Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.S(Cl)([Cl:15])=O>>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([Cl:15])=[O:12])[CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnn2cccnc12
Product: O=C(Cl)c1cnn2cccnc12
Temperature: 60 °C
Yield: 107.2 %

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (11.73 g, 71.9 mmol) was suspended in thionyl chloride (36 mL, 493 mmol) and heated at 60° C. for 2 h. Formation of the acyl chloride was monitored as follows: a sample of the reaction mixture was evaporated and added to MeOH and formation of the corresponding methyl ester was detected by UPLC. Then thionyl chloride was removed under reduced pressure to obtain pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (14 g) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.Cl.[O:25]1CCOCC1>>[OH:20][C:16]1[CH:15]=[C:14]([C:12]2[N:13]=[C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:25])[CH:7]=3)[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccc(-c2nc(-c3ccnc(F)c3)c3sccc3n2)c1
Reactant: C1COCCO1
Agent: Cl
Product: O=c1cc(-c2nc(-c3cccc(O)c3)nc3ccsc23)cc[nH]1

Procedure:
A mixture of 3-[4-(2-fluoro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-2-yl]-phenol, (60 mg), aqueous HCl (2M, 2 mL) and 1,4-dioxane (2 mL) was heated to reflux for 24 hours. Upon cooling, a precipitate formed; this was collected by filtration and washed with water and ether to yield the furnish the title compound (50 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:39])([F:38])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]4[CH:34]=[CH:33][N:32]=[C:31]4[CH2:35][CH2:36][OH:37])=[CH:22][CH:21]=3)[N:17]=2)=[CH:7][CH:6]=1.[CH:40]([N:43]=[C:44]=[O:45])([CH3:42])[CH3:41].O>ClCCl>[CH:40]([NH:43][C:44](=[O:45])[O:37][CH2:36][CH2:35][C:31]1[N:30]([CH2:29][CH2:28][CH2:27][CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:16]3[N:17]=[C:13](/[CH:12]=[CH:11]/[C:8]4[CH:9]=[CH:10][C:5]([C:4]([F:38])([F:3])[F:39])=[CH:6][CH:7]=4)[O:14][CH:15]=3)=[CH:21][CH:22]=2)[CH:34]=[CH:33][N:32]=1)([CH3:42])[CH3:41]
Reactant: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: CC(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
65% Sodium hydride (21.6 mg) was added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol (300 mg) in dichloromethane (3 ml) at 0° C., and the mixture was stirred at room temperature for 30 min. Isopropyl isocyanate (0.288 ml) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 5 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with 1N aqueous sodium hydroxide solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and recrystallized from ethyl acetate-hexane to give the titled compound (315 mg) as a colorless crystal powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)[C:15]([CH3:18])([CH3:17])[O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.Cl>O.CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=4)[C:15]([CH3:18])([CH3:17])[O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C(=O)O)cc1
Temperature: 58 °C

Procedure:
Methyl 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate (500 mg, 1.32 mmol) was added to a mixture of 1M NaOH (4 mL, 4 mmol), THF (8 mL) and MeOH (20 mL). The mixture was heated at 58° C. for 5 hours, cooled to room temp., and poured into 200 mL of water. 2M HCl was added to bring pH down to 3. The precipitates were filtered, washed with water and dried in vacuo to give 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid as an orange/red solid. Yield: 480 mg, quantitative.
Reaction SMILES: [C:1]1([CH:11]=[CH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:31]([OH:33])=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][C:16]([C:31]([OH:33])=[O:32])=[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1-c1cccc2c(CCC=Cc3cccc4ccccc34)c(C(=O)O)[nH]c12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cccc2c(CCCCc3cccc4ccccc34)c(C(=O)O)[nH]c12

Procedure:
A mixture of EXAMPLE 111D and Pd/C (catalytic) in ethyl acetate/ethanol was stirred at room temperature under hydrogen (balloon) overnight. The mixture was filtered, washed with ethyl acetate/ethanol and concentrated. The concentrate was purified on reverse phase HPLC (Zorbax SB-C18, 20100% acetonitrile/water/0.1% TFA). 1H NMR (300 MHz, DMSO-d6) δ 12.82 (brs, 1H), 10.36 (s, 1H), 8.03 (m, 1H), 7.90 (m, 1H), 7.75 (d, 1H), 7.66 (d, 1H), 7.51 (m, 2H), 7.31 (m, 6H), 7.12 (t, 1H), 7.03 (m, 1H), 3.17 (m, 2H), 3.09 (m, 2H), 2.05 (s, 3H), 1.78 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[Cl:12].[H][H]>CO.[Ni]>[Cl:12][C:4]1[C:3]([N:2]([CH3:13])[CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:9]
Reactant: CN(C)c1cccc([N+](=O)[O-])c1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CN(C)c1cccc(N)c1Cl
Yield: 49.5 %

Procedure:
30.4 g of N,N-dimethyl-2-chloro-3-nitroaniline is dissolved in about 300 ml of MeOH and hydrogenated at 20° C. and 5 bars pressure of hydrogen using Raney nickel as catalyst. The solvent is evaporated down and the product is purified by chromatography (silica gel, eluant: petroleum ether/ethyl acetate (3/1)). 12.8 g of 2-chloro-3-dimethylaminoaniline is obtained as a brown oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[CH:10][CH:9]=2)[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[CH3:2].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)C=CC=CC=1>>[CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:66]=[N+:67]=[N-:68])=[CH:10][CH:9]=2)[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1ccc(CCO)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1nc2ccccc2n1-c1ccc(CCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.9 %

Procedure:
A mixture of 2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (914 mg, 3.4 mmol) in TUF (40 mL) was added diethyl azodicarboxylate (DEAD) (1.2 mg, 7 mmol), triphenylphosphine (1.8 g, 7 mmol) and diphenylphosphoryl azide (DPPA) (1.9 g, 7 mmol). The mixture was stirred at room temperature for 4.5 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to afford 1000 mg (74%) of the title compound as a brown oil: MS (EI) m/z 291 (M+)
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][CH2:15][CH2:16]Br)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[NH2:18][CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:36]>CN(C)C=O.O.C(O)C>[N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][CH2:15][CH2:16][NH:18][CH2:19][CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[ClH:36]
Reactant: Cn1c(=O)c2c(ncn2CCCBr)n(C)c1=O
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2CCCNCCc2c[nH]c3ccccc23)n(C)c1=O

Procedure:
A stirred mixture of 3-(theophyllin-7-yl)propyl bromide (3.0 g., 0.01 mole), tryptamine base (1.60; 0.01 mole) and potassium carbonate (4 g; 0.029 mole) in dry dimethylformamide (50 cc.) was heated, under a dry nitrogen blanket, in an oil-bath maintained at 75° for 17.5 hours. After cooling, the dark mixture was diluted with water (200 cc.) and extracted with dichloromethane (2×50 cc.). The combined extracts were washed with water (2×100 cc.) and dried (MgSO4). Filtration and evaporation gave a syrup which was dissolved in a little ethanol and acidified with ethanolic hydrogen chloride. After cooling, the precipitated crystals were filtered off and washed well with ethanol and ethyl acetate to give the title compound hydrochloride, m.p. 273°-274° C. (dec.) (partial decomposition above 265° C.). The product may also be designated as 3,7-dihydro-7-[3-[[2-(1H-indol-3-yl)ethyl]amino]propyl]-1,3-dimethyl-1H-purine-2,6-dione,hydrochloride. The yield was 1.99 g.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Br)C.C(OCC)C.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[I:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)([OH:19])[CH3:17])=[CH:21][CH:22]=1
Reactant: Ic1cccnc1
Reactant: CC(=O)c1ccc(I)cc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(c1ccc(I)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-iodopyridine (0.3 g, 1.463 mmol) in THF (4 ml) was added ethylmagnesium bromide in diethylether (3M) (0.976 ml, 2.93 mmol). The mixture was stirred at room temperature overnight. GC-MS after overnight showed no starting material and the reaction mixture was cooled in an ice-bath. 4-Iodoacetophenone (0.468 g, 1.902 mmol) was added. The ice-bath was removed after 15 minutes and the reaction was stirred at room temperature for 5 hrs. The reaction mixture was quenched with aqueous saturated NH4Cl solution before dilution with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by preparative HPLC (reversed phase). Fractions containing product were pooled and worked up (addition of NaHCO3, removal of acetonitrile followed by extraction with DCM) to obtain the title compound as yellowish oil.
Reaction SMILES: C(OCC1[CH2:7][S:8][C@@H]2C(N)C(=O)N2C=1C(OC(C)(C)C)=O)(=O)C.[C:23]([O:26][CH2:27][C:28]1[CH2:29][S:30][C@@H:31]2[CH:42]([NH:43][C:44]3[NH:45][CH:46]=[C:47]([CH2:49]OC)[N:48]=3)[C:41](=[O:52])[N:32]2[C:33]=1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:27][C:28]1[CH2:29][S:30][C@@H:31]2[CH:42]([NH:43][C:44]3[NH:45][CH:46]=[C:47]([CH2:49][S:8][CH3:7])[N:48]=3)[C:41](=[O:52])[N:32]2[C:33]=1[C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])(=[O:25])[CH3:24]
Reactant: COCc1c[nH]c(NC2C(=O)N3C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@H]23)n1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Product: CSCc1c[nH]c(NC2C(=O)N3C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@H]23)n1

Procedure:
4-Chloromethyl-2-fluoro-1-triphenylmethylimidazole was treated with methanethiol and triethylamine in THF solution to give 2-fluoro-4-methylthiomethyl-1-triphenylmethylimidazole. This was condensed with t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate as for the starting material of Example 42 to give t-butyl 3-acetoxymethyl-7-(4-methylthiomethylimidazol-2-yl)aminoceph-3-em-4-carboxylate, having the following n.m.r. spectrum in d6DMSO: 1.5 (s, 9H); 2.0 (s, 6H); 3.5 (d, 2H); 3.8 (d, 2H); 4.7 (d, 1H); 5.0 (d, 1H); 5.25 (d, 1H); 5.65 (d, 1H); 7.0 (s, 1H).
Reaction SMILES: CC1N=CC=CC=1C(N)=O.[C:11]([C:15]1[N:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[C:17]([CH3:24])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[C:25]([C:27]1[C:32]2[N:33]([CH2:36][C:37](O)=[O:38])[CH:34]=[N:35][C:31]=2[CH:30]=[CH:29][CH:28]=1)#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[C:11]([C:15]1[N:20]=[CH:19][C:18]([CH:21]([NH:23][C:37](=[O:38])[CH2:36][N:33]2[C:32]3[C:27]([C:25]#[N:26])=[CH:28][CH:29]=[CH:30][C:31]=3[N:35]=[CH:34]2)[CH3:22])=[C:17]([CH3:24])[CH:16]=1)([CH3:13])([CH3:14])[CH3:12]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: Cc1cc(C(C)(C)C)ncc1C(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ncccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(C(C)(C)C)ncc1C(C)NC(=O)Cn1cnc2cccc(C#N)c21

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 2-methylnicotinamide, starting from [1-(6-tert-butyl-4-methylpyridin-3-yl)ethyl]amine (intermediate 28) (52 mg, 0.27 mmol), 7-cyanobenzimidazole-1-acetic acid (54.4 mg, 0.27 mmol), HATU (108 mg, 0.28 mmol) and DIPEA (117 μL, 2.5 mmol). Water is added and the reaction is concentrated then purified by reverse phase chromatography. (Yield 31.3 mg, 31%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.27 (s, 9 H), 1.42 (d, J=7.03 Hz, 3 H), 2.29 (s, 3 H), 5.03-5.12 (m, 1 H), 5.13-5.27 (m, 2 H), 7.17 (s, 1 H), 7.34 (dd, J−8.11, 7.71 Hz, 1 H), 7.71 (dd, J=7.62, 0.78 Hz, 1 H), 8.01 (dd, J=8.01, 0.98 Hz, 1 H), 8.34 (s, 1H), 8.47 (s, 1 H), 8.88 (d, J=7.81 Hz, 1 H). MS [MH+] calc. 376.2137 found 376.3.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][C:9](=[O:10])[CH2:8][CH2:7][C:5]=2[CH:6]=1.O>C1(C)C=CC=CC=1>[O:11]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:7][CH2:8][CH:9]1[OH:10]
Reactant: O=C1CCc2ccccc2O1
Solvent: Cc1ccccc1
Solvent: O
Product: OC1CCc2ccccc2O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
Dihydrocoumarin (5 g, 33.74 mmol) was dissolved in 50 mL of toluene and cooled to −78° C. Dibal (1 M solution in toluene, 38 mL, 38 mmol) was added to the reaction flask over a 45 minutes period. The reaction mixture was stirred at this temperature for 2 h. Water (50 mL) was added slowly along with some toluene to ensure a smooth stirring of the reaction mixture. The slurry was warmed to room temperature and stirring was continued overnight. The organic layer was decanted and dried with magnesium sulfate. Solvent was removed via rotatory evaporator to give compound 5A as a clear oil (4.5 g, 89%). MS: 149 (M−1)+
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[O:9]=[C:7]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)SC/C(=C/c1ccccc1)C(=O)O
Reactant: CCOC(=O)CCN
Product: CCOC(=O)CCNC(=O)/C(=C\c1ccccc1)CSC(C)=O
Yield: 68 %

Procedure:
The (E)-2-acetylthiomethyl-3-phenylpropenoic acid described in Example 1 (step C) is coupled with ethyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield=68% (chromatography on silica, eluent: ether/petroleum ether 6/4) m.p.<50° C. IR (nujol): 3300, 1730, 1690, 1640, 1610 cm-1 1H NMR: (CDCl3 /TMS)=7.20, (s, 5H); 6.75 (s, 1H); 6.00 (broad s, 1H); 3.95 (q, 2H, J=6, 7 Hz); 3.85 (s, 2H); 3.40 (q app., 2H, J app.=6.2 Hz); 2.30 (t, 2H, J=6.7 Hz); 2.30 (s, 3H); 1.15 (t, 3H, J=6.7 Hz). Microanalysis: C17H21O4NS Calc. % C=60.87 H=6.31 N=4.18 Found. % C=60.12 H=6.22 N=3.92
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[C:3]=1[C:16]#[N:17].[OH:18]S(O)(=O)=O>>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[C:3]=1[C:16]([NH2:17])=[O:18]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(-c2cccc([N+](=O)[O-])c2)nsc1N
Product: NC(=O)c1c(-c2cccc([N+](=O)[O-])c2)nsc1N
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A mixture of 5-amino-3-(3-nitrophenyl)isothiazole-4-carbonitrile (500 mg, 2.03 mmol) in 5 mL conc. H2SO4 was heated at 65° C. After 4 hours the mixture was slowly added to 75 mL ice water (including an additional reaction run on 0.50 mmol scale in 1.5 mL conc. H2SO4). The mixture was stirred for 10 min, and then the precipitate filtered and rinsed with water and 10% EtOAc/hexane to give the title compound as a light beige solid (572 mg, 86% combined yield).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[CH3:12]I.C>[OH-].[Na+]>[CH3:12][S:1][C:2]1[N:7]=[C:6]([OH:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: Oc1nc(S)nc2ccnn12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc(O)n2nccc2n1
Temperature: 5 °C
Reaction time: 0.29 h

Procedure:
Seven grams of 2-mercaptopyrazolo[1,5-a][1,3,5]triazin-4-ol (prepared according to the method described in Chemische Berichte, 1971, 104:3039-47) was dissolved in 5% aqueous NaOH (100 mL). The solution was cooled to 5° C. (ice bath) and 6 g. of methyl iodide was added dropwise. After 15-20 minutes, charcoal was added and the mixture was filtered then acidified with acetic acid. The precipitate (2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-ol was filtered, dried and isolated. Further recrystallization in AcOH gave 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-ol. MS (ES+): 183.0 (M+1)+.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:26]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[O:33])=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: O=C(O)c1ccncc1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)c1ccncc1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with isonicotinic acid in analogy to experiment A1 to give (2S,4R)-1-(pyridine-4-carbonyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 467.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]([CH3:39])[C:21]([OH:38])([C:26]3[CH:27]=[CH:28][C:29]4[O:34][CH2:33][C:32](=[O:35])[N:31]([CH3:36])[C:30]=4[CH:37]=3)[C:22]([F:25])([F:24])[F:23])[CH:14]=2)=[CH:7][CH:6]=1)C.[Li+].[OH-].Cl>O1CCCC1.CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:40])=[O:3])=[CH:10][CH:9]=2)=[CH:14][C:15]=1[CH:20]([CH3:39])[C:21]([OH:38])([C:26]1[CH:27]=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH3:36])[C:30]=2[CH:37]=1)[C:22]([F:23])([F:24])[F:25]
Reactant: CCOC(=O)c1ccc(COc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1cc(OCc2ccc(C(=O)O)cc2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 62 %

Procedure:
To a solution of 4-{4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenoxymethyl}-benzoic acid ethyl ester (Example 1, 83 mg) in tetrahydrofuran (0.3 ml) and methanol (0.3 ml) was added a 1 M aqueous LiOH solution (0.29 ml) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 5.5 h. The mixture was cooled in an ice bath and acidified using 1 M aqueous HCl. The mixture was concentrated to dryness. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>85:15) to give the title compound (49 mg) as colorless foam. MS (m/e, ISP neg. ion)=548.2 [M−H+].
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH2:16]([C:20]1[CH2:27][S:26][CH:25]2[N:22]([C:23](=[O:36])[CH:24]2[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:21]=1[C:37]([O:39][CH:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:17]([CH3:19])=[O:18].[C:53]1([CH3:63])[CH:58]=[CH:57][C:56]([S:59](Cl)(=[O:61])=[O:60])=[CH:55][CH:54]=1>CCCCCC.O1CCCC1.C(OCC)(=O)C.CN(P(N(C)C)(N(C)C)=O)C>[CH:40]([O:39][C:37]([C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:20]=1[CH:16]=[C:17]([O:18][S:59]([C:56]1[CH:57]=[CH:58][C:53]([CH3:63])=[CH:54][CH:55]=1)(=[O:61])=[O:60])[CH3:19])[CH:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[C:23]2=[O:36])=[O:38])([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(=O)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 28.6 %

Procedure:
A 1.6M solution of butyllithium in hexane (3.44 cc) is added, in the course of 10 minutes, to a solution of 2,2,6,6-tetramethylpiperidine (0.78 g) in tetrahydrofuran (5 cc) at 20° C. The solution is stirred for 10 minutes at 20° C. and then cooled to -70° C. A solution of 3-acetonyl-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.54 g) in tetrahydrofuran (6 cc) is then added in the course of 20 minutes, and the mixture is then stirred for 15 minutes at -70° C. Hexamethylphosphorotriamide (7 cc) is added in the course of 3 minutes, followed by a solution of p-toluenesulphonyl chloride (5.23 g) in tetrahydrofuran (7 cc) in the course of 3 minutes. The mixture is stirred for 45 minutes at -70° C., the temperature is then left to rise to 0° C. and the solution is diluted with ethyl acetate (100 cc) and washed successively with a 0.1N solution of citric acid (50 cc), a saturated aqueous solution of sodium bicarbonate (50 cc) and distilled water (100 cc). The organic phase is dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.20) (110 g) (diameter of the column: 3 cm; height: 26 cm). Elution is carried out with a 15/80 (by volume) ethyl acetate/cyclohexane mixture (1,200 cc), 60 cc fractions being collected. Fractions 3 to 15 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-tosyloxyprop-1-en-1-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.94 g) in the form of a hard, pale yellow foam.