Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]3[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:7]=3[N:6]2[CH:25]=1.C(=O)([O-])[OH:27].[Na+]>O1CCOCC1.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[CH:25]=[C:3]([CH2:2][OH:27])[N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:8]=2[CH:18]=1)([O-:24])=[O:23]
Reactant: O=C([O-])O
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nc(CCl)cn1-2
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nc(CO)cn1-2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 50.7 %

Procedure:
A solution of 5.1 g of 2-chloromethyl-8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine in 70 ml of dioxan was treated with a solution of 1.54 g of sodium hydrogen carbonate in 30 ml of water and the mixture was stirred at 80° C. for 2.5 h. The mixture was filtered and the filtrate was made weakly acidic (pH 6 to 7) with aqueous 3N hydrochloric acid. The filtrate was evaporated in a vacuum and the residue was taken up in chloroform and water. The chloroform phase was washed with water, dried over sodium sulphate and evaporated in a vacuum. The crystalline residue (3.2 g) was dissolved in chloroform and chromatographed over 130 g of silica gel. With chloroform and with chloroform/ethanol 98:2 there were eluted small amounts of various impurities, with chloroform/ethanol 97:3 and 96:4 there was eluted 8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol. After recrystallization from ethanol there were obtained 2.45 g of pure 8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 250-251° C. which was converted into the hydrochloride (m.p. 295-297° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=2[CH3:43])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=2[CH3:43])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1C
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)c1C

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (233 mg, 0.75 mmol) and 3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K18) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow oil (340 mg, 81%).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+]>CO>[C:27]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH2:14][CH2:15]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
The compound (2.00 g) prepared in step (b) was dissolved in a mixed solvent composed of tetrahydrofuran (20 ml) and methanol (10 ml), and a 1 mol/l aqueous sodium hydroxide solution (10 ml) was added to the solution. The mixture was then stirred at 65° C. for one hr. The solvent was removed from the reaction solution by distillation under the reduced pressure. Water (30 ml) was then added to the residue, and the mixture was adjusted to pH 4 by the addition of 1 mol/l hydrochloric acid. The resultant precipitate was collected by filtration, and was then dried to give 1.60 g (85.6%) of 3-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]benzoic acid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].N12CCCN=C1CCCCC2>C(#N)C>[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 72 %

Procedure:
To a suspension of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (2 g) in anhydrous acetonitrile were added 3-t-butoxycarbonylaminopyrrolidine (1.86 g) and 1,8-diazabicyclo[5,4,0]undec-7-en (DBU, 1.02 g) and then the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform (50 ml). The resulting solution was washed with 10% aqueous citric acid solution (20 ml), and with saturated saline solution successively. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was dissolved in hot methanol (20 ml) and then cooled. The resulting crystals were collected by filtration to give 7-(3-t-butoxycarbonylamino-1-pyrrolidinyl)-1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (2.25 g) as yellowish white prisms, mp 224°-226° C. (decompd.).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[CH2:18]([N:20]1[C:24]2=[N:25][C:26]([CH:43]=O)=[C:27]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:28]([C:29]3[CH:30]=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=3)=[C:23]2[CH:22]=[N:21]1)[CH3:19]>C1COCC1.O>[C:1](/[CH:3]=[CH:43]/[C:26]1[N:25]=[C:24]2[N:20]([CH2:18][CH3:19])[N:21]=[CH:22][C:23]2=[C:28]([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=2)[C:27]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])#[N:2]
Reactant: CCOC(=O)CCc1c(C=O)nc2c(cnn2CC)c1-c1cncc(C)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCc1c(/C=C/C#N)nc2c(cnn2CC)c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of diethyl (cyanomethyl)phosphonate (17.4 mg) in THF (0.5 ml) was added potassium tert-butoxide (11.3 mg) at 0° C. and the mixture was stirred at room temperature for 30 minutes. A solution of ethyl 3-[1-ethyl-6-formyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (20 mg) in THF (0.5 ml) was added at 0° C. and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography eluting with a mixture of EtOAc and n-hexane (1:1) to give ethyl 3-[6-[(E)-2-cyanovinyl]-1-ethyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (17 mg) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C[AlH]CC(C)C)C.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Br)c(OCc2ccccc2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: OCc1ccc(Br)c(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To 3.35 g (10 mmol) of 7 in 25 ml of CH2Cl2 under Ar in a dry ice-acetone bath was slowly added 20 ml 1.0 M DIBAL with stirring. After stirring for 2 h, 20 ml of 1 N HCl and 50 ml of CH2Cl2 were added, and the mixture was stirred for 0.5 h, then washed (water and brine), and dried (Na2SO4). Concentration and chromatography (EtOAc/hexane) afforded 2.78 g (91%) of 8 (white solid): 1H NMR (300 MHz, CDCl3) δ 4.63 (d, J=5.7 Hz, 2 H), 6.83 (d, J=8.1 Hz, 1 H), 7.00 (s, 1 H), 7.40-7.33 (m, 3 H), 7.5-7.42 ppm (m, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.COC1[CH:29]=[CH:28][C:27](OC)=[CH:26]O1.[OH-].[Na+]>CC(O)=O>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([N:1]2[CH:29]=[CH:28][CH:27]=[CH:26]2)=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: COC1=COC(OC)C=C1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-n1cccc1
Yield: 71.9 %

Procedure:
To a solution of 5-(5-amino-2-Isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.303 g, 1.0 mmol) in 15 mL AcOH was added 2,5-dimethoxypyran (0.152 g, 1.2 mmol). The solution was warmed to reflux. After 2 h the solution was cooled and poured over ice/H2O. The solution was converted to pH=8 with 50% NaOH and extracted with ethyl acetate (3×75 mL). The combined organics were washed with H2O, washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to give a brown solid. Purification via flash chromatography (CH2Cl2/MeOH 97:3) afforded 5-(2-isopropyl-4-methoxy-5-pyrrol-1-yl-phenoxy)-pyrimidine-2,4-diamine (0.244 g, 72%) as a pale yellow solid. (M+H)=340.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(F)cc2)cc1
Yield: 44.9 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (Example 3) (770 mg, 1.9 mmol) and p-toluenesulfonic acid monohydrate (88 mg) in toluene (80 mL) was heated to reflux for 20 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture (520 mg) was purified by chromatography on silica gel using hexane/ethyl acetate (1/1) to give pure 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole (328 mg, 44%) as a white solid: mp (DSC) 183° C. Anal. Calc'd. for C17H12N2SO2F4: C, 53.13; H, 3.15; N, 7.29. Found: C, 53.20; H, 3.22; N, 7.18.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[F:5][CH:6]([F:15])[O:7][C:8]1[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.BrBr.O>C(O)(=O)C>[F:15][CH:6]([F:5])[O:7][C:8]1[N:13]=[C:12]2[S:1][C:2]([NH2:3])=[N:14][C:11]2=[CH:10][CH:9]=1
Reactant: Nc1ccc(OC(F)F)nc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(OC(F)F)nc2s1
Temperature: 25 °C
Yield: 36.1 %

Procedure:
To acetic acid (10 mL) cooled in an ice bath was added potassium thiocyanate (3.18 g, 32.8 mmol) and 6-(difluoromethoxy)pyridin-3-amine (1 g, 4.1 mmol). The reaction was cooled in an ice-salt bath until the reaction temperature reached <0° C. A solution of bromine (0.65 mL, 12.7 mmol) in acetic acid (3 mL) was added dropwise over 2 hours at a rate that maintained the reaction temperature <0° C. This gave a very thick mixture. After the addition was complete, the mixture was left to stir and allowed to slowly warm to room temperature overnight. After stirring overnight, water (5 mL) was added and the mixture was heated to 85° C. in an oil bath. This mixture was then filtered while still hot. The yellow filter cake was returned to the reaction flask, and an additional 5 mL acetic acid was added. The mixture was heated again to 85° C., and then filtered while still hot. The combined filtrates were cooled in an ice bath and neutralized to pH 8 with concentrated ammonium hydroxide. A yellow precipitate formed which was then collected by filtration. This crude material was purified by column chromatography (12-100% ethyl acetate/hexanes) to afford 5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine (321 mg, 1.48 mmol, 36.1% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.64-7.81 (m, 2 H), 6.92 (d, J=8.53 Hz, 1 H). MS (LC/MS) R.T.=1.66; [M+H]+=218.10.
Reaction SMILES: [C:1](Cl)(=O)C.[C:5]([C@H:8]1[CH2:11][C@@H:10]([C:12]([OH:14])=[O:13])[C:9]1([CH3:16])[CH3:15])(=[O:7])[CH3:6]>CO>[C:5]([C@H:8]1[CH2:11][C@@H:10]([C:12]([O:14][CH3:1])=[O:13])[C:9]1([CH3:16])[CH3:15])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](C(C)=O)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (1.02 ml, 14.32 mmol) was added dropwise to MeOH (10 mL) at 0° C. and the resulting mixture was stirred at 0° C. for 30 mins. (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid from Step 1 (696 mg, 4.09 mmol) was added as a solution in MeOH (2 mL) and the reaction mixture was stirred overnight while warming up to room temperature. The volatiles were then removed under reduced pressure and the residue was purified by flash chromatography on silica gel (gradient elution, 2% to 20% EtOAc in Hexanes) to give methyl (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylate as a colorless oil. MS ESI calc'd. for C10H17O3 [M+H]+ 185. found 185. 1H NMR (500 MHz, CDCl3) δ 3.66 (s, 3H), 2.88 (dd, J=10.5, 7.6 Hz, 1H), 2.78 (dd, J=10.8, 8.1 Hz, 1H), 2.64 (app q, J=10.8 Hz, 1H), 2.06 (s, 3H), 1.92-1.87 (m, 1H), 1.43 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]2[O:12][C@@H:11]([CH2:13][O:14]C(=O)C3C=CC=CC=3)[S:10][CH2:9]2)[C:4](=[O:23])[N:3]=1>CO>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]2[O:12][C@@H:11]([CH2:13][OH:14])[S:10][CH2:9]2)[C:4](=[O:23])[N:3]=1
Reactant: Nc1ccn([C@@H]2CS[C@H](COC(=O)c3ccccc3)O2)c(=O)n1
Solvent: CO
Product: Nc1ccn([C@@H]2CS[C@H](CO)O2)c(=O)n1
Yield: 90.4 %

Procedure:
A suspension of (cis)-4-amino-1-(2-benzoyloxymethyl-1,3-oxathiolan-5-yl)(1H)-pyrimidin-2-one (Intermediate 3) (8.19 g) and Amberlite IRA-400 (OH) resin (8.24 g) in methanol (250 ml) was stirred and heated to reflux for 11/4 h. Solids were removed by filtration then washed with methanol. The combined filtrates were evaporated. The residue was triturated with ethyl acetate (80 ml). The resulting white solid was collected by filtration to give the title product (5.09 g), 1H NMR (DMSO-d6) 3.04 (1H), 3.40 (1H), 3.73 (2H), 5.18 (1H), 5.29 (1H), 5.73 (1H), 6.21 (1H), 7.19 (2H), 7,81 (1H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:19][C:18](=[O:20])[NH:17][CH:16]=C2C(O)=O)=[CH:10][CH:9]=1>ClCCl.CN(C=O)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[CH2:19][C:18](=[O:20])[NH:17][CH:16]=[C:1]2[C:2]([Cl:4])=[O:3])=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)O)=CN1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)Cl)=CN1
Reaction time: 0.5 h

Procedure:
Oxalylchloride (0.91 g 7.2 mmol) was added to a room temperature solution of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid (1.124 g, 4.8 mmol) in dichloromethane (10 ml) containing 2 drops of DMF. The reaction mixture was stirred for 30 minutes and then solvent was removed under reduced pressure to give crude (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid chloride, which was not removed from the flask. Dichloromethane (10 mL) was added, and the dichloromethane solution of the acid chloride was added to a stirring solution of 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine (1.51 g, 4.7 mmol) and triethyl amine (0.97 g) in dichloromethane (30 ml). The reaction was stirred at 0° C. for 10 minutes, then at ambient temperature for 20 minutes. Solvent was removed under reduced pressure and the residue was purified by flash chromatography (0 to 5% methanol in dichloromethane) to 1.776 g of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-amide as a yellowish solid (69.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.[O-]CC.[Na+].CO[CH:23]=[CH:24][C:25](=O)[CH3:26]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:10]([C:11]([OH:13])=[O:12])[C:9]2=[O:16])=[CH:6][CH:7]=1
Reactant: COC=CC(C)=O
Reactant: CCOC(=O)CC(=O)Nc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a 4-necked 3 L round bottom flask, is added EtOH (1500 mL), ethyl 3-(4-fluorophenylamino)-3-oxopropanoate (139 g, 617 mmol), sodium ethoxide (65.6 g, 925 mmol) and 4-methoxy-3-buten-2-one (103 g, 925 mmol). The mixture is refluxed for 3 hours. After the solution is cooled to RT, the reaction mixture is concentrated under reduced pressure to remove the EtOH. The residue is diluted with DCM (700 mL) and 1 M HCl (1500 mL). The aqueous phase is extracted with DCM (3×500 mL). The combined organic extracts are washed with saturated aqueous sodium chloride (1000 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue is triturated with EtOAc (150 mL) at RT (10-15° C.) for 1 hour. After filtration and washing with EtOAc (50 mL), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid is obtained as a yellow solid (85.3 g, 56% yield). MS (m/z): 248 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])=[CH:22][CH:21]=1)#[N:19]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(C#N)cc4)cc3c2C1
Yield: 46.7 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 14.9 mg (0.101 mMol) 4-cyanobenzoic acid, 6.7 mg (47%) of the title compound were recovered as a beige solid.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[N:6]=[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][N:8]2[C:9](=[O:11])[CH:10]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:28]2C=CC=CC=2C=O)[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25]>C(O)C>[CH3:27][O:26][C:22]1[CH:21]=[C:20](/[CH:28]=[CH:4]/[C:5]2[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][N:8]3[C:9](=[O:11])[CH:10]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:23]=1[O:24][CH3:25]
Reactant: Cc1cc(=O)n2ccccc2n1
Reactant: COc1cc(-c2ccccc2C=O)cc(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(/C=C/c2cc(=O)n3ccccc3n2)cc(OC)c1OC

Procedure:
To a solution of 1.3g of sodium methoxide in 75ml of absolute ethanol is added 3.2g of 2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one, followed by 4.0g of 3,4,5-trimethoxyphenyl-benzaldehyde. The mixture is stirred and heated under reflux for 24 hours. The mixture is worked up as described in Example 3 to yield the title compound, melting point 212°-214°C, dec.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:19]([O-])=O)=[C:14]([Cl:22])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl-].[NH4+]>CO.O.[Fe]>[CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH2:19])=[C:14]([Cl:22])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1cc2cc([N+](=O)[O-])c(Cl)cc2[nH]c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)c1cc2cc(N)c(Cl)cc2[nH]c1=O

Procedure:
A suspension of the compound obtained in Step C (7.0 g, 19.4 mmol), powdered iron (10.8 g, 194 mmol) and ammonium chloride (10.4 g, 194 mmol) is stirred at reflux for 1 hour in a mixture of 270 ml of methanol and 90 ml of water. The suspension is filtered hot over Celite and the solid is rinsed several times with methanol. The filtrate is evaporated to dryness and the residue is suspended in water. The solid is filtered off, rinsing with water and drying to obtain the title product in the form of orange crystals.
Reaction SMILES: [OH-:1].[Na+:2].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1>C(O)C.O>[OH2:11].[OH2:1].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([O-:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1.[Na+:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1

Procedure:
20% Aqueous solution of sodium hydroxide was added to a suspension of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 15 g.) in a mixture of ethanol (8 ml.) and water (8 ml.) at room temperature to make a solution of pH 7.5. After filtration and washing, the filtrate and washings were combined (which contained 18.3 ml. of water) and added dropwise to ethanol (46 ml.) at 20° to 25° C. under stirring and stirred at the same temperature for 30 minutes. Ethanol (28 ml.) was added dropwise to the mixture over 30 minutes, and stirred at the same temperature for 2 hours. The precipitates were collected by filtration, washed with ethanol (20 ml.) and dried in vacuo at room temperature to give plates of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate dihydrate (syn isomer, 13.5 g.), mp 260° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[C:11](O)([C:13]([F:16])([F:15])[F:14])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CNc1cc(Br)ccc1N
Reactant: O=C(O)C(F)(F)F
Product: Cn1c(C(F)(F)F)nc2ccc(Br)cc21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The mixture of 5-bromo-N1-methylbenzene-1,2-diamine (300 mg) and TFA (10 ml) was stirred at 90° C. overnight. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4, passed through NH silica gel pad and concentrated in vacuo. The precipitate was collected by filtration, washed with IPE/hexane and dried in vacuo to give the title compound (265 mg) as a purple solid.