Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:13]=[C:12]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:11]=1/[CH:37]=[CH:38]/[Si](C)(C)C>CN(C=O)C.O>[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:13]=[C:12]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:11]=1/[CH:37]=[CH:38]/[Cl:1]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(/C=C/[Si](C)(C)C)c(N)c2F)c1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(/C=C/Cl)c(N)c2F)c1F
Temperature: 50 °C
Reaction time: 24 h
Yield: 21.5 %

Procedure:
N-Chlorosuccinimide (NCS; 190 mg, 1.4 mmol, 2.0 equiv) was added to a stirred solution of (E)-benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-3-(2-(trimethylsilyl)vinyl)picolinate (350 mg, 0.70 mmol, 1.0 equiv) in DMF (7.0 mL) at 23° C. The homogeneous pale green solution was heated to 50° C. and stirred for 24 h. The cooled reaction mixture was diluted with water (400 mL) and extracted with Et2O (4×100 mL). The combined organic layers were dried (MgSO4), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to afford the desired product, (E)-benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-(2-chlorovinyl)-5-fluoropicolinate as a tan powder (70 mg, 22% yield): mp 133-135° C.; IR (thin film) 3486 (s), 3345 (s), 3215 (w), 3069 (w), 3037 (w), 2953 (w), 1719 (s), 1616 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.47-7.43 (m, 2H), 7.41-7.33 (m, 3H), 7.27 (m, 2H), 6.89 (d, J=14 Hz, 1H), 6.45 (d, J=14 Hz, 1H), 5.37 (s, 2H), 4.62 (br s, 2H), 3.97 (d, J=1 Hz, 3H); ESIMS m/z 465 ([M+H]+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][NH2:13].N1([O:25][S:26]([CH:29]([CH3:31])[CH3:30])(=O)=[O:27])C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[F:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][NH:13][S:26]([CH:29]([CH3:31])[CH3:30])(=[O:27])=[O:25]
Reactant: COc1ccc(C(C)(O)CN)c(F)c1
Reactant: CC(C)S(=O)(=O)On1nnc2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)(O)CNS(=O)(=O)C(C)C)c(F)c1
Temperature: 120 °C

Procedure:
2-(2-Fluoro-4-methoxy-phenyl)-2-hydroxy-propylamine hydrochloride was converted to the free base by partitioning between ethyl acetate and 1 M NaOH. The amine (1.0 g, 5.02 mmol) was combined with propane-2-sulfonic acid benzotriazol-1-yl ester (1.3 g, 5.52 mmol) in DMF (25 mL) and heated at 120° C. for 2 hr. then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and extracted with 1 M HCl. The organic layer was separated and washed with water and saturated NaCl, dried (MgSO4), filtered, and concentrated to a yellow oil which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][NH:15][C:14]2=[O:23])[CH2:9][CH2:8]1)=[O:6].I[CH3:31].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][N:15]([CH3:31])[C:14]2=[O:23])[CH2:11][CH2:12]1)=[O:6]
Reactant: COc1ccc(C(=O)N2CCC(N3C(=O)NCc4ccccc43)CC2)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCC(N3C(=O)N(C)Cc4ccccc43)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2,4-dimethoxybenzoylpiperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (100 mg, 2.53 mmol) from Example 35 in DMF (50 mL) was added Nail (16 mg of a 60% suspension in mineral oil, 0.40 mmol) followed by iodomethane (0.031 mL, 0.50 mmol). The reaction was stirred for 18 h at ambient temperature. More NaH (10 mg, 0.25 mmol) and iodomethane (0.031 mL, 0.50 mmol) were added and the reaction was stirred at ambient temperature for 24 h. The reaction was quenched by the addition of HOAc (0.2 mL) and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 90:10 EtOAc:hexanes as eluant. The title compound was obtained as an oil (45% yield). TLC: Rf =0.42 (97:3 CHCl3 :MeOH) HPLC (method A): retention time 8.53 min FAB MS: m/z 410 (M+ +H)
Reaction SMILES: [C:1]([NH2:5])(=[S:4])[CH2:2][CH3:3].Br[CH:7]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.C(N(CC)CC)C>C(#N)C>[CH2:2]([C:1]1[S:4][C:7]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:5]=1)[CH3:3]
Reactant: CCC(N)=S
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1nc(-c2ccc(OC)cc2)c(-c2cccnc2)s1
Yield: 84.2 %

Procedure:
In 40 ml of acetonitrile was dissolved 493 mg of thiopropionic acid amide. In the solution was suspended 2.15 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone. To the suspension was added dropwise slowly 0.78 ml of triethylamine while stirring. The mixture was stirred for 3 hours at a refluxing temperature, then the solvent was evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract was dried, then the solvent was evaporated off. The residue was recrystallised from ethyl acetate-isopropyl ether to yield 1.38 g (91%) of 2-ethyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole, m.p. 59°-60° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1.I[CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.CN(C=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:23][CH2:24][CH3:25])[CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccncc2)(c2cccc(O)c2)N=C1N
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1cccc(C2(c3ccncc3)N=C(N)N(C)C2=O)c1
Yield: 97.2 %

Procedure:
To a stirred solution of 2-amino-5-(3-hydroxyphenyl)-3-methyl-5-pyridin-4-yl-3,5-dihydro-4H-imidazol-4-one (0.13 g, 0.46 mmol) in acetone (20 mL) and DMF (1 mL) is added 1-iodopropane (0.07 mL, 0.69 mmol) and Cs2CO3 (1.50 g, 4.60 mmo). After refluxed for 1 hour, the solvent is evaporated and the crude material was purified by chromatography (silica gel, EtOAc/2M methanolic NH3: 97/3) to give the title compound (0.145 g, 97%) as a solid. mp: 173-175° C.; MS(+) ES: 325 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:25])=[O:23])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
A mixture of 1-methyl-5-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 422 μmol), morpholine (368 μl, 4.22 mmol), propylphosphonic anhydride (50% in ethyl acetate, 622 μl, 1.06 mmol) and N,N-diisopropylethylamine (215 μl, 1.27 mmol) in tetrahydrofuran (6 ml) was stirred for 18 hours at 70° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate, washed with water. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid (2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (109 mg, 60.8%) as a light yellow solid. mp: 194-197° C., MS: m/z=425.3 (M+H+).
Reaction SMILES: [CH3:1][C:2](=[N:4]O)[CH3:3].[H-].[Na+].[Cl:8][C:9]1[N:14]=[C:13](S(C)(=O)=O)[N:12]=[C:11]([NH:19][C@H:20]([C:22]([F:25])([F:24])[F:23])[CH3:21])[C:10]=1[C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:27]=1[F:34].O.C[N:37](C)C=O>>[Cl:8][C:9]1[N:14]=[C:13]([NH:37][N:4]=[C:2]([CH3:3])[CH3:1])[N:12]=[C:11]([NH:19][C@H:20]([C:22]([F:25])([F:24])[F:23])[CH3:21])[C:10]=1[C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:27]=1[F:34]
Reactant: CN(C)C=O
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Reactant: CC(C)=NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)=NNc1nc(Cl)c(-c2c(F)cc(F)cc2F)c(N[C@@H](C)C(F)(F)F)n1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
0.16 g (2.2 mmol) of acetone oxime was added to 0.065 g (2.4 mmol) of sodium hydride in 10 ml of dimethylformamide (DMF). The mixture was stirred at 20-25° C. for 1 hour, after which 1.0 g (2.2 mmol) of [6-chloro-2-methanesulfonyl-5-(2,4,6-trifluorophenyl)pyrimidin-4-yl]-((S)-1-trifluoromethylethyl)amine (abbr. sulfone 1) was added. After a further 14 hours of stirring at 20-25° C., the mixture was poured into water and extracted with dichloromethane. The combined organic phases were washed with water, then dried and finally freed from the solvent. This gave 0.6 g of the title compound of m.p. 157-159° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])=[CH:18][CH:17]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)NCc3ccc(F)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (5.0 g), 4-fluorobenzylamine (3.0 mL) and pyridine (3.5 mL) in dichloromethane (30 mL) was stirred at room temperature for 4 hours. The precipitate was filtered, washed with dichloromethane and dried to give 5.8 g (84%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid 4-fluoro-benzylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.Cl[CH2:12][CH:13]=O.C(=O)([O-])O.[Na+]>C(O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]2[N:3]([CH:12]=[CH:13][N:1]=2)[CH:4]=1)(=[O:7])[NH2:8]
Reactant: O=CCCl
Reactant: NC(=O)c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc2nccn2c1
Yield: 29.8 %

Procedure:
To 100 ml of ethanol are added 10 g of 6-aminonicotinamide, 11 g of 40% chloroacetaldehyde and 12.5 g of sodium hydrogen carbonate and the mixture is heated under reflux for 4 hours. Ethanol is evaporated off and 100 ml of water is added to the residue. The mixture is adjusted to pH 10 by adding 10% aqueous sodium hydroxide solution and then extracted four times with 50 ml portions of a mixture solvent of tetrahydrofuran-ethyl acetate (1:1). The extracts are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is recrystallized from a mixture solvent of methanol-diethyl ether to give 3.5 g of the above-identified compound as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.[CH3:20][C:21](O)=O.[BH3-][C:25]#N.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH:21]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:6]=3[CH:19]=2)[CH2:20][CH2:25]1
Reactant: CC(=O)O
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc(N)cc21
Reactant: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(NC3CC3)cc21
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
At room temperature, a methanolic solution (33 ml) of 6-amino-4-(3-methoxy-propyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (4.13 g, 15.6 mmol) is treated with AcOH (8.3 ml) and [(1-ethoxycycopropyl)-oxy]trimethylsilane (3.1 ml, 15.6 mmol), warmed to 70° C., stirred for 1.5 h under reflux. At the same temperature, to this mixture is added dropwise a methanolic solution (5.5 ml) of NaBH3CN (1.10 g, 17.5 mmol) over 5 min, and the resulting mixture is stirred at 70° C. under reflux for 2 h, and treated with CH2Cl2 (100 ml) and 5N NaOH (50 ml). After the separation of the both layers, the aq. layer is extracted with CH2Cl2 (3×30 ml). The combined org. layer is washed with brine (50 ml), dried (Na2SO4), and evaporated. A SiO2 flash chromatography (200 g, hexane/EtOAc 3:2) gives the title compound (3.03 g, 64%) as light yellow solid. Rf(hexane/EtOAc 3:2) 0.48. 1H-NMR (400 MHz, CDCl3) 0.47-0.54 (m, 2 H), 0.68-0.73 (m, 2 H), 1.55 (s), 1.88-1.96 (m, 2 H), 2.36-2.43 (m, 1 H), 3.34 (s), 3.44 (t, J=6.0), 3.97 (t, J=9.0), 4.09 (br. s), 6.45 (dd, J=9.0, 0.4), 6.53 (d, J=0.4), 6.80 (d, J=9.0). 13C-NMR (100 MHz, CDCl3) 169.2 (s), 144.3 (s), 135.5 (s), 129.6 (s), 118.1 (d), 107.9 (d), 99.9 (d), 77.2 (s), 70.1 (t), 58.7 (q), 39.2 (t), 27.6 (t), 25.7 (d), 23.6 (2q), 7.3 (2t).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:22][C:21]=3[C:38]([O:40]CC)=[O:39])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:44])[CH3:43])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:22][C:21]=3[C:38]([OH:40])=[O:39])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:44])[CH3:43])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nc(-c2ccc(C(F)(F)F)c3[nH]ccc23)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)C(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc(C(F)(F)F)c5[nH]ccc45)nc3C(=O)O)cc2)CC1(C)C

Procedure:
4-{4-[4-Ethoxycarbonyl-2-(7-trifluoromethyl-1H-indol-4-yl)-oxazol-5-yl]-phenyl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.2 g, 0.3 mmol) and NaOH (0.024 g, 0.6 mmol) in 5 mL of methanol, water and THF were stirred at 50° C. overnight. The organic solvent was removed in vacuo, the remaining solution adjusted to pH 5, and the resultant title compound was collected as a white solid by filtration, and dried under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:11])[C:4](=[S:10])[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:12](OCC)(OCC)(OCC)[CH2:13][CH3:14]>C(OC(=O)C)(=O)C>[CH2:13]([C:14]1[NH:9][C:7](=[O:8])[C:6]2[S:5][C:4](=[S:10])[N:3]([CH3:11])[C:2]=2[N:1]=1)[CH3:12]
Reactant: Cn1c(N)c(C(N)=O)sc1=S
Reactant: CCOC(CC)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCc1nc2c(sc(=S)n2C)c(=O)[nH]1
Yield: 65 %

Procedure:
The general procedure of Gewald, J. Prakt. Chem., 32, 26-30 (1966) was used to prepare 4-amino-3-methylthiazoline-2-thione-5-carboxamide, of which 27.3 g (0.14 mole) was suspended in a mixture of approximately 144 ml of acetic anhydride and about 144 ml of triethyl orthopropionate. The resultant mixture was refluxed for approximately one half hour, then cooled in an ice bath. The solid which precipitated was separated by filtration, washed with diethyl ether and dried in a vacuum oven at approximately 100° C. to provide 21.4 g (65%) of 5-ethyl-3-methyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2thione. Infrared spectral analysis confirmed the structural assignment.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CS(C)=O>[C:11]1([S:17]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1F
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
To a solution of 2-fluoro benzaldehyde (5.00 ml, 47.6 mmol) in dimethyl sulfoxide (45 ml) was added benzene sulfinic acid sodium salt (8.60 g, 52.4 mmol) and the resulting mixture heated to 100° C. Upon heating the sulfinic acid salt dissolved. The solution was heated at 100° C. for 3 days. The reaction was cooled to room temperature and water (50 ml) added. This mixture was extracted with ethyl acetate, the combined organic extracts were washed with saturated brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica eluting with 25% ethyl acetate:petroleum ether (40-60° C.) to 33% ethyl acetate:petroleum ether (40-60° C.) to give (4.12 g, 16.7 mmol, 35%). δH (300 MHz, d6-DMSO) 10.68 (1H, s, CHO), 8.26-8.17 (1H, m, Ar), 8.08-7.99 (2H; m, Ar), 7.99-7.89 (3H, m, Ar) and 7.80-7.62 (3H, m, Ar).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([OH:8])[CH3:7].[Cl:9][CH2:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].C(#N)C.CCOCC>CO>[Cl-:9].[OH:8][CH:6]([C:2]1[S:1][CH:5]=[CH:4][N+:3]=1[CH2:10][C:11](=[O:12])[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:7]
Reactant: CC(O)c1nccs1
Reactant: O=C(CCl)N1CCCC1
Solvent: CC#N
Solvent: CO
Solvent: CCOCC
Product: CC(O)c1scc[n+]1CC(=O)N1CCCC1
Product: [Cl-]
Reaction time: 6 h
Yield: 66.9 %

Procedure:
1-(2-Thiazolyl)ethanol (1.14 g, 8.8 mmole), N-chloroacetylpyrrolidine (1.30 g, 8.8 mmole), and acetonitrile (1.25 mL) were combined and heated at reflux in an oil bath at 105-110 C. for 6 hr. Acetonitrile (8 mL) was added and heating was continued 10 min. The cooled, clear solution was treated with ether (10 mL), causing an oil to separate, which crystalized on standing at room temp. overnight. Filtration and washing with 30% ether/acetonitrile gave 1.86 g crude product which was dissolved in methanol, decolorized, and evaporated to dryness. The residue was recrystalized from acetonitrile/ether and from methanol/acetonitrile/ether to yield 1.63 g of the title compound, mp 189-190 C. (dec.).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[H-].[Na+].[CH3:8][N:9]([CH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][CH:13]=1)[CH3:10]>CN(C)C=O.C(O)C>[CH3:8][N:9]([CH2:11][C:12]1[N:17]=[C:16]([S:5][CH2:4][CH2:3][NH2:2])[CH:15]=[CH:14][CH:13]=1)[CH3:10]
Reactant: NCCS
Reactant: CN(C)Cc1cccc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(C)Cc1cccc(SCCN)n1
Temperature: 80 °C
Yield: 44.2 %

Procedure:
Cysteamine hydrochloride (3.43 g, 0.030 mol) is added to a suspension of 60% sodium hydride in mineral oil (2.5 g, 0.0625 mol) in dry dimethylformamide (30 ml) and is warmed to 80° C. A solution of 6-dimethylaminomethyl-2-chloropyridine (5.0 g, 029.4 mol) in 30 ml of dry dimethylformamide is added dropwise and the reaction temperature is increased to 125° C. for 2 hours. The reaction is cooled, diluted with ethanol (60 ml) and the salts are removed by filtration before evaporating to dryness. This residue is dissolved in chloroform, washed with water and extracted into dilute hydrochloric acid. The acidic extract is neutralized with sodium carbonate and the product is extracted into chloroform, dried and evaporated to give 4.4 g. This residual oil is distilled to give 2.74 g of pure product, bp: 109°-114° C./0.25 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:26]=4)[CH2:21][CH2:20]3)=[O:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCC3)CC2)c1

Procedure:
Example 58 was prepared from 1-(4-chloro phenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propan amide according to the procedures described in Scheme 10: ESMS m/e: 482.3 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17]O)[CH2:15][S:16][C@H:11]12)=[O:8].[SH:24][C:25]1[N:29]([CH3:30])[N:28]=[N:27][N:26]=1.P(OC)(OC)OC.Cl>C(OCC)(=O)C.O.CCOCC>[CH3:30][N:29]1[C:25]([S:24][CH2:17][C:14]2[CH2:15][S:16][C@@H:11]3[C@H:10]([NH:9][C:7](=[O:8])[CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[C:22](=[O:23])[N:12]3[C:13]=2[C:19]([OH:21])=[O:20])=[N:26][N:27]=[N:28]1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: Cn1nnnc1S
Agent: COP(OC)OC
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 118.6 %

Procedure:
To 582 mg of 7β-[2-(2-thienyl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid and 174 mg of 5-mercapto-1-methyl-1H-tetrazole was added 12 ml of ethyl acetate to make a solution. To the solution were added in sequence 0.25 ml of trimethyl phosphite and 0.2 ml of ether solution of hydrogen chloride (5mol/l), and the mixture was stirred at 20 to 25° C. for 3hours. To the reaction solution was added 10 ml of water, whose pH was adjusted to 2 with 2N HCl, which was then allowed to form two layers. The aqueous layer was taken, to which was added 10 ml of ethyl acetate. The mixture was allowed to form two layers. The organic layers were combined and washed with 5 ml of aqueous saline, which was dried over anhydrous magnesium sulfate, which was then concentrated under reduced pressure. To the concentrate was added ether, then precipitating powdery product was collected by filtration, washed and dried to give 804 mg (yield: 89%) of 3-(1-methyl-1H-tetrazol-5-yl) thiomethyl-7β-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid.
Reaction SMILES: [C:1]1([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]4)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:27](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:27][N:19]1[C@H:20]2[C@@:15]([CH3:24])([C:14]3[CH:25]=[CH:26][C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)=[CH:12][C:13]=3[CH2:22][CH2:21]2)[CH:16]=[CH:17][C:18]1=[O:23]
Reactant: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)C=C[C@]2(C)c3ccc(-c4cccc5ccccc45)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(1-naphthyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one (22 mg, 0.065 mmol), 0.20 mL of t-butanol, and potassium t-butoxide (22 mg, 0.19 mmol). Methyl iodide (0.012 mL, 0.19 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 16 mg (70%) of the title compound as a yellow solid, upon trituration from diethyl ether/hexanes. mp 172°-173°. FDMS: m/e=353.