Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:42]=[CH:41][C:23]([O:24][C:25]2[CH:26]=[C:27]([NH2:40])[CH:28]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:30]=2)=[CH:22][CH:21]=1)#[N:19]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[NH:40][C:27]2[CH:28]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:30]=[C:25]([O:24][C:23]3[CH:41]=[CH:42][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[CH:26]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: N#Cc1ccc(Oc2cc(N)cc(Oc3ccc(C#N)cc3)c2)cc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1

Procedure:
Following the procedure of Example 107(e) trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid 10.4 g (42.79 mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (14.0 g, 42.79 mmol) were used to afford 12 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.31 (9H, s), 1.8 (4H, d), 2.21 (1H, t), 3.1 (1H, m), 6.81 (1H, d), 7.04 (1H, s), 7.2 (6H, m) 7.91 (4H, dd), 10.0 (1H, s).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15](O)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O.O>C(OCC)(=O)C>[Cl:26][C:15]1[N:14]=[CH:13][N:12]=[C:11]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)CC(c1cc(O)ncn1)C1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-hydroxypyrimidin-4-yl)propanoate (199 mg) and DMF (13 μL) in ethyl acetate (3.0 ml) was added oxalyl dichloride (220 μL), and the mixture was stirred at room temperature for 1 hr. Water was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (194 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]OCC(F)(F)CCC1C=CC=CC=1>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:4][CH2:3][C:2]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([F:11])[F:1]
Reactant: FC(F)(CCc1ccccc1)COCCCCCCBr
Reactant: OCC(F)(F)c1ccccc1
Product: FC(F)(COCCCCCCBr)c1ccccc1
Yield: 78 %

Procedure:
Obtained from Intermediate 6 (6.88 g, 43.5 mmol) by the procedure described in Intermediate 3. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (10:1) as eluent gave the title compound (10.9 g, 78%) as oil.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:14][C:13](=[O:15])[CH:12]=[C:11]1[OH:16])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:16][C:11]1[CH:10]([CH2:9][OH:8])[O:14][C:13](=[O:15])[CH:12]=1
Reactant: [H][H]
Reactant: O=C1C=C(O)C(COCc2ccccc2)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C(O)C(CO)O1
Yield: 94.9 %

Procedure:
386.0 mg (1.75 mmol) of 5-benzyloxymethyl-4-hydroxyfuran-2(5H)-one (Aragon, D. T. et al., J. Org. Chem. 68, 3363-3365, 2003) are initially charged in 19.3 ml of ethanol, 38.6 mg (0.27 mmol) of Pd(OH)2/C (20%) are added and the mixture is hydrogenated at room temperature until the hydrogen uptake has stopped. Removal of the catalyst by filtration and evaporation of the solvent gives 216 mg (94.7% of theory) of 4-hydroxy-5-hydroxymethylfuran-2(5H)-one which can be used without further purification for a subsequent reaction.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][CH2:9][C:10](Cl)=[O:11]>ClCCl>[Cl:8][CH2:9][C:10]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:11]
Reactant: CN1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: CN1CCN(C(=O)CCl)CC1
Temperature: 0 °C

Procedure:
To a solution of N-methylpiperazine (0.096 mL, 0.86 mmol, d=0.902) stirring in dichloromethane (5 mL) at 0° C., was added chloro acetylchloride (0.034 mL, 0.43 mmol, d=1.419). After stirring at 0° C. for an hour, the reaction mixture was diluted with dichloromethane (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain 2-chloro-1-(4-methylpiperazin-1-yl)ethanone.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:8]2[C:9](F)=[CH:10][C:11]([CH3:30])=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH:13]=2)=[N:6][N:7]=1)[CH3:2].Cl.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N:33]1([C:9]2[C:8]([C:5]3[NH:4][C:3]([CH2:1][CH3:2])=[N:7][N:6]=3)=[CH:13][C:12]([C:14]([N:16]3[CH2:17][CH2:18][CH:19]([C:22]4[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=4)[CH2:20][CH2:21]3)=[O:15])=[C:11]([CH3:30])[CH:10]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: C1CNC1
Reactant: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2F)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2N2CCC2)[nH]1
Temperature: 105 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
To a 10-mL sealed tube was added a solution of 4-(1-[[5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylphenyl]carbonyl]piperidin-4-yl)benzonitrile (compound 258.2, 83.5 mg, 0.200 mmol, 1.00 equiv) in 1,4-dioxane (5 mL). Azetidine hydrochloride (93.0 mg, 0.990 mmol, 5.00 equiv) was added to the reaction in portions. Potassium carbonate (276 mg, 2.00 mmol, 10.0 equiv) was also added to the above mixture. The resulting solution was stirred overnight at 105° C. behind a blast shield, then cooled to rt. The reaction was quenched with 20 mL of water. The mixture was extracted with 30 mL of ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product (80 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 50 mL NH4CO3 and CH3CN (41.0% CH3CN up to 43.0% in 8 min, up to 100.0% in 2 min, down to 41.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 18.0 mg (20%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.68 (d, J=6.3 Hz, 2H), 7.48 (d, J=5.7 Hz, 2H), 7.24 & 7.13 (2 singlets, amide rotamers, Ar—H, 1H), 6.52 (s, 1H), 4.91-7.77 (m, 1H partially obscured by water peak), 3.81-3.67 (m, 1H), 3.68 (t, J=5.6 Hz, 4H), 3.32-3.18 (m, 1H), 3.05-1.91 (m, 2H), 2.84 (q, J=5.8 Hz, 2H), 2.45-2.19 (m, 5H), 2.09-1.91 (m, 1H), 1.91-1.49 (m, 3H), 1.39 (t, J=5.7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:24]([O-])=O)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[Cl-].[NH4+].CO>C(O)C.O.C(Cl)Cl.[Fe]>[NH2:24][C:12]1[C:13]([CH:21]2[CH2:23][CH2:22]2)=[CH:14][C:15]2[C:10]([CH:11]=1)=[N:9][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:16]=2[C:17]([NH:19][CH3:20])=[O:18]
Reactant: CNC(=O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Br)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CNC(=O)c1c2cc(C3CC3)c(N)cc2nn1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 69.2 %

Procedure:
To a suspension of compound (viii) (500 mg, 1.20 mmol) in a mixture of ethanol (30 mL) and water (6 mL) was added ammonium chloride (450 mg, 8.43 mmol) followed by iron powder (470 mg, 8.43 mmol). The mixture was heated to 80° C. and stirred vigorously for 90 min. After cooling to RT, 5% MeOH in DCM solution (50 mL) was added to the reaction mixture. The resulting suspension was filtered through celite and washed with MeOH. The filtrate was concentrated in vacuo to give a yellow solid which was then suspended in water (40 mL) and filtered. The solid was collected and dried to give 6-amino-2-(4-bromophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide (ix) (320 mg, 68%) as a yellow solid. ESI-MS m/z calculated for [M+H]+: 385.07/387.06; found: 385.12/387.10.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:6]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:21][CH:22]([CH3:28])[CH2:23][O:24][C:25](Cl)=[O:26].O>CN(C=O)C>[CH2:1]([NH:4][C:5]1[N:14]=[C:13]([NH:15][C:25]([O:24][CH2:23][CH:22]([CH3:28])[CH3:21])=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: CC(C)COC(=O)Cl
Reactant: C=CCNc1nc(N)c2cc([N+](=O)[O-])ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNc1nc(NC(=O)OCC(C)C)c2cc([N+](=O)[O-])ccc2n1
Reaction time: 3 h
Yield: 18.6 %

Procedure:
500 mg (2.04 mmol) of 2-allylamino-4-amino-6-nitroquinazoline was dissolved in 5 ml of DMF, and then 80 mg (2.33 mmol) of 70% sodium hydride and 280 mg (2.05 mmol) of 2-methylpropoxycarbonyl chloride were added thereto under ice cooling, followed by stirring for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, successive washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 131 mg (19.1%) of the title compound.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1.II>C(OCC)(=O)C>[C:9]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][O:1]1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1CCC=CO1
Agent: II
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1CCC=CO1
Temperature: 0 °C
Yield: 86 %

Procedure:
A mixture of (±)-3,4-dihydro-2H-pyran-2-methanol (514 g, 4.51 mol, 1 eq) and acetic anhydride (621 g, 6.09 mol, 1.35 eq) was cooled to 0° C. To the resultant mixture was added pyridine (35.6 g, 0.45 mol, 0.1 eq) and the resultant reaction mixture was allowed to warm to room temperature with stirring. The resultant reaction mixture was allowed to stir for an additional 8 hours after reaching room temperature and was shown to be complete by thin-layer chromatography (2:1 hexanes:ethyl acetate, I2 staining). The reaction mixture was concentrated in vacuo at 35° C. and the resultant residue was diluted using ethyl acetate (2 L). The resultant mixture was transferred to a separatory funnel and sequentially washed with deionized water (3×1 L), saturated aqueous NaHCO3 (2×10 L), and brine (1.0 L). The organic layer was dried over sodium sulfate and concentrated in vacuo at 35° C. to provide (±)-3,4-dihydro-2H-pyran-2-yl-methyl acetate as a clear liquid (605.9 g, 86% yield). 1H NMR (300 MHz, CDCl3) δ 1.6-2.2 (m, 4H), 2.1 (s, 3H), 4.2 (m, 3H), 4.8 (m, 1H), 6.4 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1)[NH2:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH2:11]([O:10][C:8]([C:6]1[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([N:29]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]3)=[C:22]([O:21][CH3:20])[CH:23]=2)[N:7]=1)=[CH2:9])[CH3:12]
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 120 °C

Procedure:
A vial containing 2-chloro-4-(1-ethoxyvinyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (0.29 g, 0.98 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.397 g, 1.96 mmol), cesium carbonate (0.637 g, 1.96 mmol), palladium(II) acetate (0.033 g, 0.15 mmol), 2-(dicyclohexylphosphino)biphenyl (0.051 g, 0.15 mmol) and dioxane (14 mL) was capped, evacuated and flushed with nitrogen. The mixture was heated by microwave irradiation at 120° C. for 1.5 h. The volatiles were removed in vacuum and the residue was extracted with ethyl acetate (20 mL). The solution was filtered through a short pad of silica gel, the pad was washed with ethyl acetate and 10% solution of methanol in ethyl acetate. The solvents were removed in vacuum and the residue was purified by column chromatography using a 0-5% gradient of methanol in dichloromethane to yield the title compound, 418 mg (92%).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([N:7](CC2C=CC(OC)=CC=2)[S:8]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[S:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[N:6]=[C:5]([NH:7][S:8]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=4[C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)(=[O:9])=[O:10])[S:4][N:3]=1
Reactant: COc1ccc(CN(c2nc(Br)ns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C)c3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Nc3nc(Br)ns3)ccc12
Reaction time: 2.5 h
Yield: 84.6 %

Procedure:
A 10-mL round-bottom flask was charged with N-(3-bromo-1,2,4-thiadiazol-5-yl)-N-(4-methoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide (28 mg, 0.039 mmol), DCM (1 mL), and trifluoroacetic acid (60.1 μl, 0.780 mmol). The flask was sealed, and the mixture was stirred for 2.5 h. An additional portion of TFA (0.15 mL) was added, and the resulting mixture was stirred for 48 h. The volatiles were removed in vacuo, and the residue was concentrated again from DCM. The crude product was purified by chromatography on silica gel (5 to 10% MeOH/DCM) to give N-(3-bromo-1,2,4-thiadiazol-5-yl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide (19.91 mg, 0.033 mmol, 85% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=7.94-7.83 (m, 3 H), 7.75 (s, 1 H), 7.55 (d, J=8.5 Hz, 1 H), 7.46-7.35 (m, 2 H), 7.05 (s, 1 H), 6.36 (d, J=1.9 Hz, 1 H), 3.78 (s, 3 H), 3.21 (s, 3 H). m/z (ESI) 597.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([S:28]([N:31]=[CH:32][N:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>C1COCC1.O>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([S:28]([N:31]=[CH:32][N:33]([CH3:34])[CH3:35])(=[O:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[CH:7]=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(SC)c[nH]1
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(SC)cn1Cc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
5 g of 2-butyl 4-(methylthio)1H-imidazole is dissolved in 120 cm3 of THF. 1.55 g of 50% sodium hydride dispersed in oil is then added slowly to the orange-coloured solution obtained. The temperature is increased to 25° C. The reaction medium is agitated for 30 minutes at this temperature then 14 g of 4'-bromomethyl N-[(dimethylamino)methylene](1,1'-biphenyl)2-sulphonamide is introduced. Agitation is carried out at ambient temperature until evolution is complete, that is for about 3 hours. The resultant product is taken up in water, extraction is carried out with ethyl acetate, followed by separation by chromatography on silica, eluting with ethyl acetate then impasting in iso ether, filtration and drying. In this way 9.35 g of the expected product (colourless crystals) is obtained. M.p.=148° C.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].F[S:8]([C:11]1[CH:17]=[C:16]([Br:18])[CH:15]=[C:14]([Br:19])[C:12]=1[NH2:13])(=[O:10])=[O:9].Cl>O>[NH2:13][C:12]1[C:14]([Br:19])=[CH:15][C:16]([Br:18])=[CH:17][C:11]=1[S:8]([OH:10])=[O:9]
Reactant: Nc1c(Br)cc(Br)cc1S(=O)(=O)F
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1c(Br)cc(Br)cc1S(=O)O
Temperature: 70 °C
Yield: 79.4 %

Procedure:
A mixture of sodium sulfite (Na2SO3 ; 20.2 g; 0.16 mol) and water (100 ml) is stirred and heated to 70° C. and 2-fluorosulfonyl-4,6-dibromoaniline (13.3 g; 0.04 mol) is added at once. The reaction mixture cools down somewhat and is reheated to 70° C. and maintained at that temperature for 20 hours. The reaction mixture is then cooled down, acidifed with 10% hydrochloric acid to yield a white precipitate. The precipitate is filtered, washed with water and dried to afford 10 g of title product, m.p. 112° C. (decomposed).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH3:23]>CCO>[NH2:23][CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: N
Solvent: CCO
Product: CCOC(=O)C(=CN)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
12.8 g of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluoro-benzoyl)-acrylate are initially introduced into 16 ml of EtOH. A mixture of 3.3 ml of concentrated aqueous NH3 solution and 10 ml of EtOH is added dropwise with ice cooling. The mixture is subsequentially stirred for 2 hours. Ice-water is then added, and the precipitated solid is filtered off under suction.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.C[O-].[Na+].C[CH2:29][O:30]C(C)=O.O>CN1C(=O)CCC1.[Cu]I>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[O:30][CH3:29]
Reactant: CCOC(C)=O
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: [Cu]I
Agent: C[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 100 °C

Procedure:
A mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg), sodium methoxide (70 mg), CuI (5 mg) in NMP (1.0 ml) was heated at 100° C. for 2.5 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from MeOH-IPE to give 5-(5-amino-6-methoxy-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (58 mg).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.[CH:16]([Li])=[CH2:17]>>[CH3:8][C:2]([C:9]1[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([CH3:1])[CH2:3][CH2:4][C:5](=[O:7])[CH:16]=[CH2:17]
Reactant: CC1=CC=C(C(C)(C)CCC(=O)O)CC1
Reactant: [Li]C=C
Product: C=CC(=O)CCC(C)(C)C1=CC=C(C)CC1

Procedure:
reacting the 4-methyl-4(4-methyl-1,3-cyclohexadien-1-yl)pentanoic acid with vinyl lithium to form the intermediate 6-methyl-6(4-methyl-1,3-cyclohexadien-1-yl)hepten-3-one which is converted via an internal Diels-Alder reaction to form the 1,7,7-trimethyltricyclo[6.2.2.03,8 ]dodec-9-en-4-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6]1.[H-].[Na+].[CH3:40][O:41][C:42](=[O:53])[CH2:43][C:44]1[C:45]([Cl:52])=[N:46][C:47]([CH3:51])=[N:48][C:49]=1Cl.O>COCCOC>[Cl:52][C:45]1[N:46]=[C:47]([CH3:51])[N:48]=[C:49]([O:1][CH2:2][CH2:3][O:4][CH:5]2[CH:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:15][CH:16]=3)[CH2:9][CH2:8][N:7]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6]2)[C:44]=1[CH2:43][C:42]([O:41][CH3:40])=[O:53]
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1c(Cl)nc(C)nc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Reaction time: 0.5 h

Procedure:
A solution of 1.95 g of tertbutyl 3-(2-hydroxyethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 14c) in 20 ml of 1,2-dimethoxyethane is admixed in portions at 0° C. with 0.195 g of sodium hydride dispersion (60%) and stirred for 30 minutes. A solution of 0.91 g of methyl(4,6-dichloro-2-methylpyrimidin-5-yl)acetate in 5 ml of dimethoxyethane is added dropwise and the reaction mixture is stirred at room temperature over 2.5 hours. The reaction mixture is admixed with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.42 (1:1 EtOAc-heptane); Rt=6.10.
Reaction SMILES: [C:1]([NH:11][C:12]1[S:13][C:14]([F:24])=[C:15]([C:17](=[N:21][O:22][CH3:23])[C:18]([OH:20])=O)[N:16]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:25]1([CH:31]([O:38][C:39]([C:41]2[N:46]3[C:47](=[O:50])[C@@H:48]([NH2:49])[C@H:45]3[S:44][CH2:43][CH:42]=2)=[O:40])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:25]1([CH:31]([O:38][C:39]([C:41]2[N:46]3[C:47](=[O:50])[C@@H:48]([NH:49][C:18](=[O:20])[C:17]([C:15]4[N:16]=[C:12]([NH:11][C:1]([O:3][CH2:4][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:2])[S:13][C:14]=4[F:24])=[N:21][O:22][CH3:23])[C@H:45]3[S:44][CH2:43][CH:42]=2)=[O:40])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=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)OCc2ccccc2)sc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
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)OCc2ccccc2)sc1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of 2-(2-carbobenzoxyamino-5-fluoro-4-thiazolyl)-2-methoxyiminoacetic acid (207 mg) and 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (207 mg) in dichloromethane (20 ml) is added dicyclohexylcarbodiimide (142 mg), and the mixture is stirred at 23° C. for 60 minutes and concentrated to remove dichloromethane. The residue is dissolved in ethyl acetate, filtered to remove solid material, and concentrated under reduced pressure. The resultant product is purified by silica gel column chromatography to afford 7β-[2-(2-carbobenzoxyamino-5-fluoro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (281 mg).