Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:14]([C:27]([NH:29][CH2:30][CH2:31][N:32]([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[O:28])[CH2:13][CH2:12]2)C1C=CC=CC=1.CCCCC>CO.[Pd]>[CH:36]([N:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][NH:29][C:27]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([OH:8])[CH:10]=2)[CH:15]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])([CH3:37])[CH3:38]
Reactant: COc1cc2c(cc1OCc1ccccc1)CCN(C(=O)NCCN(C(C)C)C(C)C)C2c1ccccc1
Agent: [Pd]
Solvent: CCCCC
Solvent: CO
Product: COc1cc2c(cc1O)CCN(C(=O)NCCN(C(C)C)C(C)C)C2c1ccccc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
2.0 Parts of 6-benzyloxy-N-(2-diisopropylamino-ethyl)-7-methoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide is dissolved in approximately 80 parts of methanol. 0.2 Part of a 5% palladium-on-carbon catalyst is added and the mixture is shaken at room temperature and a pressure of about 2 psi for approximately 23 hours or until one molecular equivalent of hydrogen has been absorbed. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to give an oil which solidified upon trituration with n-pentane. That solid is crystallized from a mixture of methylene chloride and n-hexane to afford N-(2-diisopropylaminoethyl)-6-hydroxy-7-methoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide, melting at about 91°-92°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[H-].[Na+].[CH3:32][O:33][CH2:34]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:32][O:33][CH3:34])[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CCCOc2cccc3ccccc23)c2cccc(Br)c2n1COC
Reaction time: 0.5 h

Procedure:
To an ice bath cooled mixture of EXAMPLE 1C (2.0 g) in THF (20 mL) was added 60% oily NaH (265 mg). The mixture was stirred for 30 minutes before adding chloromethyl methyl ether (0.54 mL). The mixture was stirred for 3 hours and overnight at room temperature, quenched by adding saturated NH4Cl mixture and extracted with diethylether. The extract was washed with water and brine and dried (Na2SO4), filtered and concentrated. The concentrate was purified with flash column chromotography on silica gel with 5% ethyl acetate/hexanes.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH2:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:17]=[C:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1>C1COCC1.C(Cl)Cl>[OH:17][C@:18]1([C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH2:16])[CH:10]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1
Reactant: C=Cc1cccc(-c2cccc(Br)c2)c1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1cccc(-c2cccc([C@]3(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C3)c2)c1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
Magnesium (0.513 g, 21.11 mmol) was stirred in a round bottom flask under nitrogen for 30 min. to cause scratching of the surface of the magnesium turnings. 10 mL of THF was added to the magnesium turnings and stirred for an additional 30 min. 3-bromo-3′-vinylbiphenyl (5.21 g, 20.10 mmol) in THF (100 mL), was added in dropwise at reflux with vigorous stirring. The Grignard solution was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (5.78 g, 20.11 mmol) in DCM (110 mL) at 0° C. and stirred for 1 hr and then quenched with saturated NH4Cl solution. The aqueous layer was extracted with DCM and the combined organics were dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (5-40% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-1,2-dicarboxylate (2.9 g, 6.20 mmol, 31% yield) as a yellow foam. 1H NMR (500 MHz, CHLOROFORM-d) δ 0.05 (d, J=2.44 Hz, 9H) 0.99 (dd, J=9.77, 7.32 Hz, 1H) 1.04 (dd, J=9.61, 7.17 Hz, 1H) 1.27 (t, J=7.17 Hz, 1H) 2.38-2.53 (m, 1H) 2.66-2.82 (m, 1H) 3.67-3.83 (m, 1H) 3.82-3.89 (m, 3H) 3.96-4.09 (m, 1H) 4.17-4.32 (m, 2H) 4.52-4.69 (m, 1H) 5.32 (d, J=10.99 Hz, 1H) 5.83 (d, J=17.40 Hz, 1H) 6.80 (dd, J=17.55, 10.83 Hz, 1H) 7.39-7.46 (m, 2H) 7.46-7.52 (m, 3H) 7.55 (ddd, J=4.58, 2.14, 1.83 Hz, 1H) 7.61 (br. s., 1H) 7.73 (s, 1H). LCMS: rt=2.32 min. [M+H]+=468; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [OH2:1].[C:2](#[N:5])[CH:3]=[CH2:4]>CC(C)=O>[N+:5]([C:2]1[CH:4]=[CH:3][C:2]([NH2:5])=[CH:4][CH:3]=1)([O-:1])=[O:1]
Reactant: O
Reactant: C=CC#N
Solvent: CC(C)=O
Product: Nc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 120 parts of acrylonitrile and 1000 parts of acetone is introduced into the solution of the diazo derivative obtained from 276 parts of p-nitroaniline. Then, 40 parts of cupric chloride crystallised with 2 molecules of water are added and the mixture is stirred vigorously. The evolution of nitrogen is exothermic and the temperature should be kept at 30°-32° C. by means of a cooling bath. When the diazonium chloride has disappeared (6 hours), yellow leaflets melting at 108° C. are filtered off. After recrystallisation from methanol, one obtains 330 parts of 2-chloro-3-(4-nitrophenyl) propionitrile which melts at 112° C. This product is then dehydrohalogenated by means of 200 parts of crystallised sodium acetate in a mixture of 340 parts of water and 800 parts of ethyl alcohol. The mixture is refluxed for 12 hours and 225 parts of 4-nitrocinnamonitrile are isolated in the cold. Melting point: 202° C. The 4-nitrocinnamonitrile thus obained is then reduced by the Bechamp method in 2000 parts of water and 800 parts of ethyl alcohol. The 4-aminocinnamonitrile is obtained which melts at 109°-110° C. Yield: 76%.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][CH:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[C:10]1([C@H:9]([NH:16][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CBr
Reactant: CC(N)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
Ethyl bromoacetate (4.14 g; 24.8 mmol) was treated with (R) α-methylbenzylamine (3 g, 24.8 mmol) and ethyldiisopropylamine (3.2 g; 24.8 mmol) in toluene (100 mL). After heating at reflux for 18 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 20% ethyl acetate/pentane) to provide the title compound (3.2 g, 63% yield). MS (DCI/NH3) m/z 208 (M+H)+.
Reaction SMILES: Cl.[C:2](Cl)(=[O:4])[CH3:3].Cl.[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC.C([O-])(=O)C.[Na+]>C(O)(C(F)(F)F)=O.C(OC(=O)C)(=O)C.C(O)CCCCCCC>[CH3:3][CH:2]([OH:4])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCO
Reactant: CC(=O)Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCC(C)O

Procedure:
Assignment of the absolute configuration of the TSL-1 and ES 3,6-dideoxyhexose was achieved by GC/MS analysis of the acetylated glycosides formed from chiral 2-octanol. 3M HCl in both (-)-2 and (+)-2 octanol (available from Sigma) were prepared by the dropwise addition of about 256 μl acetyl chloride (available from Mallinkrodt, Inc., Paris, Ken.) to about 1.2 ml octanol. Derivatizations of TSL-1 and ES antigens were achieved by: (a) hydrolysis in 2M TFA at about 121° C. for about 1 hour (hr); (b) octanolysis in either (-)-2 or (+)-2 3M octanol HCl at about 80° C. for about 3 hr; (c) addition of sodium acetate; and (d) acetylation in acetic anhydride at about 100° C. for about 1 hr. The acetylated octyl glycosides were partitioned into the organic phase between about 1 ml chloroform and about 1 ml water, dried, and extracted into acetone (see, for example, Leontein et al., pp. 359-362, 1978, Carbohyd. Res., Vol. 62). Samples were analyzed by GC/MS as above for alditol acetates (total ion chromatogram) or in the selected ion monitoring mode (selecting m/z's of about 83, 85, 112, 145, and 215). Methyl tyvelose (3,6-dideoxy-D-arabinohexose) and Ascaris suum eggs (containing 3,6-dideoxy-L-arabinohexose) were also subjected to hydrolysis, (-)-2 and (+)-2 octanolysis, and acetylation. GC/MS data from the resulting acetylated 3,6-dideoxyarabinohexose octyl glycoside derivatives were compared to those obtained from the TSL-1 and ES antigen samples. Verification of absolute configuration was achieved by co-injection.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[CH2:14]([N:21]1[C:29]2[C:24](=[N:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:31][OH:32])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([N:21]1[C:29]2[C:24](=[N:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:31][O:32][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCc1cc2nc(Cl)ccc2n1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc2nc(Cl)ccc2n1Cc1ccccc1
Reaction time: 4 h
Yield: 92 %

Procedure:
tert-Butyldimethylsilyl chloride (0.12 g, 0.81 mmol) and 1H-imidazole (60. mg, 0.88 mmol) were added to a solution of (1-benzyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (0.20 g, 0.73 mmol, from Step 2) in DCM (10 mL) After stirring for 4 hours, additional tert-butyldimethylsilyl chloride (33 mg, 0.22 mmol) and 1H-imidazole (15 mg, 0.22 mmol) were added and the reaction was continued for one hour. The mixture was filtered and the filtrate was concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-10% EtOAc in hexanes to afford a white solid (0.26 g, 92%).
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][C:6]([CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)=O)C.[NH:21]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22]1>C1(C)C=CC=CC=1>[OH:20][C:4]1[N:22]2[N:21]=[CH:25][CH:24]=[C:23]2[N:26]=[C:6]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]2)[CH:5]=1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: Nc1cc[nH]n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(O)n3nccc3n2)C1
Temperature: 110 °C
Yield: 89.9 %

Procedure:
A mixture of tert-butyl 3-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate (7.00 g, 25 mmol) and 1H-pyrazol-3-amine (2.08 g, 25 mmol) in toluene 30 mL) was heated at 110° C. under argon for 18 h and concentrated in vacuo. The residue was triturated with EtOAc and the solid was collected by filtration and dried in high vacuum to give 6.84 g (90%) of the title compound as a white solid. LC/MS RT=1.40 min (5 min method). Mass calculated for, M+H 305.15, observed 305.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[C:9](=[CH2:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[F:16].C(N(CC)CC)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([NH:31][CH2:14][CH:9]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:16])[CH:4]=1)[OH:15])[C:10]([O:12][CH3:13])=[O:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C(C(=O)OC)C(O)c1ccc(Cl)c(F)c1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[(4-chloro-3-fluorophenyl)(hydroxy)methyl]prop-2-enoate (69.1 g) and triethylamine (47.3 mL) in methanol (706 mL) was added benzylamine (37.1 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (58.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=1.[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][C:7]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)=[O:9])[CH:15]=1
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: Cc1cc(Br)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
In a 250 mL round-bottomed flask at 0° C. under nitrogen was added methyl 4-methoxybenzoate (Aldrich, 3.32 g, 20.00 mmol) and 4-bromo-2-methylpyridine (Frontier, 1.72 g, 10.00 mmol) in anhydrous tetrahydrofuran (40.0 mL) to give a yellow solution. Lithium hexamethyldisilazide (1 M in tetrahydrofuran, 20 mL, 20 mmol) was added dropwise over 15 minutes via a dropping addition funnel to produce an orange transparent solution that was stirred for 18 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to a reddish oil. Purification by flash chromatography on a silica 80 g cartridge eluting with 10-60% ethyl acetate in hexane gave the title compound (2.68 g, 88%). MS (APCI+) m/z 306/308 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16]CC)=[O:15])[C:10]([CH3:19])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[C:10]([CH3:19])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nn(-c2ccc(F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nn(-c2ccc(F)cc2)c(C)c1C(=O)O
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Then, ethyl 1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxylate (15.5 g) was dissolved in a mixed solvent of ethanol (30 ml) and water (30 ml). Sodium hydroxide (2.75 g) was added and the mixture was stirred at a refluxing temperature for 30 min. After evaporation of ethanol, dilute hydrochloric acid was added to the residue. The obtained solid was recrystallized from aqueous methanol solution to give the title compound (11.5 g), melting point: 219–220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([N:16]3[C:21](=[O:22])[NH:20][CH2:19][CH:18]=[N:17]3)=[CH:11][C:10]=2[Cl:23])[C:7]#[N:8])=[CH:4][CH:3]=1.[OH:26]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([N:16]3[C:21](=[O:22])[NH:20][C:19](=[O:26])[CH:18]=[N:17]3)=[CH:11][C:10]=2[Cl:23])[C:7]#[N:8])=[CH:24][CH:25]=1
Reactant: OO
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(N2N=CCNC2=O)cc1Cl
Solvent: CC(=O)O
Product: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 20 ml of acetic acid was dissolved 2.0 g of 2-[4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one. To the solution was added three times as much mol. of 30% hydrogen peroxide. The reaction was allowed to proceed for 3 hours at 100° C. After completion of the reaction, the reaction mixture was poured into ice-water. Resulting crystalline precipitate was collected by filtration to afford 1.8 g of the titled compound as colorless crystals, m.p. 290-292° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[C:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH:36]([CH3:38])[CH3:37])[CH2:32][CH2:31]3)[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:39](NC1N=C(C2C=CC=C(C)N=2)C=C(C2C=NC=C(Br)C=2)C=1)C1C=CC=CC=1>>[CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:39])[N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[C:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH:36]([CH3:38])[CH3:37])[CH2:32][CH2:31]3)[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCN(CC#Cc2cncc(-c3cc(NCc4ccccc4)nc(-c4ccccn4)c3)c2)CC1
Reactant: Cc1cccc(-c2cc(-c3cncc(Br)c3)cc(NCc3ccccc3)n2)n1
Product: Cc1cccc(-c2cc(-c3cncc(C#CCN4CCN(C(C)C)CC4)c3)cc(NCc3ccccc3)n2)n1

Procedure:
This compound is prepared analogously to Benzyl-{5″-[3-(4-isopropyl-piperazin-1-yl)-prop-1-ynyl]-[2,2′;4′,3″]terpyridin-6′-yl}-amine (Example 2.139) by replacing Benzyl-(5″-bromo-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 1.25) with Benzyl-(5″-bromo-6-methyl-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 2.40, step1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:39][NH2:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:40][CH2:39][CH2:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCCc1ccccn1
Product: O=C(NCCc1ccccn1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(2-pyridinyl)ethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=551.01 (M+H+); retention time=0.56 minutes.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7]C[N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[CH3:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([S:30](Cl)(=[O:32])=[O:31])=[CH:27]2)=[CH:22][CH:21]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:7][C@H:3]([NH:2][S:30]([C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[CH:27]=2)(=[O:32])=[O:31])[C:4]1=[O:17])#[N:13]
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as in EXAMPLE 24, Part B substituting 3-(3-(S)-Amino-2-oxo-azetidin-1-ylmethyl)benzonitrile hydrochloride for 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride and using 7-methoxynaphthalene-2-sulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc/CH2Cl2 to 30% EtOAc/CH2Cl2 to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[OH-].[K+].[C:7](#[N:10])[CH:8]=[CH2:9].Cl>O>[CH2:8]([C:7]#[N:10])[CH2:9][O:3][CH2:2][CH2:1][O:4][CH2:9][CH2:8][C:7]#[N:10]
Reactant: OCCO
Reactant: C=CC#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CCCOCCOCCC#N
Reaction time: 8 h

Procedure:
To a 5 liter double walled (for water cooling) glass reactor with a bottom drain and stopcock was charged 930 grams (15 moles) of ethylene glycol and 45.6 grams of 40% aqueous KOH solution. Some 1620 grams (30.6 moles) of acrylonitrile (NC--CH=CH2) were then added dropwise with stirring at such a rate that the temperature was kept below 35° C. After the addition was completed the mixture was stirred an additional hour and then allowed to stand overnight. The mixture was then neutralized to a pH of 7 by the addition of 6 molar HCl. After washing with saturated NaCl solution three times, the product was separated from the aqueous layer, dried over CaCl2 and passed through an Al2O3 column to insure that all basic materials had been removed. The yield obtained was 90% of theoretical.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([O:18]CCCC)=O)[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].[CH3:25][NH2:26]>CO>[CH3:25][NH:26][C:16]([C@@H:14]1[O:13][C:12](=[O:23])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:24])[S:4][C:5]=3[CH:10]=2)[CH2:15]1)=[O:18]
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The butyl (5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2, 300 mg, 0.856 mmol) is treated with 2N methylamine in MeOH (8.6 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (10 mL) and stirred at ambient temperature for 1 h. The resulting slurry is filtered to give the title compound, mp 264–267° C.; MS (ESI+) for C13H13N3O4S m/z 308 (M+H)+; [α]25D−44 (c 0.92, DMSO).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:37])[C@@H:15]([NH:24][C:25]([C:27]2[NH:36][C:30]3=[CH:31][N:32]=[C:33]([Cl:35])[CH:34]=[C:29]3[CH:28]=2)=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:37])[C@@H:15]([NH:24][C:25]([C:27]2[NH:36][C:30]3=[CH:31][N:32]=[C:33]([Cl:35])[CH:34]=[C:29]3[CH:28]=2)=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1
Reaction time: 48 h

Procedure:
To a suspension of {1-[2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionyl]piperidin-4-yl}carbamic acid tert-butyl ester (EXAMPLE 230, 500 mg, 0.92 mmol) in methanol (12 mL) was added a solution of 4M HCl in dioxane (0.69 mL, 2.76 mmol) and the reaction stirred for 48 h. The resulting precipitate was filtered and washed with ethyl acetate to give the title compound as the hydrochloride salt as a pale yellow powder. m/z (ES+)=444.16 [M+H]+; RT=2.65 min. The product was dissolved in saturated sodium bicarbonate solution. Solvent was removed in vacuo and the crude material dissolved in THF (30 mL). The solution was filtered through celite and solvent removed in vacuo to give the title compound as a yellow powder. m/z (ES+)=444.32 [M+H]+; RT=2.59 min.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH:18]1(I)[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:18]1([N:7]2[C:2](=[O:1])[C:3]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1c[nH]c(=O)c(-c2ccccn2)c1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccccn2)c(=O)n(C2CCCC2)c1
Yield: 21 %

Procedure:
Methyl 6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxylate (Step 2, 210 mg, 0.91 mmol), cyclopentyl iodide (196 mg, 1.0 mmol) and potassium carbonate (150 mg, 1.1 mmol) were stirred at room temperature in 2 mL of DMF for 24 h. The reaction mixture was quenched with H2O and extracted 3× with EtOAc. The combined organic extracts were washed 3× with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was taken up in CH2Cl2 and loaded on to a 5 g pre-packed silica gel column and purified. Elution with 0-30% EtOAc:hexanes gave the title compound as an off-white powder (57 mg, 21%). MS m/z: 299 (M+1).