Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH:29]=[O:30])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[Si]([C:35]#[N:36])(C)C.O>C(Cl)Cl.[Zn+2].[I-].[I-]>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH:29]([OH:30])[C:35]#[N:36])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2ccc3cc(C(O)C#N)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a suspension of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthaldehyde (0.4 g, 1.01 mmol) and ZnI2 (0.07 mg, 0.02 mmol) in anhydrous CH2Cl2 (5 mL) stirring at 0–5° C. under an argon atmosphere was added trimethylsilylcyanide (0.16 mL, 1.18 mmol). The reaction mixture was stirred for 1.0 hour at 0–5° C. before it was allowed to warm to room temperature and stirred for 26 hours. It was poured into water, extracted with CH2Cl2. After removal of the solvent, the residue was dissolved in 1,3-dioxolane (10 mL) and 2N HCl added. After stirring at room temperature for 1.5 hours, it was poured into water, extracted with EtOAc, washed with water, brine and recrystallized from hexane/CH2Cl2 to afford 2-[6-(3-[1-adamantyl]-4-methoxyphenyl)-2-naphthyl]-2-hydroxy-acetonitrile as an orange powder 0.340 mg (80%). 1H NMR (300 MHz; CDCl3): δ 1.80 (s, 6H), 2.10–2.18 (m, 9H), 2.86 (s, 1H), 3.90 (s, 3H), 5.71 (s, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.51–7.61 (m, 3H), 7.78–7.82 (m, 1H), 7.90–8.02 (m, 4H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][OH:12])[CH2:2][CH:3]=[CH2:4].[CH2:13]([O:16][C:17]1([CH3:46])[CH2:22][CH2:21][N:20]([C:23]2[N:28]3[N:29]=[C:30]([CH2:32]I)[CH:31]=[C:27]3[N:26]=[C:25]([CH3:34])[C:24]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:19][CH2:18]1)[CH:14]=[CH2:15].[H-].[Na+]>CN(C=O)C>[CH2:13]([O:16][C:17]1([CH3:46])[CH2:18][CH2:19][N:20]([C:23]2[N:28]3[N:29]=[C:30]([CH2:32][O:12][CH2:11][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[CH2:1][CH2:2][CH:3]=[CH2:4])[CH:31]=[C:27]3[N:26]=[C:25]([CH3:34])[C:24]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:21][CH2:22]1)[CH:14]=[CH2:15]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CCCc1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCc1ccccc1COCc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 45.2 %

Procedure:
To a mixture of (2-(but-3-en-1-yl)phenyl)methanol (35.1 mg, 0.216 mmol) in DMF (3 mL) at 0° C. was added (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (115 mg, 0.197 mmol) and NaH (7.87 mg, 0.197 mmol). It was then stirred at 0° C. for 4 h. The reaction mixture was quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to obtain (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (55 mg, 0.089 mmol, 45.2% yield) as an oil. LCMS (M+1)=619.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[N:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][N:20]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[C:19](=[O:23])[N:18]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:24]([F:25])([F:27])[F:26]
Reactant: Cn1cc(CCl)cn1
Reactant: O=c1nc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Agent: Cl
Product: Cn1cc(Cn2ccc(OCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 4-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]oxy}-2(1H)-pyrimidinone and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 491 [M+H]+; 3.49 min (ret time).
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:24][N:25]([CH:34]=[O:35])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]([N:16]2[C@H:20]([C:21]([OH:23])=O)[CH2:19][CH:18]=[N:17]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[F:41][C:42]1[CH:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=1>CN(C)C=O>[CH:7]1([CH2:12][C@H:13]([CH2:24][N:25]([CH:34]=[O:35])[O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:48][C:45]3[CH:44]=[CH:43][C:42]([F:41])=[CH:47][N:46]=3)=[O:23])[CH2:19][CH:18]=[N:17]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O)OCc1ccccc1
Reactant: Nc1ccc(F)cn1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)cn1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
1-Methylimidazole (59.6 μl, 0.747 mmol) was added into the solution of (55)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (150 mg, 0.374 mmol) in N,N-dimethylformamide (DMF) (2.7 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (30.4 μl, 0.392 mmol) was added dropwise at 0° C. To the reaction mixture was added 5-fluoro-2-pyridinamine (46.1 mg, 0.411 mmol). After stirring for 2 h 10 min at ambient temperature, the reaction solution was purified by RP-HPLC to yield (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-N-(5-fluoro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (104 mg, 0.210 mmol, 56% yield). MS (ES+) m/z 496.0 (MH+).
Reaction SMILES: NC1C=C(/C=C/[N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])C=C(C(F)(F)F)C=1.[H][H]>[Pd].C1COCC1>[C:15]1(=[O:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[NH:14]1
Reactant: [H][H]
Reactant: Nc1cc(/C=C/N2C(=O)c3ccccc3C2=O)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1NC(=O)c2ccccc21
Yield: 41.4 %

Procedure:
A slurry of 2-{(E)-2-[3-amino-5-(trifluoromethyl)phenyl]vinyl}-1H-isoindole-1,3(2H)-dione (1.99 g, 5.98 nunol) and Pd/C (0.20 g, 10% by weight) in ETOH (123 mL) and THF (88 mL) was allowed to stir under 50 psi of hydrogen at rt until reaction was judged to be complete. The mixture was filtered through Celite and concentrated. The residue was purified by column chromatography to give 2-12-[3-amino-5-(trifluoromethyl)phenyl]ethyl)-1H-isoindole-1,3(2H)-dione (365 mg, 16% yield). LCMS: (FA) ES+ 335.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:4][CH:3]1[C:5]([NH:7][C:8](=[CH:16][CH2:17][CH2:18][CH3:19])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6].[ClH:21].C[CH2:23][O:24]CC>>[CH3:1][C:2]1([CH3:20])[CH2:4][CH:3]1[C:5]([NH:7][C:8]([O:24][CH3:23])([CH:16]=[CH:17][CH2:18][CH3:19])[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[O:6].[ClH:21]
Reactant: CCCC=C(NC(=O)C1CC1(C)C)C(=O)OC(C)(C)C
Reactant: CCOCC
Agent: Cl
Product: CCC=CC(NC(=O)C1CC1(C)C)(OC)C(=O)OC(C)(C)C
Reaction time: 17 h

Procedure:
A solution of 0.84 g (3.0 mmole) of t-butyl 2-(2,2-dimethylcyclopropanecarboxamido)-2-hexenoate in 10 ml of Et2O saturated with anhydrous HCl was allowed to stand at room temperature under a drying tube. After 17 hrs, the solution was evaporated, and the residual gum was dissolved in 10 ml of saturated NaHCO3. This solution was washed with an additional 15 ml of 0.5 N HCl, then dried (MgSO4), filtered, and concentrated to give a viscous oil. The oil was crystallized from toluene. Yield of white crystals =0.32 g (47%), m.p. 119°-122°. TLC (4:1 toluene-AcOH) showed a single spot. NMR indicated essentially pure Z-isomer. (Note: Treatment of the methanol adduct, t-butyl 2-(2,2-dimethylcyclopropanecarboxamido)-2-methoxyhexenoate, with anhydrous HCl in Et2O under similar conditions gave the same product.)
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[N:17]=2)[CH2:7]1)=[O:5])[CH3:2].[O:28]=[C:29]1[NH:34][C:33]2[CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=[CH:38][C:32]=2[S:31][CH2:30]1>>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][C:39]([C:36]2[CH:37]=[CH:38][C:32]3[S:31][CH2:30][C:29](=[O:28])[NH:34][C:33]=3[CH:35]=2)=[O:40])[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[N:17]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CCOC(=O)[C@@H]1CN(CCOc2cnc3ccc(OC)cc3n2)CC[C@@H]1N
Product: CCOC(=O)[C@@H]1CN(CCOc2cnc3ccc(OC)cc3n2)CC[C@@H]1NC(=O)c1ccc2c(c1)NC(=O)CS2

Procedure:
The title compound is prepared as a yellow oil (135 mg, 71% yield) following Scheme 1 and in analogy to Example 1 using (3R,4S)-4-amino1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidine-3-carboxylic acid ethyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [CH2:1]([C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([N:22]([CH:19]([CH3:21])[CH3:20])[NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)COc1ccccc1Cc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccccc1Cc1ccccc1
Yield: 59.8 %

Procedure:
A solution of (2-benzyl-phenoxy)-acetic acid (1.15 g, 4.74 mmol), and benzoic acid N′-isopropyl-hydrazide (704 mg, 3.95 mmol) in DMF (30 ml), was treated with diisopropyl ethyl amine (1.8 ml, 9.88 mmol), and PyBroP (2.76 g, 5.93 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was successively washed brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 50% ethyl acetate/hexanes to afford the product as a white solid (950 mg, 60%). MS m/e 403.25 (M+H+)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[N:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>C(Cl)Cl.O>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:23]3[CH:24]=[CH:25][C:26]([N:27]4[CH2:28][CH:29]([OH:31])[CH2:30]4)=[C:21]([F:20])[CH:22]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(N2CC(O)C2)c(F)c1
Reaction time: 48 h
Yield: 62.6 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (103 mg, 0.33 mmol, 1.0 eq) in DCM (10 mL) was added TEA (0.10 mL, 0.66 mmol, 2.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (100 mg, 0.33 mmol, 1.0 eq) at RT and stirred for 48 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (20 mL), washed with brine, dried over Na2SO4 and evaporated. The residue was purified by CC using 1.0% MeOH in EtOAc as eluent to obtain 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)urea (100 mg; 63%, light brown solid) (TLC: EtOAc/PE 3:2; Rf: 0.3).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5].[Cl:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[N:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[C:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:31][C:27]2[CH:28]=[N:29][CH:30]=[C:25]([Cl:24])[CH:26]=2)[N:9]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Reactant: Oc1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Oc1cncc(Cl)c1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To the product of Example 131 (100 mg, 0.2793 mmol) was added 5-chloro-3-pyridinol (181 mg, 1.397 mmol), Cs2CO3 (228 mg, 0.6983 mmol) and toluene (1.5 mL) before heating to 100° C. After stirring 14 hours the reaction solution was filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with a gradient of 1 to 3% ethyl acetate/dichloromethane affording the product. MS (electrospray) m/e 453.9 MH+ (Rt=4.1 min LC/MS).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[C:28]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:27][S:26][C:25]=4[CH:36]=3)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+]>O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[C:28]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][S:26][C:25]=4[CH:36]=3)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1csc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4c(CCC(=O)O)csc4c3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
7-{2-[3-(2-Ethoxycarbonyl-ethyl)-benzo[b]thiophen-6-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (338 mg, 0.66 mmol) was dissolved THF (5ml). Then a solution of sodium hydroxide (132 mg, 3.30 mmol) in water (1 ml) was added. The reaction was stirred at room temperature for 16 hours. After that period, the solvent was evaporated under vacuum and the crude was extracted with ethyl acetate and hydrochloric acid (1M). The organic layer was collected, dried with anhydrous sodium sulfated, filtrated and evaporated under vacuum to yield 268 mg (84%) of 7-{2-[3-(2-Carboxy-ethyl)-benzo[b]thiophen-6-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester. NMR 1H Cl3CD δ: 7.59 (d, 1H, J=8.8 Hz), 7.47 (d, 1H, J=7.7 Hz), 7.35 (d, 1H, J=2.3 Hz), 7.05 (d, 1H, J=7.6 Hz), 7.01 (s, 1H), 6.96 (dd, 1H, J=2.3, 8.8 Hz), 4.35 (t, 2H, J=6.5 Hz), 3.73 (m, 2H), 3.18 (m, 2H), 3.05 (m, 2H), 2.72 (m, 2H), 2.66 (m, 2H), 1.88 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH2:10])=[S:9].O.[CH2:12](N)[C:13]#[CH:14]>C(O)C>[CH2:14]([NH:10][C:8](=[S:9])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:13]#[CH:12]
Reactant: NC(=S)Cc1ccccn1
Reactant: C#CCN
Solvent: CCO
Solvent: O
Product: C#CCNC(=S)Cc1ccccn1
Reaction time: 8 h

Procedure:
To 4.0 g. (0.026 mole) of 2-(2-pyridyl)thioacetamide in 20 ml. of water at 0°C. is added 2.9 g. (0.053 mole) of propargylamine with stirring and the resulting suspension is allowed to stand overnight at 5°C. Ethanol (5 ml.) is added and the mixture is stirred for 5 hours, then extracted with dichloromethane. The extracts are dried and concentrated. The residue is chromatographed on a silica gel "dry-column", using 1:10 ethyl acetate/ether as the eluant. The product fraction is treated with charcoal, filtered, concentrated and the residue is recrystallized from benzene/ligroin to give N-propargyl-2-(2-pyridyl)thioacetamide, m.p. 62°-63°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([F:14])[CH:13]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])N.N([O-])=[O:16].[Na+]>OS(O)(=O)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][C@H:6]([OH:16])[C:8]([OH:10])=[O:9])[CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: O=N[O-]
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H](O)Cc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
A suspension of 1.6 g of (S)-3,5-difluoro-phenyalanine in 5.3 ml of H2SO4 (2.5N) is admixed dropwise at 0° C. with a solution of 0.829 g of sodium nitrite in 4.2 ml of H2O. The reaction mixture is stirred for 2 hours at 0° C. and then for 17 hours at ambient temperature. The reaction mixture is extracted with 2×100 ml of AcOEt. The combined organic phases are washed with 100 ml of saturated NaCl solution in H2O. Drying gives 1.197 g of yellow crystals. The acid obtained is used without further purification in the following step.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@:7]([CH3:9])([OH:8])[CH:6]=[CH:5][CH2:4]1.C(=O)(O)[O-:11].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[OH:1][CH2:2][C@@H:3]1[CH2:4][C@H:5]2[C@H:6]([O:11]2)[C@:7]1([CH3:9])[OH:8]
Reactant: O=C([O-])O
Reactant: C[C@]1(O)C=CC[C@H]1CO
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](CO)C[C@@H]2O[C@@H]21
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
To a solution of (1S,5S)-5-(hydroxymethyl)-1-methylcyclopent-2-en-1-ol (0.181 g, 0.00141 mol) in DCM (18.0 mL) was added sodium bicarbonate (237 mg, 2.82 mmol) and the mixture was cooled to 0° C. To this mixture was added 3-chloroperbenzoic acid (380. mg, 1.69 mmol) and the reaction was stirred at rt for 4 h. The solvent was removed in vacuo and silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in DCM afforded the title compound (200 mg, 98%). LC/MS: Rt=0.52 min, ES+ 145 (AA standard).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[N:6][CH:5]=[N:4]1)[CH3:2].[H-].[Na+].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:21][N:22]2[C:27]=1[CH:26]=[N:25][N:24]=[C:23]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34].O>CN(C)C=O>[CH2:1]([N:3]1[C:7]([CH2:8][O:9][C:20]2[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[F:12])=[C:27]3[N:22]([C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[N:24][N:25]=[CH:26]3)[N:21]=2)=[N:6][CH:5]=[N:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nncc3c2-c2ccccc2F)cc1
Reactant: CCn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccccc1F
Reaction time: 0.5 h

Procedure:
The title compound was prepared as part of a rapid analogue library using the following methodology. To a solution of (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (32 mg, 0.25 mmol) in dry N,N-dimethylformamide (5 ml) in a RADLEYS reaction carousel under nitrogen was added sodium hydride (60% wt in oil) (10 mg, 0.25 mmol) and the suspension was stirred for 30 min. A solution of 3,7-bis(2-fluorophenyl)-2-(p-toluenesulfonyloxy)pyrazolo[1,5-d][1,2,4]triazine (100 mg, 0.21 mmol) in dry N,N-dimethylformamide (2 ml) was then added and the solution was stirred under nitrogen for 1 h. A further amount (4 mg, 0.10 mmol) of sodium hydride (60% wt in oil) was added and the solution was stirred for 18 h. Water (25 ml) was added to quench the reaction and the solid which was precipitated was collected by filtration and washed with water. The solid was dissolved in dichloromethane, filtered and the filtrate was concentrated in vacuo to give a white solid (40 mg). Data for the title compound: mp=164° C.; 1H NMR (360 MHz, CDCl3) δ 1.31 (3H, t), 4.09-4.16 (2H, m), 5.56 (2H, s), 7.21-7.33, (3H, m), 7.37-7.43 (2H, m), 7.58-7.68 (2H, m), 7.82 (1H, m), 7.87 (1H, s), 9.28 (1H, s); MS (ES+) m/e 434 [MH]+; HPLC>97% purity (run on an HP1100, using a Hichrom KR100-5C18, 25 cm column, flow rate of 1 ml/min and 50% acetonitrile/pH 3 phosphate buffer as the mobile phase).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].[Cl:7][C:8]1[N:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[C:10](Cl)[N:9]=1>>[Cl:7][C:8]1[N:9]=[C:10]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[C:11]([Cl:15])=[C:12]([Cl:14])[N:13]=1
Reactant: CNS(C)(=O)=O
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Product: CN(c1nc(Cl)nc(Cl)c1Cl)S(C)(=O)=O

Procedure:
Following a procedure similar to that of Method 32, the title compound was prepared from N-methylmethanesulfonamide and 2,4,5,6-tetrachloropyrimidine. MS: 290 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].[C:24]1([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOCC>O1CCCC1>[OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([O:11][CH:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:10]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12

Procedure:
3-Hydroxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (500 mg.) was dissolved in dry tetrahydrofuran and treated with a solution of diphenyldiazomethane (300 mg., 1.1 equiv.) in petrol. Nitrogen was evolved slowly, and after 21/2 hours the solution was evaporated, the residue dissolved in ethyl acetate, and the solution was washed with bicarbonate solution and re-evaporated. This gave a gum which solidified on trituration with ether (0.5 g.). A sample was recrystallised from methanol, m.p. 164°, [α]D23 = + 25° (c, 1.0, dioxan), +22° (c 1.0, tetrahydrofuran). λλmax. ethanol 234 nm. E1 cm1% = 255, (ε = 13,300), 259 nm. E1cm1% = 151 (ε 7,850), νmax. (bromoform) 3420 (OH), 3280 (NH), 1750 (β-lactam), 1722 cm-1 (COOR). (Found, C, 62.2; H, 4.5; N, 5.4; S, 12.1. C27H24N2O5S2 requires C, 62.3; H, 4.7; N, 5.4; S, 12.3%) RF = 0.83 (Kieselgel G plates; ethyl acetate:benzene=1:2).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[N:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:29]2[CH2:28][CH2:27][N:26]([C:24]([CH:21]3[CH2:22][CH2:23][N:18]([C:15]4[CH:16]=[CH:17][N:12]=[CH:13][N:14]=4)[CH2:19][CH2:20]3)=[O:25])[CH2:31][CH2:30]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C(C1CCN(c2ccncn2)CC1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)N2CCN(C(=O)C3CCN(c4ccncn4)CC3)CC2)cc1
Yield: 46.2 %

Procedure:
A solution of 4-cyanobenzoyl chloride (298 mg) in dichloromethane (10 ml) was added to a stirred mixture of 1-[1 (4-pyrimidinyl) piperidin-4-ylcarbonyl] piperazine (412.5 mg) and triethylamine (0.28 ml) in dichloromethane (15 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between dichloromethane and water. The organic phase was washed with water, dried (Na2SO4) and evaporated. The residue was purified by column chromatography using 0.5 % methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-cyanobenzoyl)-4-[l-(4-pyrimidinyl)-4-piperidylcarbonyl]piperazine (280 mg), mp 192-193° C.;