Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH3:10])[C:5]([NH2:8])=[CH:6][CH:7]=1.[S:11](N)(N)(=[O:13])=[O:12].N1C=CC=CC=1.Cl>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][S:11](=[O:13])(=[O:12])[N:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: NS(N)(=O)=O
Reactant: CNc1cc(Br)ccc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1c2cc(Br)ccc2NS1(=O)=O
Temperature: 125 °C
Reaction time: 14 h

Procedure:
To a round bottom flask was added 4-bromo-N2-methylbenzene-1,2-diamine (1-2) (9.07 g, 45.1 mmol), sulfamide (8.84 g, 92 mmol), and finally anhydrous pyridine (75 mL). The reaction mixture was then heated to 125° C. while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 14 hours. The crude reaction mixture was then allowed to cool to room temperature, suspended in ethyl acetate and added 6N HCl until pH <3. Crude mixture was then filtered. Filtrate organics were separated, then washed with 6N HCl twice dried over sodium sulfate, filtered, and concentrated to give 6-bromo-1-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1-3). HRMS (M+H)+: observed=262.9486, calculated=262.9484.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OC[C@@H](C)CC)c(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC[C@H](C)COc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 80 °C
Yield: 51.5 %

Procedure:
To a solution (10 ml) of ethyl 1-(3-cyano-4-((S)-2-methylbutoxy)phenyl)-pyrazole-4-carboxylate (1.7 g) in ethanol was added 1 N aqueous sodium hydroxide solution (6.3 ml) with stirring, and the mixture was heated at 80° C. for 30 minutes. After the completion of the reaction, the reaction mixture was pouted into water and neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solvent of ethyl alcohol and water to give 0.8 g of 1-(3-cyano-4-((S)-2-methylbutoxy) phenyl)pyrazole-4-carboxylic acid, melting point 184-186° C. [α] D25 +10.49° (c=0.5,MeOH)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14]([O:16][CH3:17])=O)[CH:13]=1.Br[C:26]1[C:27](=O)[N:28](C2C=CC=CC=2)[CH:29]=[C:30](C(OC)=O)[CH:31]=1.ClC1C=CC=CC=1B(O)O.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:12]([C:14]2[O:16][C:17]3[CH:29]=[CH:30][CH:31]=[CH:26][C:27]=3[N:28]=2)[CH:13]=1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)c(=O)n(-c2ccccc2)c1
Reactant: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: OB(O)c1ccccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2Cl)cc(-c2nc3ccccc3o2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19 mg of carboxylate obtained by hydrolyzing the ester group of 3-(2-chlorophenyl)-5-(methoxycarbonyl)-1-phenyl-1,2-dihydropyridin-2-one (synthesized from 3-bromo-5-(methoxycarbonyl)-1-phenyl-1,2-dihydropyridin-2-one and 2-chlorophenylboronic acid in accordance with the method of Referential Example 3) was dissolved in 20 ml of dichloromethane. Under ice-cooling, a solution of 11 mg of oxalyl chloride in dichloromethane was added dropwise thereinto and a catalytic amount of dimethylformamide was added thereto, followed by stirring at room temperature in nitrogen atmosphere for 1 hour. The reaction solution was evaporated, and the residue was dissolved in dichloromethane. The solution was added dropwise into a solution of 19 mg of 2-aminophenol in dichloromethane under ice-cooling. After heating to room temperature, dichloromethane was evaporated. To the residue was added 1 ml of polyphosphoric acid, followed by stirring at 180° C. overnight. After cooling to room temperature, the reaction mixture was neutralized with 1N aqueous solution of sodium hydroxide and saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was extracted with ethyl acetate, and the resulting organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 3 mg of the title compound as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[O:4].[N-:21]=[N+:22]=[N-:23].[Na+]>>[N:21]([CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[O:4])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)C1CN(C(=O)CCl)CCO1
Agent: [Na+]
Product: [N-]=[N+]=NCC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Yield: 86.4 %

Procedure:
In a 25-mL round-bottom flask, the benzyl 4-(2-chloroacetyl)morpholine-2-carboxylate (0.262 g, 0.88 mmol) was dissolved in dmf (4 mL). Sodium azide (0.066 g, 1.0 mmol) was added, and the flask was placed in a 60 deg oil bath overnight. The reaction was concentrated, and the residue was taken up in 80% ether-hexane (60 mL) and the organic layer was extracted with dilute sodium bicarbonate (2×7 mL) then with saturated brine (7 mL), then was dried over magnesium sulfate, filtered, and concentrated. The residue was purified through silica gel (50 mL) which had been deactivated with TEA (5 mL) using 60% EtOAc-hexane to afford the title compound (230 mg, 0.76 mmol). MS m/z 305 (M+1).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>C1COCC1>[Br:1][C:2]1[O:6][C:5]([C:7](=[O:9])[CH2:8][C:22](=[O:23])[C:21]([F:28])([F:27])[F:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(Br)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccc(Br)o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a stirred solution of compound 43 (4.8 g, 25.4 mmol) in THF (60 mL) at −78° C., LiHMDS (38 mL, 38.1 mmol) was added dropwise and the reaction stirred −78° C. for 1 h. Ethyl 2,2,2-trifluoroacetate (4.5 g, 38.1 mmol) was then added dropwise. The reaction mixture was allowed to gradually warm to room temperature in cooling bath and stirred overnight. Solvent was removed, cold water (50 mL) was added, and the reaction mixture extracted with diethyl ether (100 mL×3). Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure. Crude compound was washed with diethyl ether and hexane to afford compound 44 (5 g, 69%) as a white solid.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH:5]([NH:22][C:23](=[O:32])[C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.O>CN(C=O)C>[F:20][CH:19]([F:21])[S:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]3[CH2:4][O:32][C:23]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])=[N:22]3)=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: O=C(NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(SC(F)F)cc3)cc2)CO1
Reaction time: 3 h
Yield: 72 %

Procedure:
A portion of 0.093 g (1.16 mmol) of sodium hydroxide solution (50%) was added dropwise to 0.53 g (1.16 mmol) of N-[2-chloro-1-[4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-yl]ethyl]-2,6-difluorobenzamide in 3.5 mL of DMF. After 3 h, a further portion, 0.045 g (0.56 mmol) of sodium hydroxide solution (50%) was added. When the reaction was completed by TLC, the mixture was poured into water (50 mL). The aqueous mixture was extracted with 3×50 mL of ethyl acetate. The combined extracts were dried and the solvent was removed under reduced pressure. The residue was dissolved in 100 mL of ether. The ethereal solution was washed with 50 mL of water, dried, and the solvent was removed under reduced pressure gave the product, 0.35 g (72% yield), as a pale yellow solid, indistinguishable from the product of Example 6.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=[O:22])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=1[O:20][CH3:21])[CH2:2]2.C([O-])(=O)/C=C/C([O-])=[O:27]>>[ClH:17].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH+:9]([O-:27])[C:10](=[O:22])[C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=1[O:20][CH3:21])[CH2:2]2
Reactant: CNc1cc(OC)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: CNc1cc(OC)c(C(=O)[NH+]([O-])C2CN3CCC2CC3)cc1Cl
Product: Cl

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide, fumarate [1:1] is converted to the free base by partitioning with aqueous sodium hydroxide and methylene chloride. Using the procedure of Example 1, the free base is reacted with peracetic acid to obtain the N-oxide and finally with hydrogen chloride in isopropanol to give the hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCOC(C)=O>C1COCC1>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=2)[CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1cc(CCl)cc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Yield: 99.9 %

Procedure:
Stir the mixture of 1-(chloromethyl)-3-nitro-5-(trifluoromethyl)benzene (640 mg, 2.68 mmol) and N-methylpiperazine (536 mg, 5.36 mmol) in THF (8 mL) for 2 hrs at 60° C. TLC (EtOAc:PE=1:1) shows the reaction is complete. Concentrate the reaction mixture under reduced pressure to obtain the crude product (812 mg, 100%). MS: (M+1): 303.1.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[S:34]([Cl:37])(=[O:36])=[O:35].N1C(C)=CC=CC=1C>O1CCCC1.CO>[ClH:37].[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][S:34]([C:28]3[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])(=[O:36])=[O:35])=[CH:15][CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN1CCC(c2cn(CCc3ccccc3)c3ccc(O)cc23)CC1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: Cc1cccc(C)n1
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(c2cn(CCc3ccccc3)c3ccc(OS(=O)(=O)c4c(F)cccc4F)cc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.1 %

Procedure:
To a solution of 1-phenethyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (175 mg, 0.52 mmol) and 2,6-difluorobenzenesulfonyl chloride (133 mg, 0.58 mmol) in tetrahydrofuran (20 mL), stirring at room temperature, was added 2,6-lutidine dropwise (134 mL, 1.16 mmol). The reaction mixture was stirred for 72 hours at room temperature, before diluting it with methanol (15 mL) and applying it directly to a 5 g SCX column. After thoroughly washing with methanol, the column was eluted with a 9:1 mixture of dichloromethane and 2 N ammonia in methanol. The eluent was concentrated in vacuo to a residue, which was purified on silica gel. Elution with a 9:1 mixture of dichloromethane and methanol provided 191 mg (64%) of the free base of the desired compound as a tan gum. The gum was further purified by preparative reverse-phase HPLC, which provided 156 mg (44%) of the title hydrochloride as an off-white solid: mp=209-212° C.; 1H NMR (400 MHz, dmso-d6): 10.55 (br s, 1H), 7.95-7.82 (m, 1H), 7.48-7.34 (m, 3H), 7.30 (s, 1H), 7.25-7.08 (m, 6H), 6.76 (br d, 1H, J=8.4 Hz), 4.29 (t, 2H, J=7.4 Hz), 3.41 (br d, 2H, J=12.4 Hz), 3.10-2.97 (m, 2H), 2.96 (t, 2H, J=7.0 Hz), 2.94-2.82 (m, 2H), 2.72 (s, 3H), 1.96-1.75 (m, 4H); MS (APCI): m/e 511.2 (M+1); Calculated (for C28H28F2N2O3S.HCl.0.6H2O): C 60.39, H 5.28, N 5.03; found: C 60.43, H 5.41, N 5.14.
Reaction SMILES: [CH3:1][C:2]1[O:3]CC[N:6]=1.[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[OH:17].[C:18](OCC)(=O)[CH3:19]>>[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:17][CH2:18][CH2:19][CH2:1][C:2]([NH2:6])=[O:3]
Reactant: Oc1ccc2ccccc2c1
Reactant: CC1=NCCO1
Reactant: CCOC(C)=O
Product: NC(=O)CCCOc1ccc2ccccc2c1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A 3-neck round bottom flask was charged with 2-methyl-2-oxazoline (5.9 mL, 69.4 mmol) followed by 2-naphthol (10.0 g, 69.4 mmol) at room temperature. The resulting mixture was heated to reflux and stirred for 6 h. Reaction was monitored by TLC analysis. Additional 2-methyl-2-oxazoline (2.5 mL, 29.4 mmol) was added to ensure complete conversion of the 2-naphthol and the reaction mixture was heated to reflux for 16 additional hours. The reaction mixture was cooled to 70° C. then poured into ethyl acetate (100 mL) and stirred for 15 min. The resulting slurry was filtered and washed with ethyl acetate (25 mL). The filter cake was further dried under vacuum to afford -(2-(naphthalen-2-yloxy)ethyl)acetamide as an off white solid (12.35 g, 77.7% yield). 1H NMR (DMSO-d6, 400 MHz) δ 8.179-8.126 (m, 1H), 8.84-7.79 (m, 3H), 7.7.48-7.43 (m, 1H), 7.37-7.32 (m, 2H), 7.18 (dd, j=2.59 Hz, 8.97 Hz, 1H) 4.11 (t, j=5.66, 2H), 3.48 (q, j=5.90 Hz, 2H), 1.85 (s, 3H).
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:36][CH2:37][CH3:38])(=[O:35])[C:31]#[C:32][CH2:33][CH3:34]>CN(C)C=O.O>[CH2:33]([C:32]1[C:31]([C:30]([O:36][CH2:37][CH3:38])=[O:35])=[C:16]2[C:17]3[CH2:23][CH2:22][O:21][C:18]=3[CH:19]=[CH:20][N:15]2[N:14]=1)[CH3:34]
Reactant: CCC#CC(=O)OCC
Reactant: N[n+]1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)nn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.2 %

Procedure:
To a mixture of 5-amino-2,3-dihydrofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (8.00 g, 25.0 mmol) and potassium carbonate (4.84 g, 35.0 mmol) in dimethylformamide (100 mL) was added ethyl 2-pentynoate (3.63 mL, 27.5 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (794 mg, yield 12%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:17])([F:16])[C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH2:7][S:8]([NH2:11])(=[O:10])=[O:9].[H][H].[Cl:20][C:21]1[N:26]=[C:25]([C:27](Cl)=[O:28])[CH:24]=[C:23]([CH3:30])[N:22]=1>C(COC)OC>[F:17][C:4]([F:16])([F:3])[C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH2:7][S:8]([NH:11][C:27]([C:25]1[CH:24]=[C:23]([CH3:30])[N:22]=[C:21]([Cl:20])[N:26]=1)=[O:28])(=[O:9])=[O:10]
Reactant: Cc1cc(C(=O)Cl)nc(Cl)n1
Reactant: [H][H]
Reactant: NS(=O)(=O)Cc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(C(=O)NS(=O)(=O)Cc2ccccc2C(F)(F)F)nc(Cl)n1
Yield: 35.4 %

Procedure:
0.44 g of sodium hydride suspension (60% strength in mineral oil) is added to a stirred solution of 2.4 g of 2-trifluoromethylbenzylsulfonamide in 40 ml of dimethoxyethane and stirring is continued until the evolution of hydrogen is complete. A solution of 2-chloro-6-methylpyrimidine-4-carbonyl chloride (from 2.1 g of carboxylic acid, 20 ml of dioxane, [lacuna] drops of dimethylformamide and 2.1 g of thionyl chloride) in 20 ml of dimethoxyethane is rapidly added dropwise to this. The mixture is then stirred at room temperature for 3 h and worked up as described in Example 13. 1.4 g of 2-trifluoromethyl-N-[(2-chloro-6-methylpyrimidin-4-yl)carbonyl]benzylsulfonamide of melting point 198°-199° C. are obtained in this way.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.CC(O[CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.Cl>C(N(CC)CC)C.O>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][S:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH2:22][S:21][C@H:16]12
Reactant: Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 53 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A solution of 72.5 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole (MTA) in 87.5 ml of triethylamine in 3 liters of water was heated to 75° C. 68 g of 7-aminocephalosporanic acid (92%) were added, to give a suspension with pH 4.35. 28 ml of triethylamine were added at the same temperature and the solution thus formed, with pH 5.20, was held for 30 min at 75° C. and 60 min at 53° C. Throughout the whole operation the reaction isoelectric pH was held to 5.25 with the gradual addition of a solution of 20 g of thiol (MTA) in 175 ml of water. The formation rate of the precipitate increased on cooling to 53° C. The mixture was adjusted to pH 4.25 at 25° C. with concentrated hydrochloric acid. It was filtered, washed with water and then acetone to give 52.8 g of the compound of the title with a 70% yield. It was recrystallised out of an aqueous hydrochloric acid solution at pH 2.20 and isolated with a m.p. 224° C. (d).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[C:4]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: Cc1cccnc1Oc1cccc(C=C2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccnc1Oc1cccc(C=C2CCN(C(=O)Nc3cccnc3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
3-Methyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (500 mg, 1.42 mmol, from Step 5), phenyl pyridin-3-ylcarbamate (333 mg, 1.56 mmol) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):CH2Cl2) to afford the title compound (445 mg) as a foamy white solid. MS (APCI 10V) AP+ 401.4, 281.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.33 (s, 3H) 2.44 (td, J=5.81, 1.29 Hz, 2H) 2.57 (td, J=5.92, 1.22 Hz, 2H) 3.50-3.57 (m, 2H) 3.61-3.68 (m, 2H) 6.44 (s, 1H) 6.83-6.94 (m, 2H) 7.00-7.09 (m, 2H) 7.28-7.41 (m, 2H) 7.64-7.74 (m, J=7.28, 2.03, 1.07, 1.07 Hz, 1H) 7.87-7.96 (m, 2H) 8.16 (dd, J=4.80, 1.44 Hz, 1H) 8.58 (dd, J=2.60, 0.72 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH:23]=O)[CH:16]=[C:17]([F:20])[C:18]=1[CH3:19]>>[F:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH:23]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)[CH:16]=[C:17]([F:20])[C:18]=1[CH3:19]
Reactant: CCc1nc(I)cn1CCN
Reactant: Cc1c(F)cc(CCC=O)cc1F
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(C)c(F)c1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (296.9 mg; 1.120 mmol) and 3-(3,5-difluoro-4-methyl-phenyl)-propionaldehyde (206.7 mg; 1.120 mmol) afforded 8-[2-(3,5-difluoro-4-methyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:10]=1[CH:11]=[N:12][NH2:13])=[O:5])C>C(O)(=O)C.C1(C)C=CC=CC=1>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:8]1[N:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:10]2[CH:11]=[N:12][NH:13][C:4](=[O:5])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1C=NN
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=c1[nH]ncc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-hydrazonomethyl-1H-imidazole-4-carboxylic acid ethyl ester (I-2f, 54 mg, 0.134 mmol) and glacial acetic acid (1 drop) in toluene (3 ml) was heated under reflux for 18 hours, at which time a white solid precipitated out of solution. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified via 1 mm chromatotron plates using 100% EtOAc as solvent to give the desired product (I-2g) as a white solid (22 mg): +APCI MS (M+1) 357.1; 1H NMR (CD2Cl2) δ 7.18–7.48 (8H, m), 8.01 (1H, s), 10.60 (1H, s).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1C=CC=CC=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.BrCCCCC(C)(C)CO.O1C=CCCC1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Agent: C1=COCCC1
Agent: CC(C)(CO)CCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CCCCBr)COC1CCCCO1
Yield: 83 %

Procedure:
According to the procedure for the preparation of 207d, (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818) 206c (521.0 g, 2.49 mol) was reacted with 3,4-dihydro-2H-pyran (278.0 g, 3.30 mol) and p-toluenesulfonic acid hydrate (3.13 g, 16 mmol) in CH2Cl2 (2.2 L) to yield 207c (603.0 g, 83%) as a pale-yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 4.55 (t, 1H, J=3.3), 3.84 (m, 1H), 3.50 (m, 1H), 3.47 (d, 1H, J=9.0), 3.42 (t, 2H, J=6.7), 2.99 (d, 1H, J=9.0), 1.88 (m, 2H), 1.75-1.33 (m, 10H), 0.91 (s, 3H), 0.90 (s, 3H). 13C NMR (CDCl3): δ 99.37, 76.58, 62.17, 38.56, 34.43, 34.19, 33.90, 30.88, 25.79, 24.80, 24.71, 22.89, 19.67. HRMS (LSIMS, nba): Calcd for C13H25BrO2 (MH+): 293.1116, found: 293.1128.