were treated in a manner similar to Example 25-(2) to give crude 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indol-3-yl 4-(difluoromethyl)phenyl methanol, which was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]([N:4]([C:11]([C:13]1[S:14][C:15]2[CH2:16][CH2:17][O:18][C:19]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:20]=3[C:21]=2[N:22]=1)=O)[NH:5][C:6](=O)[CH2:7][O:8][CH3:9])([CH3:3])[CH3:2].C(O)(=O)C.C([O-])(=O)C.[NH4+:36]>O(Cl)Cl.[P+5]>[Br:27][C:25]1[CH:24]=[CH:23][C:20]2[C:21]3[N:22]=[C:13]([C:11]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH2:7][O:8][CH3:9])[N:36]=4)[S:14][C:15]=3[CH2:16][CH2:17][O:18][C:19]=2[CH:26]=1
Reactant: COCC(=O)NN(C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: ClOCl
Agent: [P+5]
Solvent: CC(=O)O
Product: COCc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
A suspension of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid N-isopropyl-N′-(2-methoxy-acetyl)-hydrazide (2.66 g, 5.86 mmol) in phosphorus (V) oxychloride (26 mL) was stirred at 100° C. for 18 h. The reaction mixture was concentrated in vacuo and the resultant residue azeotroped with toluene (×4) affording a brown solid. The solid was treated with acetic acid (26 mL) and ammonium acetate (4.51 g, 58.6 mmol) before the mixture was stirred at 125° C. for 1 h. A further addition of ammonium acetate (2.31 g, 30.0 mmol) was made and the reaction stirred at 125° C. for 2 h before being concentrated in vacuo. The resultant residue was diluted with water and extracted with DCM (×2) before the combined organic extracts were washed with saturated sodium bicarbonate solution followed by brine, then dried (Na2SO4) and concentrated in vacuo to give a pale brown solid. The solid was treated with phosphorus (V) oxychloride (26 mL) and stirred at 100° C. for 24 h before being concentrated in vacuo then treated with acetic acid (23 mL) and ammonium acetate (4.23 g, 55.0 mmol). The mixture was stirred at 125° C. for 1.5 h then concentrated in vacuo and azeotroped with toluene (×4). The resultant residue was diluted with water and extracted with DCM (×2) and the combined organic extracts were washed with saturated sodium bicarbonate solution followed by brine, then dried (Na2SO4) and concentrated in vacuo to give a brown solid. The solid was recrystallised from methanol/chloroform to give the title compound as a dark brown solid (1.17 g, 2.69 mmol, 46%). LCMS RT=4.97 min, [M+H]+=435/437. 1H NMR 400 MHz (DMSO-d6) δ: 8.23 (1 H, d, J=8.58 Hz), 7.36 (1 H, dd, J=8.58, 2.10 Hz), 7.26 (1 H, d, J=2.07 Hz), 5.72-5.71 (1 H, m), 4.39 (2 H, s), 4.35 (2 H, t, J=5.02 Hz), 3.39 (2 H, t, J=5.02 Hz), 3.29 (3 H, s), 1.49 (6 H, d, J=6.59 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1cc(C)cc(C)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1cc(C)cc(C)c1

Procedure:
prepared by reaction of 3-chloro-3-(3,5-dimethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.97 min; [M+H]+=262.3.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:45][C:46]([O:48][CH2:49][C:50]1[CH2:59][S:58][C@@H:53]2[C@H:54]([NH2:57])[C:55](=[O:56])[N:52]2[C:51]=1[C:60]([OH:62])=[O:61])=[O:47]>O1CCCC1.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:57][CH:54]2[C:55](=[O:56])[N:52]3[C:51]([C:60]([OH:62])=[O:61])=[C:50]([CH2:49][O:48][C:46](=[O:47])[CH3:45])[CH2:59][S:58][C@H:53]23)=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: -20 °C
Yield: 88.7 %

Procedure:
A mixture of 801 mg of 2-tritylamino-4-thiazolyl-acetic acid, 10 ml of dry tetrahydrofuran and 2 ml of 1M solution of N-methyl-morpholine in tetrahydrofuran was stirred and cooled to -20° C and 2 ml of a 1M solution of isobutyl chloroformate in tetrahydrofuran were slowly added thereto. The mixture was stirred and then a solution of 544 mg of 7-amino-cephalosporanic acid in 24 ml of a 1 M solution of N-methyl-morpholine in tetrahydrofuran and 10 ml of water was added thereto. The mixture was stirred with reheating and the solvent was evaporated. The residue was diluted with water and 2 ml of 2N hydrochloric acid were added. The mixture was vacuum filtered to obtain 1.16 g of 7-[2-(2-tritylamino-4-thiazolyl)-acetamido]-3-acetoxy methyl-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=O)(C)(C)C.C1C=CC(/C(/C2C=CC([N+]([O-])=O)=CC=2)=N/O)=CC=1.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[S:50]1[CH:54]=[CH:53][CH:52]=[C:51]1[CH2:55][NH2:56]>>[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40]([N:8]2[CH2:12][CH2:11][S:10][CH:9]2[C:13]([NH:56][CH2:55][C:51]2[S:50][CH:54]=[CH:53][CH:52]=2)=[O:15])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCc1cccs1
Agent: O=[N+]([O-])c1ccc(/C(=N\O)c2ccccc2)cc1
Product: O=C(NCc1cccs1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and 2-thienylmethanamine, the title compound was obtained in 94% purity by HPLC.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11](=[O:24])/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CS(C)=O>O1CCOCC1>[O:24]=[C:11]1[C:10]2[C:2](=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=[CH:8][CH:9]=2)[O:1][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[CH:12]1
Reactant: O=C(O)c1cccc(C(=O)/C=C/c2cccc(C(F)(F)F)c2)c1O
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Yield: 69.8 %

Procedure:
A mixture of (E)-2-hydroxy-3-(3-(3-(trifluoromethyl)phenyl)acryloyl)benzoic acid 34 (0.8 g, 2.4 mmol), SeO2 (0.79 g, 7.1 mmol) and DMSO (5 mL) in dioxane (150 mL) was heated at reflux for 1 h. The black solid was filtered and the dioxane was evaporated. The remaining oil was suspended in H2O, filtered and dried to give 35 (0.56 g, 76% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:18]=[CH:17][C:13](C(O)=O)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.CN1CC[N:23]([C:26](C2C=CC(C(N=[N+]=[N-])=O)=CC=2)=[O:27])CC1.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:51]=[C:50]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[C:49]3=[CH:58][C:59]([CH2:61][N:62]([CH3:64])[CH3:63])=[CH:60][N:48]3[N:47]=2)=[CH:42][CH:41]=1>>[CH3:63][N:62]([CH2:61][C:59]1[CH:58]=[C:49]2[N:48]([CH:60]=1)[N:47]=[C:46]([C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:26]([NH:23][C:13]3[CH:12]=[CH:11][C:10]([C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[O:9])=[CH:18][CH:17]=3)=[O:27])=[CH:41][CH:42]=1)[N:51]=[C:50]2[N:52]1[CH2:53][CH2:54][O:55][CH2:56][CH2:57]1)[CH3:64]
Reactant: CN1CCN(C(=O)c2ccc(C(=O)N=[N+]=[N-])cc2)CC1
Reactant: CN1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Product: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)N5CCN(C)CC5)cc4)cc3)nn2c1
Yield: 15.1 %

Procedure:
According to the general methods described in example 13, 4-(4-methylpiperazine-1-carbonyl)benzoic acid was used as starting material, and the resulting 4-(4-methylpiperazine-1-carbonyl)benzoyl azide reacted with 13a to give a white solid (9 mg, 15.1%). 1H NMR (300 MHz, DMSO-d6): δ 9.63 (br, s, 2H), 8.16 (d, J=8.9 Hz, 2H), 7.92 (s, 1H), 7.57 (d, J=8.9 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.13 (s, 1H), 4.07 (br, s, 6H), 3.80 (br, s, 4H), 3.51 (br, s, 4H), 3.06 (br s, 2H), 2.55 (s, 6H), 2.38 (br s, 2H), 2.24 (s, 3H). ESI-MS: 598 (M+1).
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]([CH3:15])[CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:23]1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC.C(Cl)Cl>[CH3:15][N:8]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:6]([C:5]1[CH:16]=[CH:17][C:2]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:23]2)=[N:3][C:4]=1[S:18][CH2:19][CH2:20][CH3:21])=[O:7]
Reactant: COC(=O)C[C@@H]1CCCNC1
Reactant: CCCSc1nc(Cl)ccc1C(=O)N(C)C1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Solvent: ClCCl
Product: CCCSc1nc(N2CCC[C@@H](CC(=O)OC)C2)ccc1C(=O)N(C)C1CCOCC1
Yield: 57 %

Procedure:
6-chloro-N-methyl-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (0.398 g, 1.21 mmol) was added to (S)-methyl 2-(piperidin-3-yl)acetate.HCl (0.353 g, 1.82 mmol) and potassium carbonate (0.753 g, 5.45 mmol) in butyronitrile (3 mL) was heated at 150° C. for 4 hours. The reaction mixture was diluted with DCM (60 mL), and washed sequentially with water (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford methyl [(3S)-1-{5-[methyl(tetrahydro-2H-pyran-4-yl)carbamoyl]-6-(propylthio)pyridin-2-yl}piperidin-3-yl]acetate (0.310 g, 57%) as a white solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([S:17](Cl)(=[O:19])=[O:18])[CH:13]=[CH:12]2)(=[O:3])[CH3:2].C([N:23](CC)CC)C.[OH-].[NH4+]>C(Cl)Cl>[NH2:23][S:17]([C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CC(=O)NCCc1cccc2ccc(S(=O)(=O)Cl)cc12
Reactant: CCN(CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)NCCc1cccc2ccc(S(N)(=O)=O)cc12
Reaction time: 2 h

Procedure:
0.8 mmol of the compound obtained in Step B is dissolved in 10 ml of CH2Cl2 and then 1.2 mmol of triethylamine are added. The mixture is cooled with the aid of an ice bath and 1.2 mmol of ammonium hydroxide solution are added dropwise. After stirring for 2 hours, the mixture is evaporated and the residue obtained is recrystallised.