Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:8]=1.Cl.CN(C)CCCN=C=NCC.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[S:38]([NH2:41])(=[O:40])=[O:39]>CN(C)C1C=CN=CC=1.C(O)(C)(C)C.ClCCl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[S:38]([NH:41][C:12]([C:10]1[N:11]=[C:6]2[CH:5]=[N:4][C:3]([C:2]([F:1])([F:16])[F:15])=[CH:8][N:7]2[CH:9]=1)=[O:14])(=[O:40])=[O:39]
Reactant: O=C(O)c1cn2cc(C(F)(F)F)ncc2n1
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)ncc3n2)c1
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
To the product of Step B (120 mg, 0.52 mmol) was added a solution of 4-(dimethylamino)pyridine (183 mg, 1.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (248 mg, 1.3 mmol) in t-butanol (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred for 15 minutes, 2-chloro-5-methoxybenzenesulfonamide (92 mg, 0.41 mmol) was added, and stirring was continued at room temperature overnight. Dichloromethane (100 mL) was then added, the mixture was washed with 1 N hydrochloric acid (3×100 mL), and the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether and dried to afford. 89 mg of the title compound, a compound of this invention, as a white solid, m.p. 236-237° C. 1H NMR (CDCl3) δ 9.99 (br s, 1H), 9.23 (s, 1H), 8.56 (s, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.37 (d, 1H), 7.10 (dd, 1H) 3.91 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][NH:5][C:6](=[O:15])[C:7]1[CH2:8][C:9](Cl)([Cl:13])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+].[ClH:19]>>[Cl:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[Cl:19])[C:6]([NH:5][CH2:4][C:3]([OH:2])=[O:16])=[O:15]
Reactant: COC(=O)CNC(=O)C1=CC=CC(Cl)(Cl)C1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
(3,3-Dichlorobenzoylamino)acetic acid methyl ester (25.91 g, 100 mmol, 1.0 eq., see step (a) above) was added to the flask followed by aqueous sodium hydroxide (1 M, 198 mL, 200 mmol, 2.0 eq.). The mixture was heated to 50° C. using an oil bath for 2 hours. On cooling, a white precipitate formed. The mixture was cooled further to 5° C. using an ice/water bath. Concentrated hydrochloric acid (60 mL) was added very slowly to the cooled solution, ensuring that the temperature did not rise above 10° C. The mixture was stirred for 10 minutes and was then filtered. The white solid was air dried for 15 minutes and then dried in vacuo at 40° C. for 16 hours to give an off-white solid (19.15 g, 78%).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].C(N(CC)CC)C>O>[CH3:5]/[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH:2]=[O:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Temperature: -65 °C
Reaction time: 0.42 h
Yield: 100 %

Procedure:
A solution of oxalyl chloride (4.68 g, 0.037 mol) in dry CH2Cl2 under argon atmosphere was cooled to -65° C. A solution of 5.33 mL of dimethyl sulfoxide (DMSO) (0.68 mol) in CH2Cl2 (17 mL) was added rapidly, dropwise, to the cooled oxalyl chloride solution. After stirring for 7 minutes at -65° C., a 10 mL CH2Cl2 solution of (E,E)-farnesol (7.0 g, 0.032 mol) was added over 10 minutes to the reaction solution at -65° C.: a precipitate formed upon the addition of approximately half of the farnesol solution. After the addition of the farnesol solution was completed, the reaction was stirred at -65° C. for 25 minutes, and then 22.4 mL (0.16 mol) of triethylamine was added over 10 minutes. After stirring for an additional 15 minutes at -65° C., the reaction was warmed to room temperature, and then diluted with water (~200 mL). The resulting aqueous layer was extracted several times with CH2Cl2. The combined organic layers were washed once with saturated aqueous NaCl solution, once with 1% HCl, once with 5% Na2CO3 solution and once with saturated aqueous NaCl solution. The resulting organic layer was dried over MgSO4 to give 7.05 g (100%) of a clear oil after filtration and solvent removal.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]2)=[CH:17][CH:16]=1.O>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:13])[NH:14][C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(N=C=S)cc1
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(NC(=S)Nc2ccc3c(c2)NC(=O)CC3)cc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
A mixture containing 1.92 g of 4-acetamidophenylisothiocyanate and 1.62 g of 7-amino-3,4-dihydro-2(1H)quinolone in 10 ml of DMF was stirred for 6 h at 20° C. Water was added and the product filtered and washed with water. Yield 85%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[CH3:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:25][CH2:24]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Yield: 97 %

Procedure:
Method 1 was followed using 3-fluoro-4-nitrotoluene (1.0 eq), 4-(N-Boc-amino) piperidine (1.2 eq), and TEA (2.0 eq) at 55° C. for 48 hours yielding tert-butyl 1-(5-methyl-2-nitrophenyl)piperidin-4-ylcarbamate (97%). LCMS (m/z): 336.1 (MH+); LC Rt=3.32 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][O:16][CH3:17])[CH:7]=[C:6]2[C:18]1[N:26](S(C2C=CC(C)=CC=2)(=O)=O)[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][O:16][CH3:17])[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1
Reactant: COCCn1cc(-c2cc3cccnc3n2S(=O)(=O)c2ccc(C)cc2)c2cc(OC)c(OC)cc21
Agent: [K+]
Agent: [OH-]
Product: COCCn1cc(-c2cc3cccnc3[nH]2)c2cc(OC)c(OC)cc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 34.2 %

Procedure:
0.080 g of 2-[5,6-dimethoxy-1-(2-methoxyethyl)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is added, at a temperature in the region of 20° C., to a solution of 3.1 ml of methanolic potassium hydroxide (0.1 g/ml; 1.78M). The reaction medium is agitated at this same temperature for 5 hours. The reaction medium is then heated at 50° C. for 4 hours. After cooling, the solid formed is filtered off through sintered glass, washed twice with 3 ml of methanol, and then 5 times with 5 ml of water. The solid is dried in an oven (35° C.) under vacuum. 0.019 g of 2-[5,6-dimethoxy-1-(2-methoxyethyl)-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine is thus obtained, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:22][CH3:23])[C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11].C([Li])CCC.Cl.[C:30](OCC)(=[O:32])C>C1COCC1>[CH3:23][O:22][C:4]1[CH:3]=[C:2]([CH:19]=[C:6]([CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[C:5]=1[O:20][CH3:21])[CH:30]=[O:32]
Reactant: CCOC(C)=O
Reactant: COc1cc(Br)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Reaction time: 0.25 h

Procedure:
To a solution of the 3.616 g of (5-bromo-2,3-dimethoxybenzyloxy)triisopropylsilane in 60 ml of THF there was added dropwise 3.6 ml of n-butyllithium (2.66 M, hexane solution) at −78° C. under a nitrogen atmosphere. After stirring for 15 minutes, 2 ml of N-follnylmorpholine was added and the mixture was stirred at room temperature for 20 minutes. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.605 g) as an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)O1.Br[C:21]1[N:25]=[CH:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[CH:28][CH:27]=2)[N:22]=1.C([O-])(O)=O.[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:39][C:33]([F:38])([O:32][C:29]1[CH:30]=[CH:31][C:26]([N:23]2[CH:24]=[N:25][C:21]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)=[N:22]2)=[CH:27][CH:28]=1)[C:34]([F:37])([F:36])[F:35]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FC(F)(F)C(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A microwave vial was charged with methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (147 mg, 0.561 mmol), 3-bromo-1-(4-(pentafluoroethoxy)phenyl)-1H-1,2,4-triazole (200 mg, 0.559 mmol), NaHCO3 (94 mg, 1.2 mmol), and Pd(PPh3)4 (39 mg, 0.034 mmol). Dioxane (3.8 mL) and water (1.2 mL) were added, the reaction vial was capped, and the reaction was heated at 140° C. for 30 min in a Biotage Initiator® microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to RT, and allowed to stand overnight. A white solid formed, which was filtered and air-dried to give the title compound as a white solid (146 mg, 62%): mp 192-195° C., 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.28 (d, J=9.0 Hz, 2H), 8.19-8.12 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 7.45-7.38 (m, 2H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −85.90, −87.86; ESIMS m/z 414 ([M+H])+.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([OH:27])[C@H:6]1[O:11][C@H:10]([O:12][C@:13]2([CH2:22][OH:23])[O:17][C@H:16]([CH2:18][OH:19])[C@@H:15]([OH:20])[C@@H:14]2[OH:21])[C@H:9]([OH:24])[C@@H:8]([OH:25])[C@@H:7]1[OH:26]>O>[CH2:3]=[CH:2][CH2:1][O:27][CH2:5][C@H:6]1[O:11][C@H:10]([O:12][C@:13]2([CH2:22][OH:23])[O:17][C@H:16]([CH2:18][OH:19])[C@@H:15]([OH:20])[C@@H:14]2[OH:21])[C@H:9]([OH:24])[C@@H:8]([OH:25])[C@@H:7]1[OH:26]
Reactant: C=CCBr
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: C=CCOC[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
86 g of ion exchange water and 40 g (1 mole) of sodium hydroxide were added to a 1 L four-necked separable flask equipped with a stirrer, a reflux condenser and a dropping funnel to dissolve the sodium hydroxide in the ion exchange water. 68.4 g (0.2 moles) of sucrose was further added, and reacted at 80° C. for 90 minutes while stirring to obtain an alkaline sucrose aqueous solution. 121 g (1 mole) of allyl bromide was added dropwise into the alkaline sucrose aqueous solution for 2 hours while controlling rapid heating caused by an etherification reaction Thereafter, the etherification reaction was completed by aging the reaction solution at 80° C. for 3 hours. After cooling, 400 g of ion exchange water was added to the reaction solution taken from the separable flask, and unwanted oils were removed to obtain 700 g of a crude sucrose allyl ether aqueous solution. Hydrochloric acid was further added to adjust a pH value to 7, and the aqueous solution was then concentrated to 240 g using a rotary evaporator. Salts, such as sodium bromide and the like, which were by-products, were removed from the aqueous solution by adding 200 g of ethanol, followed by performing precipitation and filtration. Subsequently, 88 g of purified water-soluble sucrose allyl ether was obtained by distilling an excessive amount of water from the aqueous solution using a rotary evaporator. Here, the etherification degree of the water-soluble sucrose allyl ether was 2.8.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][O:14][C:13]1[CH:12]=[C:11]([CH:19]=[CH:18][C:16]=1[O:17][CH2:2][CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[CH:10]=[O:9]
Reactant: C[Si](C)(C)CCCCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCC[Si](C)(C)C
Temperature: 50 °C
Yield: 89.1 %

Procedure:
3-Chloropropyltrimethylsilane (33.14 g, 0.22 mol) was added dropwise over the course of 20 minutes into a mixture of vanillin (30.4 g, 0.2 mol) and potassium carbonate (30.4 g, 0.22 mol) in 150 ml of dry dimethylformamide (DMF) heated to 50° C. under nitrogen. The mixture was maintained for 4 hours at 95°-110° C. The reaction mixture was cooled and poured into ice water. The aqueous phase was extracted 3 times with dichloromethane. The organic phases were dried over sodium sulfate and concentrated in vacuo. After distillation in vacuo (0.04 mm Hg), 47.5 g (yield: 89%) of 3-methoxy-4-(3-trimethylsilanylpropyloxy)benzaldehyde were obtained in the form of a slightly pink oil distilling at 112°-114° C. and employed as such in the following step (b).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:3][C:2]=1[C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:17].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[N+:1]1([O-:33])[C:2]([C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])=[CH:3][C:4]([C:7]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(OC1CCCCC1)c1ccnc(C(=O)OC2CCCCC2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=C(OC1CCCCC1)c1cc[n+]([O-])c(C(=O)OC2CCCCC2)c1

Procedure:
From 1 g of dicyclohexyl pyridine-2,4-dicarboxylate and 0.75 g of MCPBA.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCC(OS(C)(=O)=O)CC2)cc1
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
To a solution of ethyl 4-(4-hydroxypiperidin-1-yl)benzoate (8.0 g, 32.1 mmol) in CH2Cl2 (200 mL) was added Et3N (23 mL, 165 mmol) under nitrogen, followed by MsCl (5.6 g, 48.9 mmol). The mixture was stirred for 5 minutes, washed with water (300 mL), dried over anhydrous MgSO4, filtered, and concentrated to afford ethyl 4-(4-(methylsulfonyloxy)piperidin-1-yl)benzoate as a tan solid (10.5 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7](C(F)(F)F)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:28])[C@@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClC1C=C([F:36])C=CC=1CN>>[Cl:1][C:2]1[CH:7]=[C:6]([F:36])[CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:28])[C@@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1Cl)[C@@H]1CCC(=O)N1Cc1ccccc1
Reactant: NCc1ccc(F)cc1Cl
Product: O=C(NCc1ccc(F)cc1Cl)[C@@H]1CCC(=O)N1Cc1ccccc1

Procedure:
N-[(2-chloro-4-fluorophenyl)methyl]-5-oxo-1-(phenylmethyl)prolinamide was prepared in an analogous manner to that described for the synthesis of N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-5-oxo-1-(phenylmethyl)prolinamide (Example 92) above but using [(2-chloro-4-fluorophenyl)methyl]amine in the place of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[C:12]4[C:13]([C:18](=[O:19])[C:4]2=[CH:3][CH:2]=1)=[N:14][CH:15]=[C:16](Br)[C:11]=4[CH:10]=[CH:9][N:8]=3.[N-:20]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH:1]1[CH:6]=[C:5]2[C:7]3[C:12]4[C:13]([C:18](=[O:19])[C:4]2=[CH:3][CH:2]=1)=[N:14][CH:15]=[C:16]([NH2:20])[C:11]=4[CH:10]=[CH:9][N:8]=3
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2-c2nccc3c(Br)cnc1c23
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1cnc2c3c(nccc13)-c1ccccc1C2=O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 4-bromosampangine (622 mg, 2.0 mmol) in acetone (40 mL) and sodium azide (1.30 g, 20.0 mmol) in H2O (10 mL) was heated at reflux for 1 h. The acetone was then removed by evaporation, MeOH (40 mL) added, and the mixture transferred to a three necked flask and cooled to 10° C. Piperidine (2 drops) was added and a stream of hydrogen sulfide bubbled through the reaction. After 30 min, the temperature was allowed to rise to 23° C. and the reaction continued for an additional 30 min. The solvent was then removed evaporated and the residue chromatographed as above to give 4-aminosampangine (23) (450 mg, 91%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][N:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: COc1cc(C=O)ccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc(C=C2N=C(c3cccs3)OC2=O)ccn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
A mixture of N-(2-thienylcarbonyl)glycine (454 mg, 2.45 mmol), 2-methoxy-4-pyridinecarboxaldehyde (370 mg, 2.7 mmol), sodium acetate (201 mg, 2.45 mmol) and acetic anhydride (3.0 mL) was stirred at 90° C. for 3 hours in a sealed tube. Thereafter, the temperature of the reaction solution was returned to room temperature, and water (15 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1 hour. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (50 mL) and was then dried under reduced pressure, so as to obtain 572 mg of the above-captioned compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([OH:8])[CH2:5][N:4]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[C:9]([N:4]1[CH2:5][C@H:6]([O:8][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:7][C@H:3]1[CH2:2][O:1][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)(=[O:27])=[O:26])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)N1C[C@@H](O)C[C@@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To an ice-cold solution of 150 g (596.9 mmol) of (2R,4S)-2-hydroxymethyl-4-hydroxy-N-(carbobenzyloxy)-pyrrolidine in 0.5 l of pyridine was added 250 g (1.32 mol) of 4-toluenesulfonyl chloride in 3 portions to keep the temperature of the reaction below 15° C. for 1 hour and then warmed to room temperature. After 12 hours, an additional 125 g (656 mmol) of p-toluenesulfonyl chloride was added and the mixture was allowed to stir at room temperature for 16 additional hours. The mixture was then cooled with an ice bath and 3 l of 10% aqueous HCl solution was carefully added. The mixture was extracted with 2×250 ml of methylene chloride and dried over MgSO4. Evaporation of the solvent provided 274 g of the product as an oil (82% yield). NMR(CDCl3): 7.70 & 7.40 (m,9H, aromatic), 5.0 (m,3H), 4.43 (dd,1H), 4.12 (m,1H), 4.02 (m,H), 3.70 (m,1H), 3.88 (m,1H), 2.42 (m,6H), 2.15 (m,2H).
Reaction SMILES: ClP([N:5]=[C:6]=[O:7])(Cl)=O.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1/[C:13](=[N:31]/[O:32][CH3:33])/[C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][OH:25])[CH2:22][S:23][C@H:18]12)=[O:15].C([O-])(=O)C.[Na+]>C1COCC1.O>[CH3:33][O:32]/[N:31]=[C:13](\[C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][O:25][C:6]([NH2:5])=[O:7])[CH2:22][S:23][C@H:18]12)=[O:15])/[C:9]1[O:8][CH:12]=[CH:11][CH:10]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Reactant: O=C=NP(=O)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.25 h

Procedure:
Dichlorophosphinyl isocyanate (1.46 ml,) was added to a solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in THF (50 ml) at 22°, the temperature rising to 31°. The reaction mixture was stirred for 15 minutes and then added to a solution of sodium acetate (5.72 g) in water (50 ml). More sodium acetate (1.64 g) was added over 10 minutes to give a stable pH of 4.6. This solution was stirred at 30° for 1 hour and then heated at 45° for 3.5 hours when TLC (as Example 3) showed the reaction to be complete. The solution, pH 4.6, was clarified by filtration, adjusted to pH 7.0 with aqueous NaHCO3 solution and washed twice with ethyl acetate. The aqueous phase was stirred and acidified to pH 1.9 with dilute hydrochloric acid to precipitate the title compound (2.80 g, 66.0%); purity by HPLC 95.8% and by TLC 96%.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([OH:29])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)[C:31](Cl)=[O:32]>C(Cl)Cl>[OH:32][CH2:31][C:27](=[O:29])[CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCOc1ccccc1CC(=O)O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1CC(=O)CO
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of about 50 g of 2-(octadecyloxy)phenyl acetic acid in about 400 ml of methylene chloride was added about 19.6 g of oxalylchloride. After stirring about 3 hours the solvent was removed and the residue was dissolved in hexane and filtered through celite. The hexane was removed and to the residue was added about 79.5 g of tris-trimethylsilyloxyethylene. This mixture was stirred at about 90°-95° C. for 1.5 hours, then the oil was poured into a mixture of about 30 ml of concentrated (about 12N) hydrochloric acid, about 170 ml of water and about 200 ml of tetrahydrofuran and stirred at reflux for about 1/2 hour. The tetrahydrofuran was removed and the residue was extracted with ether. The ether extract was washed with dilute sodium bicarbonate, then brine and dried. The solvent was removed and the residue recrystallized from hexane, giving about 31 g of the desired title compound as a white solid, mp 59°-60° C.