Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.[CH2:23](O)[C:24]#[CH:25].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:25][C:24]#[CH:23])[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reactant: C#CCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#CCOc1cc(OC)cc2oc(-c3cn4nc(OC)sc4n3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A solution of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 205 mgs, 0.646 mmol) in THF (10 mL) was treated at r.t. and under a nitrogen atmosphere, with propargyl alcohol (0.096 mL, 1.615 mmol), tri-n-butylphosphine (0.398 mL, 1.615 mmol) and dropwise, over a 25 min period with a solution of 1,1′-(azodicarbonyl)dipiperidine (408 mgs, 1.615 mmol) in THF (10 mL). The mixture was sonicated in a bath for 30 min and stirred at r.t. for another 30 min. The mixture was then dissolved in dichloromethane (50 mL) and washed with sat. aqueous NaHCO3, brine and dried (MgSO4). Evaporation of the solvent gave a solid that was purified by silica gel column chromatography ISCO to give the title material (180 mg, 0.507 mmol, 78% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.38 (s, 1H), 6.92 (s, 1H), 6.86 (dd, J=1.8, 1.0 Hz, 1H), 6.53 (d, J=1.6 Hz, 1H), 4.94 (d, J=2.7 Hz, 2H), 4.21 (s, 3H), 3.77-3.84 (m, 3H), 3.60-3.66 (m, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1>COCCOC.[Cu]I.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>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]#[C:22][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:20]=1
Reactant: Brc1nccs1
Reactant: C#Cc1cncc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Clc1cncc(C#Cc2nccs2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Bromo-1,3-thiazole (980 mg, 6.0 mmol) and CuI (230 mg, 1.2 mmol) were combined in DME (15 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (4.2 mL, 30 mmol) and PdCl2(PPh3)2 (420 mg, 0.60 mmol) were added, then 3-chloro-5-ethynylpyridine (820 mg, 19 mmol) was added dropwise. After stirring at ambient temperature for 16 h, GC/MS analysis showed starting material remaining. The reaction mixture was heated at reflux for 2 h. The mixture was filtered through Celite.™., the filter pad was washed thoroughly with ethyl acetate, and the combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL), and washed with water (100 mL), brine (100 mL), dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 9:1 hexane:ethyl acetate to afford 3-chloro-5-(1,3-thiazol-2-ylethynyl)pyridi-ne which contained some dimer. This material was crystallized from hot ethyl acetate to afford 3-chloro-5-(1,3-thiazol-2-ylethynyl)pyridine (300 mg 23% yield) as light orange crystals M.p. 124-125° C. 1H NMR (CDCl3, 300 MHz) Δ8.70 (d, J=1.5 Hz, 1H), 8.59 (d, J=3.0 Hz, 1H), 7.93 (d, J=3.0 Hz, 1H), 7.88)t, J=2.0 Hz, 1H), 7.48 (d, J=3.0 Hz, 2H). MS (ESI) 221.1 (M++H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([NH:12][CH3:13])[S:9]2)[C@@H:5]([OH:14])[C@@H:4]1[OH:15].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1.O>[OH:15][C@@H:4]1[C@@H:3]([CH2:2][OH:1])[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([N:12]([CH3:13])[C:22](=[O:23])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:9]2)[C@H:5]1[OH:14]
Reactant: CNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.9 %

Procedure:
To a suspension of -(3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (1.50 g, 6.40 mmol) and NaHCO3 (1.01 g, 12.0 mmol) in THF/water (40 mL, 1:3) was added benzyl chloroformate (1.70 g, 10.0 mmol). The mixture was stirred at room temperature for 4 days. The organic solvent was removed under reduced pressure to result in a precipitate. The precipitated solid was collected by filtration, washed with Et2O and dried under vacuum, affording benzyl (-(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white solid (1.72 g, 73%). 1H NMR (400 MHz, CD3OD) δ 7.44-7.32 (m, 5H), 6.13 (d, J=6.9 Hz, 1H), 5.27-5.20 (m, 2H), 4.14 (t, J=6.1 Hz, 1H), 4.02 (t, J=4.9 Hz, 1H), 3.74 (dd, J=2.4, 12.0 Hz, 1H), 3.63 (dd, J=6.1, 12.0 Hz, 1H), 3.53 (dd, J=4.5, 9.2 Hz, 1H), 3.47-3.43 (m, 1H), 3.39 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCc4ccccc4)cc3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Yield: 55.6 %

Procedure:
A stirred mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (0.500 g, 1.24 mmol), (4-(benzyloxy)phenyl)boronic acid (0.567 g, 2.49 mmol), copper(II) acetate (0.451 g, 2.49 mmol), and triethylamine (1.00 mL, 7.12 mmol) in DCM (25 mL) was treated with 1.00 g of powdered 3 angstrom molecular sieves. The resulting mixture was stirred at RT under air using a drying tube to exclude moisture. After 18 hours the mixture was treated with an additional 250 mg portion of (4-(benzyloxy)phenyl)boronic acid and stirring at RT continued. After another 8 hours the mixture was filtered through Celite and the filtrate concentrated to dryness at reduced pressure. The black residue was suspended in EtOAc and the undissolved solids removed by filtration through Celite. The filtrate was concentrated to dryness at reduced pressure and the residue subjected to flash chromatography (silica gel, gradient elution from DCM to 1:1 DCM/EtOAc to give the title compound (0.403 g, 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39-8.47 (m, 1H) 8.12-8.18 (m, 1H) 7.92-7.99 (m, 2H) 7.55 (d, J=8.9 Hz, 2H) 7.28-7.46 (m, 7H) 7.13 (s, 1H) 7.03 (d, J=9.0 Hz, 2H) 5.09 (s, 2H) 3.29 (s, 3H) 2.82 (d, J=4.5 Hz, 3H) 2.25-2.35 (m, 1H) 0.75-1.14 (m, 3H) 0.32-0.58 (m, 1H). LCMS (m/z, ES+)=585 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[CH:29][CH:28]=2)[C:7]([C:11]([O:13][C@H:14]([CH3:25])[C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>[Pd].C(O)C>[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[CH:29][CH:28]=2)[C:7]([C:11]([O:13][C@H:14]([CH3:25])[C:15]([OH:17])=[O:16])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)O[C@H](C)C(=O)OCc2ccccc2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCc1nc(Cl)c(C(=O)O[C@H](C)C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 2 h

Procedure:
10% Palladium on carbon (59 mg, 0.55 mmol) was added to a stirred ethanol (5.5 mL) solution of (1R)-2-(benzyloxy)-1-methyl-2-oxoethyl 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (332 mg, 0.55 mmol). The mixture was stirred under hydrogen for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.67-7.62 (m, 2H), 7.56-7.50 (m, 2H), 7.09 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 5.67 (d, J=16.5 Hz, 1H), 5.57 (d, J=16.5 Hz, 1H), 5.15 (q, J=6.5 Hz, 1H), 2.65 (t, J=7.5 Hz, 2H), 1.56 (quintet, J=7.5 Hz, 2H), 1.49 (d, J=7.0 Hz, 3H), 1.31 (sextet, J=7.5 Hz, 2H), 0.87 (t, J=7.5 Hz, 3H); LC-MS: m/z 509.2 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:17][OH:18])[CH2:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.Cl[Si](C)(C)C.[C:24](Cl)(=[O:26])[CH3:25].CO>N1C=CC=CC=1>[C:24]([NH:16][C:9]1[NH:10][C:11](=[O:15])[C:12]2[N:13]=[CH:14][N:6]([CH2:5][CH2:4][CH:3]([CH2:17][OH:18])[CH2:2][OH:1])[C:7]=2[N:8]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Reaction time: 0.25 h

Procedure:
To a suspension of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (0.23 g, 0.9 mmol) in pyridine (3 ml) was added chlorotrimethylsilane (0.25 ml, 2.0 mmol) and the mixture was stirred for 15 minutes. To this mixture was added acetyl chloride (0.085 ml, 1.2 mmol) and the mixture was stirred for 30 minutes. Methanol (2 ml) was the added and the mixture was stirred for a further 30 minutes. The solvent was removed and the residue purified by column chromatography on silica gel eluting with chloroform-methanol mixtures (4:1, 5:2) to give the title compound as its hydrochloride salt. This was dissolved in methanol and stirred with potassium carbonate. The solution was filtered and the solvent removed. The residue was taken up in water and passed through C18-Sep-pak cartridges. Fractions containing product were pooled and the solvent removed to afford N2-acetyl-9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (0.11 g, 41%), m.p. 143-146° C.; λmax (H2O) 260 (15,100) nm; νmax (KBr) 3420, 3200, 2940, 1685, 1615, and 1560 cm−1; δH [(CD3)2SO] 1.46 (1H, m, 3′-H), 1.77 (2H, q, J 7.1 Hz, 2′-H), 2.18 (3H, s, CH3), 3.3-3.5 (4H, m, 2×4′-H), 4.13 (2H, t, J 7.4 Hz, 1′-H), 4.42 (2H, br.t, J 5 Hz, D2O exchangeable, 2×OH), 7.98 (1H, s, 8-H), and 11.83 (2H, br, D2O exchangeable, 1-H and 2-NH).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:25]=[CH:26][CH:27]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[Br:36]N1C(=O)CCC1=O.O>O1CCCC1>[Br:36][C:25]1[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:35])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:27][CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2cccn2C(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(Br)n2C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
t-Butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate (2.70 g, 5.38 mmol) synthesized in Example (13b) was dissolved in tetrahydrofuran (50 mL), and cooled to 0° C. After addition of N-bromosuccinimide (960 mg, 5.38 mmol) with stirring under nitrogen atmosphere, stirring was carried out at room temperature for 4 hours. Water (50 mL) was added, and extraction was carried out with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%) to afford the desired compound (2.93 g, yield 94%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].Cl.Cl.[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[CH2:24][CH2:25][N:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:21][CH2:22]2)[CH2:31][CH2:30]1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)N1CCN(C2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 53.9 %

Procedure:
A mixture of 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (Example 113, Step B) (0.90 g, 4.9 mmol), 1-(methylsulfonyl)-4-(4-piperidinyl)piperazine (Example 204, step C) (1.20 g, 4.9 mmol) and K2CO3 (0.81 g, 5.8 mmol) in DMSO (15 mL) was heated at 100° C. for 48 h. The reaction was cooled to rt, poured into H2O and extracted exhaustively with DCM. The combined organics were washed with H2O then dried over MgSO4. The resultant solution was concentrated onto silica and purified by flash chromatography to afford 1-{1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.09 g, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (s, 1H), 6.69 (s, 1H), 3.90 (s, 3H), 3.29-3.38 (m, 2H), 3.06-3.15 (m, 4H), 2.87 (s, 3H), 2.68-2.79 (m, 2H), 2.59-2.66 (m, 4H), 2.40-2.48 (m, 1H), 2.20 (s, 3H), 1.80-1.92 (m, 2H), 1.49-1.67 (m, 2H).
Reaction SMILES: [S:1](=[O:4])([OH:3])[O-:2].[Na+].Cl[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1>>[S:1]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1)([OH:3])(=[O:2])=[O:4]
Reactant: O=S([O-])O
Reactant: O=C(O)Cc1ccc(CCl)cc1
Agent: [Na+]
Product: O=C(O)Cc1ccc(CS(=O)(=O)O)cc1

Procedure:
To a boiling aqueous solution of sodium bisulfite (1.47 g, 0.0141 mole) is added in portions p-chloromethylphenylacetic acid (2.6 g, 0.0141 mole). The solution is further refluxed for 30 minutes and is then evaporated to dryness to give a quantitative yield of the title compound.
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.Cl.[CH3:33][N:34]([CH3:39])[CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>O1CCOCC1>[CH3:33][N:34]([CH3:39])[CH:35]1[CH2:38][N:37]([C:24]([NH:23][C:19]2[CH:18]=[C:17]([O:16][C:13]3[CH:14]=[N:15][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3])=[O:30])=[CH:11][CH:12]=3)[CH:22]=[CH:21][N:20]=2)=[O:29])[CH2:36]1
Reactant: CN(C)C1CNC1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Agent: CN1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C1CN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)C1
Temperature: 25 °C
Yield: 12.7 %

Procedure:
A mixture of Example C2 (0.42 g, 1.02 mmol), N,N-dimethyl-3-azetidinamine dihydrochloride (0.176 g, 1.02 mmol) and N-methylpyrrolidine (0.182 g, 2.13 mmol) in dioxane (5 mL) was heated at 80° C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The resultant material was dissolved in MeCN/H2O, frozen and lyophilized to afford 3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide as a yellowish-white solid (59 mg, 11%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.45 (s, 1H), 9.51 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.13 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.46 (d, J=2.38 Hz, 1H), 6.63 (dd, J=5.7, 2.4 Hz, 1H), 4.17-4.03 (m, 4H), 3.95-3.82 (br s, 1H), 2.62 (s, 6H), 1.21 (s, 9H); MS (ESI) m/z: 456.2 (M+H+).
Reaction SMILES: C1(=O)[N:5]([C@@H:6]([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8])C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][C@@H:6]([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)[C@H](CCC(OC)OC)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](N)CCC(OC)OC
Temperature: 25 °C
Reaction time: 144 h

Procedure:
(S)-2-Phthalimido-5,5-dimethoxypentanoic acid, methyl ester [prepared as described in Example 4(f), 3.35 g., 10.43 mmol.) in methanol (70 ml.) was treated with hydrazine monohydrate (531 μl., 10.95 mmol., 1.05 eq.) and the solution was stirred at room temperature for 6 days. The mixture was filtered and the solid was washed with methanol. The filtrate was concentrated, triturated with methylene chloride, filtered again, concentrated, and dried in vacuo to yield 1.89 g. of title product as a cloudy oil. TLC (10% methanol in methylene chloride) Rf =0.39.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9](Cl)[O:8][C:7]=12.C(OC([N:33]1[C:37]2=[CH:38][N:39]=[CH:40][CH:41]=[C:36]2[C:35](B(O)O)=[CH:34]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9]([C:35]3[C:36]4[C:37](=[CH:38][N:39]=[CH:40][CH:41]=4)[NH:33][CH:34]=3)[O:8][C:7]=12
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)c2ccncc21
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)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: C1COCCO1
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5c[nH]c6cnccc56)cc34)cn2)CC1
Temperature: 120 °C
Yield: 27.9 %

Procedure:
A mixture of 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (45 mg, 0.13 mmol), [1-(tert-butoxycarbonyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]boronic acid (65 mg, 0.26 mmol), Na2CO3 (55 mg, 0.52 mmol) and Pd(PPh3)4 (10 mg, 0.0087 mmol) in 4:1 dioxane:water (5 mL) was degassed with N2 for 1 min, and then heated to 120° C. in a microwave reactor for 30 min. The mixture was filtered and the filtrate was purified by preparative TLC (5:1 DCM:MeOH) to afford 16 mg (29%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 8.79 (s, 1H), 8.28-8.27 (m, 3H), 8.16 (s, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.25 (s, 1H), 4.71-4.68 (m, 1H), 4.57-4.54 (m, 1H), 4.13-4.09 (m, 1H), 3.37 (m, 1H), 2.85 (m, 1H), 2.21 (m, 1H), 2.13 (s, 3H), 1.95 (m, 1H); MS (ESI): 442.1 [M+H]+; HPLC tR=2.08 min (ZQ3: polar—4 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[S:6][C@@H:5]2[C@H:7]([N:10]3C(C)(C)[NH:14][C@H:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:11]3=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:24]([OH:26])=[O:25].CC(C)=[O:30]>>[CH3:27][C:2]1([CH3:1])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:14])[C:18]3[CH:23]=[CH:22][C:21]([OH:30])=[CH:20][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:24]([OH:26])=[O:25]
Reactant: CC1(C)S[C@@H]2[C@H](N3C(=O)[C@@H](c4ccccc4)NC3(C)C)C(=O)N2[C@H]1C(=O)O
Reactant: CC(C)=O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O

Procedure:
The procedure of Example 1 was repeated with the substitution for the hetacillin therein of an equimolar weight of heta-amoxicillin (also called p-hydroxyhetacillin or the acetone adduct of amoxicillin) to produce the title compound. The product appeared by NMR to be 85-90% pure with respect to the acetone adduct group.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[N:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:22][CH:23]=1.O>C1COCC1>[CH3:27][O:26][C:24]([C:21]1[CH:20]=[N:19][C:18]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:23][N:22]=1)=[O:25]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (1.24 g, 6.55 mmol) in THF (12 mL) was added sodium hydride (55% dispersion in mineral oil, 0.31 g, 7.2 mmol) at 0° C. The reaction mixture was stirred for 30 min while it was allowed to warm up to room temperature. Methyl 5-chloropyrazine-2-carboxylate (1.36 g, 7.86 mmol) was added and stirring was continued for 2 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (10 mL) and dried over sodium sulfate. Concentration and purification of the residue by chromatography (SiO2, heptane:ethyl acetate=80:20 to 50:50, 1.00 g, 47%) which was obtained as a light yellow oil. MS: m/e=326.2 [M+H]+.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16](=[O:38])[NH:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@H:20]([C:35](=O)[CH3:36])[CH2:19]1)([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH2:28]([O:27][C:25]([NH:24][C@H:21]1[CH2:22][CH2:23][C@@H:18]([NH:17][C:16](=[O:38])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:19][C@H:20]1[C:35]([CH3:36])=[CH2:1])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphoniumbromide (729 mg) was dissolved in THF (4 mL) and cooled to 0° C. prior to the addition of 0.5M potassium bis(trimethylsilyl)amide (3.7 mL) in toluene. After 1 h, (1R,3R,4S)-(4-benzyloxycarbonylamino-3-acetylcyclohexyl)carbamic acid tert-butyl ester (400 mg) in THF (4 mL) was added dropwise. The reaction was warmed to rt over 2 h, before it was quenched with saturated NH4Cl solution and extracted with EtOAc (3×) The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to provide tert-butyl (1R,3S,4S)-4-benzyloxycarbonylamino-3-(prop-1-en-2-yl)cyclohexylcarbamate (380 mg). MS (ES+)=389.2 (M+H)+.