Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O>>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:13]1[CH2:14][CH2:15][C:16]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[O:9][C:10](=[O:17])[C:11]=2[CH2:12]1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: O=Cc1ccccc1Cl
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccccc1Cl)CC3
Yield: 65 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 2-chlorobenzaldehyde. Yield 65%; mp 137°-139° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:36]=[C:35]([O:37][CH3:38])[C:19]3[N:20]([CH3:34])[C:21]([C:23]4[N:31]([CH2:32][CH3:33])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:36]=[C:35]([O:37][CH3:38])[C:19]3[N:20]([CH3:34])[C:21]([C:23]4[N:31]([CH2:32][CH3:33])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(OC)c3n2C)cc2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)cc(OC)c3n2C)cc2cccnc21
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl(1-(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (4.4 g, 8.26 mmol) in dichloromethane (DCM) (20 ml) was added TFA (9 ml, 118 mmol) dropwise. The reaction mixture was stirred for 1 hour 30 minutes. LC/MS showed that that desired product had formed with no starting material remaining. The reaction mixture was concentrated under vacuum to afford an oil. The oil was dissolved in methanol and split into two equal batches and passed through two separate 70 g SCX cartridges. The columns were washed with MeOH (2CV) and the product collected from both columns as the free base with 2M ammonia in methanol (3CV). The product was concentrated under vacuo and dried under vacuum to afford the title compound as a white solid (3.46 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[SH:11][C:12]1[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:17][N:13]1[CH:14]=[CH:15][N:16]=[C:12]1[S:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1ccnc1S
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1ccc([N+](=O)[O-])cc1
Yield: 87.6 %

Procedure:
1-fluoro-4-nitrobenzene (5.0 g), 2-mercapto-1-methylimidazole (4.04 g) and potassium carbonate (14.7 g) were added to. DMF (100 ml), and the mixture was stirred for 2 hours under argon atmosphere at 130° C. After the mixture was allowed to be at room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water three times, further washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-diisopropyl ether, to give 1-methyl-2-[(4-nitrophenyl)thio]imidazole (7.29 g) as yellow crystals.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1>CN(C)C=O.Cl>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[CH:13][CH:14]=1)(=[O:19])=[O:20]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of pentane-2,4-dione (4.4 g) in N,N-dimethylformamide (10 mL) was added dropwise over a period of 15 minutes to a stirred suspension of sodium hydride (60% in oil, 1.7 g) in N,N-dimethylformamide (50 mL) at −5° C. The mixture was warmed to room temperature over 20 minutes and a solution of 1-bromomethyl-4-methanesulfonylbenzene (10 g) in N,N-dimethylformamide (20 mL) was added dropwise over a period of 10 minutes. The resulting mixture was stirred at room temperature for 17 hours and then diluted with 1.0 M aqueous hydrochloric acid (100 mL). The resulting mixture was extracted with a mixture of diethyl ether and ethyl acetate (1:1 by volume) and the combined extracts washed with a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (2:1 to 1:2 by volume) gave title compound as a colourless gum, 3.7 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][C:16]=1F>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:15][C:16]=1[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: O=Cc1ccc[nH]1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccn1-c1ccc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
A solution of pyrrole-2-carboxaldehyde (19.0 g, 0.2 mol) in N,N-dimethylformamide (50 ml) was added dropwise to a suspension of sodium hydride (80% dispersion in oil, 6.3 g, 0.21 mol) in N,N-dimethylformamide (100 ml), maintaining the temperature of the reaction between 5°-10° C. by means of ice-bath cooling. When the addition was complete, stirring was continued for 30 minutes, and then 3-chloro-4-fluorobenzotrifluoride (39.7 g, 0.20 mol) added. The mixture was stirred for 3 hours, then warmed to 50° C. for 18 hours. The mixture was cooled to room temperature and partitioned between diethyl ether and water. The ethereal extract was washed sequentially with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. Trituration with hexane gave 1-(2'-chloro-4'-trifluoromethylphenyl)pyrrole-2-carboxaldehyde as a pale yellow solid (30.6 g), m.p. 119°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22](OCC)=[O:23])=[C:12]2[CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=[O:23])=[C:12]2[CH3:27])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(F)cc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(C=O)cc(-c2ccccc2)n1S(=O)(=O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
Ethyl 1-[(4-fluorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (380 mg) was dissolved in tetrahydrofuran (15 mL), and the mixture was cooled to −78° C. A 1.5 mol/l solution (1.96 mL) of diisobutylaluminum hydride in toluene was added dropwise, and the mixture was further stirred at −78° C. for 1 hr. 1 mol/l Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 min and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1). The obtained brown oil was dissolved in acetonitrile (5 mL), and the mixture was cooled to 0° C. Tetra-n-propylammonium perruthenate (34 mg), N-methylmorpholine N-oxide (172 mg) and molecular sieves 4A powder (500 mg) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield 210 mg, 62%).
Reaction SMILES: [C:1]([NH:9][C:10](=[N:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)OC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[C:32]([CH2:34][CH2:35][CH2:36][NH2:37])[N:31]=[CH:30]1>C(#N)C>[C:1]([NH:9][C:10]([NH:37][CH2:36][CH2:35][CH2:34][C:32]1[N:31]=[CH:30][NH:29][CH:33]=1)=[N:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCc1c[nH]cn1
Reactant: O=C(NC(=NCCCOc1ccccc1)Oc1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=C(NC(=NCCCOc1ccccc1)NCCCc1c[nH]cn1)c1ccccc1

Procedure:
The previously obtained solution of 6.1 mmol of N-benzoyl-N'-(3-phenoxypropyl)-O-phenyl-isourea is concentrated by evaporation under vacuum and the residue is dissolved in acetonitrile and then heated under reflux for 3 hours after the addition of 0.8 g (6.4 mmol) of 3-(imidazol-4-yl)-propylamine. The reaction mixture obtained is then concentrated by evaporation under vacuum, the residue is taken up with dilute hydrochloric acid and the aqueous solution is extracted three times with ether. After alkalisation with sodium hydroxide solution, the reaction product is extracted from the aqueous phase with methylene chloride, the extract obtained is concentrated by evaporation, and the reaction product is crystallised from the concentrated extract by means of ethyl acetate. 0.95 g (38%) of colourless solid melting at 149° C. after recrystallisation from ethanol/water is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]([CH:27](O)[O:28]C)([F:26])([F:25])[F:24]>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:27]([OH:28])[C:23]([F:26])([F:25])[F:24])=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(O)C(F)(F)F
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Temperature: 120 °C
Yield: 37.8 %

Procedure:
3-Benzyloxy-2-methyl-1H-pyridin-4-one (1 g, 4.64 mmol) was mixed with potassium carbonate (0.2 g, 1.45 mmol) and CF3CH(OCH3)OH (4.34 g, 33.36 mmol) in sealed parallel synthesizer reactor and heated at 120° C. metal block temperature for 2 days. The mixture was cooled, and an additional amount of potassium carbonate (2 g, 14.5 mmol) and CF3CH(OCH3)OH (2 g, 15.30 mmol) was added. The mixture was again heated in a sealed tube at 120° C. for 60 hours. The mixture was cooled to room temperature and then evaporated to dryness. The residual material was purified by column chromatography (5% MeOH:dichloromethane) to give 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.55 g, 37.8% yield).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[NH:4][N:3]=1.CN(C)[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=O>C(O)(=O)C>[C:16]1([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:5]3[C:6]([C:7]#[N:8])=[C:2]4[N:1]=[CH:24][CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)[N:3]4[N:4]=3)[CH2:10][CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=CC(=O)c1ccncc1
Reactant: N#Cc1c(N)n[nH]c1N1CCN(Cc2ccccc2)CC1
Solvent: CC(=O)O
Product: N#Cc1c(N2CCN(Cc3ccccc3)CC2)nn2c(-c3ccncc3)ccnc12
Yield: 53.7 %

Procedure:
A mixture of 2.2 g of 3-amino-5-(4-phenylmethyl-1-piperazinyl)-4-pyrazolecarbonitrile (Example 1) and 1.37 g of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one U.S. Pat. No. 4,281,000, Example 63) in 25 ml of glacial acetic acid was refluxed for 6 hours. The solution was taken to dryness in vacuo. The residue was partitioned between saturated sodium bicarbonate and dichloromethane (1:2). The dichloromethane layer was separated, dried over anhydrous sodium sulfate and filtered through a short column of magnesium silicate. The effluent was refluxed on a steam bath with the gradual addition of hexane until turbidity was noted. After cooling, the precipitate was collected by filtration. The solid was recrystallized from dichloromethane/hexane and gave 1.65 g of the product of the Example as very pale yellow crystals, mp 193°-194° C.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=34)=[N:9]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1
Reactant: O=C1c2ccccc2C(=O)N1CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 3-[2-(2-phthalimidoethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (2.2 g), hydrazine monohydrate (2 ml), and ethanol (100 ml) was stirred for 1 hour under reflux. After being cooled to room temperature, the reaction mixture was concentrated, and the residue was partitioned between chloroform and water. The organic layer was separated, and extracted with 10% hydrochloric acid. The aqueous layer was washed twice with chloroform, neutralized with sodium hydroxide, and extracted three times with chloroform. The combined organic layers were washed with water and sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated to give 3-[2-(2-aminoethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (1.5 g). An analytical sample was prepared by recrystallization from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([CH3:17])[N:11]=1.O>O1CCCC1>[Cl:9][C:10]1[N:15]=[C:14]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Oc1ccc(F)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(F)cc2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
4-Fluorophenol (103 mg, 0.92 mmol) and potassium-tert-butylate (113 mg, 1.0 mmol) were dissolved in 7 mL of tetrahydrofurane. 2,4-dichloro-6-methylpyrimidine (150 mg, 0.92 mmol) was added and the mixture stirred at 20° C. overnight. Water was added and the mixture extracted with diethyl ether. Chromatography of the crude reaction product on silica gel using a heptane/ethyl acetate as an eluent gave the title compound (150 mg, 68%) as a slightly yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.50-7.40 (m, 2H), 7.28 (t, 1H), 7.14 (d, 2H), 6.57 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:4].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:45]([CH3:44])(=[O:47])=[O:46])[C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1S(C)(=O)=O
Yield: 37 %

Procedure:
To a vigorously stirred methylene chloride (10 mL) solution of compound 7 (0.8 g, 1.6 mmol) and triethylamine (4.86 g, 48 mmol ) was added methanesulfonyl chloride (5.52 g, 48 mmol) dropwise. The reaction mixture was diluted with additional CH2Cl2 and washed with pH 7.0 aqueous buffer. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 : MeOH/99:1) to afford 340 mg (37%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[N:14]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)=[C:15]=[O:16].C(N(CC)CC)C>C1COCC1>[NH:21]1[C:22]2[C:18](=[C:17]([NH:14][C:15](=[O:16])[O:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=C=Nc1cccc2[nH]ccc12
Reactant: OCc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2[nH]ccc12)OCc1ccc(OC(F)(F)F)cc1
Yield: 54.4 %

Procedure:
[4-(Trifluoromethoxy)pheny]methanol (0.13 g, 0.7 mmol) and the product of Example 80A (0.1 g, 0.63 mmol) in THF (5 mL) were heated at reflux for 16 hours with a catalytic amount of triethylamine. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether/hexane to provide the title compound as tan crystals (0.12 g). 1H NMR (300 MHz, DMSO-d6) δ 5.21 (s, 2H), 6.73 (s, 1H), 7.01 (t, 1H), 7.1 (d, 1H), 7.23 (t, 1H), 7.38 (dd, 1H), 7.4 (d, 2H), 7.6 (d, 2H), 9.5 (s, 1H), 11.06 (s, 1H). Anal. Calcd. for C17H13N2F3O3. 0.25 H2O: C, 57.55; H, 3.84; N, 7.90. Found: C, 57.42; H, 3.81; N, 7.32.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8](Cl)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN1CCCC1=O>[CH2:14]([NH:21][C:8]1[N:7]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:11]([F:12])=[CH:10][N:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)Nc1nc(Cl)ncc1F
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(NCc2ccccc2)ncc1F
Temperature: 140 °C
Reaction time: 17 h
Yield: 78.4 %

Procedure:
To 5 ml of N-methylpyrrolidone were added 1.8 g of 4-(t-butylamino)-2-chloro-5-fluoropyrimidine and 4.0 g of benzylamine, and the mixture was stirred at 140° C. for 17 hours and separated by adding 300 ml of distilled water and 40 ml of chloroform. The chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated pale yellow crystals were dispersed in diisopropylether and collected by filtration to obtain 1.9 g of the title compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[O:16][C@H:15]2[N:12]([C:13](=[O:33])[C@@H:14]2[C@@H:17]([O:19]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH3:18])[C:11]=1[C:34]([O:36]CC1C=CC([N+]([O-])=O)=CC=1)=[O:35])([CH3:9])[CH3:8])=[N+]=[N-].[H][H]>[Pd].C(OCC)(=O)C.O>[NH2:1][CH2:4][CH2:5][CH2:6][C:7]([C:10]1[O:16][C@H:15]2[N:12]([C:13](=[O:33])[C@@H:14]2[C@@H:17]([OH:19])[CH3:18])[C:11]=1[C:34]([OH:36])=[O:35])([CH3:8])[CH3:9]
Reactant: [H][H]
Reactant: C[C@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C(C)(C)CCCN=[N+]=[N-])O[C@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C(C)(C)CCCN)O[C@H]12
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
In a 100 ml two necked flask fitted with a magnetic stirrer, a rubber septum and connected to a hydrogenation apparatus palladium on carbon catalyst (10%, 300 mg) in ethyl acetate (13 ml) and water (13 ml) was prehydrogenated for 20 min at 0° C. A solution of p-nitrobenzyl (5R,6R)-3-[4-azido-1,1-dimethylbutyl]-6-[(S)-1-p-nitrobenzyloxycarbonyloxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (280 mg, 0.44 mmol) in ethyl acetate (10 ml) was then added with a syringe at 0° C. with stirring. After 50 min of stirring at 0° C. hydrogen uptake came to an end (90 ml of hydrogen was consumed). The catalyst was removed by filtration, washed with a small portion of ethyl acetate and water and the chilled two phase mixture allowed to separate. The aqueous phase was washed twice with portions (3 ml) of cold ethyl acetate and water and the ethyl acetate phases were reextracted twice with portions (3 ml) of water. Residual ethyl acetate was removed from the combined water phases in vacuum and then in high vacuum at 0° C. and the volume was reduced to 13 ml in high vacuum. The solution was lyophilized at −25° C. for three days to give (5R,6R)-3-[4-amino-1,1-dimethylbutyl]-6-[(S)-1-hydroxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (YOB) as a colourless voluminous powder (98 mg, 75%)
Reaction SMILES: CO[C:3](=[O:15])[NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].N1C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:32][NH:31][N:30]=2)=[CH:25][CH:24]=1>O1CCOCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:32][N:31]([C:3]([NH:4][S:5]([C:8]3[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=3)(=[O:6])=[O:7])=[O:15])[N:30]=2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Reactant: COC(=O)NS(=O)(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
Part A: To a solution of N-((4-chlorophenyl)sulfonyl)carbamic acid methyl ester (CAS: 34543-04-9) (2.99 gram, 12.0 mmol) and pyridine (4 mL) in 1,4-dioxane (20 mL) is added 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (3.39 gram, 13.2 mmol) and the resulting mixture is stirred for 4 hours at 100° C. After concentration in vacuo the residue is dissolved in dichloromethane, successively washed with water, 1 N HCl and water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to a volume of 20 mL. Methyl-tert-butyl ether (60 mL) is added and the resulting solution is concentrated to a volume of 20 mL. The formed crystals are collected by filtration and recrystallised from methyl-tert-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (4.75 gram, 76% yield) Melting point: 211-214° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:30])=[C:26]([CH:29]=1)[CH:27]=[O:28]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:27]([C:26]2[CH:29]=[C:22]([Br:21])[CH:23]=[CH:24][C:25]=2[CH3:30])[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1C=O
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Br)cc1C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 4-benzyloxybromobenzene (2.63 g, 10 mmol) in THF (50 mL) at −78° C. under nitrogen was slowly added n-butyllithium (2.5 M in hexanes, 4.4 mL, 11 mmol). The reaction was stirred for 30 minutes. 5-Bromo-2-methylbenzaldehyde (32, 1.99 g, 10 mmol) in THF (4 mL plus 1 mL rinse) was added slowly. The reaction was allowed to slowly warm to about 0° C. over 2 hours, then quenched with saturated aqueous NH4Cl, diluted with ether, washed with H2O and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography (gradient 0-25% EtOAc/hexanes) to give 3.12 g (82% yield) of the title compound 33 as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80 (d, J=2.3 Hz, 1 H), 7.36-7.47 (m, 4 H), 7.29-7.36 (m, 2 H), 7.18-7.24 (m, 2 H), 6.99 (d, J=8.1 Hz, 1 H), 6.88-6.97 (m, 2 H), 5.89 (d, J=3.5 Hz, 1 H), 5.06 (s, 2 H), 2.12 (s, 3 H), 2.06 (d, J=3.5 Hz, 1 H); MS (ES+) [M-OH]+=365, 367.