Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][NH2:29].Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:16])[N:29]([CH2:28][C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCc1cccs1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1cccs1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 2-thiophene-methylamine (0.13 mL, 1.3 mmol). Purification using silica gel, eluting with 3:1 CH2Cl2/acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 119 as a white solid (m.p. 220-225° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14](O)(=O)[CH3:15]>>[CH3:14][C:15]1[N:8]2[C:7]3[C:6]([O:11][CH2:10][CH:9]2[CH2:12][OH:13])=[CH:5][CH:4]=[CH:3][C:2]=3[N:1]=1
Reactant: CC(=O)O
Reactant: Nc1cccc2c1NC(CO)CO2
Product: Cc1nc2cccc3c2n1C(CO)CO3
Temperature: 95 °C
Reaction time: 8 h

Procedure:
(5-Amino-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl)-methanol (11.8 g, 21.0 mmole) was dissolved in acetic acid (400 mL) and the resulting mixture was stirred at 95° C. overnight. After completion, the reaction was cooled to room temperature and solvent was removed under vacuum and replaced with methanol. Potassium carbonate (2 g) was added and the mixture stirred at room temperature for 1 hour. The solvent was removed and the residue partitioned between 400 mL each of methylene chloride and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum. The crude residue was column chromatographed on silica gel using first methylene chloride to remove impurities and then 5% methanol/methylene chloride to elute 2.34 g of the title compound. 1H NMR (DMSO-d6): δ 7.10 (d, 1H); 7.00 (t, 1H); 6.60 (d, 1H); 5.30 (t, 1H); 4.60 (d, 2H); 4.10 (dd, 1H); 3.60 (m, 2H); 2.50 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[Cl:12][CH2:13][C:14]([NH:16]O)=[NH:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:12][CH2:13][C:14]1[N:16]=[C:6]([C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:11]=[CH:10][CH:9]=2)[O:8][N:15]=1
Reactant: N=C(CCl)NO
Reactant: O=C(O)c1cccc(CO)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCc1cccc(-c2nc(CCl)no2)c1
Temperature: 25 °C
Yield: 25 %

Procedure:
3-Hydroxymethylbenzoic acid, described in Reed, G. A.; Dimmel, D. R.; Malcolm, E. W. J. Org. Chem. 1993, 58 (23), 6372-6376, (175 mg, 1.15 mmol), 2-chloro-N-hydroxy-acetamidine (125 mg, 1.15 mmol) and HBTU was dissolved in anhydrous DMF (4 ml). Triethylamine (0.48 ml, 3.5 mmol) was added and the reaction was stirred at ambient temperature over night. The crude product was partitioned between dichloromethane and NaHCO3 (aq), the organic phase was dried (MgSO4) and the dichloromethane was removed in vacuo. The resulting DMF-solution was heated at 120° C. over night. The reaction mixture was concentrated in vacuo and the title compound (64 mg, 25%) was isolated by flash chromatography using 25-50% ethyl acetate in heptane. 1H NMR (CDCl3), δ (ppm): 8.15 (s, 1H), 8.06 (d, 1H), 7.62 (d, 1H), 7.53 (t, 1H); 4.80 (d, 2H), 4.66 (s, 1H); 1.99 (br. t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:17])C(=O)C1.[OH-].[Na+]>S(=O)(=O)(O)O.O>[Br:17][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccnc(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Cl)ncc1Br
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-4-methoxypyridine (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0° C. was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 hour and then heated at 60° C. for 5 hours. Then it was cooled to room temperature and neutralized with 1 N NaOH (pH ˜7), diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were washed with water (2×50 mL), saturated NaHCO3, brine, dried over Mg2SO4 and concentrated to provide an oil, which was chromatographed. On elution with 0-25% EtOAc/hexanes the final product was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH:3]1[CH2:6][N:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]3[CH:21]=[C:20]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29]C(=O)OCC5C=CC=CC=5)=[C:25]([F:40])[CH:24]=4)[CH:19]=[CH:18][N:17]=3)=[O:14])[CH2:9][CH2:8]2)[CH2:4]1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([N:5]4[CH2:6][CH:3]([N:2]([CH3:41])[CH3:1])[CH2:4]4)[CH2:8][CH2:9]3)=[O:14])[CH:21]=2)=[CH:24][C:25]=1[F:40]
Reactant: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)OCc5ccccc5)c(F)c4)ccn3)CC2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)c(F)c4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 20% palladium hydroxide-carbon (50 mg) to a solution of benzyl {4-[2-({4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-carbonyl}amino)pyridin-4-yloxy]-2-fluorophenyl}carbamate (135 mg) in tetrahydrofuran (10.0 ml), the mixture was stirred for 8 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and the filtrate was concentrated to 3 ml of solvent to provide a crude product of 4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]amide (ESI-MS (m/z): 429[M+H]+). Ethanol (3.0 ml) and (1S)-(+)-10-camphorsulfonic acid (68.3 mg) were added to the crude product. After stirring at room temperature for 10 minutes, 2-(4-fluorophenyl)acetyl isothiocyanate (0.2 M solution in toluene, 3.15 ml) was added and the mixture was stirred at room temperature. After 30 minutes, 2-(4-fluorophenyl)acetyl isothiocyanate (0.2 M solution in toluene, 4.26 ml) was added and stirring was continued at room temperature for 3.5 hours. Ethyl acetate and saturated aqueous sodium hydrogencarbonate were then added to the reaction solution, and the mixture was stirred at room temperature for 2 hours and then partitioned. The aqueous layer was extracted with ethyl acetate, and then the separated organic layer was washed with brine. It was then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated. Diethyl ether and hexane were added thereto, and the produced precipitate (41.3 mg) was filtered. After removing 12 mg of the powder, the remaining 29.3 mg was again purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were combined and concentrated. Diethyl ether and hexane were added thereto, and the produced precipitate was filtered. It was then subjected to aeration drying to provide the title compound (12.8 mg) as white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[O:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].Cl[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:31][C:30]1[C:25]([O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=2)[O:7][C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=2[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:26][CH:27]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:29]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)COc1ccccc1Oc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 27.2 %

Procedure:
A mixture of methyl [o-(5-hydroxy-2-nitrophenoxy)phenoxy]acetate (1.9 g, 5.9 mmol), 2,3-di-chloro-5-(trifluoromethyl)pyridine (1.92 g, 8.9 mmol) and potassium carbonate (1.23 g, 8.9 mmol) in N,N-di-methylformamide is heated at 100° C. for 12 hours, cooled to room temperature, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a yellow oil. Flash chromatography of the oil using silica gel and a (1:4) ethyl acetate/hexanes solution gives the title product as a yellow liquid (0.8 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[C:17](=O)[NH:16][C:15](=O)[N:14]([CH3:20])[C:13]1=O.[H][H]>[Pt].C(OCC)(=O)C>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]2[CH:17]=[N:16][CH2:15][N:14]([CH3:20])[CH2:13]2)[CH:4]=1
Reactant: [H][H]
Reactant: Cn1c(=O)[nH]c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CN1CN=CN(c2cc(N)c(F)cc2Cl)C1

Procedure:
A mixture of 1-(2-chloro-4-fluoro-5-nitrophenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (28.5 g, 0.09 mol) and 5% platinum on activated carbon (1 g) in ethyl acetate is hydrogenated at 55 psi until hydrogen uptake is complete. The reaction mixture is then filtered and concentrated in vacuo to give the title product as a white solid, mp 244°-245° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CN(C=O)C.[OH-].[K+]>O>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNc1ccc(F)cc1)Nc1ccccc1C(=O)O
Yield: 89.3 %

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol), para-fluoroaniline (7.34 mL, 77.5 mmol) and DMF (80 mL) was heated to 75° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature and filtered. The filter cake was rinsed with water (60 mL) and dried under high vacuum at 45° C. to yield 7.98 g (89%) of the title compound as an off-white solid; 1H NMR (DMSO-d6) δ 13.45 (broad s, 1H), 12.00 (s, 1H), 8.72 (d, J=8, 1H), 7.94 (dd, J=8, J=1.2, 1H), 7.59 (td, J=7.2, J=1.6, 1H), 7.13 (td, J=7.2, J=0.8, 1H), 6.95 (m, 2H), 6.58 (m, 2H), 6.47 (s, 1H), 3.82 (s, 2H); 13C NMR (DMSO-d6) δ 170.73, 169.04, 154.95 (J=232.0), 144.78, 140.54, 134.15, 131.13, 122.69, 119.43, 116.00, 115.38 (J=21.9), 113.22 (J=7.6), 49.31.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[N:26]1([C:30]([C:32]2[CH:37]=[CH:36][C:35](F)=[C:34]([Cl:39])[CH:33]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[N:26]1([C:30]([C:32]2[CH:37]=[CH:36][C:35]([O:1][C:2]3[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]4[CH2:23][CH2:22][N:21]([CH3:24])[C:20]4=[O:25])[CH:17]=3)[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:34]([Cl:39])[CH:33]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3Cl)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Yield: 56 %

Procedure:
A mixture of 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (136 mg, 0.4 mmol), azetidin-1-yl-(3-chloro-4-fluoro-phenyl)methanone (CAS no. 863454-79-9) (128 mg, 0.6 mmol) and potassium carbonate (111 mg, 0.8 mmol) in DMA (5 mL) was stirred at 120° C. for 16 hours. The solution was evaporated under reduced pressure, then the residue was dissolved in ethyl acetate (40 mL), washed with water (2×20 mL) and brine (10 mL), then dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by chromatography on silica eluting with 0-4% methanol/DCM to afford the product (120 mg, 56%). m/z 536 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH2:31]=O>>[CH3:31][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:12][CH:11]=3)[N:15]=[C:16]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]=2[CH2:23]1
Reactant: C=O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CNCC3)cc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CN(C)CC3)cc1
Yield: 5 %

Procedure:
6-Methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (8 mg, 5%) was synthesised from N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and formaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 419.2 (M+H)+
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[O:25][CH:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH:22]3[NH2:35])=[N:16][CH:17]=1)([O-:11])=[O:10].N1C=CC=CC=1>CN(C=O)C>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[O:25][CH:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH:22]3[NH:35][C:1](=[O:3])[CH3:2])=[N:16][CH:17]=1)([O-:11])=[O:10]
Reactant: NC1CC(c2ccccc2)Oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NC1CC(c2ccccc2)Oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc21
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Acetic anhydride (60 μl) was added into a cooled solution of 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ylamine hydrochloride (100 mg) and pyridine (41 μl) in dry DMF. Resulting mixture was stirred for a further 20 hours at 0° C. Reaction was quenched with ice water and neutralised. Resulting mixture was extracted with dichloromethane, dried with Na2SO4 and evaporated. Mixture of diastereomers of N-[6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl]-acetamide was recrystallised from dichloromethane. (M)+=405 (24%), 301 (14%), 259 (100%), 242 (55%), 224 (96%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.C[N:18](C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 72 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 10 g of 2,6-dichloro-5-fluoronicotinic acid in 30 mL of toluene, 8.5 g of thionyl chloride and 0.10 mL of N,N-dimethylformamide were added, and the mixture was stirred at 72° C. for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The resultant residue was dropped to 30 mL of 25% ammonium water at −20° C. The temperature was increased to 5 C.°, and the mixture was stirred for 30 minutes. The solid was filtered off to obtain 9.9 g of 2,6-dichloro-5-fluoronicotinamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:15][CH2:14]1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.[OH-].[K+]>O1CCOCC1.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>[CH2:22]([S:19]([N:16]1[CH2:17][CH2:18][CH:13]([C:5]2[C:4]3[C:8](=[C:9]([C:11]#[N:12])[CH:10]=[C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])[CH:3]=3)[NH:7][N:6]=2)[CH2:14][CH2:15]1)(=[O:21])=[O:20])[CH3:23]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(-c4ccccc4F)cc23)CC1

Procedure:
Following the general procedure of Example 65, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carbonitrile (Intermediate 10) (50 mg, 0.102 mmols), 2-fluorophenyl boronic acid (42 mg, 0.306 mmols), potassium hydroxide (84 mg, 0.612 mmol), and Pd(PPh3)4 (10 mg) in dioxane/water (6/1, 3.5 mL) were reacted to give the crude title compound.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:21]=[C:20]2[N:8]([CH2:9][C:10]3[C:11]2=[N:12][C:13]2[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:22])[C:6]=1[CH3:23])[CH2:3][CH3:4].[CH:24]1[C:36]2[CH:35]([CH2:37][O:38][C:39]([NH:41][CH2:42][P:43](=O)([OH:45])[OH:44])=[O:40])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1>O>[CH:33]1[C:34]2[CH:35]([CH2:37][O:38][C:39]([NH:41][CH2:42][P:43]([OH:45])([O:1][CH:2]([C:5]3[CH:21]=[C:20]4[N:8]([CH2:9][C:10]5[C:11]4=[N:12][C:13]4[C:18]([CH:19]=5)=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:7](=[O:22])[C:6]=3[CH3:23])[CH2:3][CH3:4])=[O:44])=[O:40])[C:36]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: O=C(NCP(=O)(O)O)OCC1c2ccccc2-c2ccccc21
Solvent: O
Product: CCC(OP(=O)(O)CNC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 21 except using (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one and [[[(9-fluorenylmethoxy)carbonyl]amino]methyl]phosphonic acid. Anal. Calcd for C35H32N3O6P.9/8 H2O: C, 65.49; H, 5.38; N, 6.55. Found: C, 65.83; H, 5.28; N, 6.14.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][C:21](=[CH:23][C:24]#[N:25])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1.N12CCCN=C1CCCCC2>C(#N)C>[Si:1]([O:18][CH:19]1[CH2:22][C:21]([CH2:23][C:24]#[N:25])([N:26]2[CH:30]=[C:29]([C:31]3[C:32]4[CH:39]=[CH:38][N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:33]=4[N:34]=[CH:35][N:36]=3)[CH:28]=[N:27]2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](OC1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of (3-{[tert-butyl(diphenyl)silyl]oxy}cyclobutylidene)acetonitrile (1.859 g, 4.065 mmol) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.28 g, 4.06 mmol) in acetonitrile (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.61 mL, 4.1 mmol). The reaction was stirred overnight. The solvent was remove in vacuo. The crude was purified with silica gel column to give of the product (2.7 g, 79%) as an oil. LCMS (M+H)+: 663.3.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]=[C:12]([CH:18]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cc(Br)cc(C(=O)OCC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1cc(C(=O)OCC)cc(-c2ccccc2)c1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
A mixture of Na2CO3 (776 mg, 7.32 mmol), Pd (OAc)2 (4.5 mg, 0.02 mmol), diethyl 5-bromoisophthalate (1 g, 3.66 mmol), phenyl boronic acid (670 mg, 5.49 mmol), distilled water (14 mL) and acetone (12 mL) was stirred at 35° C. for 0.5 h. The reaction solution was then extracted four times with diethyl ether (4×20 mL). The combined organic phase washed with brine, dried over sodium sulfate and then filtered. The solvent was removed under vacuum, and the crude diethyl biphenyl-3,5-dicarboxylate was taken to the next step without any further purification.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][CH2:28][C:29]([NH:31][C:32]1[S:33][C:34]([Cl:44])=[C:35]([C:37](=[N:41][O:42][CH3:43])[C:38](O)=[O:39])[N:36]=1)=[O:30]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:38](=[O:39])[C:37](=[N:41][O:42][CH3:43])[C:35]4[N:36]=[C:32]([NH:31][C:29](=[O:30])[CH2:28][Cl:27])[S:33][C:34]=4[Cl:44])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reactant: CON=C(C(=O)O)c1nc(NC(=O)CCl)sc1Cl
Solvent: ClCCl
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12)c1nc(NC(=O)CCl)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (1.10 g) in dichloromethane (120 ml) are added a solution of 2-(2-chloroacetamido-5-chloro-4-thiazolyl)-2-methoxyiminoacetic acid (1.20 g) and N,N-dicyclohexylcarbodiimide (0.80 g), and the mixture is stirred for 30 minutes at room temperature. After concentrating to remove dichloromethane, the obtained residue is treated with a small amount of ethyl acetate and filtered to remove insoluble material. The solution is concentrated in vacuo, and the residue is purified by chromatography on silica gel affording 7β-[2-methoxyimino-2-(2-chloroacetamido-5-chloro-4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (1.49 g). mp. 149°-151° C. when crystallized from benzene. Similarly prepared are compounds of Table 1.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][N:14]=[C:13]([OH:16])[C:12]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].FC1C=C[C:28]([C:31]2[C:32](O)=[N:33]NC=2C2C=CC(S(C)(=O)=O)=CC=2)=[CH:27]C=1>O>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]3[O:16][C:31]([C:32]#[N:33])=[C:28]([CH3:27])[N:14]3[N:15]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2[nH]nc(O)c2-c2ccc(F)cc2)cc1
Reactant: NS(=O)(=O)c1ccc(-c2[nH]nc(O)c2-c2ccc(F)cc2)cc1
Solvent: O
Product: Cc1c(C#N)oc2c(-c3ccc(F)cc3)c(-c3ccc(S(N)(=O)=O)cc3)nn12

Procedure:
The desired compound was prepared according to the method of Example 54C, substituting 5-(4-(aminosulphonyl)phenyl)-4-(4-fluorophenyl)-3-hydroxypyrazole prepared according to the method of Example 55C in place of 4-(4-fluorophenyl)-3-hydroxy-5-(4-(methylsulphonyl)phenyl)pyrazole (yield: 35 mg, 13%). MP 231-232° C.; MS (APCI+) m/z 397 (M+H)+; (APCI−) m/z 395 (M−H)−, 431 (M+Cl)−; 1H NMR (300 MHz, DMSO-d6) δ2.65 (s, 3H), 7.30 (m, 4H), 7.47 (s, 2H), 7.67 (d, J=9 Hz, 2H), 7.88 (d, J=9 Hz, 2H); Anal. calc. for C19H13FN4O3S.1.5 H2O: C, 53.89; H, 3.80; N, 13.23. Found: C, 53.82; H, 3.93; N, 11.38.