Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[C:5]([F:31])=[C:4]([NH:32][CH:33]2[CH2:36][CH2:35][CH2:34]2)[N:3]=1>CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:31])=[C:4]([NH:32][CH:33]2[CH2:36][CH2:35][CH2:34]2)[N:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NC2CCC2)c1F)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NC2CCC2)c1F
Reaction time: 4 h
Yield: 11 %

Procedure:
[(2R)-3-{2-[2-Chloro-6-(cyclobutylamino)-5-fluoro-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.055 g, 0.106 mmol) was dissolved in MeOH (5 mL) at room temperature. Pd(OH)2 (0.006 g) was added and the contents were stirred under a hydrogen balloon for 4 hours. The contents were filtered to remove the catalyst, and the filtrate was concentrated in vacuo. The above procedure was repeated 3 more times. Twice Pd(OH)2 (0.010 g) was used and the third time Pd(OH)2 (0.015 g) was used and The reaction was stirred for 5.5 hours. The contents were filtered to remove the catalyst, and the filtrate was concentrated in vacuo. The resulting crude product was purified by RP-HPLC to provide [(2R)-3-{2-[2-chloro-6-(cyclobutylamino)-5-fluoro-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a tan solid (0.005 g, 11%). LCMS: (M+H)+=428.9.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[S:18][C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21]=3[O:22][CH3:23])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:57][C@H:56]([CH2:55][O:54][C:51]1[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=1)[CH2:58][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[S:18][C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21]=3[O:22][CH3:23])=[O:16])[CH2:13][CH2:14]2)=[CH:28][CH:29]=1
Reactant: COc1c(C(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)sc2ccccc12
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: COc1c(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)sc2ccccc12
Yield: 30.6 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(3-methoxy-1-benzothiophen-2-yl)methanone (0.189 g, 0.461 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.187 g, 0.461 mmol) according to Procedure G to give the title compound (0.119 g, 0.141 mmol).
Reaction SMILES: [CH:1]1([C:15]([O:17][CH3:18])=[O:16])[CH:6]=[CH:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:2]1[C:11]([O:13][CH3:14])=[O:12].[H][H]>C(Cl)Cl.[Pd]>[CH:1]1([C:15]([O:17][CH3:18])=[O:16])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:2]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: [H][H]
Reactant: COC(=O)C1C=CC(C(=O)OC)C(C(=O)OC)C1
Agent: [Pd]
Solvent: ClCCl
Product: COC(=O)C1CCC(C(=O)OC)C(C(=O)OC)C1

Procedure:
A solution of trimethyl cyclohex-5-ene-1,2,4-tricarboxylate (0.50 g, 1.9 mmol) in methylene chloride (15 ml) containing a catalytic amount of palladium on carbon (150 mg, 5 percent Pd/C, 7.5 mg Pd, 4 mole percent) is stirred at room temperature under balloon pressure of hydrogen gas for 2 hours, at which point GC-MS analysis shows complete conversion. Filtration and removal of the solvent provides trimethyl cyclohexane-1,2,4-tricarboxylate as a clear, colorless gel (0.42 g, 1.6 mmol, 85 percent yield).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:40][CH3:41])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:41][O:40][C:22]1[CH:21]=[C:20]([CH:39]=[CH:38][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:19][O:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (406 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate-layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give methyl [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetate (595 mg, yield 55%), which was then recrystallized from ethyl acetate-hexane. melting point: 107–108° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][O:5][C:6](=[O:30])[C:7]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[CH:10]=[CH:9][C:8]=1[CH:21]=[CH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[H][H]>CCO.[Pd]>[CH3:31][Si:2]([CH3:1])([CH3:32])[CH2:3][CH2:4][O:5][C:6](=[O:30])[C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)OCC[Si](C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1C(=O)OCC[Si](C)(C)C

Procedure:
A solution of 5-benzyloxy-2-(2-tert-butoxycarbonyl-vinyl)-benzoic acid 2-trimethylsilanyl-ethyl ester (6.20 g, 13.6 mmol) in EtOH (95 mL) was treated with Pd/C (5%, 0.775 g). The resulting suspension was treated with hydrogen at 60 psi for 6 h at room temperature. The catalyst was filtered through a pad of Celite, and the filtrate was concentrated to an oil (4.30 g, 86%). 1H NMR (400 MHz, CDCl3): δ 0.07 (s, 9H), 0.96 (t, 1H, J=8.8 Hz), 1.12 (t, 1H, J=8.8 Hz), 1.40 (s, 9H), 2.52 (t, 1H, J=7.8 Hz), 3.13 (t, 1H, J=7.8 Hz), 3.73 (t, 1H, J=8.5 Hz), 4.36 (t, 1H, J=8.5 Hz), 5.00 (br s, 1H), 6.88 (dd, 1H, J=2.4, 8.3 Hz), 7.14 (d, 1H, J=8.3 Hz), 7.35 (d, 1H, J=2.4 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[CH:17][C:16]([C:27]([O:29]C)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3cccc(F)c3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of methyl 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate (1.45 g, 3 mmol) in tetrahydrofuran (10 mL) and methanol (10 ml) was added 1N sodium hydroxide (6 mL). The obtained mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-n-hexane to give 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (1.34 g, 95.7%) as crystals.
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)[CH3:3].[K+].C([Si](C)(C)O[C:13]1[CH:21]=[CH:20]C=[C:18]2[C:14]=1[CH2:15][CH2:16]C2=O)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+]>CCOCC>[CH2:18]=[C:14]1[C:13]2[CH:21]=[CH:20][CH:3]=[C:2]([OH:5])[C:1]=2[CH2:16][CH2:15]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOCC
Product: C=C1CCc2c(O)cccc21
Reaction time: 0.25 h
Yield: 71629.4 %

Procedure:
To a suspension of CH3PPh3I (924 mg, 2.29 mmol) in Et2O (20 mL) was added t-BuOK (256 mg, 2.29 mmol). The mixture was stirred for 15 minutes, to which was added dropwise 4-(tert-butyl-dimethyl-silanyloxy)-indan-1-one (500 mg, 1.91 mmol). The mixture was stirred at room temperature overnight and then diluted with diethylether. The mixture was filtered on a pad of celite. The remaining precipitate was washed with diethylether. The combined filtrate was concentrated under reduced pressure. The crude compound was dissolved in THF and then was added 1M-TBAF (in THF, 1.2 eq). The reaction mixture was stirred for 30 min at room temperature, treated with saturated ammonium chloride, and then extracted with EtOAc. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography to give 1-methylene-indan-4-ol (200 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](#[N:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]Br>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:16]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:8]=2)[CH:7]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Brc1ccc2nc(-c3ccccc3)nn2c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A mixture of 5-bromopyridin-2-amine (2 g, 11.6 mmol), benzonitrile (26.2 g, 26.1 ml, 254 mmol), 1,10-phenanthroline monohydrate (115 mg, 578 μmol) and copper (I) bromide (82.9 mg, 578 μmol) was placed in a 100 ml 2 necked flask. The mixture was heated to 135° C. while air was bubbled gently through the mixture for 2 days. Another portion of copper (I) bromide (82.9 mg, 578 μmol) and 1,10-phenanthroline monohydrate (115 mg, 578 μmol) was added and bubbling and heating was continued for further 8 hours. The solvent was evaporated. Purification by flash chromatography on a 20 g silicagel column using heptane/ethyl acetate 10-50% as eluent and evaporation of the solvents afforded 6-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1.19 g, 38%) as light yellow solid. Mp.: 146° C. MS: m/z=274/276 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13]([NH:15][C@@H:16]1[C:21](=[O:22])[O:20][C:18](=[O:19])[CH2:17]1)=[O:14].Cl>O>[CH:13]([NH:15][C@H:16]([C:21]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:22])[CH2:17][C:18](=[O:19])[OH:20])=[O:14]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To 200 ml of water, 50% caustic solution is added to adjust the pH to 9.5. To the aqueous solution, L-phenylalanine (30 g, 0.181 mole) is dissolved while adding 11.8 ml of 50% caustic solution. After cooling the resultant solution to between -3° C. to +3° C., 14.5 ml of 50% caustic solution and formyl-L-aspartic anhydride (28.6 g, 0.199 mole) is added over a 1 hour period and the resulting reaction mixture is stirred for 1/2 hour at between -3° C. to 3° C. Upon lowering the pH of the mixture using 34.4 ml of hydrogen chloride, a solid precipitate is produced and it is separated by filtration. The precipitate is dried to obtain the desired formyl-α-L-aspartyl-L-phenylalanine (42.6 g, 0.138 mole). The remaining filtrate is collected and acidified to a pH of 6.0 with 9.4 ml of concentrated hydrogen chloride to produce the precipitate. The precipitate is filtered and dried to obtain additional formyl-α-L-aspartyl-L-phenylalanine (2.9 g, 0.009 mole). TLC analysis shows that there is no trace of β-isomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([CH2:32][O:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[N:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:75]1([NH:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[C:82]([O:86][CH3:87])[C:81]=2[CH3:88])[CH2:77][CH2:76]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([CH2:32][O:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[N:29][CH:28]=3)=[C:13]2[C:24](=[O:25])[N:78]([CH:75]2[CH2:77][CH2:76]2)[CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[C:82]([O:86][CH3:87])[C:81]=2[CH3:88])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(CNC2CC2)c1C
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cnc(COCCO[Si](C)(C)C(C)(C)C)s3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(COCCO[Si](C)(C)C(C)(C)C)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Reaction time: 168 h
Yield: 33.2 %

Procedure:
To a stirred sol. of the compound D8 (2.75 g, 4.30 mmol) in CH2Cl2 (21.5 mL) were added EDC.HCl (2.06 g, 10.75 mmol), HOBt (0.789 g, 5.16 mmol), DMAP (13 mg, 0.108 mmol), and DIPEA (3.378 mL, 19.3 mmol). After 15 min cyclopropyl-(3-methoxy-2-methylbenzyl)amine (prepared by reductive amination from 3-methoxy-2-methylbenzaldehyde, Comins, D. L.; Brown, J. D., J. Org. Chem., 1989, 54, 3730 and cyclopropylamine, 2.47 g, 12.9 mmol) was added, and stirring was continued over 7 days. Three times were added cyclopropyl-(3-methoxy-2-methylbenzyl)amine (823 mg, 4.30 mmol), and HOBt (290 mg, 2.15 mmol), and once was added DIPEA (3.38 mL, 19.3 mmol). The reaction mixture was partitioned between aq. 1M HCl and CH2Cl2, and the phases were separated. The org. layer was washed with aq. sat. NaHCO3, dried over MgSO4, filtered, and the solvents were removed in vacuo. Purification of the residue by FC (heptane/EtOAc 7/3) yielded an impure product, which was purified again by HPLC. The title compound (1.16 g, 33%) was obtained as a yellow oil. LC-MS: tR=1.26 min, ES+: 813.59.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
4-Bromophenol (25.00 g, 145 mmol), para-methoxybenzyl chloride (24.89 g, 159 mmol), potassium iodide (2.17 g, 14.45 mmol), and potassium carbonate (39.9 g, 289 mmol) in acetone (600 mL) was heated to reflux for 18 h. The crude reaction mixture was then cooled to room temperature and filtered through a sintered glass funnel. The filtrate was concentrated in vacuo, and the white solid was recrystallized from ethanol yielding the product as a white solid (33.44 g, 79%). 1H NMR (300 MHz, CDCl3) δ 3.80 (s, 3H), 4.95 (s, 2H), 6.85 (d, 2H), 6.92 (d, 2H), 7.32-7.40 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[N:5][C:4]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17](C(O)=O)[CH2:16][CH2:15]1.C(OC(N1CCC(NC2N=NC(C(F)(F)F)=CC=2OC)CC1)=O)(C)(C)C>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[N:6]=[N:5][C:4]=1[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: COc1cc(C(F)(F)F)nnc1NC1CCN(C(=O)O)CC1
Agent: COc1cc(C(F)(F)F)nnc1NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Product: COc1cc(C(F)(F)F)nnc1NC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
A mixture of 4-(4-Methoxy-6-trifluoromethyl-pyridazin-3-ylamino)-piperidine-1-carboxylic acid tent-butyl ester (D7) (0.73 g, 1.93 mmol) and Amberlyst® 15 ion exchange resin, acidic form (4.1 mmol/g) (2.35 g, 9.65 mmol) in methanol (20 ml) was shaken at room temperature for 18 h. After this period, the mixture was filtered and then a 7M solution of ammonia in methanol was added. The mixture was shaken for 1 h, filtered and the filtrate evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. to yield D8 (0.49 g, 92%) as a yellow syrup. C11H15F3N4O requires 276; Found 277 (MH+).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[CH:70]=[N:69][N:68]([CH3:71])[N:67]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[CH:70]=[N:69][N:68]([CH3:71])[N:67]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: Cn1ncc(SCC2=C(C(=S)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)[C@H]3SC2)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Product: Cn1ncc(SCC2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)n1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(2-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (1.39 g: 1.34 mMol.) in a mixture anisole (5 ml) and nitromethane (20 ml) is added dropwise a solution of aluminum chloride (1.43 g: 10.8 mMol.) in anisole (5 ml) at -40° C. After stirring at -30° to -40° C. for 1 hour, the mixture is diluted with 1N-hydrochloric acid (11 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove organic solvents and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with methanol-water (4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(2-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (534 mg). Yield: 75%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[C:23][Si](C)(C)C)=[CH:13][CH:14]=2)[C:9]([C:28]2[N:33]=[C:32]([O:34][C@H:35]3[CH2:42][N:41]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][CH2:39][C:36]43[CH2:38][CH2:37]4)[CH:31]=[N:30][CH:29]=2)=[N:8]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[C:9]2[C:28]1[N:33]=[C:32]([O:34][C@H:35]2[CH2:42][N:41]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][CH2:39][C:36]32[CH2:38][CH2:37]3)[CH:31]=[N:30][CH:29]=1)#[CH:23]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5ccccc5C#C[Si](C)(C)C)cc34)n2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccccc1-c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(2-((trimethylsilyl)ethynyl)phenyl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (110 mg, 0.162 mmol) and potassium carbonate (112 mg, 0.811 mmol) in MeOH (1623 μL) was stirred at RT for 2 h. The mixture was diluted with EtOAc (150 ml), added to a separatory funnel, and washed with water (2×100 ml) before the organic layer was separated, dried over Na2SO4, and concentrated to give (4R)-tert-butyl 4-(6-(5-(2-ethynylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (80 mg, 0.132 mmol, 81% yield) as a yellowish oil. MS (ESI, pos. ion) m/z: 606.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C@@H:19]([NH2:21])[CH3:20])[CH3:2].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>>[CH2:1]([N:3]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C@@H:19]([NH:21][C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2)[CH3:20])[CH3:2]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CCn1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c([C@H](C)Nc2ncnc3[nH]cnc23)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 90 °C
Yield: 31.1 %

Procedure:
A mixture of (S)-1-(1-ethyl-6-fluoro-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.203 g, 0.715 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (145 mg, 0.60 mmol) and DIPEA (543 μL, 3.0 mmol) were added and the reaction mixture heated at 90° C. for 16 hours. The reaction mixture was loaded onto an SCX column to remove the THP group. The column was washed with MeOH and the product was eluted with 2M NH3 in MeOH. The product fractions were collected, concentrated in vacuo and the resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-7% MeOH in DCM) to give 412 as a white solid (75 mg, 25%). LCMS (Method K): RT 2.76 min [M+H]+ 403. 1H NMR (DMSO, 400 MHz): δ 12.83 (1H, br s), 8.68 (1H, d, J=4.8 Hz), 8.12 (2H, d, J=14.3 Hz), 7.95 (1H, br s), 7.91 (1H, td, J=7.7, 1.7 Hz), 7.68-7.62 (2H, m), 7.46 (1H, d, J=7.2, 5.0 Hz), 7.11 (1H, dd, J=10.4, 9.0 Hz), 5.78-5.67 (1H, m), 3.91-3.71 (2H, m), 1.63 (3H, d, J=6.8 Hz), 0.71 (3H, t, J=6.9 Hz)
Reaction SMILES: [C:1]([NH:9][C:10](=[S:24])[NH:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.CS(C)=O>C(O)(=O)C>[C:21]([NH:20][C:14]1[C:13]2[S:24][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:11][C:12]=2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=1)(=[O:23])[CH3:22]
Reactant: COc1ccc(NC(C)=O)cc1NC(=S)NC(=O)c1ccccc1
Agent: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COc1ccc(NC(C)=O)c2sc(NC(=O)c3ccccc3)nc12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
To a suspension of 15.0 g (43.7 mmol) N-[3-(3-benzoyl-thioureido)-4-methoxy-phenyl]-acetamide in 200 ml glacial acetic acid was added 7.65 ml (43.6 mmol) of a 5.7 M solution of HBr in acetic acid, and the mixture was heated at 90° C. for 1 h. 2.5 ml (48.0 mmol) DMSO was then added, and stirring continued at 90° C. for 1.5 h. After cooling to room temperature, the reaction mixture was poured onto 1000 ml distilled water, and the resulting slurry stirred for 15 min. The mixture was then filtered, and the filter cake washed with water, then dried in vacuo at 50° C., affording 12.8 g (86%) N-(7-acetylamino-4-methoxy-benzothiazol-2-yl)-benzamide as a light brown solid. ES-MS m/e (%): 342 (M+H+, 100).