Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)([O-:22])=[O:21]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Product: CCOC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 160 °C

Procedure:
A mixture of ethyl 4-aminobenzoate (1.00 g, 6.05 mmol) and 2-fluoronitrobenzene (0.64 mL, 6.05 mmol) was heated at 160° C. for 18 h. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc-70:30, to give the title compound. MS: m/z=287 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.CN([CH:17]=[O:18])C.P(Cl)(Cl)(Cl)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][C:6]=1[CH:17]=[O:18]
Reactant: Cc1ccc(C)n1-c1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)c(C)n1-c1ccccc1
Temperature: 80 °C
Yield: 29.2 %

Procedure:
To a well stirred solution of 2,5-dimethyl-1-phenyl-1H-pyrrole (7.65 g, 44.7 mmol) and DMF (3.6 g, 49.2 mmol) in 70 mL of dry toluene, phosphorus oxychloride (6.9 g, 44.7 mmol) was added in small portions. The mixture was heated to 80° C. for 3 hrs. The solution was allowed to cool to room temperature, then 100 mL of saturated aqueous Na2CO3 was added. The aqueous layer was extracted with EtOAc (100 mL×3). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure, the residue was purified by column chromatography (hexane:EtOAc=10:1) to give 2.6 g of 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carbaldehyde (29%). MS [M++1]=200, LC-MS: tR=1.96 mm.
Reaction SMILES: CO.C([O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([N:29]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]4[O:42][CH2:43][CH2:44][O:45][C:40]=4[CH:39]=3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]2)[C:13](=[O:48])[CH:12]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[O:42]1[C:41]2[CH:46]=[CH:47][C:38]([CH2:37][N:29]([CH:26]3[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:14]4[C:15]5[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:11]([OH:10])=[CH:12][C:13]4=[O:48])[CH2:24][CH2:25]3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:39][C:40]=2[O:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(OCc3ccccc3)c3ccccc32)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(O)c3ccccc32)CC1
Reaction time: 3.5 h

Procedure:
To a mixed solution of 130 mL methanol and 10 mL tetrahydrofuran containing 1.76 g of tert-butyl (1-(2-(4-benzyloxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 0.86 g of 5% palladium on carbon was added, and stirred under hydrogen atmosphere for 3.5 hours. The insoluble material was filtered off, and the solvent was removed under reduced pressure to afford 1.48 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-hydroxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:5]=[CH:6][C:7]=1[O:8][CH3:9].C(O)C.C(N(CC)CC)C>O.[Pd]>[CH3:9][O:8][C:7]1[CH:6]=[N:5][N:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:3](=[O:16])[CH:2]=1
Reactant: COc1cnn(C2CCCCO2)c(=O)c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COc1cnn(C2CCCCO2)c(=O)c1
Temperature: 43 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
4-Chloro-5-methoxy-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone (2486 g, 10.16 moles), ethanol (8 L), triethylamine (2 L, 14.23 moles) and 5% Pd-C (100 g of 50% water-wet Pd-C) were added to a 5 gallon (18.9 L) autoclave. The mixture was hydrogenated at 50-60 psi (344-413 kilo Pascals) of H2 and heated to a maximum temperature of 43° C. After 24 h., the reaction was complete. The reaction mixture was diluted with a small amount of water and vacuum filtered through celite. The filtrate was concentrated and partitioned with 10 L of ethyl acetate and 8 L of H2O. The aqueous phase was extracted with ethyl acetate (2×2 L). The combined organics were washed with 5 L brine, dried (MgSO4) and vacuum filtered. The solution was concentrated in vacuo to give 2133 g (100% yield) of 5-methoxy-2-(tetrahydro-2H-pyran-2-yl)-3(2H) -pyridazinone as a dark oil which later crystallized to give a tan product suitable for further transformations. The product was purified by recrystallization from ethyl acetate/cyclohexane to give a white solid, mp=76°-78° C. Anal. Calc. for C10H14N2O3 : C,57.13; H,6.71; N,13.32
Reaction SMILES: [CH2:1]([N:6]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11](C(O)=O)[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)[C:61](O)=[O:62].[CH2:66]([O:73][C:74]([N:76]([CH2:80][C:81](=[O:83])[NH2:82])[CH2:77][CH2:78][NH2:79])=[O:75])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1.C(N(CC)CC)C>>[CH2:66]([O:73][C:74]([N:76]([CH2:77][CH2:78][NH:79][C:61]([C@@H:11]1[CH2:10][N:9]([C:7](=[O:8])[N:6]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:14][CH2:13][N:12]1[C:15](=[O:29])[N:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:62])[CH2:80][C:81](=[O:83])[NH2:82])=[O:75])[C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NCCN(CC(N)=O)C(=O)OCc1ccccc1
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)[C@H](C(=O)NCCN(CC(N)=O)C(=O)OCc2ccccc2)C1
Yield: 69.6 %

Procedure:
According to the procedure of Example 1, Step E above, 60 mg (0.12 mmole) of (S)-4-(dipentylcarbamoyl)-1-(N,N-diphenylcarbamoyl)piperazine-2carboxylic acid, 18 mg (0.13 mmole) of HOBt, 32 mg (0.17 mmole) of EDAC, 86 mg (ca. 0.24 mmole) of N-(benzyloxycarbonyl)-N-(carbamoylmethyl)ethylenediamine trifluoroacetic acid salt and 33 microliters (0.24 mmole) of triethylamine after purification by flash chromatography on 16 g of silica gel eluting with 450 mL of 100:3.5 CH2Cl2 :methanol followed by flash chromatography on 16 g of silica with 450 mL of 100:3 CH2Cl2 :methanol then 200 mL of 100:5 CH2Cl2 :methanol gave 62 mg (70%) of an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=S)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29].C(Cl)CCl>CC#N>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[NH:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=4)=[CH:11][C:12]=3[N:17]=2)=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: CSc1nccc(Oc2ccc(N)c(N)c2)n1
Solvent: ClCCCl
Solvent: CC#N
Product: CSc1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(C(F)(F)F)c4)nc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methylsulfanyl-pyrimidin-4-yloxy)-benzene-1,2-diamine (Example 18, Step B, 400 mg, 1.6 mmol, 1.0 eq.) in anhydrous CH3CN (20 mL) was added drop wise a solution of 1-chloro-4-isothiocyanato-2-trifluoromethylbenzene (380 mg, 1.6 mmol, 1.0 eq.) in anhydrous CH3CN (10 mL). The solution was stirred for 16 h at RT. EDC (470 mg, 2.4 mmol, 1.5 eq.) was added and the reaction was heated to 80° C. and stirred for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2, and the solution was washed with H2O (25 mL), NaHCO3 (aq., 25 mL) and brine (25 mL). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-100% EtOAc/hexanes) to yield (4-chloro-3-trifluoromethyl-phenyl)-[5-(2-methylsulfanyl-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine. MS m/z=452.1 (M+H)+; MW Calc'd for C19H13ClF3N5OS: 451.86.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10](Cl)[C:11]([F:14])([F:13])[F:12].[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:18][N:17]=[N:16]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1N=C(Cl)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccccc1-n1nnnc1C(F)(F)F
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Four grams (16.8 mmol) of N-(2-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 9, 1.98 g (30.2 mmol) of sodium azide, 1.16 g (8.42 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 14 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×2). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.01 g of 1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 97.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:20][C:21]([F:29])([F:28])[C:22]([C:24]([F:27])([F:26])[F:25])=[S:23]>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:22]([C:24]([F:27])([F:26])[F:25])([C:21]([F:29])([F:28])[F:20])[SH:23])[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2cc[nH]c2-c2ccc(F)cc2)cc1
Reactant: FC(F)(F)C(=S)C(F)(F)F
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cc(C(S)(C(F)(F)F)C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Yield: 22.9 %

Procedure:
Into a solution of 2.6 g (0.01 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole in 100 ml toluene was distilled 2.0 g (0.011 mole) of hexafluorothioacetone, prepared by pyrolysis of the dimer according to the method of W. J. Middleton et al., J. Org. Chem., 30, 1375 (1965). The mixture was stirred at room temperature approximately one-half hour, then was concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with hexane/toluene (80/20). The chromatographed product was recrystallized from hexane to give 1.0 g of product, m.p. 114°-115°.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:12]([C:17]([CH:19]=[CH2:20])=[CH2:18])[CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:12]([C:17]1[CH2:19][CH2:20][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:3][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CC(=C)CCCCC
Reactant: C=CC(=O)OCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCC1=CCC(C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Ethyl acrylate (1.92 ml) is added to toluene (15 ml) and aluminum chloride (215 mg). The resulting solution is cooled to 0° C., after which 2-pentyl-1,3-butadiene (2.0 g) is added dropwise over a period of 30 minutes. The reaction mixture is then stirred for 5 hr at 0° C., and stored in a 4° C. refrigerator overnight. The resulting mixture is placed in an extraction funnel, and washed with two 200 ml aliquots of 1% HCl. The reaction mixture is further washed with 100 ml water, then with 100 ml saturated sodium chloride, and dried over a combination of sodium sulfate and potassium carbonate. The mixture is filtered through celite, and the solvent removed in vacuo. The resulting liquid is distilled at 107°-109° C. at 1 mm Hg to produce ethyl 4-pentyl-3-cyclohexen-1-carboxylate.
Reaction SMILES: [S:1]([O:6][CH3:7])([O:4]C)(=[O:3])=[O:2].C[C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH3:14][O:15][CH2:16][CH2:17]O>>[CH3:14][O:15][CH2:16][CH2:7][O:6][S:1]([O-:4])(=[O:2])=[O:3].[CH3:11][N+:10]1[CH:17]=[CH:16][N:13]([CH3:12])[CH:9]=1
Reactant: COCCO
Reactant: COS(=O)(=O)OC
Reactant: Cc1ncc[nH]1
Product: COCCOS(=O)(=O)[O-]
Product: Cn1cc[n+](C)c1
Temperature: 130 °C

Procedure:
In a 100 ml Schlenk flask, 32.16 g (0.255 moles) of dimethyl sulfate was slowly added dropwise to 20.94 g (0.255 moles) of methylimidazole with ice cooling and under a blanket gas. Stirring of the mixture was continued at room temperature over night. After the addition of 30.82 g (0.510 moles; 2 equ.) of 2-methoxyethanol, the mixture was heated at reflux at 130° C. for 48 hours. The volatile fractions were removed under high vacuum at 80° C. The product, 1,3-dimethyl-imidazolium 2-methoxyethyl sulfate, was obtained as a low-viscous, slightly yellow liquid in quantitative yield.
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[CH:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH2:9].CC(O)=[O:17]>>[C:8]([NH:10][CH:11]([CH:1]=[CH2:2])[C:12]([OH:14])=[O:13])(=[O:17])[CH3:9]
Reactant: C=CNCC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Product: C=CC(NC(C)=O)C(=O)O
Reaction time: 0.5 h
Yield: 55 %

Procedure:
Acetic anhydride (2.50 g, 24.50 mmol) was added slowly into a cooled (-10° C.) solution of vinyl glycine (2.20 g, 21.78 mmol) in AcOH (100 mL). The mixture was stirred at this temperature (30 min) and then at room temperature (3 h). The solution was concentrated repeatedly from H2O. The residue was dissolved in absolute EtOH (200 mL) and then decolorized (norit, 60° C.), and filtered. The filtrate was concentrated in vacuo, and the residue was triturated with Et2O to give 1.70 g (55%) of the desired product as a low melting yellow solid: 1H NMR (DMSO-d6) δ 1.87 (s, C(O)CH3), 4.75 (dd, J=6.2, 7.5 Hz, α-CH), 5.13-5.27 (m, CH=CH2), 5.84-5.96 (m, CH=CH2), 8.24 (d, J=7.5 Hz, NH).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[C:16]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[C:16]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCOc1ccc(C(=O)n2c(C)cc3c(C=CC(=O)O)cccc32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCOc1ccc(C(=O)n2c(C)cc3c(CCC(=O)O)cccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To a solution of 3-(1-(4-butoxybenzoyl)-2-methylindol-4-yl)acrylic acid (300 mg; prepared in Example 4) in methanol-ethyl acetate (5 ml+5 ml) was added palladium on activated carbon (100 mg) at room temperature. The inside of the vessel was replaced with hydrogen and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through Celite (trademark). The filtrate and washing with chloroform were combined, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform-methanol) to give the title compound (25 mg) having the following physical data.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1O.[C:11](=[O:14])([O-])[O-].[K+].[K+]>CN(C)C=O>[I:8][CH:6]1[CH2:5][CH:4]([I:9])[CH2:3][CH:7]1[CH2:2][O:14][C:11]1[C:6]([I:8])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1c(I)cc(I)cc1I
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ccccc1OCC1CC(I)CC1I
Temperature: 100 °C
Yield: 108.3 %

Procedure:
A stirred mixture of 36.2 g (0.08 mol) of 2,4,6-triiodophenol, 12.5 g (0.08 mol) of bromomethyleyelopentane [Noller and Adams, J. Org. Chem., 48, 1080-9 (1926)] and 10.6 g (0.08 mol) of milled anhydrous potassium carbonate in 100 ml dry dimethylformamide was heated at 100° C. under argon for 3.5 hrs. The mixture was cooled and concentrated in vacuo. The resulting residue was combined with 100 ml of ice-cold water and the oily product was extracted with ethyl acetate (3×100 ml). The combined ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to a dark oil. The oil was purified by chromatography (neutral alumina eluted by hexanes) to yield 24.0 g (57%) of the desired product as an oil. Bp: 220°-5° C./1 atm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH2:17])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Yield: 87.5 %

Procedure:
A solution of 1-tert-butyloxycarbonyl-4-[(2-phenyl)allyl]4-hydroxypiperidine (1.67 g, 5.26 mmol) in ethyl acetate (25 ml) was hydrogenated over 1% palladium on activated carbon (0.8 g) at room temperature and 1 atm pressure of hydrogen for 1.5 hours. The mixture was filtered and the filtrate was concentrated to yield the title compound (1.47 g, 87%) as a pale yellow glass. δH (250 MHz, CDCl3) 1.27 (3 H, d, J=7), 1.36-1.60 (13 H, m), 1.73 (1 H, dd, J=15 and 4), 2.01 (1 H, dd, J=15 and 10), 2.98-3.06 (3 H, m), 3.60-3.88 (2 H, m) and 7.16-7.36 (5 H, m); m/z (ES) 320 (M+ +1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[NH:25])[C:10]([C:23]#[N:24])=[C:11]([SH:22])[NH:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.BrBr.O>C(#N)C>[C:16]1([O:15][C:13](=[O:14])[NH:12][C:11]2[S:22][N:25]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[C:23]#[N:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CC(C(=N)OCc1ccccc1)=C(S)NC(=O)Oc1ccccc1
Agent: BrBr
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1c(OCc2ccccc2)nsc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. suspension of the adduct, 2-cyano-3-mercapto-3-phenoxycarbonylaminoacrylimidic acid benzyl ester (282 g, 798 mmol) in acetonitrile (2 L) was added pyridine (129 mL, 1.60 mol). Next was added a solution of bromine (41.1 mL, 798 mmol) in acetonitrile (200 mL) over 15 minutes. The reaction was stirred at 0° C. for an additional 1 hour and then at ambient temperature for 2 hour. The mixture was placed in the refrigerator and held at SIC overnight. The solid product was filtered and washed with 0° C. ether (1 L), dried in the same funnel by drawing air through the solid for 4 hours. The solid was added to water (1 L), stirred vigorously for 1 hour, filtered and dried in the same funnel by drawing air through the solid overnight to afford a white solid (320 g pure though still containing some water) that was used, as is, in the next step. 1H NMR (400 MHz, DMSO) δ 5.35 (s, 2H), 7.25-7.45 (m, 10H), 13.20 (broad s, 1H) ppm; MS (APCI, m/z): 350 [M−H]−.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:24])[CH2:20][C:21]([OH:23])=O)[N:18]=2)[CH:11]=[CH:12][CH:13]=1.[CH3:25][NH2:26].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:24])[CH2:20][C:21]([NH:26][CH3:25])=[O:23])[N:18]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(CC(=O)O)n1nnc(-c2cccc(Cl)c2)n1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)CC(C)n1nnc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
Oxalylchloride (2 mL, 3.9 mmol) was added during 5 minutes to 3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]butanoic acid in DCM (40 mL) and DMF (5 drops) under argon. The mixture was stirred at r.t. for 3 h and then was MeNH2 (2M in THF, 3.6 mL, 7.2 mmol) added and the resulting mixture was stirred o.n. Saturated NaHCO3 (75 mL) was added and the mixture was extracted with CHCl3 (3×100 mL). The combined organic phases were dried (MgSO4) and concentrated. The crude was purified by flash column chromatography (SiO2, Heptane-EtOAc 1:2) to give 0.74 g (74%) of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C:9](O)([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8]1)=[O:6])[CH:2]=[CH2:3].S(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:15])[CH3:16])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC(O)(C#C[Si](C)(C)C)C1
Solvent: c1ccncc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: C=CCOC(=O)N1CC=C(C#C[Si](C)(C)C)C1
Yield: 43.2 %

Procedure:
To a solution of 1-allyloxycarbonyl-3-hydroxy-3-trimethylsilylethynylpyrrolidine (18.0 g) in pyridine (180 ml) was added dropwise thionyl chloride (29 ml) below 20° C. The resultant mixture was stirred for 1 hour and slowly poured into cooled water. The solution was extracted three times with n-hexane The extracts were combined, washed with 1N hydrochloric acid (4 times), saturated aqueous sodium hydrogen carbonate, water and brine successively, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel to give 1-allyloxycarbonyl-3-trimethylsilylethynyl-3-pyrroline (7.25 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][NH2:10])=O.[CH2:11]([N:18]=[C:19]=[S:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:11]([N:18]1[C:19]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][N:9]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNC(=O)c1ccccn1
Reactant: S=C=NCc1ccccc1
Reactant: BrCc1ccccc1
Product: c1ccc(CSc2nnc(-c3ccccn3)n2Cc2ccccc2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-pyridinecarboxylic acid hydrazide, benzyl isothiocyanate and benzyl bromide as the starting materials. (M+H)+−359.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=O)[NH:19][CH:20]([C:37]2[C:42]([Cl:43])=[N:41][CH:40]=[CH:39][N:38]=2)[C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:28]3)=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN(C=O)C>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][C:18]2[N:38]3[CH:39]=[CH:40][N:41]=[C:42]([Cl:43])[C:37]3=[C:20]([C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[N:28]4)=[CH:23][CH:22]=3)[N:19]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC1CCN(C(=O)OCc2ccccc2)CC1)NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)CC1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A solution of 4-({[(3-chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-methyl)-piperidine-1-carboxylic acid benzyl ester in anhydrous acetonitrile (165 mL) was charged with POCl3 (2.03 mL, 21.84 mmol) and DMF (2.15 mL) and heated to 55° C. under N2 condition. After 2 h, LC/MS and TLC analysis showed the reaction to be completed. The reaction mixture was concentrated in vacuo, diluted with CH2Cl2, and quenched with 2N (7N NH3) in 2-propanol to pH 9. 2-Propanol was removed in vacuo. The crude product was purified by silica gel flash chromatography (loaded with 40% EtOAc/Hexanes, and run 50% EtOAc/Hexanes→80% EtOAc/Hexanes), which afforded the desired product; NMR (400 MHz, DMSO-d) δ ppm 8.53 (1H, d, J=8.52), 8.45 (1H, d, J=5.00), 8.31 (3H, m), 8.21 (1H, d, J=8.66), 8.08 (1H, d, J=8.47), 7.56 (3H, m), 7.49 (1 H, d, J=5.00), 7.34 (5H, m), 5.07 (2H, s), 4.02 (2H, d, J=12.8), 3.32 (2H, s), 3.11 (2H, d, J=6.92), 2.82 (1H, m), 2.13 (1H, m), 1.73 (2H, d, J=12.26), 1.21 (2H, m); MS (ES+): m/z 589.97 (5) [MH+]; HPLC: tR=3.72 min (OpenLynx, polar—5 min).