Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[S:11][C:12]([CH:15]3[CH2:18][CH2:17][CH2:16]3)=[CH:13][N:14]=2)C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]2>O1CCOCC1>[CH:15]1([C:12]2[S:11][C:10]([NH:9][C:8]([NH:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]4)=[O:19])=[N:14][CH:13]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: O=C(Nc1ncc(C2CCC2)s1)Oc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc2cc(NC(=O)Nc3ncc(C4CCC4)s3)ccc2n1
Yield: 92.3 %

Procedure:
A solution of (5-cyclobutyl-thiazol-2-yl)-carbamic acid phenyl ester (Example 2; 35 mg, 0.128 mmol) and 6-amino-2-methyl-quinoline (50 mg, 0.128 mmol) in 1,4-dioxane (500 μl) were heated at about 70° C. for 24 hours. Purification by silica gel chromatography (1:3 hexanes-ethylacetate; 40:1→20:1 chloroform-methanol) and subsequent conversion to the HCl salt afforded 40 mg of the title compound. 1HNMR (400 MHz, CDCl3) δ 8.11(s,1H), 7.87 (s,7.88,1H), 7.85 (s,1H), 7.45 (d, J=7.6 Hz,1H), 7.16 (d, J=8.4 Hz, 1H), 6.94 (s,1H), 3.55 (m,1 H), 2.67 (s,3H), 2.35 (m,2H), 2.15-1.80 (m,4H). LRMS m/z (APCl+) 339.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[C@@H:16]2[O:17][C:18]([CH3:21])([CH3:20])[O:19][C@@H:15]2[C@@H:14]([OH:22])[CH2:13][N:12]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:49]([O-])(=[O:51])[CH3:50].[Cs+].C1OCCOCCOCCOCCOCCOC1>C(Cl)Cl.N1C=CC=CC=1.C(#N)C.C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([C@H:11]1[C@@H:16]2[O:17][C:18]([CH3:21])([CH3:20])[O:19][C@@H:15]2[C@H:14]([O:22][C:49](=[O:51])[CH3:50])[CH2:13][N:12]1[S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)(=[O:25])=[O:24])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@H]3OC(C)(C)O[C@H]3[C@@H]2C(=O)OCc2ccccc2)cc1
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2C[C@@H](OC(C)=O)[C@H]3OC(C)(C)O[C@H]3[C@@H]2C(=O)OCc2ccccc2)cc1
Temperature: -20 °C
Yield: 17.7 %

Procedure:
The above compound (5) (4.1 g) was dissolved in methylene chloride/pyridine (60–10 mL) and trifluoromethanesulfonic anhydride (2.89 mL) was adding under stirring at −20° C., and then the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added chloroform (50 mL) and, after washing with 1N hydrochloric acid and saline, the solution was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane 1:1) to obtain a compound, which was dissolved in acetonitrile (60 mL) and cesium acetate (1.77 g) and 18-Crown-6 (3.05 g) were added, followed by stirring at room temperature for 2 hours. To the reaction solution was added ethyl acetate (100 mL) and, after washing with saturated saline, the solution was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:cyclohexane=1:4→1:3) to obtain the titled compound (791 mg) as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][CH2:32][C:33]([CH3:36])([OH:35])[CH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:31][CH2:32][C:33]([OH:35])([CH3:36])[CH3:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: CC(C)(O)CN
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Product: Cc1cc(F)ccc1-c1nc(NCC(C)(C)O)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 79.3 %

Procedure:
Following the general procedure outlined in Example 225, the product of Example 121 (120 mg, 0.28 mmol) and 1-amino-2-methyl-2-propanol (76 mg, 0.85 mmol) were reacted to give the crude material. Purification by flash chromatography eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), followed by recrystallization from dichloromethane and hexane, afforded the desired product 96 mg (79%). LC-MS: 433.4 (MH+, m/z), 1.87 (Rt, min).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:24][C:25]1[S:26][C:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][C:29]=1[CH3:30].[Sn](Cl)(Cl)(Cl)Cl>CN(C)C=O.C(Cl)Cl>[CH2:31]([C:27]1[S:26][C:25]([CH3:24])=[C:29]([CH3:30])[C:28]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Reactant: Cc1cc(Cc2ccccc2)sc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C(C)C

Procedure:
Using 3,5-diisopropyl-p-anisic acid (5.0 g, 21.2 mmol, RN-117439-59-5), oxalyl chloride (2.2 mL, 25.4 mmol), N,N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (4.3 g, 21.2 mmol), tin(IV) chloride (5.0 mL, 42.7 mmol), and anhydrous methylene chloride (82 mL) the title compound was prepared according to the procedure in Example 2, step 1 to give 4.1 g (45%) NMR (DMSO-d6) δ 7.47 (s, 2 H), 7.23-7.12 (m, 3 H), 7.02-6.99 (m, 2 H), 3.86 (s, 2 H), 3.73 (s, 3 H), 3.31-3.20 (m, 2 H), 2.27 (s, 3 H), 1.82 (s, 3 H), 1.15 (d, 12 H). MS(EI), [M+] 420.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:9](Br)[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.Cl[P:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:9]([P:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(Br)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)P(c1ccccc1)c1ccccc1
Temperature: -65 °C
Yield: 56.6 %

Procedure:
Into a reactor were introduced 0.907 g (2.93 mmol) of the 1,1-bis(4-fluorophenyl)-2-bromopropene and 20 mL of THF under a nitrogen atmosphere. The contents were cooled to −65° C., and 2.0 mL (2.9 mmol; 1.5 M hexane solution) of butyllithium was gradually added dropwise thereto. The resultant mixture was stirred for 40 minutes. Thereafter, a mixture of 0.58 mL (3.2 mmol) of chlorodiphenylphosphine and 5 mL of THF was added thereto, and the resultant mixture was stirred at that temperature for 2 hours and then heated to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The resultant organic layer was washed with water and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from methanol to obtain 0.687 g (57%) of the target compound as white crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:22][C:23]([NH2:25])=[O:24]>CN(C)C=O>[C:23]([CH2:22][N:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][CH:5]1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(=[O:24])[NH2:25]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC2C=CC(I)=CN2CC(N)=O)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product (1.60 g, 4.27 mmol) from Step A in 8.0 mL of dry N,N-dimethylformamide was added sodium hydride (188 mg of 60 weight % dispersion in mineral oil, 4.44 mmol). After 15 min, the solution was warmed to 60° C. for 10 min, and was then cooled to room temperature. Chloroacetamide (420 mg) was added in one portion, and the solution was then warmed to 100° C. After 2.5 h, the solution was cooled to room temperature and poured into 70 mL of ice-water. The resultant precipitate was collected, washed with water and air-dried overnight. The crude product was subsequently stirred with 20 mL of methanol for several minutes, and the product was collected by filtration to afford the title compound as a white powder. LC/MS 414.9 (M+1-H2O).
Reaction SMILES: Br[C:2]([CH2:4][CH:5]([OH:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:3].C[O-].[Na+].Cl>CN1CCCC1=O>[C:7]1([CH2:6][CH:5]([OH:13])[CH2:4][C:2]#[CH:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=C(Br)CC(O)Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C#CCC(O)Cc1ccccc1

Procedure:
20.00 Grams of the 2-bromo-5-phenyl-1-penten-4-ol obtained above were dissolved in 160 g of N-methyl-2-pyrrolidone, and 11.20 g of sodium methylate were added. The mixture was allowed to react at 30° C. for 14 hours, and then was neutralized with concentrated hydrochloric acid. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resultant oily substance was purified by silica gel column chromatography to give 9.96 g of 5-phenyl-1-pentyn-4-ol, nD25 =1.519, FI-MS m/e 160(M+), propargyl compound/allene compound 97.9/2.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[N:15][C:16]#[N:17])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[N:15][C:16]#[N:17])=[CH:8][CH:9]=1
Reactant: N#CN=C1NCCN1c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N#CN=C1NCCN1c1ccc(N)cc1
Yield: 95.4 %

Procedure:
3.47 g (15 mmol) of 1-(4-nitrophenyl)imidazolidin-2-ylidene cyanamide are hydrogenated in 35 ml of methanol using hydrogen on 5% palladium on carbon. Conventional work-up gives 2.88 g of 1-(4-aminophenyl)imidazolidin-2-ylidene cyanamide in the form of a pale-brown solid (ESI: 202).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:20])([CH3:19])[C@H:3]1[OH:21].C(N(CC)CC)C.Br[CH2:30][C:31]1[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=[CH:38][C:32]=1[C:33](OCC)=[O:34].Cl>CN(C)C=O>[CH3:20][C:4]1([CH3:19])[C@@H:3]([OH:21])[C@H:2]([N:1]2[CH2:30][C:31]3[C:32](=[CH:38][CH:39]=[CH:40][C:41]=3[N+:42]([O-:44])=[O:43])[C:33]2=[O:34])[C:7]2[CH:8]=[C:9]([S:12]([C:15]([F:17])([F:18])[F:16])(=[O:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3c(cccc3[N+](=O)[O-])C2=O)[C@@H]1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
0.362 g of trans-4 amino-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran-3-ol (prepared from its hydrochloride, in turn prepared as described in Preparation 9) and 0.30 ml of triethylamine were added to a solution of 0.367 g of ethyl 2-bromomethyl-3-nitrobenzoate in 7.4 ml of dimethylformamide, and the resulting mixture was stirred at 100° C. for 1 hour in an atmosphere of nitrogen. The reaction mixture was then stirred under reflux of the solvent (at 152° C.) for a further 1 hour, after which the mixture was poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extract was then washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and a with saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:1:1 by volume mixture of ethyl acetate, cyclohexane and tetrahydrofuran as the eluent. The product obtained from the eluate was recrystallized from a mixture of tetrahydrofuran and hexane to give 0.295 g of the title compound, melting at 292°-295° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:14][O:15][C:16]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[CH:18][C:16]([O:15][CH3:14])=[O:17]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1OC
Yield: 99.7 %

Procedure:
A solution of 2-methoxy-4-nitrobenzaldehyde (904 mg, 4.99 mmol) and methyl (triphenylphosphoranylidene) acetate (2.04 g, 5.86 mmol) in CH2Cl2 (25.0 mL) was stirred at 20° C. for 14 h. The solvent was evaporated under reduced pressure and the residue was chromatographed (SiO2 230-400 mesh, 4/1 hexanes/EtOAc) to give the title compound (1.18 g, 4/1 E/Z isomeric mixture, quant.) as a white solid. MS (electrospray, +ions) m/z 238 (M+H).
Reaction SMILES: [C:1]([S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[CH3:32][N:33]1[C:37]([NH2:38])=[CH:36][C:35]([CH3:39])=[N:34]1>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH3:32][N:33]1[C:37]([NH:38][C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[S:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:14])=[CH:36][C:35]([CH3:39])=[N:34]1
Reactant: Cc1cc(N)n(C)n1
Reactant: O=C(Sc1ccccc1C(=O)O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2ccccc2SC(=O)c2ccccc2)n(C)n1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of 2-Benzoylsulfanyl-benzoic acid (as prepared in step 1 above; 1 g, 3.88 mmol) in anhydrous CH2Cl2 (40 mL), was added oxalyl chloride (2 mL, 22.5 mmol) followed by 2 drops of DMF. The suspension was stirred at room temperature until a clear solution was obtained. The solvent was evaporated under reduced pressure and the remaining crude solid was dissolved in anhydrous THF (40 mL). NEt3 (0.29 g, 2.5 mmol) and 2,5-Dimethyl-2H-pyrazol-3-ylamine (0.432 g, 3.88 mmol) were then added and the solution was allowed to stir at 50° C. overnight. The reaction mixture was diluted with EtOAc (60 mL) and extracted with H2O (3×50 mL) and saturated NaHCO3(aq). The organics were then dried over Na2SO4, filtered, concentrated in vacuo. The crude residue was purified via column chromatography (30% EtOAc/Hexanes) to give pure thiobenzoic acid S-[2-(2,5-dimethyl-2H-pyrazol-3-ylcarbamoyl)-phenyl]ester in 71% yield (0.966 g, 2.75 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([F:30])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]3[CH2:29][CH2:28][NH:27][CH2:26][C:19]3=[N:20][C:21]=2[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]1.[CH:31](OC1C=CC=CC=1)=[O:32]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([F:30])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]3[CH2:29][CH2:28][N:27]([CH:31]=[O:32])[CH2:26][C:19]3=[N:20][C:21]=2[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC([C@@H](F)c3ccc(F)cc3F)CC1)CCNC2
Reactant: O=COc1ccccc1
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC([C@@H](F)c3ccc(F)cc3F)CC1)CCN(C=O)C2
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of (R)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (50.5 mg, 0.120 mmol) in THF (602 μL) at room temperature was treated with phenyl formate (232 μL, 1.806 mmol). The reaction mixture was stirred at 60° C. for 15 min. The reaction mixture was removed from heat and allowed to continue stirring at room temperature for 2 h. The reaction was purified by HPLC Method B using a 50% to 80% ACN gradient to give the title compound, as a TFA salt, as a pale yellow solid (6.0 mg, 8.9% yield). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.30 (m, 7H), 1.45 (d, J=13.2 Hz, 1H), 1.67 (m, 2H), 2.01 (m, 1H), 2.11 (m, 1H), 2.79 (m, 4H), 3.51 (m, 2H), 3.77 (t, J=5.9 Hz, 1.4H), 3.83 (t, J=6.1 Hz, 0.6H), 4.13 (m, 1H), 4.51 (s, 0.6H), 4.56 (s, 1.4H), 5.53 (m, 1H), 7.02 (m, 2H), 7.50 (m, 1H), 8.19 (s, 0.7H), 8.24 (s, 0.3H); ESI-MS m/z [M+H]+ 447.95.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[C:11]#[N:12])[CH3:2].Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.[Ag-]=O>[CH2:14]([O:10][C:5]1[C:4]([C:11]#[N:12])=[C:3]([CH2:1][CH3:2])[CH:8]=[C:7]([CH3:9])[N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: CCc1cc(C)[nH]c(=O)c1C#N
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: CCc1cc(C)nc(OCc2ccccc2)c1C#N
Temperature: 110 °C
Yield: 82.8 %

Procedure:
A mixture of 4-ethyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (Cpd AA, 1.1 g, 6.8 mmol), (chloromethyl)benzene (1.1 mL, 9.4 mmol, 1.4 equiv) and silver(I) oxide (1.8 g, 7.7 mmol) in anhydrous toluene (22.7 mL) was heated at 110° C. for 17 hours. The reaction mixture was cooled to 23° C. then filtered through CELITE®. The filtrate was concentrated under vacuum. The residue was purified by column chromatography (heptane/EtOAc) to give 2-(benzyloxy)-4-ethyl-6-methylpyridine-3-carbonitrile (Cpd BB, 1.42 g, 83%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].O.O.O.[OH-].[Na+].Cl.CC([OH:34])C>O>[CH3:1][C:2]1([CH3:24])[S:6][C@H:5]([C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[C:8]([OH:9])=[O:34])[NH:4][C@H:3]1[C:21]([OH:23])=[O:22]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CC(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)S[C@H]([C@H](NC(=O)[C@H](N)c2ccccc2)C(=O)O)N[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
Ampicilloic acid was prepared in the following manner. Ampicillin trihydrate (10 gm, Sigma) was suspended in 50 ml of water and dissolved by the addition of 10N NaOH. The pH was maintained at 12 by the addition of 10N NaOH. After 1 hour, the pH was adjusted to 7.0 with 6N HCl. 2-Propanol (140 ml) was then added, and the solution allowed to stand for 4 hours at 4° C., after which time crystals had formed. The crystals were filtered and washed several times with cold 2-propanol:water (3:1) and allowed to dry at room temperature. Thin layer chromatography confirmed that this material was essentially all ampicilloic acid. Yield was 1.97 gm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:27])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:27]([S:29]([CH3:28])(=[O:31])=[O:30])[S:29]([CH3:28])(=[O:31])=[O:30])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3ccc(N)cc3nc2-c2ccc(OC)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc3ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc3nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-bis(4-methoxyphenyl)quinoxalin-6-amine (123.2 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (20 mL) was added methanesulfonyl chloride (47.2 mg, 0.41 mmol, 1.20 equiv) and triethylamine (174.3 mg, 1.73 mmol, 5.00 equiv). The resulting solution was stirred for 1.5 h at room temperature. The resulting mixture was concentrated in vacuo, resulting in 179.55 mg (81%) of N-(2,3-bis(4-methoxyphenyl)quinoxalin-6-yl)-N-(methylsulfonyl)methanesulfonamide as a brown solid.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)(C2C=CC=CC=2)=[O:41])C=CC=CC=1.N1CCOCC1.BrBr.Cl>O1CCCC1.ClCCl.C(O)(=O)C.N1C=CC=CC=1.C(N(CC)CC)C>[O:1]([CH2:8][C:9]([NH:10][CH:11]1[C:12](=[O:33])[N:13]2[C:16]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])=[C:30]([OH:32])[CH2:31][S:15][C@H:14]12)=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: BrBr
Agent: Cl
Solvent: C1COCCN1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (9.38 g) in tetrahydrofuran (120 ml) under a nitrogen atmosphere at 20° C. was added triethylamine (3.21 ml) followed by diphenylphosphoryl chloride (4.77 ml). The reaction mixture was then stirred for 2 hours and cooled to 0° C. Morpholine (4.01 ml) was added and the reaction mixture stirred for 2 hours at 0°-5° C. The reaction mixture was next cooled to -30° to -35° C. and pyridine (1.62 ml) added followed by the dropwise addition of bromine (1.00 ml) over a period of 10 minutes. The reaction mixture was stirred at -30° to -35° C. for 20 minutes and 5% hydrochloric acid (144 ml) added, followed by further stirring at room temperature for 3 hours. The reaction mixture was then stood at 0° C. overnight. The reaction mixture was extracted with dichloromethane and the organic extracts washed with water then saturated sodium chloride solution, dried with magnesium sulphate and evaporated to dryness. The product thus obtained was dissolved in dichloromethane and acetic acid added, the dichloromethane removed under reduced pressure and then ether was added with stirring to complete crystallization. The product was isolated by filtration, washed with ether then dried in vacuo at 40° C. for 5 hours. The yield of p-nitrobenzyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate acetic acid solvate was 9.16 g (84%).
Reaction SMILES: [C:1]([C:4]1[CH:21]=[C:20]2[C:7]([C:8](=[O:26])[C:9]3[CH:10]([OH:25])[CH:11]4[C:16](=[C:17]([OH:22])[C:18]=3[CH2:19]2)[CH2:15][CH2:14][CH2:13][CH:12]4[O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>CN(C)C=O>[C:1]([CH:4]1[CH2:21][C:20]2[CH:19]=[C:18]3[C:9]([C:10](=[O:25])[C:11]4[C:12]([O:23][CH3:24])=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:22])=[C:8]([OH:26])[C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC1CCCC2=C(O)C3=C(C(=O)c4ccc(C(C)=O)cc4C3)C(O)C21
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)c1c(cc3c(c1O)CCC(C(C)=O)C3)C2=O
Reaction time: 2 h

Procedure:
A solution of (7) (0.4 g, 1.1 mmol) in dimethylforamide (40 mL) was heated at 110° C. Simultaneously, oxygen was bubbled through it. After 2 hrs., flow of oxygen was terminated and 2 mL of water was added. Upon cooling, the reaction mixture gave orange crystals of (8). ##STR14## These crystals were collected by filtration, washed with water and dried: yield 0.37 g (94% yield) of (8) with mp 222°-225° C. (lit. mp 223°-226° C.), 1H NMR (CDCl3) δ 13,36 (s, 1H), 8.08-7.22 (m, 4H), 4.07 (s, 3H), 3.30-2.40 (m, 4H), 2.27 (s, 3H), 2.27 (m, 1H), 2.0-1.4 (m, 2H), mass spectrum, m/z 350 (M30 ). Anal. Calcd. for C21H18O5 (350.35): C, 71.99; H, 5.18. Found: C, 71.70; H, 5.30.