Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH2:30])[CH2:25][O:24]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH:30][C:19]([C:18]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)=[O:20])[CH2:25][O:24]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@H](CONC(=O)c2ccc3[nH]ncc3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.5 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (150 mg, 0.38 mmol) and O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (83 mg, 0.57 mmol) in DMF (4 mL) was added EDCI (80 mg, 0.42 mmol), HOBt (56 mg, 0.42 mmol) and DIPEA (70 μL, 0.42 mmol). The reaction mixture was stirred at room temperature for 3.5 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (135 mg, 68%). LCMS (Method B): RT=3.45 min, [M+H]+=527.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[C:4](/[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:5]\[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.[H-].[Na+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])/[C:4](/[C:16]1[CH:17]=[CH:18][C:19]([O:22][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)=[CH:20][CH:21]=1)=[CH:5]\[C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)/C(=C\c1cc(OC)cc(OC)c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C(=C\c1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Yield: 74.2 %

Procedure:
Under argon, 20 (0.60 g, 1.9 mmol) was dissolved in dry DMF (4 mL) and to this sodium hydride (60% in oil, 0.09 g, 2.28 mmol) was added. To the resulting orange solution, 4-fluorobenzaldehyde (0.25 mL, 2.28 mmol) was added and heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The crude product obtained after evaporation was purified by chromatography over silica gel and elution with a mixture of hexane-ethyl acetate (4:1) to yield 21 as white solid (0.59 g, 74%): 1HNMR(400 MHz, CDCl3) δ 9.93 (s, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.10 (overlapped d, J=8.8 Hz, 2H), 7.08 (overlapped d, J=8.8 Hz, 2H), 6.96 (s, 1H), 6.53 (dd, J=2.8 Hz, 2H), 6.43 (t, J=2.0 Hz, 1H), 3.80(s, 3H), 3.79 (s, 6H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.C[O:9][CH:10](OC)[C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1>CN(C=O)C.C(Cl)(Cl)Cl.O.[Cu]>[N:3]1([C:14]2[CH:15]=[CH:16][C:11]([CH:10]=[O:9])=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: COC(OC)c1ccc(Br)cc1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of sodium hydride (60% in oil: 0.82 g, 20.5 mmol) in dry DMF (4.5 ml) under nitrogen atmosphere is added imidazole (1.37 g, 20.1 mmol) with stirring at room temperature. After being stirred for 20 min. 4-bromobenzaldehyde dimethyl acetal (4.63 g, 20 mmol) and copper powder (0.13 g, 2.0 mmol) are added and the reaction mixture is stirred at 130° C. for 2 h, then at 150° C. for 2.5 h. The mixture is cooled to room temperature, diluted with chloroform and water. The solution is stirred for 1 h and filtered on Celite. The organic layer is separated, washed wit water, dried over sodium sulfate, and concentrated in vacuo. The residue is dissolved in 1N hydrochloric acid (20 ml) and stirred at room temperature for 4 h. The reaction mixture is diluted with 5N NaOH (4 ml), and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and concentrated in vacuo. The solid obtained is washed with hexane and dried in vacuo to give 4-(1-imidazolyl)benzaldehyde.
Reaction SMILES: [C:1]1([C@H:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:37][C:38]1[CH:39]=[N+:40]([O-:58])[CH:41]=[C:42]([Cl:57])[C:43]=1[CH2:44][C@@H:45]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=1)O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:57][C:42]1[CH:41]=[N+:40]([O-:58])[CH:39]=[C:38]([Cl:37])[C:43]=1[CH2:44][C@H:45]([O:18][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:10]2[CH:22]=[CH:23][CH:24]=[C:8]([C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:25][C:26]([O:28][C@@H:29]3[CH:34]4[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]4)[CH2:30]3)=[O:27])[CH:9]=2)=[CH:21][CH:20]=1)[C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.6 %

Procedure:
To a stirred solution of 4-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)-benzoic acid (I17, 243 mg, 0.5 mmol) in DMF (2 mL) was added a solution of (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)-ethanol (172 mg, 0.5 mmol) in DMF (5 mL), followed by DMAP (31 mg, 0.25 mmol) and EDC.HCl (192 mg, 1 mmol). The mixture was allowed to stir at room temperature for 18 h and then the solvent was removed in vacuo. The residue was partitioned between DCM (15 mL) and saturated sodium bicarbonate solution (15 mL). The organic phase was washed with brine (15 mL), passed through a hydrophobic frit and the solvent was removed in vacuo. Purification was achieved by preparative HPLC to afford the title compound as a white solid (169 mg, 42%). 1H NMR (400 MHz, DMSO): δ 8.58 (s, 2 H), 8.27 (s, 1 H), 8.02 (d, J=8.1 Hz, 2 H), 7.59 (d, J=8.0 Hz, 2 H), 7.36-7.19 (m, 6 H), 7.10-6.88 (m, 6 H), 6.25 (dd, J=9.5, 4.4 Hz, 1 H), 5.84 (d, J=9.4 Hz, 1 H), 5.20 (s, 2 H), 4.64-4.57 (m, 1 H), 3.81 (s, 3 H), 3.78 (s, 3 H), 3.67 (dd, J=14.7, 9.7 Hz, 1 H), 3.37 (dd, J=14.1, 4.2 Hz, 1 H), 3.14 (t, J=11.7 Hz, 1 H), 2.83-2.52 (m, 5 H), 1.98-1.90 (m, 1 H), 1.88-1.76 (m, 1 H), 1.69-1.57 (m, 1 H), 1.57-1.44 (m, 1 H), 1.44-1.32 (m, 1 H). LCMS (Method 1): [MH+]=812 at 2.97 min.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1>C(Cl)Cl>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][C:9]=2[CH2:8][CH2:7]1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chlorosulphonic acid (43.4 g, 0.366 mol) in DCM (10 mL) was added to a cold solution (5° C.) of 2,3-dihydrobenzofuran (20 g, 0.166 mol) in DCM (200 mL). After the addition the reaction was left with stirring at room temperature overnight. The reaction mixture was quenched with water (150 mL) keeping the temperature below 10° C. The organic phase was separated and washed with an aqueous solution of NaHCO3 (13.9 g dissolved in 150 mL of water). The organic solvents were evaporated to yield the title compound as a solid residue 3.3 g (23%). 1H NMR 270 MHz (CDCl3) δ ppm 3.32 (t, J=8.91 Hz, 2H) 4.75 (t, J=8.91 Hz, 2H) 6.90 (d, J=9.15 Hz, 1H) 7.78-7.90 (m, 2H)
Reaction SMILES: [C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:26])=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCc3ccccc32)cc1
Reactant: NS(=O)(=O)c1ccccc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCc3ccccc32)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Prepared by coupling 2m and benzene sulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (65%); ESI m/z: 490 (M−H−, 100%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].[CH3:17]C([N-]C(C)C)C.CI.[NH4+].[Cl-]>C1COCC1>[CH3:17][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-18a, 2.14 g, 10 mmol) was dissolved in dry THF (20 mL) and the solution was cooled to −78° C. LDA (1.8 M in THF, 6.6 mL) was added to the mixture dropwise and the mixture was stirred for 15 min. Then CH3I (1.87 mL, 30 mmol) was added to the mixture at −78° C. and the reaction was allowed to warm up to room temperature. The reaction was stirred overnight. NH4Cl (aq.) was added to quench the reaction which was extracted with ethyl acetate (50 mL×3). The combined organics was washed with water and brine and dried over Na2SO4. After concentration, the residue was purified by column chromatography (0-50% ethyl acetate in hexane) which gave ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-18b) (2.09 g) as an oil. HPLC-MS tR=1.68 min (UV254 nm); mass calculated for formula C12H20O4 228.1, observed LCMS m/z 229.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.C(OCC)(=O)C>ClCCl>[N+:28]([C:27]1[CH:22]=[CH:23][C:24]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)=[CH:25][CH:26]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1ccc([N+](=O)[O-])cc1
Yield: 16 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using p-nitrophenol (18 mg, 0.13 mmol) as the coupling partner. Chromatography (1:1 ethyl aceate:dichloromethane) through SiO2 yielded 11 mg (16%) of the titled compound. ESI-MS m/z 413 (MH+), 411 (M−H−).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH2:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.C(OCC)C>[Br:1][C:2]1[C:3]([O:15][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cccc(I)c1Br
Reactant: CC(C)(C)CO
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: Cc1cccc(OCC(C)(C)C)c1Br
Temperature: 110 °C

Procedure:
A vial was charged with 2-bromo-1-iodo-3-methylbenzene (677 mg, 2.28 mmol), neopentyl alcohol (2.21 g, 25.08 mmol), copper(I) iodide (43.4 mg, 0.228 mmol), 1,10-phenanthroline (82 mg, 0.456 mmol) and cesium carbonate (1.04 mg, 3.19 mmol). The vial was sealed under air atmosphere and heated to 110° C. for 24 h. The reaction mixture was cooled to rt and diethyl ether was added. The suspension was filtered through a pad of silica gel. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (100% hexanes). 2-Bromo-1-methyl-3-(neopentyloxy)benzene was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: OCc1cccc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C

Procedure:
A mixture 3-bromobenzyl alcohol (500 mg, 2.70 mmol), 4-(triflouromethyl)benzeneboronic acid (1.01 g, 5.35 mmol), Pd(PPh3)4 (68 mg, 0.06 mmol) and Na2CO3 (740 mg, 7.02 mmol) in a mixture of DME (20 mL) and water (10 mL) was heated at reflux for 3 hours. The mixture was allowed to cool to rt, and then partitioned between EtOAc and water. The layers were separated and the aqueous re-extracted with EtOAc (2×) and the combined organic layer washed with water and then brine, dried (Na2SO4), filtered and reduced to give an oil. Purification by flash chromatography (silica) eluting with cyclohexane:EtOAc (5:2) afforded the title compound as a clear oil which crystallised on standing (654 mg).
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](O)(=[O:15])=[O:14])=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=1.O=S(Cl)[Cl:22]>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:22])(=[O:15])=[O:14])=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Temperature: 90 °C

Procedure:
DMF (0.06 ml, cat) was added to a solution of 4-chloro-2-nitro-benzenesulfonic acid (600 mg, 2.5 mmol) in SOCl2 (3.1 ml) and the mixture was heated at 90° C. for 3 h. After cooling, the solvent was removed in vacuo. The mixture was diluted with water and extracted repeatedly with chloroform. The combined organic layers were washed with saturated NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo to give the title compound (560 mg) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[F:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1O>>[F:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1[O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:10]
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: Oc1ccc(F)cc1F
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3ccc(F)cc3F)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and 2,4-difluorophenol, to afford 500 mg of the title compound as a powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:24][N:25]1[C:34](=[O:35])[CH:33]2[CH:28]([CH:29]3[CH2:36][CH:32]2[CH:31]=[CH:30]3)[C:26]1=[O:27].[CH:37]1([N:43]=[C:44]=[N:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>O1CCCC1>[OH:24][N:25]1[C:34](=[O:35])[CH:33]2[CH:28]([CH:29]3[CH2:36][CH:32]2[CH:31]=[CH:30]3)[C:26]1=[O:27].[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:46]1([NH:45][C:44]([NH:43][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)=[O:8])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.67 h

Procedure:
A solution of the N-hydroxy-5-norbornene-2,3-dicarboximide active ester of N-benzyloxycarbonyl-L-leucylglycine was prepared according to the general procedure of M. Fujino, et al [Chem. Pharm. Bull. Japan, 22, 1857 (1974)]. A solution of 1.27 g. of N-benzyloxycarbonylleucylglycine and 0.72 g. of N-hydroxy-5-norbornene-2,3-dicarboximide in 5 ml. of tetrahydrofuran was cooled in an ice bath and 0.83 g. of N,N'-dicyclohexylcarbodiimide was added to the cold solution together with 1 ml. of tetrahydrofuran. The reaction mixture was stirred at low temperature for 40 minutes and then at room temperature for 21/2 hours. The N,N'-dicyclohexylurea formed during the reaction was collected on a filter and washed with three 1-ml. portions of tetrahydrofuran.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=1[NH:60][C:61](=[O:73])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][CH2:71][NH2:72])=[N:64][CH:63]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=1[NH:60][C:61](=[O:73])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][CH2:71][NH:72][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:21])=[N:64][CH:63]=1
Reactant: NCCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.9 %

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (300 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-fluorophenyl)-6-(3-aminopropylamino)nicotinamide (318 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (456 mg, 78%) as a yellow solid. 1H NMR (DMSO-d6)δ 1.78 (m, 2H, CH2), 2.42 (s, 3H, pyrrole-CH3), 2.44 (s, 3H, pyrrole-CH3), 3.30 (m, 2H, CH2), 3.38 (m, 2H, CH2), 5.18 (s, 2H, benzene-NH2), 6.33 (m, 1H), 6.51 (m, 2H), 6.84 (m, 1H), 6.90 (m, 1H), 7.06 (t, J=8.0 Hz, 1H), 7.20 (s, 1H), 7.71˜7.76 (m, 3H), 7.91 (d, J=8.0 Hz, 1H), 8.63 (s, 1H), 9.30 (s, 1H, benzene-NH), 10.90 (s, 1H, indolinone-NH), 13.68 (s, 1H, pyrrole-NH). LC-MS (m/z) 586 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH3:25])=[N:16][N:15](COC(=O)C(C)(C)C)[C:12]3=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([C:5]3[CH:4]=[C:3]([CH:2]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)[OH:1])[CH:8]=[CH:7][CH:6]=3)[CH:10]=2)[NH:15][N:16]=1
Reactant: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(-c3cccc(C(O)c4ccccn4)c3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(O)c4ccccn4)c3)cc12
Reaction time: 5 h
Yield: 42.1 %

Procedure:
200 mg (0.38 mmol) of 2,2-dimethyl-propionic acid 5-[3-(hydroxy-pyridin-2-yl-methyl)-phenyl]-3-(2-methoxy-phenyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester was dissolved in 10 mL of ethanol. 10 mL of 2 M aqueous sodium hydroxide was added and the resulting mixture was left at room temperature for 5 h. The pH was adjusted to 8 by addition of concentrated aqueous hydrochloric acid and the resulting solution was distributed between chloroform and saturated aqueous sodium bicarbonate. The aqueous layer was extracted three times with chloroform. The combined organic phases were dried over sodium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes and then by mass-triggered reverse-phase HPLC to afford 67 mg (0.16 mmol, 43%) of {3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-pyridin-2-yl-methanol as an off-white solid. 1H NMR (500 MHz, DMSO-d6) α 13.84 (s, br., 1H), 8.80 (d, 1H), 8.46 (ddd, 1H), 8.28 (d, 1H), 7.80 (ddd, 1H), 7.77 (m, 1H), 7.67 (dd, 1), 7.64 (d, 1H), 7.61 (m, 1H), 7.47 (ddd, 1H), 7.43-7.42 (m, 2H), 7.24 (d, 1H), 7.23 (dd(d), 1H), 7.10 (ddd, 1H), 6.19 (s, br., 1H), 5.82 (s, br., 1H) 3.86 (s, 3H); MS: m/z 409.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[B:10]([OH:17])[O:11][CH:12]([CH2:13][N+:14]([O-])=O)[C:8]=2[C:7]([CH:18]=[CH2:19])=[CH:6][CH:5]=1)[CH3:2].N>CCO.[Ni]>[NH2:14][CH2:13][CH:12]1[O:11][B:10]([OH:17])[C:9]2[C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=[C:7]([CH:18]=[CH2:19])[C:8]1=2
Reactant: C=Cc1ccc(OCC)c2c1C(C[N+](=O)[O-])OB2O
Agent: [Ni]
Agent: N
Solvent: CCO
Product: C=Cc1ccc(OCC)c2c1C(CN)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-ethoxy-3-(nitromethyl)-4-vinylbenzo[c][1,2]oxaborol-1(3H)-ol (205 mg, 0.78 mmol), Raney-Ni (50 mg) and 2 M NH3 in EtOH (5 mL) in EtOH (10 mL) was shaken under an atmosphere of H2 for 2 h at room temperature. The mixture was filtered through a bed of Celite and the filtrate was concentrated in vacuo. The crude amine was dissolved in EtOAc (2 mL) and HCl in Et2O (20 mL) was added immediately. After 1 h, the suspension was filtered and the resulting solid was used directly for the next step without further purification.