Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:40]=[CH:39][C:13]2[C:14]([NH:27][C:28]([C@H:30]3[CH2:35][CH2:34][C@H:33]([N:36]([CH3:38])[CH3:37])[CH2:32][CH2:31]3)=[O:29])=[C:15]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=3)=[O:18])[O:16][C:12]=2[CH:11]=1)=[O:7])(C)(C)C>Cl.O1CCOCC1.C(OCC)C>[ClH:26].[C:6]([CH2:8][O:9][C:10]1[CH:40]=[CH:39][C:13]2[C:14]([NH:27][C:28]([C@H:30]3[CH2:35][CH2:34][C@H:33]([N:36]([CH3:37])[CH3:38])[CH2:32][CH2:31]3)=[O:29])=[C:15]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=3)=[O:18])[O:16][C:12]=2[CH:11]=1)([OH:7])=[O:5]
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cc(OCC(=O)OC(C)(C)C)ccc23)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cc(OCC(=O)O)ccc23)CC1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
Trans-6-t-butoxycarbonylmethyloxy-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (21 mg) obtained in Example 153 is suspended in 4N hydrogen chloride in dioxane (8 ml), and the mixture is stirred at room temperature for 28 hours. The reaction solution is diluted with diethyl ether, and the precipitates are collected by filtration, washed several times with diethyl ether, and dried to give the title compound (17 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]#[N:23]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:21]2[N:17]([CH3:16])[C:18]([C:22]#[N:23])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: Cn1cccc1C#N
Product: Cn1c(C#N)ccc1-c1ccc(C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from (4-bromophenyl)-phenyl-methanone and 1-methyl-2-cyanopyrrole according to the coupling procedure as described in example 1. MS (ES) m/z 287.1; HRMS: calcd for C19H14N2O+H+, 287.11789; found (ESI, [M+H]+), 287.1185.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:38])[C@H:21]([NH:30]C(=O)OC(C)(C)C)[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[NH:7][CH:6]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:30][C@H:21]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[C:20]([N:17]1[CH2:16][CH2:15][N:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:7][CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:13]=23)[CH2:19][CH2:18]1)=[O:38]
Reactant: CC(=O)Nc1c[nH]c2nccc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1c[nH]c2nccc(N3CCN(C(=O)[C@H](N)Cc4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
(R)-tert-Butyl 1-(4-(3-acetamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate (0.047 g, 0.087 mmol) was placed in DCM (5 mL) at room temperature. TFA (0.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The crude residue was then dissolved in minimal DCM and added dropwise to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(4-(2-amino-3-(4-chlorophenyl)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.04 g, 90% yield) as the dihydrochloride salt. MS APCI (+) m/z 441 detected.
Reaction SMILES: [F:1][C:2]([F:13])([S:9](Cl)(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].C(=O)([O-])O.[Na+].[OH:19][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].O>C(#N)C>[F:1][C:2]([F:13])([S:9]([O:19][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26])(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6]
Reactant: O=C1CCC(=O)N1O
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCC(=O)N1OS(=O)(=O)C(F)(F)C(F)(F)CCO
Temperature: 0 °C
Yield: 71 %

Procedure:
In 100 mL of acetonitrile, 25 g of a liquid of 1,1,2,2-tetrafluoro-4-hydroxybutanesulfonyl chloride (purity: 90%, equivalent to 0.102 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 10.3 g (0.123 mol) of sodium hydrogencarbonate and 12.9 g (0.112 mol) of N-hydroxysuccinimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water and subjected to concentration. With this, 23.4 g of the target compound was obtained as a pale yellow oily substance (yield: 56%, purity: 79%, pure content: 18.5 g).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].F[C:8]1[CH:9]=[C:10]([CH3:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].C(=O)(O)[O-].[Na+]>CO>[CH3:17][C:10]1[CH:9]=[CH:8][C:13]([N+:14]([O-:16])=[O:15])=[C:12]([S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:11]=1
Reactant: COC(=O)CS
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CSc1cc(C)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 89.9 %

Procedure:
Methyl thioglycolate (3.18 g) was added to a mixture of 3-fluoro-4-nitrotoluene (4.65 g), sodium bicarbonate (3 g) and methanol (46 ml) and the mixture was heated to 70° C. for 5 hours. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and with brine, dried (MgSO4) and evaporated. The residue was recrystallised from a mixture of diethyl ether and hexane to give methyl 2-(5-methyl-2-nitrophenylthio)acetate (6.5 g, 90%), m.p. 74°-75° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.N1CCCCC1>C(O)C>[OH:13][C:8]1[N:3]2[N:4]=[C:5]([SH:7])[N:6]=[C:2]2[N:1]=[C:10]([CH3:12])[CH:9]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1n[nH]c(S)n1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(O)n2nc(S)nc2n1
Yield: 37.6 %

Procedure:
A mixture of 3-amino-5-mercapto-s-triazole (10 g), ethyl acetoacetate (34 g), piperidine (10 ml) and ethanol (300 ml) was refluxed for four hours. After removing the solvent by distillation under reduced pressure, 150 ml water was added, the mixture was neutralized to pH 7.0 with hydrochloric acid and cooled, giving 5.9 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.N1C=CN=C1.[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)C>[Si:23]([O:9][CH2:8][C:6]1[CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[N:3]=[C:2]([Cl:1])[CH:7]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(Cl)nc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](OCc1cc(Cl)nc(C(F)(F)F)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of [2-chloro-6-(trifluoromethyl)pyridin-4-yl]methanol (142 mg, 0.671 mmol, Example 121, Step A) in methylene chloride (1.0 mL) at 0° C. was added 1H-imidazole (55 mg, 0.80 mmol) followed by tert-Butylchlorodiphenylsilane (190 μL, 0.74 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol). The reaction was stirred with warming to room temperature for 64 hours. The reaction mixture was diluted with diethyl ether and was washed with water followed by brine, dried over sodium sulfate, decanted and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-4% EtOAc in hexanes afforded product as a white solid (0.20 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.58 (m, 4H), 7.55-7.34 (m, 8H), 4.77 (s, 2H), 1.12 (s, 9H); 19F NMR (282 MHz, CDCl3) δ−68.49 (s); LCMS (M+H)+: 450.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17](O)[C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=3)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(C(=O)Nc3ccc(Cl)cc3)nc2)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 5-[Hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridine-2-carboxylic acid (4-chloro-phenyl)-amide (71, 100.0 mg, 0.19 mmol) in acetonitrile (10.0 mL) were added trifluoroacetic acid (0.20 mL, 2.6 mmol) and triethylsilane (0.40 mL, 2.5 mmol). The reaction was stirred at 80° C. for 2 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a yellow solid compound (P-0076, 5.5 mg, 8.1%).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([CH:29]=1)[O:21][CH2:22][C:23]1[N:24]=[N:25][N:26]([CH3:28])[CH:27]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:16]3[CH:17]=[CH:18][C:19]([F:30])=[C:20]([O:21][CH2:22][C:23]4[N:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:29]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Cn1cc(COc2cc(Br)ccc2F)nn1
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Product: Cn1cc(COc2cc(-c3cnc4c(F)c(C(F)(F)F)ccn34)ccc2F)nn1

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine was coupled to 4-(5-bromo-2-fluorophenoxymethyl)-1-methyl-1H-[1,2,3]triazole as described in Example 6 to give 8-fluoro-3-[4-fluoro-3-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)phenyl]-7-trifluoromethylimidazo[1,2-α]pyridine as an off-white solid: δH (400 MHz, d6-DMSO) 4.07 (3H, s), 5.53 (2H, s), 7.14 (1H, dd, J 7 and 7), 7.29-7.31 (1H, m), 7.44 (1H, dd, J 11 and 8), 7.73 (1H, dd, J 8 and 2), 8.06 (1H, s), 8.23 (1H, s), 8.62 (1H, d, J 7); m/z (ES+) 410 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=2[N:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](=[O:21])[NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=2[N:28]=1)[CH3:34])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21)C(=O)OC(C)(C)C
Reactant: NCCOCCO
Agent: CN(C)C(On1nnc2ccccc21)=[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: CN(CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21)C(=O)OC(C)(C)C
Yield: 42.9 %

Procedure:
(2-{2-(6-Chloro-benzothiazol-2-ylamino)-5-[2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-benzoimidazol-1-yl}-ethyl)-methyl-carbamic acid tert-butyl ester (73 mg) was prepared by following General Procedure F starting from 1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (145 mg), 2-(2-amino-ethoxy)-ethanol (35 mg), HBTU (125 mg), and DIEA (100 uL) in DMF (1 mL).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)[N:9]=1.Br[CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C=O)C.O>[CH3:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:15]=2)[N:11]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=3)[N:22]=2)[N:9]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(O)c1
Reactant: BrC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(OC2CCOCC2)c1
Temperature: 140 °C

Procedure:
A mixture of Cs2CO3 (62.5 mg, 0.192 mmol), 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenol (Example 59; 40.0 mg, 0.096 mmol) and 4-bromotetrahydro-2H-pyran (21.7 uL, 0.192 mmol) in DMF (0.48 mL) was heated at 140° C. for 1 h under microwave irradiation. The mixture was diluted with H2O and extracted with 4:1 CHCl3:i-PrOH. The organic layer was dried over MgSO4 and concentrated under reduced pressure; the residue was dissolved in DMSO and purified using Prep-HPLC to furnish the title compound; MS (ES+) C24H22F3N5O4 requires: 501. found 502 [M+H]+; 1H-NMR (600 MHz, CD3OD) δ ppm 8.29 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.28 (m, 1H), 6.89 (dd, J=8.1, 2.4 Hz, 1H), 6.80 (m, 2H), 5.41 (s, 2H), 4.47 (m, 1H), 3.95 (m, 2H), 3.57 (m, 2H), 2.54 (s, 3H), 2.01 (m, 2H), 1.75 (m, 2H).
Reaction SMILES: C(O)(C)C.N12CCCNC1CCCC=C2.[CH3:16][C:17]1([CH3:29])[C:21]([CH3:23])([CH3:22])[O:20][B:19]([C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[O:18]1.[C:30]([CH:32]=[C:33]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1)#[N:31]>CCCCCCC>[C:30]([CH2:32][C:33]1([N:27]2[CH:28]=[C:24]([B:19]3[O:20][C:21]([CH3:22])([CH3:23])[C:17]([CH3:29])([CH3:16])[O:18]3)[CH:25]=[N:26]2)[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1)#[N:31]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Agent: C1=CN2CCCNC2CCC1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a 1-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were sequentially added isopropanol (IPA, 200 mL), 1,8-diazabicyclo[5,4,0]undec-ene (DBU, 9.8 g, 64.4 mmol, 0.125 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 101 g, 520.51 mmol, 1.01 equiv) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 100 g, 514.85 mmol) at ambient temperature to generate a reaction mixture as a suspension. The resulting reaction mixture was heated to reflux in 30 minutes to provide a homogenous solution and the mixture was maintained at reflux for an additional 2-3 hours. After the reaction was complete as monitored by HPLC, n-heptane (400 mL) was gradually added to the reaction mixture in 45 minutes while maintaining the mixture at reflux. Solids were precipitated out during the n-heptane addition. Once n-heptane addition was complete, the mixture was gradually cooled to ambient temperature and stirred at ambient temperature for an additional 1 hour. The solids were collected by filtration, washed with n-heptane (200 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (3, 181 g, 199.9 g theoretical, 90.5%) as a white to pale yellow solid. For 3: 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.74 (s, 1H), 4.45-4.23 (m, 2H), 4.23-4.03 (m, 2H), 3.56 (s, 2H), 1.38 (s, 9H), 1.25 (s, 12H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 155.34, 145.50, 135.88, 116.88, 107.08 (br), 83.15, 79.36, 158.74 (br), 56.28, 27.96, 26.59, 24.63 ppm; C19H29BN4O4 (MW 388.27), LCMS (EI) m/e 389 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][OH:23])[C:3]=1[F:24].Cl[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27].O>N1C=CC=CC=1>[CH2:29]([O:28][C:26]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:6]3[C:5]([F:21])=[C:4]([CH2:22][OH:23])[C:3]([F:24])=[C:2]([NH2:1])[C:7]=3[C:8](=[O:20])[CH:9]=2)=[CH:13][C:14]=1[F:19])=[O:27])[CH:30]=[CH2:31]
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(CO)c(F)c3o2)cc1F
Reactant: C=CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: C=CCOC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)c(CO)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
6.72 mg (20.0 mmol) of Compound 118 obtained in Example 118 was dissolved in 200 mL of pyridine, 10.6 mL (100 mmol) of allyl chloroformate was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration. The crystals were dissolved in 500 mL of ethanol, 18 mL of a 2N aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration, to give 6.92 g of Compound P (yield: 82%).
Reaction SMILES: S([O-])(=O)(=O)C.[N-]=[N+]=[N-].[Na+].[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][CH2:18][C@@H:19]1[C@H:24]([N:25]=[N+:26]=[N-:27])[CH2:23][C@H:22]2[CH2:28][C@@H:20]1[C:21]2([CH3:30])[CH3:29]>>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][CH2:18][C@H:19]1[C@H:24]([N:25]=[N+:26]=[N-:27])[CH2:23][C@H:22]2[CH2:28][C@@H:20]1[C:21]2([CH3:30])[CH3:29]
Reactant: CC1(C)[C@H]2C[C@@H](N=[N+]=[N-])[C@@H](CCOC3CCCCO3)[C@@H]1C2
Agent: CS(=O)(=O)[O-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC1(C)[C@H]2C[C@@H](N=[N+]=[N-])[C@H](CCOC3CCCCO3)[C@@H]1C2

Procedure:
Diethyl azadicarboxylate (20 g) was added dropwise to a suspension of the alcohol 1(2R-c) (6.11 g), triphenylphosphin (30 g) and zinc dimethanesulfonate (5.83 g) in benzene (350 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 3 h, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel in hexane ethyl acetate (5:1) to give the crude mesylate (6.7 g). The mesylate was treated with sodium azide by the same procedure cited for the preparation of 15 (IV-2, Example 2 (2)), 2.05 g, 31.3%. nmr δ (CDCl3) 0.86(3H, s), 1.21(3H,s), 1.28(1H,d, J=10 Hz), 1.40-2.50(14H), 3.22-4.00(5H), 4.57(1H,m).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:50])[C:19]([C:25]3[N:26]=[C:27]([NH:30]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:28][CH:29]=3)=[N:20][O:21][CH2:22][CH:23]=[CH2:24])[C:15](=[O:51])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(O)=O>O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:50])[C:19]([C:25]3[N:26]=[C:27]([NH2:30])[S:28][CH:29]=3)=[N:20][O:21][CH2:22][CH:23]=[CH2:24])[C:15](=[O:51])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 60 °C
Yield: 29.6 %

Procedure:
A mixture of 610 mg of the product of Example 8 and 3 ml of 50% aqueous formic acid was heated at 60° C. for 15 minutes and 4 ml of water were added. The mixture was stirred and vacuum filtered. The filtrate was rinsed with water and concentrated to dryness under reduced pressure. The residue was taken up in water and was effloresced. The mixture was vacuum filtered and the product was rinsed to obtain 120 mg of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(2-propenyl) oxyiminoacetamido]-ceph-3-eme-4-carboxylic acid with a melting point of about 160° C. and a syn configuration.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:23][N:22](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:21]3)=[N:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(S)CCCCCC>C1COCC1.C1CCN2C(=NCCC2)CC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:21][NH:22][CH2:23]3)=[N:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnc(C3CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)o2)CC1
Agent: CCCCCCCS
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnc(C3CNC3)o2)CC1
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a solution of 4-[1-phenyl-1-(5-(N-(9-fluorenylmethoxycarbonyl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.161 g, 0.260 mmol) and heptanethiol (0.398 mL, 2.60 mmol) in THF (2.6 mL) at rt was added DBU (2 drops). The mixture was allowed to stir for 18 h and then the solvent was removed in vacuo. The residue was dissolved in MeOH and purified by preparative HPLC(NH4OAc) to afford the title compound (0.077 g, 74%) as a colorless solid:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[F:13][C:14]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:15]=1[CH2:16]Br.O>C(O)C>[F:13][C:14]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:15]=1[CH2:16][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1c(F)c(F)c(CSc2nc3ccccc3[nH]2)c(F)c1F
Reaction time: 1 h

Procedure:
To a slurry of 1.50 g of the 2-mercaptobenzimidazole in 28.5 ml of 95% ethanol was added 0.4 g of sodium hydroxide. After all materials had dissolved, the mixture was added to 2.80 g of 2,3,4,5,6-pentafluorobenzyl bromide. The mixture was stirred at 28°-32° C. for 1 hr, then poured into 150 ml water. The product precipitated, was filtered and dried to yield 2.50 g, mp 189°-196° C. Recrystallization from aqueous methanol yielded 1.95 g, mp 193°-195° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)CC4=O)[CH2:20][CH2:19]3)=[O:17])=[CH:8][N:9]2[CH2:12][CH2:13][NH:14][CH3:15])=[CH:5][CH:4]=1.Cl.N1CCC([N:41]2C3C=CC=CC=3N=[N:42]2)CC1.C(N(CC)C(C)C)(C)C>>[ClH:2].[N:24]1([CH:21]2[CH2:22][CH2:23][N:18]([C:16]([C:7]3[C:6]4[C:5](=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=4)[N:9]([CH2:12][CH2:13][NH:14][CH3:15])[CH:8]=3)=[O:17])[CH2:19][CH2:20]2)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:42]=[N:41]1
Reactant: CNCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21
Reactant: c1ccc2c(c1)nnn2C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CNCCn1cc(C(=O)N2CCC(n3nnc4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedures described for the preparation of 1-{1-[6-chloro-1-(2-methylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one hydrochloride using 1-(4-piperidyl)-1H-1,2,3-benzotriazole hydrochloride instead of 1,3-dihydro-1-(piperidin-4-yl)-(2H)-indol-2-one and a total of 3.2 molar equivalents of N,N-diisopropylethylamine instead of 2.2 molar equivalents in step a).