Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]=[C:30]1[C:34](=[CH:35][C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[S:33][C:32](=[S:44])[NH:31]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:40][C:39]3[CH:38]=[CH:37][C:36](/[CH:35]=[C:34]4/[C:30](=[O:29])[NH:31][C:32](=[S:44])[S:33]/4)=[CH:43][CH:42]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C=C2SC(=S)NC2=O)cc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C1NC(=S)S/C1=C\c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 610.0.
Reaction SMILES: [ClH:1].C(OC([NH:12][CH:13]([C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:38])[NH2:37])=[CH:32][CH:31]=1)[P:14]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:22])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)C1C=CC=CC=1.[H][H]>CO.Cl.[Pd]>[ClH:1].[ClH:1].[NH2:12][CH:13]([C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:37])[NH2:38])=[CH:32][CH:31]=1)[P:14]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:22])[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: N=C(N)c1ccc(C(NC(=O)OCc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc(C(N)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1

Procedure:
A sample of 1.8 g of diphenyl N-benzyloxycarbonylamino(4-amidinophenyl)methanephosphonate hydrochloride was dissolved in 150 ml of 2N HCl methanol solution and after addition of 5% Pd/C catalyst, the solution was stirred under an atmosphere of hydrogen until the theoretical amount of hydrogen was consumed. The catalyst was removed by filtration and after evaporation of the methanol, the residue was crystallized from ethanol-ether. In several experiments, the yields were 60-80%; mp. 213°-215° C.; Anal. Calcd. for C20 H22N3ClP.1/2 H2O: C,51.85; H, 4.97; N, 9.08; Cl, 15.34. Found: C, 51.73; H, 5.02; N, 9.10; Cl, 15.36.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].N1C=CC=CC=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:6]1(=[O:16])=[O:15]
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccccc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 9.3 %

Procedure:
A solution of 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.46 g, 1.75 mmol) in dichloromethane (10 mL) was treated with pyridine (0.16 mL, 2.6 mmol), phenylboronic acid (0.43 g, 3.5 mmol) and copper(II) acetate (0.48 g, 2.6 mmol) and stirred at 23° C. for 16 hours. The reaction mixture was quenched by the addition of ammonium hydroxide (10 mL), diluted with methanol (2.0 mL), extracted with dichloromethane (3×10 mL), dried (Na2SO4), and evaporated. Flash chromatography (SiO2, 3-40% ethyl acetate/hexanes) provided 3-(3-chloropropyl)-1-phenyl-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.055 g, 9.4%) as a yellow film:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[H-].[Na+].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br>C1COCC1>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCO
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCOCC(OC)OC
Temperature: 40 °C
Yield: 33.5 %

Procedure:
Pent-4-yn-1-ol (4.5 mL, 48 mmol) was dissolved in anhydrous THF (50 mL). Sodium hydride (60% w/w in mineral oil, 1.95 g, 49 mmol) was added portionwise over a 10 min period. The resulting slurry was heated at 40° C. for 30 min. and then allowed to cool to room temperature. 2-Bromoacetaldehyde dimethylacetal (5.67 mL, 48 mmol) was added and the reaction mixture was heated at 40° C. for 18 h, and it was quenched with water (2 mL). The resulting solution was concentrated and then partitioned between dichloromethane (2×100 mL) and 1N HCl (100 mL). The organic phases were then removed and washed with saturated NaHCO3 solution (100 mL), and saturated brine (100 mL); and then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product (2.91 g) was then chromatographed using a silica gel column and eluting under 10 psi of nitrogen pressure with dichloromethane; 2% v/v methanol in dichloromethane; and then 4% v/v methanol in dichloromethane. The appropriate fractions were combined and concentrated to give the title intermediate (2.78 g, 16.1 mmol, 33.5% yield—contained 0.5 molar equivalents of dichloromethane). NOTE: Due to the volatility of this intermediate, this compound should not be dried on a high vacuum line.
Reaction SMILES: [OH-:1].[Na+].CC(O)(C)CN[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[N:17]=[N:18][N:19]=[C:9]2[C:8]=1[N+:20]([O-:22])=[O:21]>O>[N+:20]([C:8]1[C:9]2[N:10]([N:17]=[N:18][N:19]=2)[C:11]2[C:16]([C:7]=1[OH:1])=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-:22])=[O:21]
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])c2nnnn2c2ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(O)c2ccccc2n2nnnc12

Procedure:
Aqueous sodium hydroxide (30 g of 50%) was added to a suspension of 2-methyl-[(4-nitro-5-tetrazolo[1,5-a]quinolinyl)amino]-2-propanol (34.0 g, 0.1125 mole, Example 3) in water (500 mL). The mixture was heated on a steam bath and the solid dissolved rapidly. The solution was heated for about 30 minutes and then upon stirring a solid began to precipitate. The mixture was made acidic with 6N hydrochloric acid. The resulting solid was isolated by filtration; washed in succession with water, ethanol and ether; then dried under vacuum at 100° C. to provide 23.2 g of crude product as a pale yellow/green solid. A sample (3.2 g) was recrystallized initially from methanol/dichloromethane and then from toluene to provide 4-nitrotetrazolo[1,5-a]quinolin-5-ol. Analysis: Calculated for C9H5N5O3: % C, 46.76; % H, 2.18; % N, 30.29. Found: % C, 46.85; % H, 2.23; % N, 29.91.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]=O.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C1(C)C=CC=CC=1.O>[O:12]1[CH2:13][CH2:14][N:9]([CH:7]=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: O=CCc1cccs1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C(=CN1CCOCC1)c1cccs1

Procedure:
A mixture of 1.5 g of 2-thienylacetaldehyde, 1.4 mL of morpholine, and 0.012 g of p-toluenesulfonic acid hydrate in 7.5 mL of toluene is heated at reflux under a Dean-Stark Trap with azeotropic removal of water for 3 hours. The solution is cooled, neutralized by the addition of solid sodium methoxide, and concentrated in vacuo. The residue is taken up in toluene, filtered, and concentrated in vacuo to afford the desired enamine as an oil.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([O:38][C:39]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:50][O:49]2)=[CH:44][C:40]=1[C:41]([NH2:43])=[O:42])C1C=CC=CC=1>>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:50][CH:48]([C:45]3[CH:46]=[CH:47][C:39]([OH:38])=[C:40]([C:41](=[O:42])[NH2:43])[CH:44]=3)[OH:49])=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: NC(=O)c1cc(C2CO2)ccc1OCc1ccccc1
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNCC(O)c3ccc(O)c(C(N)=O)c3)cc2)CC1
Yield: 23.2 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.50 g, 1.18 mmol) was reacted with 2-(benzyloxy)-5-(2-oxiranyl)benzamide (0.255 g, 0.95 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.143 g, 0.22 mmol).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1>C(O)C.[Pd]>[F:19][C:2]([F:1])([F:18])[C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[NH2:15])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cccc(-c2ncccc2C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2ncccc2C(F)(F)F)c1
Yield: 95.7 %

Procedure:
A suspension of 3-(3-trifluoromethylpyridin-2-yl)nitrobenzene (500 mg) in ethanol (10 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 167 mg) under a hydrogen atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(3-trifluoromethylpyridin-2-yl)aniline (425 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12](=O)[NH:11]2)=[CH:6][CH:5]=1.P(Cl)(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:20][C:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:17])([F:16])[F:1])=[CH:5][CH:6]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCN(c2ccc(OC(F)(F)F)cc2)N1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(N2CCC(Cl)=N2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The general procedure was taken from Wang et al. Tetrahedron Lett. 2005, 46, 2631. To a solution of 1-(4-trifluoromethoxyphenyl)-pyrazolidin-3-one (120 mg, 0.49 mmol, 1.00 eq) in toluene (20 mL) was slowly added phosphoryl chloride (22.5 mg, 1.47 mmol, 3.00 eq). The mixture was then heated at 80° C. for 1 h before cooling to room temperature and quenching with H2O (10 mL). The vessel was stirred under an atmosphere of nitrogen (N2) for 8 h before the product was extracted into EtOAc (200 mL), dried (MgSO4), and concentrated under reduced pressure. GC-MS proved 88% formation of the desired intermediate, which was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[C:25]([NH:1][C:2]1[C:3]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: CC(NC(=O)c1ncccc1N)c1ccc(OCC(F)(F)F)nc1
Product: CC(C)C(=O)Nc1cccnc1C(=O)NC(C)c1ccc(OCC(F)(F)F)nc1
Yield: 52 %

Procedure:
The title compound is prepared in 52% yield (15 mg) from 3-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)picolinamide (24 mg, 0.071 mmol, Step-1, single enantiomer) and isobutyryl chloride (23 mg, 0.21 mmol) by the similar manner in Step-2 of Example-8.
Reaction SMILES: [C:1]([CH2:9][C:10]([CH3:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:15](OC)[N:16](C)[CH3:17]>>[CH3:15][N:16]([CH3:17])[CH:9]([C:10](=[O:11])[CH3:12])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)c1ccccc1
Product: CC(=O)C(C(=O)c1ccccc1)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 1-benzoylacetone (24.00 g, 0.15 mole) and dimethylformamide dimethylacetal were stirred overnight at room temperature under argon. The resulting reddish-colored mixture was concentrated on the rotary evaporator, then dissolved in THF (tetrahydrofuran). The resulting solution was stirred and heated to boiling the slowly diluted with hexane. At the point of turbidity heating was discontinued. An orange gum precipitated and rapidly solidified. The mixture was chilled in an ice bath and filtered yielding 25.5 g (78%) of 2-(dimethylamino)-1-phenyl-1,3-butanedione m.pt. 72°-74° C.
Reaction SMILES: CO.[F:3][C:4]1[CH:31]=[CH:30][C:7]([NH:8][C:9]2[CH:17]=[C:16](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:30][CH:31]=1
Reactant: O=C(O)c1ccc(/C=C/c2ccc(C(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(CCc2ccc(C(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 92.9 %

Procedure:
To a mixed solution of methanol 4.0 mL and ethyl acetate 4.0 mL of 2-(4-fluoroanilino)-4-((E)-2-(4-(trifluoromethyl)phenyl)vinyl)benzoic acid 15 mg was added 5% palladium-carbon 8.0 mg at room temperature, and it was stirred under hydrogen atmosphere at room temperature for 10 hours. The solvent was removed under reduced pressure after insoluble matter was filtrated to give 2-(4-fluoroanilino)-4-(2-(4-(trifluoromethyl)phenyl)ethyl)benzoic acid 14 mg of white solid.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].C(=S)=S>Cl>[Cl:18][CH2:19][C:20]([C:8]1[CH:9]=[CH:10][C:5]([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)=[CH:6][CH:7]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C1(c2ccccc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)C1(c2ccc(C(=O)CCl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum trichloride (7.9 g, 0.060 mol) was added in portions to a mixture of methyl 1-phenylcyclopropanecarboxylate (3.5 g, 0.020 mol) and chloroacetyl chloride (2.0 mL, 0.026 mol) in carbon disulfide (40 mL, 0.7 mol) at 15-25° C. and then the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into conc. HCl (10 mL) in ice (100 g) and then extracted with ether. The ether extract was washed with brine, dried and concentrated. The product was purified by CombiFlash using hexane/EtOAc (max.EA 20%). The final product was analysized by 1H NMR, which showed that the product was a mixture of para and meta substituted isomers with a ratio of 3:2.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:12][CH2:11][O:10][CH3:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCNc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask was added 4-fluoroaniline (383 μL, 3971 μmol, Aldrich), 2-bromoethyl methyl ether (552 μL, 3971 μmol, Aldrich), sodium carbonate (667 mg, 7943 μmol), DMF (2 mL). The reaction mixture was stirred at 80° C. for overnight (ca 17 h). The mixture was cooled down to RT. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with water (20 mL), saturated NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give 4-fluoro-N-(2-methoxyethyl)benzenamine. MS (ESI pos. ion) m/z: 170 (M+1).
Reaction SMILES: [CH3:1][C:2]([OH:19])([CH3:18])[CH2:3][N:4]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[N:5]1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>O>[Cl:20][C:21]1[N:26]=[C:25]([C:7]2[CH:6]=[N:5][N:4]([CH2:3][C:2]([CH3:1])([OH:19])[CH3:18])[CH:8]=2)[CH:24]=[CH:23][N:22]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)Cn1cc(-c2ccnc(Cl)n2)cn1
Temperature: 120 °C
Yield: 58.1 %

Procedure:
To a mixture of the product from Step 1 (84 mg, 0.31 mmol), 2,4-dichloropyrimidine (47 mg, 0.31 mmol), potassium phosphate, tribasic (167 mg, 0.79 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (26 mg, 0.031 mmol) was added THF (2 mL) and water (0.2 mL). The mixture was heated to 120° C. for 15 minutes under microwave irradiation, cooled to room temperature, quenched with 1:1 water:brine, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (Biotage 10 G, eluting with 0:100 to 100:0 ethyl acetate:hexanes) afforded 1-[4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl]-2-methylpropan-2-ol (44 mg, 0.18 mmol, 56% yield) as a yellow solid. MS ESI: [M+H]+ m/z 253.0.
Reaction SMILES: BrCC(N[CH:6]1[C:28](=[O:29])[N:8]2[C:9]([C:25]([OH:27])=[O:26])=[C:10]([CH2:13][NH:14][C:15](=[O:24])[C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH2:11][S:12][C@H:7]12)=O.[SH:30][C:31]1[S:35][N:34]=[N:33][N:32]=1>>[S:35]1[C:31]([S:30][CH:6]2[C:28](=[O:29])[N:8]3[C:9]([C:25]([OH:27])=[O:26])=[C:10]([CH2:13][NH:14][C:15](=[O:24])[C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:23])[CH:11]([NH:14][C:15](=[O:24])[CH3:16])[S:12][C@H:7]23)=[N:32][N:33]=[N:34]1
Reactant: Sc1nnns1
Reactant: O=C(CBr)NC1C(=O)N2C(C(=O)O)=C(CNC(=O)c3c(Cl)cccc3Cl)CS[C@H]12
Product: CC(=O)NC1S[C@@H]2C(Sc3nnns3)C(=O)N2C(C(=O)O)=C1CNC(=O)c1c(Cl)cccc1Cl
Yield: 65 %

Procedure:
1.0 g. of 7-bromoacetamido-3-(2,6-dichlorobenzoylamino)methylceph-3-em-4-carboxylic acid and 0.24 g. of 5-mercapto-1,2,3,4-thiatriazole were reacted and worked up according to the method of Example 15. Thus 0.73 g. (65%) of 7-(1,2,3,4-thiatriazole-5-ylthio)-acetamido-3-(2,6-dichlorobenzoylamino)methylceph-3-em-4-carboxylic acid were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])#[N:2].[C:13](Cl)(=O)C>CO>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(F)cc1C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cc(F)ccc1C#N

Procedure:
To a stirred suspension of 16.0 g (96.9 mmol) 2-Cyano-5-fluoro-benzoic acid (Apollo) and 161 ml methanol were added 30.4 g (387.6 mmol) acetyl chloride drop wisely at 0° C. The reaction mixture was stirred over night, filtered and concentrated. The residue was diluted with dichloromethane, washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (hexane:ethylacetate). The desired product 21a was obtained in 86.0 yield (14.9 g; 83.3 mmol)
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:1][N:2]2[N:11]=[C:10]([CH3:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:13])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Cc1nn(N)c(=O)c2ccccc12
Product: Cc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 28A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.54 (s, 3H) 3.74 (s, 2H) 6.94-7.09 (m, 1H) 7.10-7.20 (m, 3H) 7.85-7.98 (m, 1H) 7.95-8.11 (m, 2H) 8.32 (d, J=7.93 Hz, 1H) 11.47-11.69 (m, 1H); MS (ESI) m/z 328 (M+H)+.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[N:11][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:13][N:14]=1>C(OCC)(OCC)OCC>[S:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:12]1[N:11]=[C:10]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:2]=[N:8][C:9]2=[N:14][CH:13]=1
Reactant: Nc1ncc(-c2cccs2)nc1NCc1ccc(O)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: Oc1ccc(Cn2cnc3ncc(-c4cccs4)nc32)cc1
Yield: 67.6 %

Procedure:
A solution of 4-[(3-amino-6-thiophen-2-yl-pyrazin-2-ylamino)-methyl]-phenol trifluoroacetic acid salt (10 mg, 0.024 mmol) in triethyl orthoformate (1.5 mL) was refluxed for 4 hours. The starting material was disappeared completely. After evaporation of triethyl orthoformate, the crude product was crystallized in hexane-dichloromethane system to provide 4-(6-thiophen-2-yl-imidazo[4,5-b]pyrazin-1-ylmethyl)-phenol as a brown solid (5 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][S:10]/[C:9]/1=[N:13]\[C:14]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)=[O:15])(=O)=O.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[N:26]1([CH2:6][CH2:7][N:8]2[CH:12]=[CH:11][S:10]/[C:9]/2=[N:13]\[C:14]([C:16]23[CH2:23][CH:22]4[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]4)[CH2:17]2)[CH2:25]3)=[O:15])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCn1ccs/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C(/N=c1\sccn1CCN1CCOCC1)C12CC3CC(CC(C3)C1)C2
Reaction time: 16 h
Yield: 28 %

Procedure:
To a solution of Example 79A (0.22 g, 0.57 mmol) in 3 mL of acetonitrile was added morpholine (50 μL, 0.63 mmol), potassium iodide (0.11 g, 0.63 mmol), and potassium carbonate (0.17 g, 1.3 mmol). The mixture stirred for 16 hours and then diluted with methylene chloride and was washed with water, saturated aqueous potassium carbonate and brine. The organic phase was dried over anhydrous potassium carbonate, filtered and concentrated tinder reduced pressure. Purification by preparative HPLC afforded 60 mg (28%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ ppm 1.69-1.79 (m, 6 H), 1.96 (d, J=2.8 Hz, 6 H), 2.03 (s, 3 H), 2.48-2.58 (m, 4 H), 2.75 (t, J=6.3 Hz, 2 H), 3.64-3.72 (m, 4 H), 4.28 (t, J=6.3 Hz, 2 H), 6.55 (d, J=4.6 Hz, 1 H), 6.99 (d, J=4.6 Hz, 1 H); MS (DCI/NH3) m/z 376 (M+H)+. Anal. Calculated for C20H29N3O2S: C, 63.97; H, 7.78; N, 11.19. Found: C, 63.85; H, 7.42; N, 10.91.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH2:12][N:13]([CH3:20])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:3]=1.[NH2:21][C:22]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]2[C:25]([CH:26]3[CH2:36][CH:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:21][C:22]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]3[C:25]([CH:26]4[CH2:36][CH:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:10])=[O:9])=[C:4]([CH2:12][N:13]([CH3:20])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:3]=1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: CN(Cc1cc(F)ccc1S(=O)(=O)Cl)C(=O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CN(C)C(=O)C(F)(F)F)ccc2c1OCC1CC21
Yield: 109.1 %

Procedure:
A mixture of 4-fluoro-2-[N-methyl-N-(2,2,2-trifluoroacetyl)aminomethyl]benzenesulfonyl chloride (Intermediate 158, 0.182 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.100 g) in DCM (3 mL) and pyridine (1 mL) and the resultant mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-40% to give methyl (1aRS,7bSR)-5-(4-fluoro-2-[N-methyl-N-(2,2,2-trifluoroacetyl)aminomethyl]benzenesulfonyl-amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.257 g) as a solid.