Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[OH:5].[Cl:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][NH:22][C:23]([C:25]2[C:26](=[O:37])[C:27]3[CH:34]=[C:33]([CH2:35]Cl)[O:32][C:28]=3[N:29]([CH3:31])[CH:30]=2)=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][NH:22][C:23]([C:25]2[C:26](=[O:37])[C:27]3[CH:34]=[C:33]([CH2:35][N:2]([CH2:3][CH:4]([OH:5])[C:6]4[CH:15]=[CH:14][C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]=4)[CH3:1])[O:32][C:28]=3[N:29]([CH3:31])[CH:30]=2)=[O:24])=[CH:19][CH:18]=1
Reactant: CNCC(O)c1ccc2ccccc2n1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccc2ccccc2n1
Temperature: 90 °C
Yield: 48.6 %

Procedure:
N,N-biisopropylethylamine (0.11 mL) and rac-2-(methylamino)-1-quinolin-2-ylethanol (Preparation 47, 0.125 g) were added to a suspension of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The reaction mixture was allowed to cool to room temperature, poured into water (25 mL), and was extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2, 97/3, 9515). The product was then recrystallized from ethyl acetate and then methanol to yield 0.106 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 154-159° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.64, 8.48, 8.29-8.27, 7.94-7.87, 7.70-7.66, 7.62-7.60, 7.57-7.52, 7.41-7.33, 6.85, 5.53, 4.95-4.91, 4.55, 3.74, 3.74-3.72, 2.89-2.85, 2.79-2.74, 2.36; MS (ESI+) m/z 531 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:21])[C:6]1[C:7](=[C:12]([CH2:16][NH:17][C:18]([NH2:20])=[O:19])[CH:13]=[CH:14][CH:15]=1)[C:8]([O:10]C)=[O:9]>O.C(O)C>[NH:17]([CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:6]([C:5]([OH:21])=[O:4])[C:7]=1[C:8]([OH:10])=[O:9])[C:18]([NH2:20])=[O:19]
Reactant: COC(=O)c1cccc(CNC(N)=O)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)NCc1cccc(C(=O)O)c1C(=O)O
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of sodium hydroxide (0.4 g, 10.5 mmol) in water (10 mL) was added to a stirred suspension of 3-ureidomethyl-phthalic acid dimethyl ester (1.4 g, 5.3 mmol) in ethanol (30 mL). The mixture was refluxed for one hour and then cooled to room temperature. The mixture was concentrated, and the residue was dissolved in water (30 mL). The mixture was acidified with 4N HCl to pH 1. The mixture was filtered to give 3-ureidomethyl-phthalic acid (1.0 g, 76%): 1H NMR (DMSO-d6) δ 4.22 (d, J=5.9 Hz, 2H, CH2), 5.68 (s, 2H, NH2), 6.40 (t, J=6.0 Hz, 1H, NH), 7.46-7.56 (m, 2H, Ar), 7.73 (d, J=6.9 Hz, 1H, Ar), 13.23 (b, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13](O)O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O[CH2:19][CH3:20])C>Cl>[Cl-:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][N+:9]3[CH:20]=[CH:19][CH:3]=[CH:4][CH:8]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC(O)c1noc(-c2cccc(Cl)c2)n1
Reactant: CCOCC
Agent: Cl
Product: Clc1cccc(-c2nc(C[n+]3ccccc3)no2)c1
Product: [Cl-]
Reaction time: 0.33 h

Procedure:
The title compound was synthesized according to the method described in Palazzo et al. J. Heterocycl. Chem. (1979) 16:1469. 1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-pyridinium chloride (1.81 g, 5.87 mmol) was dissolved in water (20 ml). To this solution, 4-nitroso-N,N-dimethylanilin (0.88 g, 5.86 mmol) dissolved in ethanol (50 ml) was added, followed by slow addition of 1 molar aq. sodium hydroxide (5.9 ml, 5.9 mmol) over a 3 min period. After 1 h the formed precipitate was filtered, washed with water and air-dried to give the title compound (2.08 g, wet) which was used immediately in the next step MS (ESI) m/z 344 (M+1). Step 2: [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanediol: N-{4-[(Z)-{[5-(3-Chlorophenyl)-1,2,4-oxadiazol-3-yl]methylene}(oxido)amino]phenyl}-N,N-dimethylamine (2.08 g wet) was suspended in diethyl ether (30 ml), followed by the addition of 1 molar aqueous hydrochloric acid. The mixture was stirred vigorously for 20 min, transferred to a separation funnel and diluted with diethyl ether and 1 molar aqueous hydrochloric acid. After extraction, the aqueous layer was extracted two more times with diethyl ether. Combining the organic layers, drying over magnesium sulfate, followed by evaporation to dryness and drying in vacuo gave the title compound as crude (0.56 g, 42% from 1-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-pyridinium chloride). MS (ESI) m/z 227 (M+1). Step 3: [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol: Step 3: [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol: 1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-pyridinium chloride (99.3 mg, 0.44 mmol) was dissolved in methanol (4 ml) followed by the addition of sodium borohydride (32 mg, 0.84 mmol). More sodium borohydride was added after 2 h and the reaction was allowed to run over night. The reaction mixture was diluted with dichloromethane and aq. ammonium chloride and stirred vigorously. After separation of the layers and washing of the organic layer with brine, followed by evaporation to dryness, crude product was obtained. This was purified by flash chromatography using heptane/ethyl acetate which gave the title compound (32.0 mg, 32%). 1H NMR (CDCl3), δ (ppm): 8.11 (s, 1H), 8.00 (apparent d, 1H), 7.56 (apparent d, 1H), 7.46 (apparent t, 1H), 4.87 (d, 2H), 2.91 (t, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=3)[C:10](=[O:22])[C:9]=2[N:8]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2].[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)=[O:32].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH:31]=[O:32])=[CH:17][CH:16]=3)[C:10](=[O:22])[C:9]=2[N:8]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(I)cc1)C2=O
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(-c3ccccc3C=O)cc1)C2=O
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Method A. A suspension 1-(4-methoxy-phenyl)-6-(4-iodo-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (55, 2.0 g, 3.87 mmol), 2-formylphenylboronic acid (13, 870 mg, 5.81 mmol, 1.5 equiv), and K2CO3 (1.60 g, 11.6 mmol, 3.0 equiv) in toluene (18 mL), ethanol (6 mL) and H2O (6 mL) at room temperature was degassed three times under a steady nitrogen stream before being treated with Pd(PPh3)4 (22 mg, 0.02 mmol, 5% equiv) at room temperature under N2. The reaction mixture was subsequently degassed three times again before being warmed to reflux for 12 h. When HPLC showed the Suzuki coupling reaction was complete, the reaction mixture was cooled down to 5-10° C. before being treated with water (20 mL) at 5-10° C. with good stirring. The mixture was stirred for an additional 1 h at 5-10° C. before the solids were collected by filtration. The wet cake was then thoroughly washed with water (2×30 mL) and 30% EtOAc/hexane (2×20 mL), dried in vacuo at 40-45° C. for 12 h to afford the crude desired 6-(2′-formyl-biphenyl-4-yl)-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (56, 1.61 g, 1.915 g theoretical, 84%) as off-white solids, which was found to be pure enough to do the following reaction without further purification. For 56, CIMS m/z 496 (M++H, C29H25N3O5).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]5[O:35][CH2:36][O:37][C:30]=45)=[N:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:38][CH3:39])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:14][C:11]1([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]5[O:35][CH2:36][O:37][C:30]=45)=[N:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:38][CH3:39])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
A mixture of 7-[2-(N-tert-butoxycarbonyl-4-hydroxypiperidin-4-yl)ethoxy]-6-methoxy-4-(2,3-methylenedioxyanilino)quinazoline (0.067 g), trifluoroacetic acid (0.5 ml) and methylene chloride (3 ml) was stirred at ambient temperature for 1 hour. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. There was thus obtained the title compound (0.015 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.75 (m, 4H), 2.05 (t, 2H), 3.1 (m, 4H), 4.0 (s, 3H), 4.35 (t, 2H), 6.1 (s, 2H), 6.95 (m, 3H), 7.4 (s, 1H), 8.1 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 439.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH:28]12[O:37][CH:32]([O:33][CH:34]1[CH2:35][OH:36])[CH2:31][NH:30][CH2:29]2>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:30]2[CH2:31][CH:32]3[O:37][CH:28]([CH:34]([CH2:35][OH:36])[O:33]3)[CH2:29]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: OCC1OC2CNCC1O2
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CC4OC(CO)C(C3)O4)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (400 mg; 0.96 mmol; 1 eq), is dissolved in anhydrous DCM (40 ml). The reaction is put under nitrogen. Triethylamine (0.67 ml; 4.81 mmol; 3 eq) and (6,8-Dioxa-3-aza-bicyclo[3.2.1]oct-7-yl)-methanol (349.2 mg; 2.41 mmol; 2.5 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (450 mg; 77%).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[C:15]3[C:16]([NH2:20])=[N:17][CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH2:29][C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH2:29][C:30]([N:6]1[C:7]2[C:3](=[C:2]([F:1])[C:10]([C:11]3[C:15]4[C:16]([NH2:20])=[N:17][CH:18]=[CH:19][C:14]=4[O:13][CH:12]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)=[O:31]
Reactant: Nc1nccc2occ(-c3ccc4c(c3F)CCN4)c12
Reactant: O=C(O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccc2occ(-c3ccc4c(c3F)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A mixture of 3-(4-fluoro-2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (190 mg, 0.555 mmol), 2,5-difluorophenylacetic acid (100 mg, 0.583 mmol), HATU (232 mg, 0.611 mmol), and Hunig's base (0.388 mL, 2.221 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was stirred at room temperature for 2 hours. HPLC indicated complete consumption of starting material, so the mixture was poured into water (30 mL), the suspension was stirred for a few minutes, and the precipitate was collected by vacuum filtration and dried in the vacuum oven overnight to give 3-{1-[(2,5-difluorophenyl)acetyl]-4-fluoro-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (209 mg, 0.469 mmol, 84% yield) as a light tan solid. LC/MS (ES) m/z=424 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.26-3.31 (d, J=8.34 Hz, 2H), 3.97 (s, 3H), 4.38 (t, J=8.46 Hz, 2H), 5.48 (s, 2H), 6.95 (d, J=5.81 Hz, 1H), 7.14-7.35 (m, 4H), 7.87 (d, J=6.06 Hz, 1H), 7.93 (d, J=8.08 Hz, 1H), 7.96 (s, 1H).
Reaction SMILES: C(O[C:4]([S-:6])=[S:5])C.[Na+].Cl[C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>CN(C)C=O>[SH:6][C:4]1[S:5][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: Nc1ccccc1Cl
Reactant: CCOC(=S)[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Sc1nc2ccccc2s1
Temperature: 80 °C
Yield: 94.4 %

Procedure:
A solution of 216.2 g of sodium ethylxanthate in 250 ml of dimethylformamide is added dropwise to a solution, heated to 140°-150° C., of 63.8 g of 2-chloroaniline in 150 ml of dimethylformamide in the course of one hour, under a nitrogen atmosphere. During this addition, the internal temperature is kept at 150° C. by removing some of the distillate. The reaction mixture is then subsequently stirred under reflux for about 12 hours, cooled to about 80° C. and stirred into 1.2 l of ice-water. The resulting cloudy solution is acidified and the 2-mercaptobenzothiazole which has precipitated is filtered off. After washing and drying, 79 g (94.6% of theory) of 2-mercaptobenzothiazole of melting point 179°-180° C. are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][NH:19][CH2:20][CH2:21][OH:22].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][NH:19][CH2:20][CH2:21][O:22][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNCCO
Reactant: Clc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CNCCOc1ncccc1OCCO
Reaction time: 48 h
Yield: 14.4 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 2-(methylamino)ethanol (47 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of 1.0 M NaOH and 1 mL of brine. The organic phase was shaken with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of chloroform. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 12 mg (0.056 mmol, 14%) of the title compound as a colorless oil. LC-UV purity 90%. MS m/z 213 (M+1)+, calc. 213 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[NH2:21].Cl>C(#N)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[CH3:26][O:25][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[CH:24]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Reactant: COc1cc(N)cc(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1cc(OC)cc(OC)c1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A 200 mL RB flask was charged with ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (2.76 g, 11.1 mmol) in 40 mL acetonitrile. To the solution was added 3,5-dimethoxy aniline (1.784 g, 11.4 mmol), and conc. HCl solution (494 uL, 5.6 mmol), the reaction mixture was stirred at 60˜70° C. for 2 hours. The mixture was diluted with ethyl acetate and saturated aqueous NaHCO3 solution. It was stirred for an additional 5 minutes. The separated organic layer was dried over MgSO4, and condensed under reduced pressure yielding the residue. The residue was recrystallized from acetonitrile, dried under reduced pressure providing pale yellow solids (2.92 g, 72%). MS m/z: 364.1 (M+H)+.
Reaction SMILES: SC1([CH:13](Br)[C:14](=O)/[C:15](=[N:19]/[O:20][CH3:21])/[C:16]([O-:18])=O)NN=C(C2C=CC=CC=2)O1.[NH2:24][C:25]([NH2:27])=[S:26].C([O-])(=O)C.[Na+].[CH3:33][C:34]([O:36][CH2:37][C:38]1[CH2:47][S:46][C@@H:41]2[C@H:42]([NH2:45])[C:43](=[O:44])[N:40]2[C:39]=1[C:48]([OH:50])=[O:49])=[O:35]>O1CCCC1.O.C(N(CC)CC)C>[CH3:33][C:34]([O:36][CH2:37][C:38]1[CH2:47][S:46][C@@H:41]2[C@H:42]([NH:45][C:16](/[C:15](/[C:14]3[N:24]=[C:25]([NH2:27])[S:26][CH:13]=3)=[N:19]\[O:20][CH3:21])=[O:18])[C:43](=[O:44])[N:40]2[C:39]=1[C:48]([OH:50])=[O:49])=[O:35]
Reactant: CO/N=C(\C(=O)[O-])C(=O)C(Br)C1(S)NN=C(c2ccccc2)O1
Reactant: NC(N)=S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
2-Mercapto-5-phenyl-1,3,4-oxadiazolyl-(Z)-4-bromo-2-methoxyimino-3-oxo-butyrate (46.0 g) was taken in a mixture of tetrahydrofuran (250 ml) and water (150 ml). The solution was cooled to 10° C. and the thiourea (20.47 g) and sodium acetate (4.32 g) were added. The reaction mixture was stirred for 1.0 hr. 7-amino cephalosporanic acid (25.0 g) was added followed by slow addition of triethylamine (20.4 g) the progress of the reaction was monitored by HPLC. The reaction was completed in 6-8 hr. The reaction mixture was extracted with dichloromethane (3×200 ml). The aqueous layer was acidified with dil. HCl to obtain cefotaxime, 38.0 g.
Reaction SMILES: Cl[S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:17][CH3:18])=[N:9][C:10]3[S:16][CH:15]=[CH:14][C:11]=32)[N:6]=1)(=[O:4])=[O:3].[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:21]=1[NH2:22].N1C=CC=CC=1.CS(C)=O>C(#N)C>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:21]=1[NH:22][S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:17][CH3:18])=[N:9][C:10]3[S:16][CH:15]=[CH:14][C:11]=32)[N:6]=1)(=[O:4])=[O:3]
Reactant: COc1nc2sccc2c2nc(S(=O)(=O)Cl)nn12
Reactant: Nc1c(Cl)cccc1Cl
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1nc2sccc2c2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Reaction time: 8 h
Yield: 47.4 %

Procedure:
2-Chlorosulfonyl-5-methoxythieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (1.5 g, 4.9 mmol) and 2,6-dichloroaniline (1.59 g, 9.8 mmol) were dissolved in 20 mL of acetonitrile and to this was added under nitrogen at ambient temperature with stirring 0.40 mL (4.9 mmol) of pyridine and 0.05 mL of dimethyl sulfoxide. The mixture was allowed to stir overnight and was then concentrated by evaporation under reduced pressure. The residue was flash chromatographed on silica gel and fractions containing the major product were recovered. Evaporation of the solvents under reduced pressure gave a white powder. This was extracted with 200 mL of hexane and the insoluble white solid was dried to obtain 1.0 g of the title compound melting at 224°-226° C. The proton NMR spectra of this was consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:34]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>O1CCCC1.C(OCC)(=O)C.O>[CH2:42]([N:41]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:11](=[O:12])[CH2:10][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH3:14])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(CCC(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(CCC(=O)N(Cc1ccccc1)Cc1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 39.9 %

Procedure:
A solution of 4,4-bis-(4-hydroxyphenyl)pentanoic acid (2.00 g, 6.99 mmol) in 40 mL anhydrous tetrahydrofuran was treated with carbonyl diimidazole (3.76 g, 23.2 mmol) and the resulting solution heated at reflux under a N2 atmosphere for 24 hours. Dibenzylamine (5.38 mL, 28 mmol) was then added, and the reaction refluxed again for 48 hours. The reaction mixture was cooled and treated with 10% aqueous HCl solution (50 mL), followed by water (100 mL) and ethyl acetate (200 mL). The organic phase was collected and washed sequentially with water (100 mL) and brine (100 mL). The organic phase was dried (MgSO4), filtered and concentrate. The residue was purified by chromatography (silica gel, 50% ethyl acetate/hexane) to give the title compound (1.30 g, 40%) as a solid, mp=203-207° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:29][C:30]1[N:34]=[CH:33][N:32]([C:35]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:36]=2[O:37][CH2:38][CH2:39][CH2:40][NH2:41])[N:31]=1>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:41][CH2:40][CH2:39][CH2:38][O:37][C:36]2[CH:42]=[C:43]([N+:46]([O-:48])=[O:47])[CH:44]=[CH:45][C:35]=2[N:32]2[CH:33]=[N:34][C:30]([CH3:29])=[N:31]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)c(F)c1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCN)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCNc2nc(Cl)nc3c2CCC3c2ccc(F)cc2F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 2,4-dichloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation T, 0.717 g, 2.38 mmol) in acetonitrile (40 mL) was added diisopropylethylamine (0.420 g, 3.25 mmol) followed by 3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propan-1-amine (Preparation K, 0.60 g, 2.164 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane (10 mL) and silica (2 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 50% ethyl acetate in pet-ether) to get 2-chloro-7-(2,4-difluorophenyl)-N-(3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (0.65 g, 55.4%) as a light yellow solid. LC-MS (M+H)+=542.0. 1H NMR (400 MHz, CDCl3) δ ppm 8.95 (1H, s), 8.05-7.93 (3H, m), 6.95-6.77 (3H, m), 4.86 (1H, br s), 4.86-4.85 (1H, m), 4.37-4.34 (2H, m), 3.75-3.75 (2H, s), 2.69-2.50 (3H, m), 2.50 (3H, s), 2.29-2.26 (2H, m), 2.01-1.98 (1H, m).