Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[N:17]=1>CN(C=O)C.C(OCC)C>[Cl:14][CH2:15][C:16]1[N:17]=[C:18]([CH3:22])[C:19]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[CH:20][CH:21]=1
Reactant: ClCc1cccc(CCl)n1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(CCl)nc1C
Reaction time: 168 h
Yield: 59.9 %

Procedure:
To a solution of acetylsalicylic acid (1.6 g, 8.88 mmoles) in N,N′-dimethylformamide (20 ml) and under stirring sodium ethylate (0.64 g, 8.88 mmoles) is added. After 30 minutes the obtained solution is added to a solution of 2,6-bis-(chloromethyl)pyridine (4.72 g, 26.81 mmoles) in N,N′-dimethylformamide (20 ml). The solution is left at room temperature for 7 days, under stirring, then it is diluted with ethyl ether and washed with water. The separated organic phases are anhydrified with sodium sulphate and the solvent is evaporated at a reduced pressure. The reaction raw product is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. 1.7 g of the product as yellow oil are obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](O)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([Cl:22])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
4′-Trifluoromethyl-biphenyl-2-carboxylic acid (25 g, 94 mmol) was combined with thionyl chloride (35 ml, 470 mmol) and the mixture was heated at reflux. After 2 h, the mixture was concentrated under vacuum to afford 26.5 g of the title product as a light yellow oil.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:26])([F:25])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22](O)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1.S(Cl)([Cl:29])=O>CN(C=O)C>[F:8][C:9]([F:26])([F:25])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]([Cl:29])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a nitrogen purged 3 liter 4-neck flask fitted with a condenser, mechanical stirrer, temperature probe, and connected to a 2M aqueous NaOH scrubber was added toluene (1 L), 4′-trifluoromethyl-biphenyl-2-carboxylic acid (250 g, 0.94 mol, 1 equiv), and DMF (5 mL). 4′-Trifluoromethyl-biphenyl-2-carboxylic acid can be obtained from Aldrich, Milwaukee, Wis. The solution was heated to 60° C. and thionyl chloride (110 mL, 1.5 mol, 1.6 equiv) was added at such a rate as to maintain the temperature below 65° C. The addition was complete after 30 minutes and the reaction was heated to reflux. After 4 hours, the heating was stopped and the reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was used in the next step without further purification. The material crystallized to a solid at room temperature.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].S(OC)(OC)=O>>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH3:14])[CH:1]=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: [K+]
Solvent: COS(=O)OC
Product: COc1cc(C=O)cc(OC)c1OC
Temperature: 100 °C
Yield: 59.5 %

Procedure:
In an apparatus as in Example 1, 10.0 g (0.054 mol) of syringaldehyde and 5.00 g (0.036 mol) of potassium carbonate were heated to 100° C. and 8 ml (0.094 mol) of dimethyl sulfite was added over a 5 minute period. The pasty mixture was heated to 100° C. for 3 hours then cooled to 25° C. and quenched with 50 ml water. The mixture was extracted with 100 ml of methylene chloride. The extracts were washed with water and concentrated in vacuo to get 4.2 g (54% based on recovered syringaldehyde) of 3,4,5-trimethoxybenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO>[NH2:1][C:2]1[C:7]([O:11][CH3:10])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(N)c(Br)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cnc1N
Temperature: 25 °C
Yield: 75 %

Procedure:
2-Amino-3-bromo-5-methylpyrazine (0.374 g) was added to a freshly prepared solution of sodium methoxide in methanol (made by addition of sodium (0.115 g) to methanol (6 ml)). The reaction was heated under reflux for 18 hours, cooled to ambient temperature and the solvent removed by evaporation. Water (5 ml) was added to the residue and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give 2-amino-3-methoxy-5-methylpyrazine as a white crystalline solid (0.208 g, 75%), m.p. 67-69° C.; mass spectrum (+ve CI): 140 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][C:14](OC)=[O:15]>C(OC)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:14](=[O:15])[CH2:13][O:12][CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: COCC(=O)OC
Solvent: COC(C)(C)C
Product: COCC(=O)NC(C)c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
At room temperature, a solution of 7.8 g (0.05 mol) of racemic 1-(4-chloro-phenyl)-ethylamine in 40 ml of methyl tert-butyl ether is mixed with stirring with 10.4 g (0.1 mol) of methyl methoxyacetate and then with 0.45 g of Novozym 435® (=immobilized lipase from Candida antarctica; 7300 U/g). Stirring is continued at 60° C. and the progress of the reaction is monitored by gas chromatographic sample analysis. After 3 hours, the conversion is 54%. At this stage, the reaction is terminated by filtering off the enzyme. In the filtrate that remains, the (S)-enantiomer of 1-(4-chlorophenyl)-ethylamine has an ee value of 98.8%, while the (R)-enantiomer of N-(1-(4-chlorophenyl)-ethyl]-methoxyacetamide obtained has an ee value of 94.4%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[N+:13]([CH3:16])([O-:15])=[O:14].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1([CH2:16][N+:13]([O-:15])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCCCC1

Procedure:
14.8 g (0.088 mol) of the cyclohexylideneacetic acid ethyl ester produced according to 1.1 were dissolved in 50 ml of tetrahydrofuran, 7.11 ml (0.132 mol) of nitromethane and 88 ml of tetrabutylammonium fluoride (1 molar in tetrahydrofuran) were added under a nitrogen atmosphere and refluxed for 20 hours. After cooling, the mixture was diluted with 50 ml of water and extracted three times with dieethyl ether. The organic phase was washed with 10 wt. % aqueous potassium hydrogensulfate solution and then washed with water, dried over magnesium sulfate and evaporated. (1-Nitromethylcyclohexyl)acetic acid ethyl ester was obtained as an orange-yellow oily liquid. The yield amounted to 19.8 g (98% of theoretical).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1.ClC1C=C(Cl)C=CC=1C(O)=O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Agent: O=C(O)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 72.05 %

Procedure:
Into a 300 ml glass reactor equipped with a reflux condenser and a stirrer, and 50 g (0.207 mol) of the mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone, 59.3 g (0.31 mol) of 2,4-dichlorobenzoic acid and 100 ml of xylene were charged, and the mixture was reacted at 150° C. for 12 hours with vigorous stirring. Then, the reaction mixture was separated by distillation to obtain 32.8 g of tetrafluorophthalic anhydride. The yield was 72.05%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[N+:15]([O-])([OH:17])=[O:16].O>OS(O)(=O)=O>[N+:15]([C:7]1[CH:6]=[C:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH:10]=[CH:9][C:8]=1[NH:11][C:12](=[O:14])[CH3:13])([O-:17])=[O:16]
Reactant: CCC(=O)c1ccc(NC(C)=O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of N-(4-propionylphenyl)acetamide (1.91 g, 10 mmol) in 20 mL of concentrated H2SO4 was added 2 mL 98% HNO3 over 10 minutes while maintain the temperature at −10° C. After stirring for 0.5 h, the mixture was poured into 100 mL of cold water. The precipitate was collected by filtration and washed with water to give the crude product (1.18 g, 50%), which was used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.[H][H].[CH:10](=[C:17]([CH2:21][OH:22])[C:18]([OH:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.[C].[Pd]>[OH:22][CH2:21][CH:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19]
Reactant: [H][H]
Reactant: O=C(O)C(=Cc1ccccc1)CO
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)C(CO)Cc1ccccc1
Yield: 65.7 %

Procedure:
The product (107.8 g) in Reference Example 3, namely 2-benzylidene-3-hydroxypropionic acid, is dissolved in methanol (500 ml), followed by addition of triethylamine (100 ml; 717 mmol) and 5% palladium-carbon (5.00 g; water content of 52.7%) for catalytic reduction in a hydrogen atmosphere for 50 hours. The reaction solution is filtered through Celite to remove the palladium-carbon. The resulting filtrate is subjected to HPLC analysis, indicating that the filtrate contains the title compound (71.0 g; 394 mmol) (at a yield of 65.7% (on a benzaldehyde basis)). The filtrate is concentrated under reduced pressure, and the resulting residue is dissolved in ethyl acetate (600 ml), followed by addition of water (600 ml) and 37% hydrochloric acid (150 ml) and subsequent agitation, to extract the resulting organic phase. The organic phase is washed with an aqueous mixture solution of water (240 ml) and 37% hydrochloric acid and then with saturated saline (300 ml), and dried over anhydrous sodium sulfate. By filtering off the resulting dried matter, the solution is concentrated under reduced pressure, to give a crude product of the title compound. The crude product is dissolved in ethyl acetate (150 ml) , followed by addition of hexane (450 ml), and the resulting mixture is gradually cooled from 60° C. to 5° C., to precipitate crystal, which is then filtered and dried to recover the title compound (48.45 g at a purity of 96.5%; 295.5 mmol).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([N:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:3][CH:2]=1.C1C(=O)N([Br:34])C(=O)C1.O>CN(C=O)C>[Br:34][C:23]1[CH:24]=[CH:25][C:26]2[N:14]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: c1ccc2c(c1)sc1c(-n3c4ccccc4c4ccccc43)cccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9-(dibenzo[b,d]thiophen-4-yl)-9H-carbazole (6 g, 17.17 mmol) was dissolved in 100 mL of DMF. The solution was cooled to 0° C. To the solution was added NBS (3.36 g, 18.89 mmol) in 20 mL of DMF dropwise. After stirring at this temperature for 1 h, HPLC indicated there was very little reaction. The reaction was warmed to room temperature and monitored by HPLC. After 24 h, 500 mL of water was added to the reaction and stirred at room temperature for 2 h. The white precipitate was filtered and washed with water. The solid was dissolved in DCM and washed with water and dried over MgSO4. The residue was used directly for the next step. The product contains 10% of starting material, 80% of desired product and 10% of dibrominated product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:13][CH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(=O)oc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=c1ccc2ccc(CBr)cc2o1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
To a solution of 7-methylcoumarin (50 g) in acetonitrile (1.2 L), N-bromosuccinimide (56 g) and α,α′-azobisisobutylonitrile (510 mg) were added, and the mixture was stirred for 30 minutes at 78° C. of inside temperature. The reaction mixture was concentrated, and water was added. The crystal was collected by filtration to give the title compound (76 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH3:11][N:12]=[C:13]=[O:14].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:11][NH:12][C:13]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:14]
Reactant: CN=C=O
Reactant: CC(C)(C)c1cc(N)no1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 3-amino-5-t-butylisoxazole (16.82 g) in anhydrous benzene (140 ml), methyl isocyanate (8.90 g) and triethylamine (0.5 ml) are added. The resulting mixture is stirred at room temperature for about 8 hours, allowed to stand overnight and refluxed for 1 hour. After ice cooling, the reaction mixture is filtered to give a precipitate which is recrystallized from ethyl acetate to give 1-methyl-3-(5-t-butyl-3-isoxazolyl)urea (21.61 g) as colorless needles melting at 187.0° to 187.5° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]([NH2:14])([CH3:13])[CH3:12]>CCO>[CH:11]([NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCO
Product: CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (4.406 g, 31.22 mmol) in EtOH (32 mL) was added at 0° C. isopropyl amine (2.97 mL, 32.80 mmol). The mixture turned from light yellow to bright orange instantly. It was stirred overnight at RT. Another 1 eq of isopropyl amine (2.97 mL, 32.80 mmol) was added and after 3 h of stirring 2 eq of isopropyl amine were added (6 mL, 64 mmol) and the resulting solution was kept at room temperature overnight. The reaction mixture was concentrated and another equivalent of isopropyl amine was added (2.97 mL) following by EtOH (2 mL). For completion, the reaction was heated at 50° C. for 2 h. Mixture was evaporated to dryness and dissolved in EtOAc (25 mL) and the organic phase was washed with water (3*10 mL). Aqueous phase was re-extracted with EtOAc (10 mL) and the combined organics were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure to afford 5.24 g of N-isopropyl-2-nitrobenzenamine (Yield: 93%) as an orange liquid
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.CS(O)(=O)=O.O>C1(C)C(C)=CC=CC=1>[N:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:4](=[O:5])[CH2:3][CH2:2][C:1]2=[O:7])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccncc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CCC(=O)N1c1ccncc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The starting material is prepared as follows: The mixture of 500 g of succinic acid anhydride, 471 g of 4-aminopyridine and 5,200 ml of xylene is heated to reflux while stirring and separating the water formed. After 30 minutes 15 ml of methane sulfonic acid are added and refluxing is continued until 5 moles of water are collected, requiring about 4 days. The mixture is cooled to room temperature, the supernatant is decanted off and the suspension combined with 1000 ml of isopropanol. It is stirred for 5 minutes, filtered, the residue washed with 250 ml of isopropanol and dried for 3 days under reduced pressure at room temperature and shortly at 50°, to yield the 1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 232°-235°.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:53])[C:7]([S:25][C@@H:26]1[CH2:30][CH2:29][O:28][C@@H:27]1[CH2:31][NH:32][C:33](=[O:52])[C@@H:34]([NH:38]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH:35]([CH3:37])[CH3:36])=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].O>C(OCC)(=O)C.[Pd]>[NH2:38][C@@H:34]([CH:35]([CH3:37])[CH3:36])[C:33]([NH:32][CH2:31][C@@H:27]1[C@H:26]([S:25][C:7]2[C@H:6]([CH3:53])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:30][CH2:29][O:28]1)=[O:52]
Reactant: CC(C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[C@H](N)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reaction time: 20 h
Yield: 77.7 %

Procedure:
To a mixture of 5.064 g of 4-nitrobenzyl (4R,5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}amino)-butanoyl]amino}methyl)tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in 120 ml of ethyl acetate is added 5 ml of water, (about a 4% water:ethyl acetate biphasic solvent mixture) and after standing for about 5 minutes, gives a clear biphasic solvent mixture. An additional 55 ml of water is added followed by 2.5 g of 10% palladium-on-carbon. The reaction mixture is then hydrogenated in a Parr apparatus at 54 psi for 20 hours. The mixture is transferred to a separatory funnel and 100 ml of water is added. The aqueous layer is separated and the ethyl acetate layer washed with 20 ml of water. The combined aqueous layers are filtered through a pad of diatomaceous earth and the pad washed with an additional 30 ml of water. The combined aqueous layers are washed with 200 ml of ethyl acetate and lyophilized to afford 2.3 g(78%) of the desired product. MS (ES), m/z:442.3 (M+H)+, 98.9% area percent pure by analytical HPLC.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 25.72 mL (336 mmol) of diketene in 100 mL of toluene is added dropwise at 90° C. to a solution of 51.0 g (288 mmol) of 4-bromoaniline in 200 mL of toluene and the reaction mixture is kept for 5 hours at this temperature. The reaction solution is cooled in the ice bath, and the precipitate formed is filtered and then washed with toluene until the product is virtually colorless. Subsequently it is dried at 50° C. in the circulating air dryer until the weight is constant. Yield: 50.0 g (68% of theoretical); C10H10BrNO2 (M=256.096); calc.: molpeak (M+H)+: 256/258 (Br); found: molpeak (M+H)+: 256/258 (Br); HPLC-MS: 4.7 min (method B).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:18][F:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.C(OCC)(=O)C.[Pd]>[F:19][CH2:18][C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CCOC(=O)C1(CF)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C1(CF)CCNC1
Yield: 50 %

Procedure:
To a solution of 1.27 g (4.8 mmol) of ethyl 1-benzyl-3-(fluoromethyl)pyrrolidine-3-carboxylate in 20 mL of methanol was added 500 mg of Pd/C (10% on carbon) and 1.5 g (24 mmol) of HCOONH4. The reaction mixture was refluxed for 1 h, filtered through celite pad and evaporated to give a residue. The residue was then dissolved in ethyl acetate, the resulting solution was washed with saturated NaHCO3 aqueous solution, brine, dried over Na2SO4, evaporated to give the final crude product (426 mg, 2,4 mmol, yield: 50%): MS (m/e): 176 (M+H)+.
Reaction SMILES: Cl.[CH:2]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=1.C(N(CC)CC)C>C(#N)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:8]2[CH:5]3[CH2:6][CH2:7][CH:2]2[CH2:3][CH2:4]3)=[CH:11][C:12]=1[C:19]([F:20])([F:21])[F:22])([O-:18])=[O:17]
Reactant: C1CC2CCC1N2
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Temperature: 80 °C
Yield: 88 %

Procedure:
To a flask containing 7-azabicyclo[2.2.1]heptane hydrochloride 7a (4.6 g, 34.43 mmol, obtained from Tyger Scientific Inc., 324 Stokes Avenue, Ewing, N.J., 08638 USA under a nitrogen atmosphere was added a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene 18 (6.0 g, 28.69 mmol) and triethylamine (8.7 g, 12.00 mL, 86.07 mmol) in acetonitrile (50 mL). The reaction flask was heated at 80° C. under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool and then was partitioned between water and dichloromethane. The organic layer was washed with 1 M HCl, dried over Na2SO4, filtered, and concentrated to dryness. Purification by silica gel chromatography (0-10% ethyl acetate in hexanes) yielded 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane 19 (7.2 g, 88% yield) as a yellow solid. 1H NMR (400.0 MHz, DMSO-d6) δ 8.03 (d, J=9.1 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (dd, J=2.6, 9.1 Hz, 1H), 4.59 (s, 2H), 1.69-1.67 (m, 4H), 1.50 (d, J=7.0 Hz, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:14](=[O:16])[CH3:15])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:21]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure D described for example 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-chloro-5-methanesulfonyl-benzoic acid (Example B), 72%, white solid, M+H+: 439.1)
Reaction SMILES: C(N(CC)CC)C.S(=O)(=O)(O)O.[C:13](#[N:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>C1(C)C=CC=CC=1>[C:14]1([C:13]2[NH:23][N:22]=[N:21][N:20]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: c1ccc(-c2nnn[nH]2)cc1
Yield: 98 %

Procedure:
Into the same device as used in Example 1 were placed 6.58 g (0.065 mole) of triethylamine and 52 ml of toluene. To the mixture were added 3.19 g (0.033 mole) of concentrated sulfuric acid with stirring. Further added were 5.16 g (0.050 mole) of benzonitrile and 4.23 g (0.065 mole) of sodiumazide. The mixture was heated to a temperature from 95° to 100° C. to undergo a reaction for 7 hours. The same subsequent treatment as in Example 1 was conducted, giving 7.11 g (0.049 mole) of 5-phenyl-1H-tetrazole (yield 97.3% based on benzonitrile).