Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]([NH2:17])([CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]#[N:5].C(N(CC)CC)C.[C:25](Cl)(=[O:35])[C:26]1[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:28](Cl)=[O:29].C1(=O)NC(=O)C2=CC=CC1=C2>ClCCl>[F:1][CH2:2][C:3]([N:17]1[C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]2[C:25]1=[O:35])([CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]#[N:5]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: N#CC(N)(CF)CCCOCc1ccccc1
Agent: O=C1NC(=O)c2cccc1c2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC(CF)(CCCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a stirred solution of 2-fluoromethyl-2-amino-5-benzyloxypentanenitrile (74.8 g), triethylamine (100 g), and dry dichloromethane (450 ml), cooled in an ice bath, a solution of phthaloyldichloride (58 g) in dichloromethane (300 ml) is added slowly. Stirring is continued at room temperature overnight. The mixture is extracted with 2N HCl (2×750 ml), washed with water (2×750 ml), dried carefully (Na2SO4), evaporated to give a brown oil which, according to NMR analysis, contains some iso-phthalimide. The oil is dissolved in dry dichloromethane (500 ml), triethylamine (100 g) is added, and the mixture is refluxed for 3 hours. Work-up as described above gives an oil which is purified by flash-chromatography on silica (2 kg, petroleum ether/ethyl acetate 4:1). Crystallization from ether gives 2-fluoromethyl-2-phthalimido-5-benzyloxypentanenitrile (49.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[N+:17]([C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[CH:23]=[CH:24][C:25](O)=O)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)/[CH:23]=[CH:24]/[C:25]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1)([O-:19])=[O:18]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cccc([N+](=O)[O-])c3)nc2n(CCC)c1=O
Yield: 56.9 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 4.0 g (17.7 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.8 g (19.5 mmol) of 3-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from toluene to give 3.86 g (yield 57%) of Compound 35 as pale yellow needles.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)[C:18](=O)[CH3:19].C(Cl)(=O)C>O>[CH3:18][C:19]1[O:11][C:10]([CH2:9][O:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:12][N:13]=1
Reactant: NNC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)N(C)C
Solvent: O
Solvent: CC(=O)Cl
Product: Cc1nnc(COc2ccc([N+](=O)[O-])cc2)o1
Reaction time: 2 h
Yield: 56 %

Procedure:
To a mixture of 2-(4-nitrophenoxy)acetohydrazide (1.57 g) and N,N-dimethylacetamide (50 mL) was added dropwise acetyl chloride (0.70 g) at room temperature. The reaction mixture was stirred for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue, diphosphorus pentaoxide (1.76 g), hexamethyldisiloxane (4.03 g) and 1,2-dichlorobenzene (10 mL) was stirred at 140° C. for 3 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-methyl-5-[(4-nitrophenoxy)methyl]-1,3,4-oxadiazole as colorless crystals (0.41 g, yield 56%) from a fraction eluted with hexane-ethyl acetate (3:2-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 105-106° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[O:8].[CH3:9][Mg]Br.C1COCC1>C(OCC)C>[CH3:9][C:2]1([OH:8])[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2
Reactant: C[Mg]Br
Reactant: O=C1CC2CCC1C2
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)CC2CCC1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of bicyclo[2.2.1]heptan-2-one (25 g, 0.23 mol) in diethyl ether (250 mL) was added a solution of methylmagnesium bromide in THF (3 mol/L, 90 mL, 0.27 mol) over 1 h at 0° C. The reaction mixture was stirred for an additional 30 min as it was warmed to room temperature. Then the reaction was quenched with 40 mL saturated aqueous ammonium chloride solution. The resulting mixture was extracted with diethyl ether (3×80 mL). The organic layers were combined and concentrated to give the desired product (26 g, 0.205 mol, yield: 90%). 1H NMR (400 MHz, CDCl3) δ ppm 2.20 (s, 1H), 2.01 (s, 1H), 1.94 (s, 1H), 1.61-1.49 (m, 3H), 1.34-1.20 (m, 7H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[Li]CCCC>C1COCC1.CCCCC>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:13][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:11][C:10]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCBr
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 1.00 g (3.25 mmol) of 5-(Benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyrimidine and 415 mg (2.16 mmol) of 1-bromononane in 30 mL of anhydrous THF were added 2.70 mL (4.32 mmol) of a 1.60 M solution of n-BuLi in pentane. The reaction mixture was stirred at 23° C. for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and then poured into 70 mL of water. The mixture was then extracted with two 70-mL portions of diethyl ether. The combined organic layer was then washed with a 100-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 4:1 hexanes-diethyl ether afforded the expected product as light colorless oil: yield 502 mg (53%); silica gel TLC Rf 0.60 (4:1 hexanes-diethyl ether); 1H NMR (CDCl3) δ0.89 (t, 3H, J=7.2 Hz), 1.20-1.30 (m, 14H), 1.75 (m, 2H), 2.31 (s, 6H), 2.48 (s, 3H), 2.77 (dd, 2H, J=7.6, 7.6 Hz), 4.90 (s, 2H), 5.86 (s, 2H) and 7.40-7.44 (m, 5H); 13C NMR (CDCl3) δ 14.10, 14.33, 19.28, 22.67 27.74, 29.29, 29.29, 29.41, 29.51, 29.57, 31.62, 31.88, 75.72, 107.91, 128.01, 128.22, 128.72, 129.30, 129.30, 136.22, 147.35, 147.35, 152.59, 161.59 and 165.09; mass spectrum (APCI), m/z 434.3172 (M+H)+ (C28H40N30 requires 434.3171).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: CCI
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 70 °C
Yield: 39.6 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (26 mg, 0.19 mmol) and iodoethane (11 μL, 0.14 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 70° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/dichlrormethane (3.5:0.5:4) followed by trituration with diethyl ether afforded 11 mg (39%) of 3-(2-pyridyl)-5-(3-cyano-5-ethoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.91 (m, 1H), 7.49 (m, 1H), 7.38 (s, 1H), 4.17 (q, 2H), 1.49 (t, 3H).
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[CH3:31][C:32]1[N:33]=[N:34][S:35][C:36]=1[C:37]([NH:39][NH2:40])=O>ClCCl>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:37]([C:36]3[S:35][N:34]=[N:33][C:32]=3[CH3:31])=[N:39][N:40]=[C:26]2[CH2:25]1)=[O:23]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: Cc1nnsc1C(=O)NN
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1nnsc1-c1nnc2n1CCN(C(=O)c1ccc(Cl)c(F)c1Cl)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Triethyloxonium tetrafluoroborate (330 mg, 1.738 mmol) was added to a suspension of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (460 mg, 1.580 mmol) in dry Dichloromethane (DCM) (3.9 ml). The reaction mixture was stirred at room temperature 45 mins—mixture became clear. 4-Methyl-1,2,3-thiadiazole-5-carbohydrazide (300 mg, 1.896 mmol, commercially available) was added and the resulting reaction mixture was stirred at room temperature 2 h 10 min. The solvent was evaporated under reduced pressure. The residue was dissolved in 1-butanol (3.90 ml) and the reaction mixture was stirred at reflux for 17 h. The reaction mixture was diluted in ethyl acetate (150 mL) and washed with water (2×25 mL), sat. NaHCO3 (25 mL) and brine (2×25 mL). The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by MDAP (basic method). The resulting residue was triturated with ether (5×2 mL) and then dried under vacuum at 50° C. to afford the desired product in 117.4 mg as a cream powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:24][CH2:23]3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[NH:20][N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:22]3[CH2:24][CH2:23]3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[N:20]([CH2:38][C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[C:35]([F:34])([F:44])[F:45])[N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=c1n(S(=O)(=O)c2ncn[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: FC(F)(F)c1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1n(S(=O)(=O)c2ncnn2Cc2ccccc2C(F)(F)F)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
37 mg (0.10 mmol) of the compound from Example 93A were dissolved in 3 ml of dichloromethane, and 21 μl (0.13 mmol) of N,N-diisopropylethylamine were added. 30 mg (0.13 mmol) of 2-(trifluoromethyl)benzyl bromide dissolved in 1 ml of dichloromethane were then added, and the mixture was stirred at RT for 48 h. For work-up, the mixture was concentrated under reduced pressure and the crude product was purified chromatographically [Method 19]. This gave 33 mg (63% of theory) of the target compound.
Reaction SMILES: C(OC([NH:8][CH2:9][C@:10]1([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:16][C@H:15]2[C@:11]1([CH3:17])[CH:12]=[CH:13][CH2:14]2)=O)(C)(C)C.C(N(CC)CC)C>Cl.C(OCC)(=O)C>[NH2:8][CH2:9][C@:10]1([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][C@H:15]2[C@:11]1([CH3:17])[CH:12]=[CH:13][CH2:14]2
Reactant: CC(C)(C)OC(=O)C[C@@]1(CNC(=O)OC(C)(C)C)C[C@@H]2CC=C[C@@]21C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@]12C=CC[C@H]1C[C@]2(CN)CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
Tert-butyl(±)-[(1S,5R,6S)-6-(tert-butoxycarbonylaminomethyl)-5-methylbicyclo[3.2.0]hept-3-en-6-yl]acetate (120 mg, 0.34 mmol) was dissolved in a 4 N hydrochloric acid-ethyl acetate solution (2 mL), and the solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (2 mL). To the solution, triethylamine (0.048 mL, 0.34 mmol) was added dropwise at room temperature, and the mixture was stirred for 2 hours. The resulting powder was collected by filtration and dried to obtain the compound of interest as a white solid (22 mg).
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:46]([CH2:56][C:57](O)=[O:58])[C:47]2[C:52]([C:53](=[O:55])[N:54]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:46]([CH2:56][C:57]([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH:14]2[CH2:13][CH2:12][N:11]([C:2]([CH3:1])([CH3:10])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH2:16][CH2:15]2)=[O:58])[C:47]2[C:52]([C:53](=[O:55])[N:54]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2
Reactant: CC(C)(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1,1-dimethylethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B4) (1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C1) (1.2 equiv), DIPEA (3 equiv) and DMF (1.0 ml) is stirred at room temperature for 5 min. HATU (1.5 equiv) is added in 1 portion and stirred an additional 5 min. The crude reaction mixture is concentrated, filtered through a plug of silica eluted with acetone and evaporated to obtain crude 1,1-dimethylethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl} {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:18][CH:14]4[CH2:15][CH:16]([CH2:17]2)[C:12]([NH2:19])([CH2:13]4)[CH2:11]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.O>[CH2:26]([O:33][C:34](=[O:35])[NH:19][C:12]12[CH2:13][CH:14]3[CH2:18][C:10]([C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=4)([CH2:17][CH:16]1[CH2:15]3)[CH2:11]2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2)OCc1ccccc1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a stirred mixture of 1-(4-nitrophenyl)tricyclo[3.3.1.03,7]nonan-3-amine (2.0 g, 8.0 mmol) obtained in step III, K2CO3 (3.5 g, 24 mmol) in THF (80 mL), cooled to ice-bath temperature was added benzylchloroformate (50% w/v in Toluene, 2.2 mL, 12 mmol). After stirring the reaction mixture at r.t for 2 h, it was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain benzyl[2-(4-nitrophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]carbamate as an off-white solid (2.1 g) in 70% yield. M.R: 104.1-105.9° C.; m/z (M+1) 393; IR cm−1 3440, 2952, 1714, 1518, 1349, 1216, 757; 1H NMR (CDCl3) 300 MHz δ 8.12 (d, J=8.8 Hz, 2H), 7.50-7.27 (m, 7H), 5.20-5.0 (s (br), 2H), 2.65-2.55 (m, 1H), 2.50-1.55 (m, 11H). 13C NMR (CDCl3) 75 MHz δ 155.1, 154.2, 146.1, 136.4, 131.1, 128.5 (2C), 128.1 (2C), 126.6 (2C), 123.4 (2C), 66.3, 64.4, 49.248.0, 47.5, 43.8, 42.1, 40.8, 37.0.
Reaction SMILES: BrC1C=NC(N2C3C(=CC=C(C(N4CCOCC4)=O)C=3)C(CO)=C2)=NC=1.Br[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1.FC1C=CC=CC=1C1C=NC(N2C3C(=CC=C(C(N4CCOCC4)=O)C=3)C(C=O)=C2)=NC=1.FC1C=CC=CC=1[C:74]1[CH:75]=[N:76][C:77]([N:80]2[C:88]3[C:83](=[CH:84][CH:85]=[C:86]([C:89]([N:91]4[CH2:96][CH2:95][O:94][CH2:93][CH2:92]4)=[O:90])[CH:87]=3)[C:82]([CH:97]([OH:99])[CH3:98])=[CH:81]2)=[N:78][CH:79]=1>>[OH:99][CH:97]([C:82]1[C:83]2[C:88](=[CH:87][C:86]([C:89]([N:91]3[CH2:92][CH2:93][O:94][CH2:95][CH2:96]3)=[O:90])=[CH:85][CH:84]=2)[N:80]([C:77]2[N:78]=[CH:79][C:74]([C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=3)=[CH:75][N:76]=2)[CH:81]=1)[CH3:98]
Reactant: Cc1ccnc(Br)c1
Reactant: CC(O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Agent: O=C(c1ccc2c(CO)cn(-c3ncc(Br)cn3)c2c1)N1CCOCC1
Agent: O=Cc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: Cc1ccnc(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1

Procedure:
(1-(5-Bromopyrimidin-2-yl)-3-(hydroxymethyl)-1H-indol-6-yl)(morpholino)methanone (intermediate 27c) was converted into a boronic ester that was subsequently reacted with 2-bromo-4-methylpyridine under Suzuki conditions. The resulting product was oxidized to the corresponding aldehyde and then submitted to a Grignard reaction analogously to the protocols 28a) and 28b), respectively. Light yellow solid. Yield: 70 mg
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>O1CCCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:26]([NH:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=3)=[O:27])=[N:13][CH:14]=2)[O:5]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)nc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ambient solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.350 g, 1.59 mmol) in tetrahydrofuran (4 mL) was added 3-trifluoromethylphenyl isocyanate (1.59 mmol). The solution was stirred at room temperature for 1 hour and was then concentrated under reduced pressure. The solid was washed with diethyl ether (2 mL) and air-dried to give the title compound. MS (ESI) m/z 408 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[C:11]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:7]=[CH:6][CH:5]=3)[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[C:11]2[CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(-c2nn3ccc(CO)cc3c2-c2ccncn2)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn3ccc(CO)cc3c2-c2ccncn2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a suspension of [2-(3-aminophenyl)-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridin-5-yl]methanol (600 mg, 1.90 mmol) in DCM (60 mL), benzoyl chloride (0.440 mL, 3.79 mmol) was added dropwise at rt. The mixture was stirred for overnight. The reaction mixture was quenched to add MeOH, then the solvent was evaporated under reduced pressure. The residue was recrystallized from DCM (excess) and small amount of acetone. The title compound was obtained as yellow solid (820 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@H:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][OH:25]>>[OH:25][CH2:24][C@H:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N[C@@H](CO)Cc3ccccc3)cc2c1=O
Yield: 65 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (R)-2-amino-3-phenyl-propan-1-ol according to the GPA affording 22.2 mg (65%) of a purple powder. Rt=4.40 min.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38]#[N:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38]#[N:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(N)n3)[C@H]2SC1
Yield: 70 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.1 g.) and conc. hydrochloric acid (1.6 g.) in methanol 21 ml.) and tetrahydrofuran (5 ml.) was treated in a similar manner to that of Example 9-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.40 g.).
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](Cl)=[O:20].[OH-].[Na+]>O>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:20]
Reactant: O=C(Cl)c1ccco1
Reactant: C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccco1)N1CCNCC1
Reaction time: 1 h
Yield: 60 %

Procedure:
This compound and its preparation has been described in Great Britain Patents 1,390,014 and 1,390,015. Piperazine hexahydrate (194 g, 1 mole) was dissolved in 250 ml H2O. The solution was acidified to pH 4.5 with 6N HCl. Furoyl chloride (130.5 g, 1 mole, Aldrich) was added along with 10% NaOH solution at such a rate that the pH was maintained at 4.5. After 1 hour, the solution was made basic (pH=8.5) with NaOH solution. The reaction mixture was continuously extracted with chloroform for 36 hours. The CHCl3 extract was dried over MgSO4, and filtered. Distillation gave 108.2 g product (60%), b.p. 132°-138° C./0.6 mm Hg, m.p. 69°-70° C.