Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:13]([N:15](CC)CC)[CH3:14].BrCC#N>CCOC(C)=O>[C:13]([CH2:14][O:11][C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])#[N:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCN(CC)CC
Agent: N#CCBr
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)OCC#N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution containing 2.0 g (11.4 mmol) of Nα-Boc-glycine in 25 mL of EtOAc was added 1.73 g (2.38 mL, 17.1 mmol) of triethylamine followed by 2.05 g (1.19 mL, 17.1 mmol) of bromoacetonitrile. The reaction mixture was stirred at 60° C. under an argon atmosphere for 16 h. The heterogeneous mixture was cooled to room temperature and filtered through a short pad of silica, washing with EtOAc to remove the precipitated triethylamine hydrobromide. The filtrate was concentrated under diminished pressure to give Nα-Boc-glycine cyanomethyl ester as a colorless syrup which solidified upon standing. The crude product was used directly in the next step without further purification: yield 2.12 g (87%); 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 9H), 4.05 (d, 2H, J=5.5 Hz) and 4.79 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:29][CH2:30][CH2:31][CH2:32]O>>[Br:29][CH2:30][CH2:31][CH2:32][O:27][C:26](=[O:28])[C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: OCCCBr
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCCCBr

Procedure:
Following General Procedure B and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared by coupling N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine (Aldrich) using General Procedure B) and 3-bromo-1-propanol (Aldrich), the title compound was prepared as a solid (mp=138-142° C.). The reaction was monitored by tlc (Rf=0.75 in 60% EtOAc/hexanes) and the product was purified by flash column chromatography using 60% EtOAc/hexanes as the eluent.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.C(C1OC(C2C=CC=CC=2)C(C2C=CC=CC=2)[N:23]=1)=O>C(O)C.C(O)(=O)C.[Zn]>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1=NC(c2ccccc2)C(c2ccccc2)O1
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: NN
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: NN(Cc1ccccc1)c1ccccc1
Temperature: 10 °C
Yield: 17.8 %

Procedure:
1-benzyl-1-phenylhydrazine was prepared in the same manner as Synthesis Example 1 except for using 208.6 g (1.14 mol) of N-benzylaniline in place of diphenylamine. Said hydrazine was dissolved in a mixture of 1 l of ethanol and 50 ml of acetic acid, and 286 g (1.14 mol) of 2-formyl-4,5-diphenyloxazoline, represented by the formula ##STR9## was added. The resulting mixture was cooled to 10° C., and 250 g (3.82 mol) of zinc metal was added with caution not to raise the temperature over 20° C. After completion of the reaction, the reaction mixture was filtered and the filtrate was poured into water, thus giving a yellow precipitate. Recrystallization of the precipitate from a methyl ethyl ketone-ethanol (1:1) mixture gave 87.5 g of yellow crystals (yield 17.8% based on the amine).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15]>C(O)C.C(O)(=O)C>[C:18]([O:17][C:13]([NH:14][N:15]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1ccc2c(c1)CCC2=O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)CCC2=NNC(=O)OC(C)(C)C

Procedure:
A solution of 5-methoxyindan-1-one (5.46 g) and tert-butyl carbazate (4.45 g) in ethanol (100 ml) and glacial acetic acid (1 drop) was stirred and boiled under reflux for 2 hours. The volume was reduced by half under reduced pressure and the solid which crystallized was collected by filtration to give 5-methoxyindan-1-one tert-butyloxycarbonylhydrazone.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[C:5]2[NH:6][C:7](=[O:20])[C:8]3[C:13]([CH3:14])=[N:12][C:11]4[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:10]=4[C:9]=3[N:4]2[N:3]=1.Cl[CH2:23][CH2:24][NH2:25].CN(CCCCl)C>>[NH2:25][CH2:24][CH2:23][N:6]1[C:7](=[O:20])[C:8]2[C:13]([CH3:14])=[N:12][C:11]3[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:10]=3[C:9]=2[N:4]2[N:3]=[C:2]([CH3:1])[CH:21]=[C:5]12
Reactant: CCn1ncc2c1nc(C)c1c(=O)[nH]c3cc(C)nn3c12
Reactant: NCCCl
Agent: CN(C)CCCCl
Product: CCn1ncc2c1nc(C)c1c(=O)n(CCN)c3cc(C)nn3c12

Procedure:
By substituting the 2,6-dimethyl-8-ethyl-4H-pyrazolo-[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one obtained in Example 16 in the procedure of Example 4 and substituting 2-chloroethylamine for the dimethylaminopropyl chloride, 4-(2-aminoethyl)-2,6-dimethyl-8-ethyl-4H-pyrazolo-[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]([NH:27]S(C(C)(C)C)=O)/[CH:19]=[N:20]/S(C(C)(C)C)=O)=[CH:11][CH:10]=2)[CH2:4][O:3]1.[CH2:35]([Mg]Cl)[CH2:36][CH3:37].C([Mg])CC>C1COCC1.C(OCC)C>[NH2:27][CH:18]([CH:19]([NH2:20])[CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])=[CH:14][CH:13]=1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCC(/C=N/S(=O)C(C)(C)C)NS(=O)C(C)(C)C)cc2)O1
Reactant: CCC[Mg]Cl
Agent: CCC[Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(N)C(N)CCCc1ccc(OC[C@@H](O)CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid (4-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-1-{[(E)-2-methyl-propane-2-sulfinylimino]-methyl}-butyl)-amide (907 mg, 1.7 mmol) in THF (20 ml) at 0° C. n-propylmagnesium chloride (1.76 ml of a 2M solution in diethyl ether, 3.52 mmol). The solution is stirred at 0° C. for 30 minutes then at room temperature for 3 hours. A further portion of n-propylmagnesium (1.76 ml of a 2M solution in diethyl ether, 3.52 mmol) is added and the mixture is stirred at room temperature overnight. The resulting mixture is quenched with sat. aq. NH4Cl solution (50 ml) and extracted with EtOAc (2×50 ml). The organic phase is dried (MgSO4) and concentrated in vacuo. The residue is dissolved in EtOAc (10 ml) and treated with 4M HCl/dioxan (10 ml). After 10 minutes, the solution is concentrated in vacuo and the residue diluted with DCM (100 ml). This is treated with sat. aq. NaHCO3 solution (100 ml) and the organic phase is removed and dried (MgSO4). The DCM solution is applied to a SCX-2 cartridge (10 g) and this is eluted with DCM and MeOH. The product is released with 2M NH3 in MeOH, and the methanolic ammonia fraction concentrated to give (S)-3-[4-(4,5-Diamino-octyl)-phenoxy]-propane-1,2-diol as a mixture of diastereomers as a gum; [M+H]+ 515.38
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH2:23][F:24])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C@:27]1([OH:35])[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1)#[CH:26].C(N(CC)CC)C.N>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)C=O>[CH2:1]([C:8]1[C:13]([C:26]#[C:25][C@:27]2([OH:35])[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH2:23][F:24])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OCF
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1OCF
Temperature: 75 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A mixture of 43.9 mg of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]-3-iodopyridine, 16.5 mg of (3R)-3-ethynyl-3-quinuclidinol, 11.5 mg of tetrakis(triphenylphosphine)palladium(0), 0.9 mg of cuprous iodide, 42 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring for 1 hours at 75° C. in a nitrogen atmosphere. The reaction solution was poured into an aqueous dilute ammonia, and then the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 33 mg of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].P(OC)(OC)(O[CH3:18])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:13])([F:14])[F:12])=[N:8][N:9]([CH3:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: COP(=O)(OC)OC
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Product: CCOC(=O)c1cn(C)nc1C(F)(F)F
Temperature: 180 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of 4.16 g of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (20 mmol) and 10 ml of trimethyl phosphate (86.4 mmol) is stirred at a temperature of 180° C. for 16 hours. 200 ml of an ice-water mixture are then added. The resulting reaction product is filtered, washed with water and dissolved in 50 ml of ethyl acetate. The organic phase is washed twice with 50 ml of saturated sodium chloride solution each time and dried over sodium sulfate and concentrated by evaporation. 4.0 g (90% of theory) of 3-trifluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester are obtained in the form of crystals (m.p. 55-57° C.).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:25][CH2:26][CH:27]=C)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14].[O:29]=[O+][O-]>C(Cl)Cl.CO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([CH2:25][CH2:26][CH:27]=[O:29])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:14]
Reactant: C=CCCC(C(=O)NCCCc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: O=CCCC(C(=O)NCCCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Dissolve 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl-5-hexenylamine (1.2 g, 3.19 mmol) in methylene chloride (40 mL) and methanol (4 mL) and cool to -78° C. under a nitrogen atmosphere. Treat with ozone until a blue color persists, degas with nitrogen for 20 minutes and add pyridine (0.2 mL). Quench with dimethylsulfide (4 mL) and stir overnight at room temperature. Dilute with methylene chloride (75 mL) and wash with 5% sulfuric acid (40 mL) and brine (40 mL). Dry (Na2SO4), evaporate the solvent in vacuo and purify by chromatography (hexane/ethyl acetate) to give 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl-5-oxo-pentylamine as a white solid (972 mg, 80%).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH3:43][S:44]([N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][C:19]2[N:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]3=[C:17]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[CH:16][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8]4)=[CH:13][CH:12]=3)[N:18]=2)[CH2:29][CH2:30]1)(=[O:46])=[O:45]
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reaction time: 0.17 h

Procedure:
1-(2-phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine (110.00 mg, 0.25 mmol) in a dried 15 mL round-bottom flask was dissolved in 2.00 mL of CH2Cl2 and charged with PS-DIEA (150.00 mg, 0.46 mmol). Methanesulfonyl chloride (10 μL, 0.47 equiv) was added in one portion. After 10 min., another 5 μL of methanesulfonyl chloride (0.24 equiv) was added. After another 10 min., another 2.1 L of methanesulfonyl chloride (0.1 equiv) was added. The reaction was filtered through a fritted funnel, and the resins were rinsed multiple times with CH2Cl2. The crude product was purified by 5 g Jones silica gel (wetted with 100% CH2Cl2, dry loaded with silica, and eluted with 2% (7N NH3) in MeOH/CH2Cl2→5% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1H, d, J=0.85), 8.29 (1H, d, J=8.86), 8.20 (2H, dd, J=1.51, J=1.12), 7.97 (2H, m), 7.86 (1H, dd, J=1.72, J=1.72), 7.53 (4H, m), 7.24 (1H, d, J=5.26), 7.08 (1H, d, J=6.75), 3.85 (2H, d, J=11.88), 2.98 (2H, d, J=7.08), 2.68 (2H, t), 2.20 (1H, m), 1.94 (2H, d, J=10.92), 1.50 (2H, m); MS (ES+): m/z 513.02/514.03 (80/70) [MH+]; HPLC: tR=2.17 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1.CC1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:21][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccnc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CN2CCC(=Nc3cccnc3)CC2)cc1

Procedure:
A mixture of 19 parts of 1-(phenylmethyl)-4-piperidinone, 11.8 parts of 3-pyridinamine, 120 parts of methylbenzene and a small volume of 4-methylbenzenesulfonic acid is stirred and refluxed for 5 hours. (The reaction vessel is provided with reflux-condensor and water-separator). After the calculated amount of water is separated, the solvent is evaporated. The oily residue is dissolved in 800 parts of 2,2'-oxybispropane and evaporated again, yielding 27 parts of N-[1-(phenylmethyl)-4-piperidinylidene]-3-pyridinamine as a yellow-brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH:10]1([CH:16]=[CH:17]B(O)O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:10]1(/[CH:16]=[CH:17]/[C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OB(O)C=CC1CCCCC1
Reactant: N#Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(/C=C/C2CCCCC2)cn1
Temperature: 90 °C
Yield: 75.9 %

Procedure:
Combine a mixture of 5-bromo-2-cyano-pyridine (2 g, 10.93 mmol), 2-cyclohexylvinyl boronic acid (2.52 g, 16.39 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (446 mg, 0.546 mmol) and 2M aqueous Na2CO3 (18.2 mL, 36.07 mmol) in 1,4-dioxane (110 mL). Purge with nitrogen and heat at 90° C. overnight. Cool the reaction to room temperature and partition between EtOAc and water. Separate the aqueous phase and extract with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (120 g, pre-packed cartridge) eluting stepwise with hexane/EtOAc (1:0 over 5 min, 49:1 over 5 min and 19:1 over 5 min; 50 mL/min) to obtain the desired intermediate (1.76 g, 76%). MS (APCI+) m/z: 213 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[O:20])=[CH:14][CH:13]=1.Cl>C(Cl)Cl.N1C=CC=CC=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([CH:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)Cc2ccc(F)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid, 8.0 g, 56 mmol) dissolved in anhydrous methylene chloride (100 mL) and pyridine (11 mL), at 0° C. under nitrogen atmosphere, was slowly added 2-(4-fluorophenyl)acetyl chloride (7.6 mL, 9.6 g, 56 mmol). The red solution was stirred at 0° C. for 1.5 h. The reaction mixture was treated with 1 N HCl (13 mL) and diluted with methylene chloride (200 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium chloride, dried and concentrated in vacuo to give 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione. The crude intermediate was suspended in absolute EtOH (150 mL) and the resulting mixture was refluxed for 4 hours. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (SiO2, 230-400 mesh, 8:1 hexane-ethyl acetate gradient elution) to afford the desired product (4.6 g, 37%). 1H NMR (CDCl3) δ 7.23-7.15 (m, 2H), 7.05-6.98 (m, 2H), 4.18 (q, 2H, J=7.0 Hz), 3.81 (s, 2H), 3.46 (s, 2H), 1.26 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 225 (M+H)+.
Reaction SMILES: [C:1]([NH:9][CH2:10][C@@H:11]([C@@H:22]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:23]([NH:25][N:26]1[C:30](=[O:31])[C@H:29]([CH:32]([CH3:34])[CH3:33])[NH:28][C:27]1=[O:35])=[O:24])[C:12](=[O:21])[NH:13][O:14]C1CCCCO1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([NH:9][CH2:10][C@@H:11]([C@@H:22]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:23]([NH:25][N:26]1[C:30](=[O:31])[C@H:29]([CH:32]([CH3:33])[CH3:34])[NH:28][C:27]1=[O:35])=[O:24])[C:12](=[O:21])[NH:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)N[C@@H](C(C)C)C1=O)[C@H](CNC(=O)c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)N[C@@H](C(C)C)C1=O)[C@H](CNC(=O)c1ccccc1)C(=O)NO
Reaction time: 2.5 h
Yield: 75.2 %

Procedure:
A solution of 0.22 g of 2(R)-[2-benzamido-1(R)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]ethyl]-N-(4(S)-isopropyl-2,5-dioxo-1-imidazolidinyl)-4-methylvaleramide in 5 ml of methanol was treated with 0.022 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2.5 hours and evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate and then saturated aqueous sodium chloride. The organic fraction was dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with diethyl ether to give 0.14 g of 2(R)-[2-benzamido-1(R)-(hydroxycarbamoyl)ethyl]-N-(4(S)-isopropyl-2,5-dioxo-1-imidazolidinyl)-4-methylvaleramide in the form of a white solid.
Reaction SMILES: C([O:5][CH2:6][CH:7]1[N:11]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([Cl:20])[CH:13]=2)[C:10](=[O:21])[C:9]([CH3:23])([CH3:22])[C:8]1=[O:24])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>O>[Cl:20][C:14]1[CH:13]=[C:12]([N:11]2[CH:7]([CH2:6][OH:5])[C:8](=[O:24])[C:9]([CH3:22])([CH3:23])[C:10]2=[O:21])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC(C)(C)OCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)C(=O)C(CO)N(c2ccc(C#N)c(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To 4-[5-(tert-butoxy methyl)-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl]-2-chlorobenzonitrile (900 mg) was added trifluoroacetic acid (10 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was cooled to 0° C., and neutralized with saturated sodium hydrogen carbonate solution. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:4), and recrystallized from hexane-ethyl acetate to give the title compound as colorless crystals (yield: 655 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.I[C:22]1[NH:26][N:25]=[CH:24][CH:23]=1.C(Cl)Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:22]1[NH:26][N:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Ic1ccn[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(-c2ccn[nH]2)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
To methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 800 mg, 2.9 mmol) in dioxane (30 mL) was added 5-iodo-1H-pyrazole (674 mg, 3.5 mmol), and Pd(dppf)Cl2.DCM (237 mg, 0.29 mmol). The mixture was degassed with argon and stirred for 10 minutes then an aqueous potassium carbonate solution (2 M, 8 mL) was added. The mixture was heated at 90° C. for 18 h, then cooled and diluted with EtOAc and filtered through Celite®. The filtrate was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-30% EtOAc in hexanes) to yield 258 mg (41%) of the title compound as a solid. m/z (ES+) 217 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1.[CH3:12]O>C(Cl)Cl>[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:12])=[O:8])=[CH:5][N:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
Hydrochloric acid (gas) was bubbled through a solution of 6.11 g (38.8 mmol) of 6-chloronicotinic acid in approximately 350 ml of methanol. The resultant reaction mixture was reacted for approximately two hours at reflux temperature, then cooled to room temperature and concentrated in vacuo to provide a white residue. This residue was redissolved in methylene chloride and the resultant solution was washed with a saturated sodium bicarbonate solution. The organic portion was dried over sodium sulfate, filtered and then reduced to dryness in vacuo to provide 7.28 g of a tan solid. This solid was crystallized from pentane, followed by recrystallization from hexane to provide the desired titled compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[OH-].[Na+].CN(C)[CH:23]=[O:24]>>[Cl:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=1[N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:23]=[O:24]
Reactant: Clc1cccc(Cl)c1-n1cccc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
Under ice-cooling, 7.67 g of phosphorus oxychloride was added dropwise to 4 g of N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes, and 2.1 g of 1-(2,6-dichlorophenyl)-1H-pyrrole was added thereto. The resulting mixture was stirred at 60° C. for 2 hours, allowed to cool to room temperature, and then poured into ice water. The mixture was adjusted to pH 4 by an addition of a 2N aqueous sodium hydroxide solution, and then extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.80 g of 1-(2,6-dichlorophenyl)-1H-pyrrole-2-carbaldehyde of the formula: