Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([O:26]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].Br.[OH-].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Tert-butyl[6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.54 g, 1 mmol) was suspended in 48% aqueous solution (20 ml) of hydrogen bromide and the obtained mixture was refluxed under heating for 3 h. The reaction mixture was neutralized with 1N sodium hydroxide aqueous solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 ml) and di-t-butyl dicarbonate (0.28 ml, 1 mmol) was added thereto. The obtained mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-(4-chlorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.32 g, 71.1%) as crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6]1.O1CCOCC1.[NH:40]1[C:48]2[C:43](=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=2)[CH:42]=[N:41]1.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH:40]1[C:48]2[C:43](=[C:44]([C:2]3[CH:3]=[C:4]4[C:31](=[CH:32][CH:33]=3)[O:30][CH2:29][C:25]3([CH2:28][O:27][CH2:26]3)[C:5]34[CH2:9][O:8][C:7]([NH2:10])=[N:6]3)[CH:45]=[CH:46][CH:47]=2)[CH:42]=[N:41]1
Reactant: OB(O)c1cccc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OCC21COC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(CO1)c1cc(-c3cccc4[nH]ncc34)ccc1OCC21COC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
Under argon atmosphere, to a mixture of di-tert-butyl (6′-bromodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (300 mg, 0.571 mmol), dioxane (3.0 mL) and water (1.5 mL) were added 1H-indazol-4-ylboronic acid (185 mg, 1.14 mmol), K2CO3 (237 mg, 1.71 mmol) and bis(triphenylphosphine)palladium(II) dichloride (40 mg, 0.057 mmol), and the mixture was stirred for 3 hours at 100° C. The reaction mixture was cooled down to ambient temperature, partitioned between H2O and 10% MeOH in CHCl3. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated at reduced pressure. The residue was dissolved with dioxane (3.0 mL), and silica gel (neutral; 900 mg) was added to the mixture. After stirring for 2.5 hours at 110° C., the reaction mixture was cooled down to ambient temperature, and concentrated at reduced pressure. Purification of the residue with column chromatography on silica gel (CHCl3-EtOH, a linear gradient of EtOH from 0 to 20%) afforded 6′-(1H-indazol-4-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (142 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH2:15])[CH2:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O[CH:19](O)[CH:20]([F:22])[F:21])C>C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10](/[N:15]=[CH:19]/[CH:20]([F:22])[F:21])[CH2:11][CH:12]([CH3:13])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H](N)CO[Si](C)(C)C(C)(C)C
Reactant: CCOC(O)C(F)F
Solvent: c1ccccc1
Product: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)F

Procedure:
A mixture of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (8.5 g, 36.8 mmol) and difluoroacetaldehyde ethyl hemiacetal (5.0 g, 39.7 mmol) in benzene was refluxed with a Dean-stark trap overnight. Solvent was removed in vacuo. The residue was passed through a short silica column and eluted with hexanes:EtOAc (10:1) to give the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH2:20].O>[Pd].C1(OC)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:29])[C@@H:19]([NH:20][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: COc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 59.3 %

Procedure:
A stirred mixture of 92 g (0.45 mol) 2-benzoyl-cyclohexanone, (Denny, W. A. et. al. J. Med. Chem. 1978, 21(5), 430-7) 78 g (0.40 mol) L-Tyrosine methyl ester, 17.0 g Palladium on activated carbon (10%) was refluxed for 2 h in 1 L anisole while the resulting water was removed by a Dean-Stark apparatus. The mixture was cooled to 80° C. and the Pd/C was filtered, and washed with 50 mL anisole three times. The mixture was cooled to 40° C., 1 L hexane was added and kept at −20° C. for 48 h. The solid was filtered, washed with 200 mL hexane five times to yield 89.0 g crude (S)-2-(2-Benzoyl-phenylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester. This solid was mixed with 220 mL of MeOH, and the slurry was refluxed for 30 min. The mixture was cooled to 0° C., the product was filtered and washed with 50 mL cold (−20° C.) MeOH twice, then dried under reduced pressure to yield 67.4 g the of the title compound. mp 185-6° C.; low resolution MS (ESP+) m/e 376 (MH+).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:44][O:45][C:46](=[O:56])[CH:47]([C:49]1[CH:54]=[CH:53][C:52](Br)=[CH:51][CH:50]=1)[OH:48].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH3:44][O:45][C:46](=[O:56])[CH:47]([C:49]1[CH:54]=[CH:53][C:52]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[CH:51][CH:50]=1)[OH:48]
Reactant: COC(=O)C(O)c1ccc(Br)cc1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)OC)cc2)c(C)c1
Temperature: 90.5 °C
Reaction time: 4 h
Yield: 37.5 %

Procedure:
Degassed N,N-dimethylformamide (0.60 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 61.4 mg, 0.101 mmol), 4-bromo-phenyl-hydroxy-acetic acid methyl ester (Example 154-(1); 49.8 mg, 0.203 mmol), tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.016 mmol) and potassium phosphate (65 mg, 0.31 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 86 to 95° C. for four hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1) to give the title compound (24.4 mg, 37%).
Reaction SMILES: Br[C:2]1[N:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:11])[C:3]=1[C:4]#[N:5].[C:12]1(C)[CH:17]=CC=C[C:13]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[NH2:11][C:6]1[C:3]([C:4]#[N:5])=[C:2]([CH2:13][CH2:12][CH3:17])[N:9]=[C:8]([NH2:10])[CH:7]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCCc1nc(N)cc(N)c1C#N
Temperature: 85 °C
Yield: 65.3 %

Procedure:
To 5 mg (0.023 mmol) of palladium(II)acetate, 213 mg (1.00 mmol) of 2-bromo-4,6-diaminonicotinonitrile, and 60 mg (0.20 mmol) of tri(o-tolyl)phosphine was added 0.5 mL of DMF. The flask was purged with N2 while stirring, then 5.0 mL of the n-propylzinc iodide solution was via syringe. The mixture was heated at 85° C. for 2.5 hours then cooled. The mixture was poured into a stirred mixture of 20 mL ethyl acetate and 20 mL water, filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (2×5 mL), and the layers were separated. The organic layer was extracted with water (2×20 mL), and brine (1×20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to an oil. The oil was purified via silica gel chromatography, eluting with 75% ethyl acetate:hexanes to provide 23 mg (13%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 6.17 (s, 2H), 6.09 (s, 2H), 5.52 (s, 1H), 2.50 (t, 2H, J=7.6 Hz), 1.62 (m, 2H), 0.90 (t, J=7.3 Hz, 3H); MS (ESI) m/e 177 (M+H)+, 175 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[CH:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(=O)Cc1ccnc(Cl)c1
Reactant: C1COCCN1
Product: CC(=O)Cc1ccnc(N2CCOCC2)c1

Procedure:
A stirred solution of 1-(2-chloro-pyridin-4-yl)-propan-2-one (1.6 g, 9.47 mmol) in morpholine is heated to 105° C. for 3 days. The morpholine is removed in vacuo to yield the crude product. Purification by chromatography on silica, eluting with 1:1 ethyl acetate-hexane affords the title compound.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]([NH:22]C(=O)OC(C)(C)C)[CH2:10][N:11]([CH3:21])[C:12]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:4][CH2:3]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>CCOCC.CCO>[NH2:22][C@@H:9]([CH2:8][CH:5]1[CH2:4][CH2:3][C:2]([F:30])([F:1])[CH2:7][CH2:6]1)[CH2:10][N:11]([CH3:21])[C:12](=[O:13])[O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:20])[CH3:18]
Reactant: CN(C[C@H](CC1CCC(F)(F)CC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CN(C[C@@H](N)CC1CCC(F)(F)CC1)C(=O)OCC[Si](C)(C)C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
(S)-tert-Butyl 1-(4,4-difluorocyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (6.25 g, 0.0139 mol) was dissolved in a minimal volume of ether (100 mL) and added to a solution of toluenesulfonic acid (2.71 g, 0.0142 mol) in absolute EtOH (20 mL). This solution was placed on a rotary evaporator and the Et2O was removed at ambient temp. The flask was then lowered into the water bath (temperature: 60° C.) and the selective removal of the Boc group proceeded concurrently with removal of the remainder of solvent. The reaction was completed by 2 h and gave a white solid, which was washed with hexanes:EtOAc (5:1, v/v, 3×10 mL), basified with 1N NaOH (pH>10), and extracted with Et2O (3×50 mL) The combined Et2O extracts were washed with 1N aq NaOH (3×5 mL), brine (3×5 mL), dried, decanted and stripped to give the free base (S)-2-(trimethylsilyl)ethyl 2-amino-3-(4,4-difluorocyclohexyl)propyl(methyl)carbamate (3.68 g, 76%). 1H NMR (400 MHz, CD3OD): 4.17 (t, J=8.4Hz, 2H), 3.15 (m, 1H), 2.93 (s, 3H), 2.61 (dd, J=12.0 & 4.0Hz, 1H), 2.36 (dd, J=12.0 & 8.4 Hz, 1H), 2.12-1.16 (m, 11H), 1.00 (t, J=8.4Hz, 2H), 0.04 (s, 9H); MS (E/Z): 351 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19](=[S:30])[NH:20][S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH2:31](N(CC)CC)C.CI>CC(C)=O>[CH3:31][S:30][C:19]([N:10]1[CH2:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9]1)=[N:20][S:21]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:22])=[O:23]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(NC(=S)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)N1CCCCC1
Solvent: CC(C)=O
Solvent: CI
Product: CSC(=NS(=O)(=O)N1CCCCC1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
Part B: To a stirred solution of 3-(4-chlorophenyl)-4-phenyl-N-((piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (30 gram, 64.9 mmol) in acetone (1 L) is added triethylamine (18.0 mL, 130 mmol). To the resulting yellow solution is added methyl iodide (9.12 g, 64 mmol) and the resulting solution is stirred for 16 hours at room temperature. The formed precipitate is removed by filtration. The filtrate is washed with water, concentrated in vacuo to give a yellow solid. Recrystallisation from MTBE gives 3-(4-chlorophenyl)-N-((piperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester (27.9 gram, 90% yield). MP: 192-194° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].I[CH2:34][C:35]([NH2:37])=[O:36].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[CH:16][C:15]([O:26][CH2:34][C:35]([NH2:37])=[O:36])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(O)ccc2c1=O
Reactant: NC(=O)CI
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(OCC(N)=O)ccc2c1=O
Yield: 60.3 %

Procedure:
A solution of tert-butyl[4-(2-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.44 g, 1 mmol), 2-iodoacetamide (0.37 g, 2 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.30 mL, 2 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(2-amino-2-oxoethoxy)-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.30 g, 61.2%) as crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:8][C:4]1[N:3]=[C:2]([C:10]([CH3:12])([CH3:11])[C:9]#[N:13])[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(F)n1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a 0° C. solution of 2,6-difluoropyridine (69.6 g, 605 mmol, 1.0 equiv) and isobutyronitrile (41.7 g, 610 mmol, 1.0 equiv) in toluene (500 mL) was added sodium hexamethyldisilazide (2.0 M in THF, 302 mL, 605 mmol, 1.0 equiv) in a dropwise manner. The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was then quenched with water (500 mL), and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (2×300 mL), and the combined organic phases were washed with saturated brine solution (2×400 mL), dried over Na2SO4, concentrated to give a crude yellow oil, and chromatographed with silica gel (2-10% EtOAc/hex) to give 2-(6-fluoropyridin-2-yl)-2-methylpropanenitrile (55.7 g, 56%) as a clear oil.
Reaction SMILES: [CH3:1][C@H:2]1[N:7](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([O:36]CC3C=CC([N+]([O-])=O)=CC=3)=[O:35])[CH2:25][N:24]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:22])[CH2:3]1.[ClH:67]>O1CCCC1.O>[ClH:67].[CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([OH:36])=[O:35])[CH2:25][NH:24]2)=[O:22])[CH2:3]1
Reactant: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)CCN1

Procedure:
175 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3R)-3-methyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 35 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.20 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 175 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 8(b), to give 28.0 mg of the title compound as a powder.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[NH:10][CH2:11][CH2:12][CH2:13][NH2:14].[Br:15][C:16]1[C:17]([CH3:24])=[C:18]([CH:22]=O)[S:19][C:20]=1[Br:21]>>[Br:15][C:16]1[C:17]([CH3:24])=[C:18]([CH2:22][NH:14][CH2:13][CH2:12][CH2:11][NH:10][C:2]2[NH:1][C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[N:3]=2)[S:19][C:20]=1[Br:21]
Reactant: Cc1c(C=O)sc(Br)c1Br
Reactant: NCCCNc1nc2ccncc2[nH]1
Product: Cc1c(CNCCCNc2nc3cnccc3[nH]2)sc(Br)c1Br
Yield: 39 %

Procedure:
Using the general method for reductive amination a mixture of N-(3H-imidazo[4,5-c]pyridin-2-yl)propane-1,3-diamine (0.037 g, 0.19 mmol) and 4,5-dibromo-3-methylthiophene-2-carbaldehyde (0.054 g, 0.19 mmol) gave the title compound as a white solid (0.034 g, 49%). m/z (ES+) 459 (100% M+).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: OCc1ccc(C#CCCCOc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: OCc1ccc(CCCCCOc2ccccc2)cc1
Yield: 96.7 %

Procedure:
A solution of 0.54 g of 4-(5-phenoxy-1-pentyn-1-yl)benzyl alcohol in 100 ml methanol was treated with 230 mg of 5% palladium on charcoal and 58 PSI hydrogen for 3.5 hours The product mixture was filtered using celite and the filtrate was evaporated in vacuo to yield 0.53 g of the compound in the heading in the form of a light tan solid which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])[CH:5]=[CH:6][CH:7]=1.[N:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:18]2=[C:17]([C:24](O)=[O:25])[CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH:14][C:24]([C:17]3[CH:16]=[N:15][N:19]4[CH:20]=[CH:21][CH:22]=[N:23][C:18]=34)=[O:25])=[C:10]([CH3:13])[NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2cccnc12
Reactant: Cc1n[nH]c(-c2cccc(Cl)c2)c1N
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]nc(-c2cccc(Cl)c2)c1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 15 h
Yield: 45.1 %

Procedure:
A mixture of 5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-amine (113.3 mg, 0.546 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (109.5 mg, 0.6712 mmol), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (338.2 mg, 0.652 mmol), N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), and 4-dimethylaminopyridine (19.1 mg, 0.156 mmol) in 8.0 mL N,N-dimethylformamide was stirred at 50° C. for 15 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 86.9 mg (45%) of N-(3-(3-chlorophenyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=353.0; 1H NMR (400 MHz, DMSO-d6) δ: 12.90 (s, 1H), 9.37 (d, J=7.0, 1H), 9.30 (s, 1H), 8.86 (dd, J=4.1, 1.3, 1H), 8.69 (s, 1H), 7.80 (d, J=12.1, 1H), 7.72 (d, J=7.6, 1H), 7.37 (t, J=7.8, 1H), 7.32 (dd, J=6.9, 4.4, 2H), 2.18 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.[OH:27][C:28]1[CH:39]=[CH:38][C:31]2[NH:32][C:33]([C@@H:35]([NH2:37])[CH3:36])=[N:34][C:30]=2[CH:29]=1.ClCCl.C(O)C.N>O1CCCC1>[OH:27][C:28]1[CH:39]=[CH:38][C:31]2[NH:32][C:33]([C@@H:35]([NH:37][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:36])=[N:34][C:30]=2[CH:29]=1
Reactant: C[C@H](N)c1nc2cc(O)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: N
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(O)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 12 %

Procedure:
Prepared analogously to Example 1g from 3-methyl 4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TB TU, diisopropylethyl amine, and (1S)-1-(5-hydroxy-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 12%; Rf value: 0.40 (silica gel: dichloromethane/ethanol/ammonia=9:1:0.1); C22H24N4O3 (392.457); mass spectrum: (M+H)+=393