Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.Cl.[NH:22]1[C:26]2[CH2:27][NH:28][CH2:29][C:25]=2[CH:24]=[N:23]1>>[NH:22]1[C:26]2[CH2:27][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:29][C:25]=2[CH:24]=[N:23]1
Reactant: c1n[nH]c2c1CNC2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3Cc4cn[nH]c4C3)n2)c1

Procedure:
B51 was prepared following the general procedure reported for B10 using A1 and 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole dihydrochloride; yield: 194.9 mg (52%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 4.23 (s, 2H), 4.58 (s, 2H), 4.64 (s, 2H), 6.83 (s, 2H), 7.00 (d, J=7.7 Hz, 1H), 7.26-7.34 (m, 1H), 7.58 (s, 1H), 7.71-7.78 (m, 1H), 7.86 (s, 1H), 8.27 (s, 1H), 9.73 (s, 1H), 12.73 (s, 1H). MS (ES) C15H16N8O2S requires: 372. found: 373 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([CH3:31])=[CH2:30])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([C:9]2[CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=[CH:7][C:8]=2[OH:11])([CH3:31])[CH3:30])=[CH:27][CH:26]=1
Reactant: C=C(C)c1ccc(OC)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)(C)c2cc(C(C)(C)C)ccc2O)cc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a three-necked 500 mL flask equipped with a mechanical stirrer, 37 g of 4-tert-butylphenol, 100 mL of toluene and 2.4 g of p-toluenesulfonic acid are charged and heater to 55° C. The 4-methoxy-α-methylstyrene (40 g) prepared in Example 1 is added over 2.5 hours. The reaction mass is stirred for an additional three hours at 65° C. The reaction mass is then washed twice with 200 mL of saturated sodium bicarbonate solution and thrice with 100 mL of water. The solvent is removed by vacuum distillation and unreacted phenol and alkene are moved by Kugelrohr distillation at 100° C./0.16 mm Hg. The title compound is prepared in a yield of 78 g as a light brown oil whose structure is consistent with 1Hnmr and mass spectroscopy.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:33])([N:6]1[CH2:11][CH2:10][CH:9]([S:12][C:13]2[CH:14]=[CH:15][C:16]3[O:25][CH2:24][CH2:23][N:22]4[C:18](=[N:19][C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)=[CH:21]4)[C:17]=3[CH:32]=2)[CH2:8][CH2:7]1)[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[CH3:33][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([S:12][C:13]2[CH:14]=[CH:15][C:16]3[O:25][CH2:24][CH2:23][N:22]4[C:18](=[N:19][C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)=[CH:21]4)[C:17]=3[CH:32]=2)[CH2:10][CH2:11]1)([CH3:5])[CH2:3][OH:2]
Reactant: COC(=O)C(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CO)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of 2-methyl-2-[4-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl)piperidin-1-yl]propionic acid methyl ester (0.438 mmol) in THF (20 mL) was added LiAlH4 (1.0M in THF, 1.32 mL) and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added EtOAc (0.5 mL) and stirring was continued for 10 min. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and 10% aq. solution of Rochelle's salt. The suspension was then filtered through a pad of Celite®. The filtrate was extracted with additional DCM and the combined organic phases were washed with water, then brine, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-13% 2M NH3/MeOH in DCM) affording 2-Methyl-2-[4-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl)piperidin-1-yl]propan-1-ol as a colorless gum (190 mg, 96% over two steps). LCMS: RT 1.799 min [M+H]+ 451.1
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH:41]1([NH2:45])[CH2:44][CH2:43][CH2:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([NH:45][CH:41]4[CH2:44][CH2:43][CH2:42]4)=[O:40])=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Reactant: NC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NC4CCC4)c3)ccc2n1CC1CCOCC1
Reaction time: 0.33 h

Procedure:
DIPEA (0.1 mL, 74 mg, 0.57 mmol) was added to a solution of 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (0.078 mmol) (see following step B for preparation) and cyclobutylamine (0.1 mL, 83 mg, 1.17 mmol) in DMF (5 mL) at 0° C. Stirring for 20 min, HATU (100 mg, 0.31 mmol) was added at 0° C. The reaction mixture was stirred overnight at room temperature, diluted with H2O (50 mL) and extracted with EtOAc (3×25 mL). The combined organic phases were washed with H2O (2×10 mL), NaCl (10 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to 30 mg (78%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.57 (m, 4 H), 1.60 (s, 9 H), 1.66-1.78 (m, 2 H), 1.95-2.09 (m, 2 H), 2.20-2.35 (m, 3 H), 3.25-3.34 (m, 2 H), 3.85-3.93 (m, 2 H), 4.33-4.41 (m, 1 H), 4.43 (d, J=7.62 Hz, 2 H), 6.67 (dd, J=3.32, 1.56 Hz, 1 H), 7.28 (dd, J=3.32, 2.34 Hz, 1 H), 7.81-7.84 (m, 1 H), 7.91-7.95 (m, 1 H), 7.95-7.99 (m, 1 H), 8.26 (dd, J=1.66, 0.68 Hz, 1 H); MS (ESI) (M+H)+=498.8; Anal. Calcd for C26H34N4O4S+0.90 TFA+0.80H2O (615.68): C, 54.23; H, 5.98; N, 9.10. Found: C, 54.25; H, 6.02; N, 9.12.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@@H:10]1[C@@H:13]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:15]2=[O:30])[NH:12][C:11]1=[O:31])[CH3:9])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:39]([O:42][C:43](=[O:47])[C:44](Cl)=[O:45])[CH:40]=[CH2:41]>ClCCl.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@@H:10]1[C@@H:13]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[C:15]2=[O:30])[N:12]([C:44](=[O:45])[C:43]([O:42][CH2:39][CH:40]=[CH2:41])=[O:47])[C:11]1=[O:31])[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(=O)Cl
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@@H]1CCCC(CCO[Si](C)(C)C(C)(C)C)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(=O)C(=O)OCC=C)[C@@H]1[C@@H]1CCCC(CCO[Si](C)(C)C(C)(C)C)C1=O
Reaction time: 3 h

Procedure:
In dichloromethane (2.5 ml) was dissolved the (3S,4R)-3-[(R)-1-(allyloxycarbonyloxy)ethyl]-4-[(1S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-2-oxocyclohexan-1-yl]azetidin-2-one (0.56 g) obtained in Reference Example 3 and while the solution was stirred, a solution of triethylamine (0.7 ml) in dichloromethane (2.5 ml) was added. Then, a solution of allyloxyoxalyl chloride (0.55 g) in dichloromethane (2.5 ml) was added dropwise at -78° C. over a period of 10 minutes. The reaction mixture was stirred at -78° C. for 5 minutes and, then, at 0° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with phosphate buffer (pH 7) and aqueous sodium chloride in that order and, after addition of triethylamine (0.2 ml), dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (stationary phase: silica gel 15 g; ethyl acetate-hexane 1:6) to give allyl [(3S,4R)-3-[(R)-1-(allyloxycarbonyloxy)ethyl]-4-[(1S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-2-oxocyclohexan-1-yl]-2-oxoazetidin-1-yl]glyoxylate.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>CCO.[Pd]>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:4]2[CH:3]=[CH:2][N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: Clc1ccc(-c2cc(Cl)n3nccc3n2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1ccc(-c2ccn3nccc3n2)cc1
Yield: 67.5 %

Procedure:
A mixture of 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.5, step 2) (1.06 g, 4.0 mmol), triethylamine (0.84 mL), and 5% Pd—C (0.1 g) in EtOH (40 mL) was stirred in an atmosphere of hydrogen for 1.5 h. The catalyst was filtered off, the solution was evaporated in vacuo and the residue was crystallized from EtOAc/cyclohexane to give 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (0.62 g, 67%) as a pale-yellow solid. MS (ISP) 230.4 [(M+H)+]; mp 178-180° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1>C1(C)C=CC=CC=1>[C:2]1([CH:1]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCCNC1
Solvent: Cc1ccccc1
Product: C(=NC1CCCNC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
Benzaldehyde (21.2 g; 0.2 mol) was added, dropwise, to a solution of 3-aminopiperidine (20 g; 0.2 mol) in toluene (80 ml). The solution thus obtained was stirred at room temperature, After 3 h the solvent was removed by evaporation at reduced pressure and the residue was taken up twice with toluene. 29 g N-(phenylmethylene)piperidine-3-amine was thus obtained, and was used in the subsequent reactions without further purification.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=[O:6])[CH2:3][CH2:2]1.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Mg]Br.[NH4+].[Cl-].O>C1COCC1>[CH:1]1([CH2:4][CH:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[OH:6])[CH2:3][CH2:2]1
Reactant: O=CCC1CC1
Reactant: Br[Mg]c1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: OC(CC1CC1)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyclopropylacetaldehyde (1.00 g, 11.89 mmol, purchased from Beta Pharma, Inc., Branford, Conn.) in THF (15 mL) at 0° C. under N2 was added 2-pyridylmagnesium bromide (47.6 mL×0.25 M, purchased from Rieke Metals, Inc., Lincoln, Nebr.) dropwise over 15 min. The mixture was stirred at 0° C. after 30 min, allowed to warm to rt and stirred at rt for 3.5 hr. To the reaction mixture was added saturated aqueous NH4Cl solution (5 mL) followed by water (15 mL). The mixture was extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4. After removal of organic solvents, purification of the residue by flash chromatography on silica gel with 40-70% EtOAc/hexanes the title compound was obtained as a white solid. Mass Spectrum (ESI) m/z=164.1 (M+1).
Reaction SMILES: [C:1](/[C:3](/[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)=[CH:4]\[C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([O-:22])=O)[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)#[N:2].[Cl:34]C1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH2:52]([N:54]([CH2:58][CH3:59])[CH2:55][CH2:56][NH2:57])[CH3:53]>C(Cl)Cl>[ClH:34].[CH2:52]([N:54]([CH2:58][CH3:59])[CH2:55][CH2:56][NH:57][C:20](=[O:22])[CH2:19][CH2:18][C:17]([O:16][CH:13]1[CH2:12][CH2:11][N:10]([C:8]2[S:9][C:5](/[CH:4]=[C:3](\[C:1]#[N:2])/[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)=[O:23])[CH3:53]
Reactant: CCN(CC)CCN
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(OC(=O)CCC(=O)[O-])CC3)s2)cc1OC
Reactant: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCN(CC)CCNC(=O)CCC(=O)OC1CCN(c2ccc(/C=C(\C#N)c3ccc(OC)c(OC)c3)s2)CC1
Product: Cl
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Compound 18 (235 mg) was dissolved in methylene chloride (10 mL), and 2-chloro-4,6-dimethoxy-1,3,5-triazine (105 mg) and N-methylmorpholine (66 μL) were added to the solution, followed by stirring for 30 minutes with ice cooling. Subsequently, N,N-diethylethylenediamine (85 μL) and N-methylmorpholine (110 μL) were added to the mixture, followed by stirring at room temperature for 17 hours. The solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (CHCl3-MeOH), to thereby yield the target product (yield: 287 mg, 95%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[I:10].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[N:11]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[I:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(CBr)c(I)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(F)cc1I
Temperature: 50 °C

Procedure:
A suspension of 1-(bromomethyl)-4-fluoro-2-iodobenzene (15.68 g, 47.8 mmol) and sodium azide (4.21 g, 64.7 mmol) in dry DMF (30 mL) was heated to 50° C. for six hours. The reaction was filtered and the filtrate was concentrated in vacuo to a volume of about 10 mL. The crude was purified by flash column chromatography (ISCO column, 110 g silica gel) eluting with 100% hexane to afford the desired product as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:5]=[CH:6][CH:7]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Brc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To the suspension of 4-(3-bromo-phenyl)-1H-indole (1.48 g, 5.44 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (66 mL) was added pyridinium tribromide (90% purity from Aldrich, 5.80 g, 16.3 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (26 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (1.02 g, 65%) as a tan solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:19]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCON=C(C(C)=O)C(=O)OCC
Yield: 97.3 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 100 g.), N,N-dimethylformamide (300 ml.), potassium carbonate (130 g.) and bromooctane (121 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-n-octyloxyimino-3-oxobutyrate (syn isomer, 165.5 g.), oil.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]O)=[C:19]([F:25])[CH:18]=1)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:19]([F:25])[CH:18]=1)[CH3:16]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1ccc(CO)c(F)c1
Product: CCc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-ethyl-2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.66 (2H, q, J=7.6 Hz), 5.26 (2H, s), 5.81 (1H, d, J=2.0 Hz), 6.95 (1H, d, J=11.2 Hz), 7.00 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=8.0 Hz), 7.38 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.57 (1H, d, J=1.6 Hz), 8.00-8.01 (1H, m), 8.69 (1H, d, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C18H15FN4O, 323; Found, 323.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[CH2:12][O:13][C:14]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]([O:22][CH3:23])=[N:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:24][Si:25]([CH3:39])([CH3:38])[CH2:26][CH2:27][O:28][CH2:29][N:30]1[C:34](B(O)O)=[CH:33][CH:32]=[N:31]1.C([O-])([O-])=O.[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.CN(C=O)C>[CH3:23][O:22][C:17]1[CH:18]=[C:19]([C:14]([O:13][CH2:12][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[N:3][C:2]=2[C:34]2[N:30]([CH2:29][O:28][CH2:27][CH2:26][Si:25]([CH3:39])([CH3:38])[CH3:24])[N:31]=[CH:32][CH:33]=2)=[CH:15][N:16]=1)[CH:20]=[O:21]
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Reactant: COc1cc(C=O)c(OCc2c(Cl)ncc3ccccc23)cn1
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: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2c(-c3ccnn3COCC[Si](C)(C)C)ncc3ccccc23)cn1
Temperature: 125 °C
Yield: 40.8 %

Procedure:
To a mixture of 5-((3-chloroisoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (18 mg, 0.05 mmol, 1 equiv), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-ylboronic acid (20 mg, 0.08 mmol, 1.5 equiv), Pd(PPh3)4 (12 mg, 0.01 mmol, 0.2 equiv), K2CO3 (30 mg, 0.22 mmol, 4 equiv) in a 5 mL microwave tube were added DMF (2 mL). The mixture was heated 30 min at 125° C. in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)isonicotinaldehyde (10 mg, 38%) as a white solid. LRMS (M+H+) m/z 491.1.
Reaction SMILES: C([CH:8]([C:37](=[O:39])[OH:38])[C@@H:9]([C:21]([CH:23]1[CH2:25][C:24]1([NH2:36])[C:26]([O:28][CH:29]1[CH:33]([CH3:34])[CH2:32][CH2:31][CH:30]1[CH3:35])=[O:27])=[O:22])[NH:10]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.C1CC=CCC=1>[Pd].C(O)C>[NH2:10][C@H:9]([C:21]([CH:23]1[CH2:25][C:24]1([NH2:36])[C:26]([O:28][CH:29]1[CH:33]([CH3:34])[CH2:32][CH2:31][CH:30]1[CH3:35])=[O:27])=[O:22])[CH2:8][C:37](=[O:38])[OH:39]
Reactant: CC1CCC(C)C1OC(=O)C1(N)CC1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CC1CCC(C)C1OC(=O)C1(N)CC1C(=O)[C@@H](N)CC(=O)O
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A mixture of compound 3 (0.31 g), 1,4-cyclohexadiene (0.46 g), 10% palladium-on-carbon (0.3 g) and 95% ethanol (10 ml) was placed in an ultrasonic bath for 10 minutes. The mixture was then filtered through Celite, and the solvent was evaporated to yield 130 mg of a colorless oil which solidified upon standing. This was purified by HPLC using a reverse phase C18 column, 60% methanol in water as eluent to yield the desired product as a white solid (72 mg, 40%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)CC)C.[NH2:33][C:34]1[C:35]([CH3:40])=[CH:36][CH:37]=[CH:38][CH:39]=1.C(P(C#N)(CC)=O)C>ClCCl>[CH3:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[NH:33][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:25][CH:24]=1
Reactant: Cc1ccccc1N
Reactant: O=C(O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: CCP(=O)(C#N)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 54.6 %

Procedure:
A mixture of 0.332 g of 4-(5H-pyrrolo[2,1-c]-[1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid, 0.111 g of triethylamine, 0.107 g of o-toluidine, and 0.15 ml of diethylphosphoryl cyanide in 20 ml of dichloromethane is heated on a steam bath overnight. The mixture is washed with water, 1M NaHCO3, 1N HCl, brine and dried (Na2SO4). The dichloromethane solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is crystallized from dichloromethane-hexane to give 0.23 g of white crystals, m.p. 228°-231° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH:9]([CH3:20])[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17]([OH:19])=O)=[O:11])=[O:7])=[CH:4][C:3]=1[Cl:23].[O:24]=[C:25]1[O:29][CH:28]([O:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=CC=2)[CH:27]([NH:39]C(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)[CH2:26]1>>[CH:31]1([O:30][CH:28]2[CH:27]([NH:39][C:17]([CH:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:21]=[CH:22][C:2]([NH2:1])=[C:3]([Cl:23])[CH:4]=3)[CH3:20])=[O:19])[CH2:26][C:25](=[O:24])[O:29]2)[CH2:32][CH2:33][CH2:38][CH2:37][CH2:36]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OC1CCCCC1
Yield: 47 %

Procedure:
Prepared from syn-(2-cyclohexyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 97a following the method used for 98a to give the title compound (153 mg, 47% yield). 1H-NMR (500 MHz, CD3OD) δ 1.06-2.38 (m, 14H), 1.42 (d, 3H), 2.50-2.66 (m, 1H), 2.69-2.82 (dd, 1H), 3.06-3.75 (m, 2H), 3.80-3.94 (m, 1H), 4.40-4.52 (m, 1H), 4.57-4.65 (m, 1H), 4.70-4.80 (m, 1H), 5.72 (d, 1H), 6.71 (m, 1H), 7.50-7.63 (m, 1H), 7.78 (d, 0.6H), 8.42 (d, 0.4H). Analytical HPLC 10.30 min. LC-MS (ES4) m/e=521.2 (MH+).