Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][C@@H:11]2[CH3:29])=[O:9])=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)(C)C>[ClH:1].[CH3:29][C@H:11]1[CH2:12][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:14][CH2:15][N:10]1[C:8]([C:5]1[CH:4]=[CH:3][C:2]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:7][CH:6]=1)=[O:9]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: CC(C)O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1ccc(N2CCOCC2)nc1
Product: Cl
Temperature: 120 °C
Yield: 86 %

Procedure:
(2S)-1-[(6-Chloro-3-pyridinyl)carbonyl]-2-methyl-4-{[4-(trifluorom ethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Example 26) (67 mg, 0.15 mmol) was weighed into a microwave vial, suspended in isopropanol (1.5 ml) and treated with morpholine (0.261 ml, 2.99 mmol). The mixture was heated in the microwave to 120° C. for 18 h with stirring. LCMS analysis showed clean conversion to product. The reaction mixture was concentrated to give the crude material as a colourless gum. This was purified by MDAP (High pH system) to give the free base of the title compound as a colourless gum (69 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2=[C:6]3[C:11](=[C:12]([NH2:14])[N:13]=[C:4]2[CH:3]=1)[N:10]=[CH:9][C:8](/[CH:15]=[CH:16]/[CH3:17])=[CH:7]3.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2=[C:6]3[C:11](=[C:12]([NH2:14])[N:13]=[C:4]2[CH:3]=1)[N:10]=[CH:9][C:8]([CH2:15][CH2:16][CH3:17])=[CH:7]3
Reactant: C/C=C/c1cnc2c(N)nc3cc(C)ccc3c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1cnc2c(N)nc3cc(C)ccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of (E)-8-methyl-2-(prop-1-enyl)benzo[f][1,7]naphthyridin-5-amine (from the previous step) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vaccuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 8-methyl-2-propylbenzo[f][1,7]naphthyridin-5-amine as offwhite solid. 1H NMR (CDCl3): δ 8.59 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.43 (s, 1H), 7.13 (dd, 1H), 5.94 (bs, 2H), 2.78 (t, 2H), 2.44 (s, 3H), 1.75 (m, 2H), 0.95 (t, 3H). LRMS [M+H]=252.1
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][CH2:1][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cccc(CNc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 101.9 %

Procedure:
To a stirred solution of methyl 3-formylbenzoate (0.5 g, 3.046 mmol) in anhydrous DCM (15 mL) was added 4-fluoroaniline (0.303 mL, 3.198 mmol) followed by glacial acetic acid (0.174 mL, 3.046 mmol). The reaction was stirred at room temperature for 64 hours. Sodium triacetoxyborohydride (1.614 g, 7.615 mmol) was added, and the reaction was stirred at room temperature for 2 hours. Water was added to quench the reaction and the mixture was diluted with DCM. The organic layer was washed with brine, passed through a hydrophobic fit and the solvent was removed in vacuo to afford the title compound as a red oil (0.805 g, quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:24])[CH:3]=1.Cl[CH2:26][CH2:27][N:28]=[C:29]=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([NH:16][C:14]([C:10]1[S:9][C:8]([N:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:26][CH2:27][NH:28][C:29]3=[O:30])=[CH:3][C:4]2=[O:24])=[N:12][C:11]=1[CH3:13])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(-n2ccc(N)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: O=C=NCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(-n2ccc(N3CCNC3=O)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 85 °C
Yield: 6 %

Procedure:
To a solution of 2-(4-amino-2-oxopyridin-1(2H)-yl)-N-benzyl-4-methylthiazole-5-carboxamide (0.14 g, 0.41 mmol) in N,N-dimethylformamide (10 mL) was added 2-chloroethyl isocyanate (0.05 mL, 0.58 mmol) at ambient temperature. The resulting reaction mixture was heated at 80-90° C. for 7 hours. Potassium carbonate (0.10 g, 0.72 mmol) was added and the reaction mixture was heated for 18 hours. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound in 6% yield (0.01 g): mp>300° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.76 (t, J=6.0 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 7.64-7.17 (m, 7H), 6.08 (d, J=2.1 Hz, 1H), 4.38 (d, J=6.0 Hz, 2H), 3.85-3.79 (m, 2H), 3.42-3.37 (m, 2H), 2.60 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.9, 160.7, 157.8, 153.8, 150.7, 150.4, 139.9, 130.9, 128.7, 127.7, 127.2, 123.7, 101.4, 98.8, 44.3, 43.1, 36.5, 17.5; MS (ES+) m/z 410.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([NH:8][C@:9]([C:31]2[CH:39]=[CH:38][C:34]([C:35](F)=[O:36])=[CH:33][CH:32]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:42]([F:45])([F:44])[F:43].[NH3:46]>C(#N)C>[C:35]([C:34]1[CH:33]=[CH:32][C:31]([C@@:9]([NH:8][C:6](=[O:7])[C:5]2[CH:40]=[CH:41][C:2]([F:1])=[C:3]([C:42]([F:43])([F:45])[F:44])[CH:4]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:39][CH:38]=1)(=[O:36])[NH2:46]
Reactant: O=C(F)c1ccc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1
Reactant: N
Solvent: CC#N
Product: NC(=O)c1ccc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1
Reaction time: 24 h
Yield: 67.7 %

Procedure:
To a suspension of (R)-4-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)benzoyl fluoride (20 mg, 0.03 mmol) in acetonitrile (1 mL) was added ammonia (7 M in methanol, 20 μL, 0.14 mmol). The reaction mixture was stirred for 24 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (4 g silica gel; 0-100% ethyl acetate, hexane gradient over 14 min., 18 mL/min) to provide (R)—N-(1-(4-carbamoylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 320, 13 mg, 65% yield). LCMS: RT=1.81 min [M+H] 631 (Chromolith Performance 18e 4.6×100 mm column, 50-90% methanol, water with 0.1% trifluoroacetic acid gradient over 2 min, 5 mL/min). 1H NMR (400 MHz, CDCl3) ppm 7.86 (1H, d, J=4.83 Hz), 7.77 (1H, dt, J=8.35, 2.20 Hz), 7.71 (2H, d, J=8.35 Hz), 7.14-7.25 (3H, m), 7.08 (3H, t, J=7.47 Hz), 6.85-6.90 (3H, m), 6.71 (1H, s), 6.63 (2H, d, J=7.03 Hz), 6.05 (1H, s), 5.88 (1H, tt, JHH=2.75 Hz, JHF=53 Hz), 5.70 (1H, s), 3.86 (2H, dd, J=37.4, 13.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[C:11]([OH:13])=O)[C:7](=[O:21])[CH:6]=1.[CH3:26]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[OH:48][C@@H:49]([CH2:79]O)[CH2:50][N:51]1[CH:55]=[CH:54][C:53]([NH:56]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:52]1>ClCCl>[OH:48][C:49]([CH3:79])([CH3:26])[CH2:50][N:51]1[CH:55]=[CH:54][C:53]([NH:56][C:11](=[O:13])[CH:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[Cl:1])=[CH:6][C:7]2=[O:21])[CH2:14][CH:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])=[N:52]1
Reactant: CC(CC(C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O)C(F)(F)F
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(CC(C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-methyl-pentanoic acid (575 mg, 1.52 mmol) in dichloromethane (25 mL). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (296 μL, 1.67 mmol) and 1-hydoxybenzotriazole (216 mg, 1.59 mmol) and stirred at 25° C. for 2 h. After this time, 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in US20080021032, Example 80, 283 mg, 1.83 mmol) was added and the mixture stirred for 16 h at 25° C. After this time, the mixture was diluted with dichloromethane (10 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), water (10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL) dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (12 g column, 20% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (460 mg, 59%) as a yellow foam: HR-ES-MS m/z calculated for C23H26N4O4ClF3 [M+H]+ 515.1668, observed 515.1664; 1H NMR (300 MHz, CDCl3) δ ppm 1.15 (s, 3H), 1.16 (s, 3H), 1.20 (d, J=6.6 Hz, 3H), 1.89-2.19 (m, 2H), 2.30 (m, 1H), 3.94 (s, 2H), 4.28 (m, 1H), 4.31 (m, 1H), 4.90, 4.91 (2×s, 1H), 5.00 (dd, J=4.8, 10.9 Hz, 1H), 6.68 (br. s., 1H), 7.20-7.37 (m, 4H), 7.49 (d, J=7.9 Hz, 1H), 8.65, 8.89 (2×br. s., 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])/[C:12]([OH:14])=O)=[CH:7][CH:6]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:48][N:49]([CH3:60])[CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:48][N:49]([CH3:60])[CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][C:12](=[O:14])/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:55][CH:54]=1
Reactant: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
Method A; To a mixture of 3 (2.50 g, 8.00 mmol), EDC.HCl (1.84 g, 9.60 mmol) and HOBt (1.30 g, 9.62 mmol) in DMF (50 ml) was added a solution of 4-(2-(dimethylamino)ethoxy)benzene-amine dihydrochloride (2.23 g, 8.81 mmol) and N,N-Diisopropylethylamine (4.13 g, 32.0 mmol) under ice cooling, and the mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with AcOEt, the organic layer was washed with H2O×2, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: AcOEt then CHCl3/MeOH, 10:1) and recystallization from AcOEt-hexanes gave 4 (43%). 4: colorless powder; 1H-NMR (CDCl3) δ 1.05 (3H, t, J=7.4), 2.33 (6H, s), 2.71 (2H, t, J=5.7 Hz), 2.77 (2H, q, J=7.4 Hz), 3.43 (3H, s), 4.04 (2H, t, J=5.7 Hz), 5.09 (2H, s), 6.78 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=9.0 Hz), 7.00 (2H, d, J=8.8 Hz), 7.00 (1H, brs) 7.06 (2H, m), 7.12-7.23 (3H, m), 7.41 (2H, d, J=9.0 Hz).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:10]=[N:11][C:12]([Cl:16])=[CH:13][C:14]=1Cl.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]1>CN(C=O)C.O>[Cl:8][C:9]1[N:10]=[N:11][C:12]([Cl:16])=[CH:13][C:14]=1[N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]1
Reactant: CC(=O)C1CCNCC1
Reactant: Clc1cc(Cl)c(Cl)nn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)C1CCN(c2cc(Cl)nnc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Triethylamine (2.2 g, 20.0 mmol), 3,4,6-trichloro-pyridazine (1.8 g, 10.0 mmol) and 1-(piperidin-4-yl)ethanone (1.3 g, 10.0 mmol) was dissolved in DMF (20 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were combined and washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in hexanes) to give 1-(1-(3,6-dichloropyridazin-4-yl)piperidin-4-yl)ethanone (1.0 g, 3.8 mmol, 39% yield) as white solid. ESI-MS (M+1): 274 calc. for C11H13ClN3O 273.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:13]([O:11][C:9]1[CH:8]=[CH:7][C:6]([OH:12])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(OC(=O)c2ccccc2)ccc1O

Procedure:
Using 6.65 g of 2-tert-butyl-1,4-dihydroxybenzene, 4.6 ml of benzoyl chloride and 200 ml of pyridine, reaction and workup carried out as in Reference Example gave 9.35 g of 4-benzoyloxy-2-tert-butylphenol as white crystals, m.p. 120-121° C. Using. 9.35 g of the white crystals, 1,47 g of sodium hydride, 6.27 g of benzyl bromide and 40 ml of DMF, reaction and workup carried out as in Example 12 gave 6.07 g of yellow oil.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][O:36]C=O)[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:39].O1CCCC1>CO>[ClH:39].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][OH:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCCOC=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCCO)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 23.7 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.1 g.), conc. hydrochloric acid (1.35 g.), tetrahydrofuran (23.0 ml.), and methanol (23.0 ml.) was stirred at room temperature for 6.5 hours. After concentrating the resultant solution in vacuo, methanol (50 ml.) was added to the residue. After concentrating the solution to a half volume of the initial, the precipitates were collected by filtration, washed with diethyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 0.71 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[ClH:1].[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[C:4]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:3][C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][N:6]=2)[S:10][CH:11]=1
Reactant: Cc1csc(Nc2ncc(Cl)cc2Oc2ccccc2)n1
Reactant: OB(O)c1ccccc1
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: COCCOC
Product: Cc1csc(Nc2ncc(-c3ccccc3)cc2Oc2ccccc2)n1
Product: Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 7.2 %

Procedure:
5-Chloro-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine (0.150 g, 0.472 mmol), phenylboronic acid (0.0691 g, 0.566 mmol), Pd(PPh3)4 (0.0545 g, 0.0472 mmol), in DME (10 mL), and 2M Na2CO3 (5 mL) were placed in a round bottom flask, heated to 80° C. and stirred overnight. An extra equivalent of Pd(PPh3)4 (0.0545 g, 0.0472 mmol), and phenylboronic acid (0.0691 g, 0.566 mmol) were added and the reaction mixture was heated for 2 weeks. The reaction mixture was cooled to room temperature and partitioned between CH2Cl2 and water. The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography and then by reverse phase chromatography to give the title compound (0.0134 g, 7.17% yield) after salt formation. 1H NMR (d6-DMSO) δ 8.53 (d, 1H), 7.65 (m, 3H), 7.45 (m, 4H), 7.37 (m, 1H), 7.21 (t, 1H), 7.16 (d, 2H), 6.78 (s, 1H), 2.29 (s, 3H); Mass spectrum (apci) m/z=360.3 (M+H—HCl).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.[CH2:39]1[C@@H:42]([C:43]([OH:45])=[O:44])[NH:41][CH2:40]1>C(Cl)Cl>[C:2]([O:4][CH:5]1[C:14]2[C:15]3([CH3:30])[C:16]([C:17](=[CH:18][N:41]4[CH2:40][CH2:39][CH:42]4[C:43]([OH:45])=[O:44])[C:23](=[O:24])[O:25][CH:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: O=C(O)[C@@H]1CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1OC(=O)C(=CN2CCC2C(=O)O)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added L-azetidine-2-carboxylic acid (47 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 533 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[K].[SH:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.SC1C=CN=CC=1.[OH-].[K+]>CO>[N+:10]([C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:3][CH:4]=1)([O-:12])=[O:11]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1ccncc1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Sc2ccncc2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 1 h

Procedure:
5-Chloro-2-nitroanisole (9.38 g) was added to a solution of 4-mercaptopyridine potassium salt prepared by adding 4-mercaptopyridine (6.67 g) to a solution of potassium hydroxide (3.37 g) in methanol (30 ml) followed by evaporation of the methanol) and DMF (40 ml). After stirring for 1 hour, the mixture was heated at 110° C. for 4 hours and allowed to stand overnight. The reaction mixture was poured into ice-water (1 liter), stirred for 15 minutes, and the yellow solid was filtered off. The solid was stirred with 3M hydrochloric acid (800 ml) for 1 hour, filtered, and the filter cake was washed with 3M hydrochloric acid then water. The filtrate was cooled in an ice-bath and made basic with 28% aqueous ammonium hydroxide to yield approximately 2 g of the title compound. The filter cake was suspended in water (100 ml) with stirring and the mixture was made basic with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organics were combined, dried, filtered and evaporated to give a yellow solid that was triturated with hexane and filtered to give additional title compound (total yield 6.49 g). M.p. 97-100° C.; MS: 263 (M+H); NMR: 3.94 (s, 3H), 7.17 (dd, 1H, J=1.8, 8.4), 7.27-7.7.29 (m, 2H), 7.51 (d, 1H, J=1.8), 7.97 (d, 1H, J=8.4), 8.48-8.50 (m, 2H).
Reaction SMILES: O[CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.Cl.[NH2:13][OH:14]>CO>[N:3]1([CH2:2][N:13]([CH2:2][N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[N:4]2)[OH:14])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1
Reactant: NO
Reactant: OCn1nnc2ccccc21
Agent: Cl
Solvent: CO
Product: ON(Cn1nnc2ccccc21)Cn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.2 %

Procedure:
To a stirred solution of 1-(hydroxymethyl)benzotriazole (44.8 parts) in 375 parts of methanol at room temperature was added 10.4 parts of hydroxylamine hydrochloride. The reaction mixture was stirred at room temperature for about five hours and then placed in a freezer for about six hours. The precipitated white solid was filtered, washed with cold water and dried in vacuo (in presence of phosphorus pentoxide). The dried product, m.p. 175°-7° C. (reported m.p. 173°-4° C.), 24 parts: was identified as N,N-bis (benzotriazol-1-yl methyl) hydroxylamine (54.2% yield) by 1H and 13C NMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.[CH2:14](N(CC)CC)[CH3:15].C(#N)C.C([Cl:29])(=O)OCC>O(CC)CC>[ClH:29].[CH2:14]([N:13]1[CH:12]=[CH:11][N:10]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:15]
Reactant: COc1ccc(-c2ncc[nH]2)cc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: CC#N
Product: CCn1ccnc1-c1ccc(OC)cc1
Product: Cl
Temperature: 180 °C
Reaction time: 8 h

Procedure:
To a stirred and cooled (10° C.) mixture of 7 parts of 2-(4-methoxyphenyl)-1H-imidazole, 4.2 parts of N,N-diethylethanamine and 40 parts of acetonitrile is added dropwise a solution of 6.5 parts of ethyl carbonochloridate in a small amount of 1,1' -oxybisethane at a temperature below 10° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto 175 parts of 1,1'-oxybisethane and the whole is stirred. The precipitate is filtered off and the filtrate is washed three times with water, dried, filtered and evaporated. The oily residue is heated to 180° C., cooled and dissolved in 1,1'-oxybisethane. The undissolved material is filtered off and the ether-phase is saturated with hydrogen chloride. The formed hydrochloride salt is filtered off and triturated in 2-butanone, yielding 3 parts of 1-ethyl-2-(4-methoxyphenyl)-1H-imidazole monohydrochloride.