Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([N:19]([CH3:31])[C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:42][C@@H:43]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:70]([NH2:72])=[O:71])[CH2:66][CH2:67][S:68][CH3:69])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1.CC(O)=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[N:1]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([N:19]([CH3:31])[C@H:20]([C:28]([NH:42][C@@H:43]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:70]([NH2:72])=[O:71])[CH2:66][CH2:67][S:68][CH3:69])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60])=[O:55])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Reactant: CN(C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 31 %

Procedure:
Condensation of BocPro-DTrp-MePheOH (0.800 g.) and HDTrp-Leu-MetNH2 acetate salt (part B of Example 17, 0.721 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-MePhe-DTrp-Leu-MetNH2 in 31% yield. De-t-butoxycarbonylation of BocPro-DTrp-MePhe-DTrp-Leu-MetNH2 (0.400 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-MePhe-DTrp-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:2) salt dihydrate in 23% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=1>N1C=CC=CC=1.O.C(OCC)(=O)C.[Cu]>[CH3:33][S:32][C:29]1[CH:30]=[CH:31][C:26]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)cc2)cc1
Reactant: CSc1ccc(Br)cc1
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CSc1ccc(-n2ncc(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(F)cc3)c2=O)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of the product from Example 11, 4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (344 mg, 1.0 mmol), 4-bromothioanisole (812 mg, 4.0 mmol), and copper (70 mg, 1.1 mmol) in 20 mL of pyridine was stirred at reflux under a nitrogen atmosphere for 18 hours. After cooling to room temperature, the reaction mixture was diluted with a mixture of water and ethyl acetate. The two layers were filtered through Celite®, and separated. The organic layer was washed with 10% aqueous citric acid, with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography (silica gel, 93:7 dichloromethane/ethyl acetate) to provide the title compound as a foam (yield: 380 mg, 81.5%). 1H NMR (300 MHz, CDCl3) δ 2.55 (s, 3H), 3.05 (s, 3H), 6.98 (t, J=9 Hz, 2H), 7.22 (dd, J=9 Hz, 6 Hz, 2H), 7.38 (dd, J=8 Hz, 2 Hz, 4H), 7.64 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 7.98 (s, 1H). MS (DCI/NH3) m/z 467 (M+H)+. Anal. calc. for C24H19FN2O3S2.0.5H2O: C, 60.63; H, 4.21; N, 5.90. Found: C, 60.72; H, 3.96; N, 5.70.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.I[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.CN1CCCC1=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[N:14]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Reactant: Cc1ccc(I)cc1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1ccc(-n2ccc(C)c(N3CCc4nc(N)ncc4C3)c2=O)cc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 38.6 %

Procedure:
A degassed solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one (25 mg, 0.097 mmol), 1-iodo-4-methylbenzene (20 mg, 0.097 mmol), N1,N2-dimethylethane-1,2-diamine (5 mg, 0.049 mmol), Copper Iodide (5 mg, 0.024 mmol), and Potassium Phosphate (41 mg, 0.194 mmol) 2 mL of N-methylpyrrolidone was heated to 70° C. After allowing the reaction to stir overnight (17 h) at 70° C., the reaction was complete and allowed to cool to room temperature. The reaction was extracted with EtOAc (3×5 mL) and with NaHCO3 (2×10 mL). The crude organic layers were combined, dried over anhydrous Na2SO4 (s), filtered and then concentrated in vacuo. The crude mixture was then purified using the ISCO flash chromatography system using a CHCl3/EtOAc gradient. Upon reaching a 1:1 mixture of EtOAc and CHCl3, 3% MeOH was added and increased to 6% MeOH which, after concentrating the appropriate fractions afforded the title compound as a tan solid (13 mg, 38%). 1H NMR (DMSO) δ: 7.90 (s, 1H), 7.50-7.59 (m, 2H), 7.44 (d, J=6.7 Hz, 1H), 7.25-7.32 (m, 2H), 6.19 (s, 2H), 6.08 (d, J=7.0 Hz, 1H), 3.89 (br. S, H), 3.29 (s, 2H), 2.64(t, j=5.3 Hz, 2H), 2.13 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[N:15]1([C@H:12]2[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCCCC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@H](N2CCCCC2)CC1

Procedure:
1.7 g (4.8 mmol) of trans-dibenzyl-4-piperidino-cyclohexylamine are dissolved in 35 mL MeOH and hydrogenated on 350 mg of Pd/C (10%) at 20° C. The solvent is eliminated in vacuo and the residue crystallised from ethanol and concentrated HCl.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][O:12][C:11]2[CH:15]=[CH:16][C:17](B(O)O)=[CH:18][C:10]=2[S:9]1(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1([O-])O[O:25]1.O.O.O.O.[Na+].[NH4+].[Cl-]>C1COCC1.O>[OH:25][C:17]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:9](=[O:23])(=[O:22])[C:10]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2S1(=O)=O
Reactant: [O-]B1OO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(O)cc2S1(=O)=O

Procedure:
A suspension of 4.7 g (13.69 mmol) of the product of Step G of Example 1 in a mixture of 90 ml of THF and 90 ml of water is stirred at ambient temperature in the presence of 5.27 g (34 mmol) of sodium perborate tetrahydrate overnight. The reaction mixture is diluted by adding saturated aqueous NH4Cl solution and is then extracted with CH2Cl2. The organic phases are combined, washed (saturated NaCl), dried (MgSO4) and evaporated using a rotary evaporator. The residue from evaporation is taken up and triturated in heptane in the presence of a few drops of isopropyl ether; a precipitate is formed which is filtered off to yield the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.[NH2:25][C:26]([CH3:31])([CH2:29][CH3:30])[C:27]#[CH:28]>O.O1CCCC1>[CH3:31][C:26]([NH:25][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[N:3][CH:4]=1)([CH2:29][CH3:30])[C:27]#[CH:28]
Reactant: Nc1ncc(C(=O)O)cc1Cl
Reactant: C#CC(C)(N)CC
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CC(C)(CC)NC(=O)c1cnc(N)c(Cl)c1
Temperature: -30 °C
Yield: 43 %

Procedure:
In a 300 mL, three-necked, round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer were placed 5 g (0.03 mole) of 6-amino-5-chloronicotinic acid, 150 mL of tetrahydrofuran and 6.67 g (0.066 mole) of triethylamine. The resulting well-stirred mixture was cooled to -30° C. and 2.24 ml (0.03 mole) of methane sulfonyl chloride were added dropwise keeping the reaction temperature at -30° C. The resulting suspension was stirred at -30° C. during 30 minutes, after which 4.01 g (0.03 mole) of 3-amino-3-methyl-1-pentyne hydrochloride were added slowly over a 20 minute period. After the addition was completed, the reaction mixture was stirred at -30° C. for an additional 30 minutes. The reaction mixture was poured into water and extracted with methylene chloride (3×450 ml). The combined organic phases were washed with water (1×200 ml), and dried over anhydrous magnesium sulfate. The solvent was removed using a rotary evaporator, yielding the crude product. After purification by chromatographic column (silica gel, 1:1 ethyl acetate:hexane), 3.25 g N-(3-methylpent-1-yn-3-yl)-6-amino-5-chloronicotinamide were obtained as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[ClH:7].Cl[C:9]([CH2:16][Cl:17])([CH2:12][CH2:13][C:14]#[N:15])[CH:10]=O>CN(C=O)C>[Cl:7][C:14]1[CH:13]=[CH:12][C:9]([CH2:16][Cl:17])=[CH:10][N:15]=1
Reactant: N#CCCC(Cl)(C=O)CCl
Reactant: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: ClCc1ccc(Cl)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a three necked, 100-mL round bottom equipped with a reflux condenser, gas inlet tube and a thermometer was charged 50 mL of N,N-dimethylformamide. Phosphorous pentachloride (2.3 g, 11 mmol) was added in several portions and anhydrous hydrogen chloride was introduced slowly. The reaction temperature was kept around 60° C.-85° C. by means of a water bath. 2-Chloro-2-chloromethyl-4-cyanobutyraldehyde in 5 mL of DMF was added at 80° C., through a syringe pump within a period of 1 h. The resulting mixture was then heated to 100° C. under stirring for 8 h, quenched with water, neutralized using NaHCO3 to a pH of 5, extracted with methylene chloride, dried over MgSO4, and concentrated and distilled to give 0.5 g of 2-chloro-5-chloromethylpyridine. Purity by GLC analysis was 95%.
Reaction SMILES: C(C(CCCC)CO[C:6](=O)[CH2:7][CH2:8][S:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]1[N:20]=[N:21][N:22]=[C:15]1[CH:14]=[CH:13]2)C.FC1[N:34]=[C:33]([C:35]2([C:41]#[N:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=CC=1.CC(C)([O-])C.[K+]>CN(C=O)C>[N:20]1[N:16]2[C:17]3[C:12]([CH:13]=[CH:14][C:15]2=[N:22][N:21]=1)=[CH:11][C:10]([S:9][C:8]1[N:34]=[C:33]([C:35]2([C:41]#[N:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[CH:6][CH:7]=1)=[CH:19][CH:18]=3
Reactant: N#CC1(c2cccc(F)n2)CCOCC1
Reactant: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nnnn32)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5nnnn54)c3)n2)CCOCC1
Temperature: 90 °C

Procedure:
9e (110 mg, 0.28 mmol) and 4-(6-fluoro-pyridin-2-yl)-tetrahydro-pyran-4-carbonitrile (9f, 60 mg, 0.28 mmol) were dissolved in DMF and degassed with N2 for 10 minutes. Potassium tert-butoxide (38 mg, 0.34 mmol) was added, and the reaction was degassed with N2 for another 10 minutes, and then heated to 90° C. for 2 hours. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography to obtain the desired product, 9g.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:47][O:48][C:49]([C:51]1[N:52]([CH2:69][C:70]2[CH:78]=[CH:77][C:73]3[O:74][CH2:75][O:76][C:72]=3[CH:71]=2)[C:53](=[O:68])[C:54]2[C:59]([C:60]=1[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[CH:58][C:57](Br)=[CH:56][CH:55]=2)=[O:50].[CH2:79]([NH2:86])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:47][O:48][C:49]([C:51]1[N:52]([CH2:69][C:70]2[CH:78]=[CH:77][C:73]3[O:74][CH2:75][O:76][C:72]=3[CH:71]=2)[C:53](=[O:68])[C:54]2[C:59]([C:60]=1[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[CH:58][C:57]([NH:86][CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)=[CH:56][CH:55]=2)=[O:50]
Reactant: NCc1ccccc1
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(NCc3ccccc3)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reaction time: 0.08 h

Procedure:
Palladium(II) acetate (15 mg) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (130 mg) were added to toluene (20 ml) at room temperature, and the mixture was stirred for 5 min. under a nitrogen atmosphere. To the reaction mixture were added 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (1.0 g) and benzylamine (0.33 ml) at room temperature, and the mixture was stirred for 10 min under a nitrogen atmosphere. To the reaction mixture was further added sodium tert-butoxide (270 mg) at room temperature, and heated under reflux under a nitrogen atmosphere for 4 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) to give the title compound (1 g).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([OH:17])[CH2:14][C:15]#[CH:16].COC(C)(C)C>C(N(CC)CC)C.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:7]1[C:2]([C:16]#[C:15][CH2:14][CH2:13][OH:17])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9]
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: C#CCCO
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: OCCC#Cc1c(F)c(F)c(F)c(F)c1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a solution of 1-bromo-2,3,4,5,6-pentafluorobenzene (50 g) in triethylamine (200 mL), 3-butyn-1-ol (15 g), triphenylphosphine (2.7 g), dichlorobistriphenylphosphinepalladium (3.6 g) and copper (I) iodide (1.9 g) were added, followed by stirring at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, and tert-butyl methyl ether (500 mL) was added thereto, followed by stirring at 0° C. for 30 minutes. The reaction mixture was filtered through Celite®, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (hexane:ethyl acetate=95:5→65:35) to give the title compound (43 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]>O1CCOCC1.O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Yield: 73 %

Procedure:
A solution of 25.5 g of (2-chloro-4,5-difluorobenzoyl)propanedioic acid, diethyl ester in 500 ml of p-dioxane and 2.74 ml of water was refluxed for 3 hours, then evaporated to dryness and distilled on a Kugelrohr, giving 14.6 g of the desired compound as a bright yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([CH3:16])=[C:10]([C:13](=[O:15])[CH3:14])[C:11]=1[CH3:12])=[O:6].CCN(CC)CC>C(Cl)Cl>[C:13]([C:10]1[C:11]([CH3:12])=[C:7]2[C:5](=[O:6])[NH:4][CH2:3][CH2:2][N:8]2[C:9]=1[CH3:16])(=[O:15])[CH3:14]
Reactant: CC(=O)c1c(C)[nH]c(C(=O)NCCCl)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1c(C)c2n(c1C)CCNC2=O
Temperature: 25 °C
Yield: 96.9 %

Procedure:
4-Acetyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (2-chloro-ethyl)-amide (12.664 g, 52.18 mmol) was slurried in DCM (100 mL) and Et3N (20 mL) and heated to 50° C. for 16 hours. After cooling to room temperature and removal of solvent, the residue was treated with cold water. The resulting off white precipitate filtered off and shown to be the target compound (10.424 g, 50.54 mmol, 97% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.O1CCCC1.C(=O)(O)[O-].[Na+]>>[N:13]1([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
m-Nitrobenzoic acid (2.00 g, 0.0120 mol), Morpholine (1.25 g, 0.0144 mol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.29 g, 0.0120 mol) and 1-Hydroxybenzotriazole (0.40 g, 0.0030 mol) were dissolved in Tetrahydrofuran (35 mL, 0.43 mol) and the reaction was allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 2.79 g of Morpholin-4-yl-(3-nitro-phenyl)-methanone. (M+H)=237.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31]([OH:34])(=[O:33])=O)[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6](/[CH:7]=[CH:8]/[C:9]2[N:17]([CH3:18])[C:16]3[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=3[N:10]=2)=[C:5]([S:31]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH:4]=1
Reactant: C1CCNCC1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)N3CCCCC3)n2C)n(CCC)c1=O
Yield: 54.7 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.00 g (1.96 mmol) of Compound 1 obtained in Example 1 and 1.93 ml (19.6 mmol) of piperidine. The resulting crude crystals were recrystallized from dimethylsulfoxide/water to give 600 mg (yield 55%) of Compound 4 as a pale yellow powder.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][CH:13]([O:16]CC)[CH:14]=[CH2:15])[CH3:11].C(N(CC)CC)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][CH2:15][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: C=CC(OCC)OCC
Reactant: O=Cc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 711.8 %

Procedure:
To a solution of 4-iodobenzaldehyde (0.116 g, 0.5 mmol), acrolein diethylacetal (0.3 mL, 1.5 mmol), tetra-n-butylammonium chloride (0.139 g, 0.5 mmol) and triethylamine in anhydrous dimethylformamide (2 mL), palladium acetate (0.003 g, 0.015 mmol) was added. The reaction mixture was heated at 90° C. and stirred for 16 h. The reaction mixture was diluted with 2 N hydrochloric acid and extracted with diethyl ether. The solvent was evaporated in vacuo to leave a residue which was purified by column chromatography (silica gel) employing 1-5% ethyl acetate in hexane as eluents to obtain 3-(4-formyl-phenyl)-propionic acid ethyl ester (0.734 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][C@@H:11]([OH:16])[CH2:12][C:13]([NH2:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:17])[CH2:10][C@@H:11]([O:16][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:12][C:13]([NH2:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(=O)C[C@H](O)CC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
(S)-Benzyl-3-hydroxyglutaramate (49.5 g) was dissolved in anhydrous dimethylformamide (50 ml) and added to a 500 ml flask containing solid imidazole (17.1 g). To this a solution of tert-butyldimethylsilyl chloride (34 g) in dimethylformamide (120 ml) was added and reaction flask was cooled in an ice-bath. The reaction was quenched by addition of water-saturated ethyl acetate. The mixture was stirred at ambient temperature. To this water was added and the biphasic mixture was stirred for 1 hour. The mixture was then washed with water. The organic phases were mixed and washed with water to remove traces of dimethylformamide. The organic phase was evaporated under reduced pressure to yield (S)-benzyl-3-(tert-butyl dimethylsilyloxy)glutaramate.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[CH2:19][CH2:18][C:17]2[C:20](=O)[NH:21][C:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)=[N:23][C:16]=2[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Cl-].C([N+](CC)(CC)CC)C.C(#N)CC>[CH2:6]([N:13]1[CH2:19][CH2:18][C:17]2[C:20]([Cl:3])=[N:21][C:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)=[N:23][C:16]=2[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(Cc2cccc(Cl)c2)nc2c1CCN(Cc1ccccc1)CC2
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CCC#N
Product: Clc1cccc(Cc2nc(Cl)c3c(n2)CCN(Cc2ccccc2)CC3)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Phosphoryl chloride (1.33 ml, 14.3 mmol) and tetra-ethyl ammonium chloride (472 mg, 2.85 mmol) were added to a solution of the product of Step A (361 mg, 0.95 mmol) in propionitrile (10 ml) and heated to 100° C. for 17 h. The reaction mixture was concentrated in vacuo then azeotroped with toluene then dichloromethane. The residue was partitioned between dichloromethane (30 ml) and water (20 ml), stirred for 30 min then the organic layer was separated, dried over magnesium sulphate and concentrated in vacuo to give the title compound as a foam in 87.7% yield, 332 mg.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][CH:8]=[N:9][C:10]=1[C:11]([CH3:15])([CH3:14])[CH:12]=[CH2:13])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH3:15][C:11]([C:10]1[N:9]=[CH:8][NH:7][C:6]=1[CH2:4][OH:3])([CH3:14])[CH:12]=[CH2:13]
Reactant: C=CC(C)(C)c1nc[nH]c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)(C)c1nc[nH]c1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.7 %

Procedure:
A solution of 5-(1,1-dimethyl-allyl)-3H-imidazole-4-carboxylic acid ethyl ester (3.13 g, 15.0 mmol) in THF (60 ml) was added dropwise to a suspension of lithium aluminium hydride (95% suspension, 1.00 g, 25.0 mmol) in THF (40 ml) and the mixture was stirred at room temperature for 4 h. Water was added until the evolution of gas ceased, the mixture was stirred for 10 min, then was filtered through a sintered funnel. The precipitate was washed with THF, then with methanol, the filtrate and washings were combined, evaporated, then freeze-dried to afford [5-(1,1-dimethyl-allyl)-3H-imidazol-4-yl]-methanol (2.56 g, 102%). Residual water was removed by azeotroping with chloroform prior to further reaction. (See Hayashi et al., J. Org. Chem., 65:8402-8405 (2000)).