Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.O1CCCC1.CN(C)C=O>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: Cc1ccc2oc(C(Cl)C3CCCCC3)c(C)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc2oc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 67.3 %

Procedure:
A mixture of 2-[chloro(cyclohexyl)methyl]-3,5-dimethyl-1-benzofuran (400 mg) synthesized above, ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (343 mg) synthesized in Example 1(2), sodium iodide (327 mg), sodium carbonate (231 mg) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (45% ethyl acetate/hexane) to give a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) 1N aqueous sodium hydroxide solution (2.00 mL) were added, and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (436 mg, 67%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:24][CH2:25][CH2:26][NH:27][C:28]2[C:29](=[O:45])[N:30]([C:41]([CH3:44])([CH3:43])[CH3:42])[S:31](=[O:40])(=[O:39])[C:32]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=O)=O)=CC=1>>[C:41]([N:30]1[C:29](=[O:45])[C:28]([NH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)=[C:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[S:31]1(=[O:39])=[O:40])([CH3:42])([CH3:43])[CH3:44]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: COC(=O)Cc1ccc(O)cc1
Product: COC(=O)Cc1ccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Yield: 75 %

Procedure:
The title compound was prepared as described for Example 12 from methyl (4-hydroxyphenyl)acetate and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 30 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 25% EtOAc in hexane as eluent to give the title compound (0.079 g, 75%). 1H NMR (500 MHz CDCl3): δ 7.52-7.44 (m, 2H), 7.14-7.38 (m, 3H), 7.17 (d, 2H), 6.78 (d, 2H), 5.72 (t, 1H), 3.85 (t, 2H), 3.68 (s, 3H), 3.56 (s, 2H), 3.10-3.00 (m, 2H), 1.84-1.78 (m, 2H), 1.72 (s, 9H); 13C NMR (125 MHz CDCl3): δ 172.5, 159.8, 157.7, 135.3, 131.8, 130.7, 130.5, 129.7, 128.8, 126.8, 125.3, 115.7, 114.7, 107.2, 66.1, 61.7, 52.2, 42.4, 40.5, 28.9, 27.8; Mass Spectrum: M+H+ 487.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[CH2:30][C@@:28]2([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]2[OH:31])[C@@:23]2([CH:32]=[CH2:33])[C@H:14]1[C:15]1[CH:16]=[CH:17][C:18]([OH:34])=[CH:19][C:20]=1[CH2:21][CH2:22]2>>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]3[OH:31])[C@@:23]3([CH:32]=[CH2:33])[C@H:14]2[C:15]2[CH:16]=[CH:17][C:18]([OH:34])=[CH:19][C:20]=2[CH2:21][CH2:22]3)[CH2:2][CH2:3]1
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCBr)C[C@@]1(C)[C@H]2CC[C@@H]1O
Reactant: C1COCCN1
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCN1CCOCC1)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with morpholine (10 equivalents) analogously to instructions 17.2, 30 mg of bromide 30a yields 10 mg of amine 35a as a colorless foam (GC-MS: m/z theor.: 453, pract.: 453).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:23][CH:22]=3)[CH2:16][CH2:15]2)=[O:11])[CH:3]=1.[NH2:32][CH2:33][CH2:34][OH:35]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([NH:32][CH2:33][CH2:34][OH:35])[N:5]=[C:4]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:23][CH:22]=3)[CH2:16][CH2:15]2)=[O:11])[CH:3]=1
Reactant: Nc1cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)nc(Cl)c1Cl
Reactant: NCCO
Solvent: CC(=O)N(C)C
Product: Nc1cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)nc(NCCO)c1Cl
Temperature: 160 °C
Yield: 56.3 %

Procedure:
The compound prepared in Example 407 (0.065 g) and 2-aminoethanol (0.008 g) were suspended in dimethyl acetamide (3 mL) and heated at 160° C. for 30 minutes. The reaction mixture was heated at 200° C. for 1 hour. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were washed with brine, dried, magnesium sulfate and concentrated under reduced pressure to afford the crude material. The crude material was purified by flash column chromatography (eluant: 1-4% (9:1=methanol:ammonium hydroxide)/ethyl acetate) to furnish the title compound (0.037 g), possessing the following physical data.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][O:16][C:17](=[O:19])[CH3:18]>CN(C)C=O>[C:1]1([S:7]([CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][O:16][C:17](=[O:19])[CH3:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OCC=C(C)CCl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC=C(C)CS(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 24.2 g. of sodium benzenesulfinate in 150 ml. of dimethylformamide (DMF) was added 19.9 g. of 1-chloro-2-methyl-4-acetoxybut-2-ene in 50 ml. of DMF. The mixture was then heated to 60°C. for 4.5 hours. A second portion, 19.0 g. of sodium benzenesulfinate was added and the heating continued for 1.5 hours. The reaction mixture was poured into 1.5 l. of water and filtered to remove the solid which was dissolved in 500 ml. of ethyl acetate. This solution was washed with three 300 ml. portions of water and dried over magnesium sulfate. Evaporation of the solvent afforded 25.2 g. of crude sulfone acetate, m.p. 86°-92°C. Ethyl acetate extraction, washing and drying of the aqueous filtrate afforded an additional 6.07 g. of less pure product. Recrystallization of the main portion from ethyl acetate gave analytically pure 1-phenylsulfonyl-2-methyl-4-acetoxy-but-2-ene, m.p. 93°-94°C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]([CH2:9][C:10](OCC)=[O:11])[O:7][CH2:8][C:4]=2[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]([CH2:9][CH2:10][OH:11])[O:7][CH2:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1OCc2cc(Cl)ccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCC1OCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl (5-chloro-1,3-dihydro-2-benzofuran-1-yl)-acetate (2.79 g, 11.6 mmol) in THF (60 mL) was cooled to −78° C. and di-isobutylaluminium hydride (1M in toluene) (12.7 mL, 12.7 mmol) was added dropwise. After 1 h, the reaction mixture was quenched with a saturated solution of sodium tartrate (150 mL), allowed to warm to room temperature and stirred for 1 h. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and evaporated in vacuo. The resultant crude intermediate was dissolved in methanol (50 mL), cooled to 0° C., and sodium borohydride (0.48 g, 12.7 mmol) added in portions. The reaction was quenched with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by column chromatography, eluting with ethyl acetate/hexane (1:2), to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([C:24]([CH3:32])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[NH:47][C:48](N1C=CN=C1)=[O:49]>CN(C=O)C>[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[NH:47][C:48]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH2:17][C:18]2[C:23]([C:24]([CH3:32])([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:16][CH2:15]1)=[O:49]
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccccc2)C2CCNCC2)c(C)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccccc2)C2CCN(C(=O)Nc3ncc[nH]3)CC2)c(C)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a warm (70° C.), stirred, solution of (3,5-Dimethyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-piperidin-4-yl-amine (0.211 g, 0.49 mmol) and DIPEA (0.51 mL, 2.92 mmol) in DMF (5 mL) was added imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equivs). After 2 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL) and washed with water (5×10 mL). The organic phase was dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 213 mg (76%) of COMPOUND 276 as a white solid. 1H NMR (CDCl3) δ 1.13-1.27 (m, 2H), 1.54-1.62 (m, 8H), 2.26 (s, 6H), 2.47-2.595 (m, 3H), 3.37 (s, 2H), 3.62 (s, 2H), 4.03-4.07 (m, 2H), 6.69 (s, 2H), 6.99-7.10 (m, 3H), 7.14-7.20 (m, 4H), 7.84 (d, 1H, J=7.2 Hz), 8.08 (s, 1H), 8.50 (d, 1H, J=3.6 Hz); 13C NMR (CDCl3) δ 17.31, 17.84, 27.16, 30.28, 41.87, 43.64, 53.13, 54.60, 57.03, 120.55, 125.05, 125.26, 127.82, 130.57, 132.31, 133.09, 138.09, 142.53, 144.49, 145.58, 145.90, 148.90, 154.11, 154.58, 157.80; ES-MS m/z 538 (M+1). Anal. Calcd. For C32H39N700.4H2O.0.3CH2Cl2: C, 68.02; H, 7.14; N, 17.19. Found: C, 67.67; H, 7.01; N, 17.32.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.I[C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[CH:25][N:26]2[CH3:29])=[CH:22][CH:21]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CC(C)([O-])C.[Na+].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>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][N:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:28]=2)[CH:24]=[CH:25]1
Reactant: Cn1ccc2ccc(I)cc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Product: Cn1ccc2ccc(N3CCOCC3)cc21
Reaction time: 5 h
Yield: 93.4 %

Procedure:
An oven dried flask was flushed with argon and charged with 18-crown-6 (15 g, 56.7 mmol), 6-iodo-1-methyl-1H-indole (10.4 g, 40.46 mmol), morpholine (4.3 mL, 48.6 mmol), sodium t-butoxide (5.42 g, 54.7 mmol), tris(dibenzylidene acetone)dipalladium (0) (186 mg, 0.20 mmol) and 2,2′-bis(diphenylphosphino)-1,1-binaphthyl) (380 mg, 0.61 mmol). The flask was flushed with argon for 10 min and dry THF (80 mL) was added. The mixture was stilled at room temperature for 5 h, then diluted with ether and washed with brine. The organic layer was dried (MgSO4), evaporated and the crude product was purified by chromatography on silica gel using 5-30% ether/hexanes to give 1-methyl-6-morpholin-4-yl-1H-indole (8.17 g, 94%). [Ref: Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 6066.]
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14]O)=[NH:4].N[N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22].[ClH:23]>C(O)(C)C>[ClH:23].[ClH:23].[OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22])=[NH:4]
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Reactant: Nc1nccn1N
Agent: Cl
Solvent: CC(C)O
Product: N=C(NO)c1cccc2c1CCC2=Nn1ccnc1N

Procedure:
A mixture of 0.837 g (4.079 mmol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.40 g (4.077 mmol) of 1,2-diamino-imidazole, 23 ml of isopropanol and 1.33 ml of concentrated hydrochloric acid is heated under reflux for 22 hours. Filtration of the hot reaction mixture, washing of the crystallizate with isopropanol and diethyl ether and drying under a high vacuum yield the title compound, m.p. 258°-260° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.29 (d, 1H); 7.80 (d, 1H); 7.65 (t, 1H); 7.55 (d, 1H); 7.13 (d, 1H); 3.22-3.32 (m 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(N(CCCC)CCCC)CCC.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27]>CN(C=O)C.[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1/[CH:27]=[CH:26]/[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:11])[CH3:10]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(Cl)cc1Br
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Cl)cc1/C=C/C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
To a degassed solution of 1-(2-bromo-4-chlorophenyl)ethanone (1.0 g, 4.28 mmol), tributylamine (2.041 mL, 8.57 mmol), and tert-butyl acrylate (1.255 mL, 8.57 mmol) in DMF (10 mL) was added palladium on carbon (0.456 g, 0.428 mmol) and palladium (II) acetate (0.096 g, 0.428 mmol). The reaction mixture was warmed to 100° C. After 16 h, the reaction was cooled to rt and filtered. The solid was rinsed with DMF and the filtrate was diluted with EtOAc and washed with H2O (2×) followed by brine. The crude product was then dried over Na2SO4, filtered and concentrated. Purification by normal phase chromatography afforded Intermediate 4A (0.760 g, 63%), as a brown oil. MS (ESI) m/z: 225.0 (M-C4H8+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:12](=[O:30])[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH:31]([Sn](CCCC)(CCCC)CCCC)=[CH2:32].[Cl-].[Li+]>O1CCOCC1>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([S:7]([C:5]3[S:6][C:2]([CH:31]=[CH2:32])=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH2:11][C:12]2=[O:30])[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(Br)s3)CC2=O)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)C(=O)C2)s1
Yield: 116.3 %

Procedure:
A mixture of 4-(5-bromo-2-thiophenesulfonyl)-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (200 mg), vinyltributyltin (365 mg), lithium chloride (50 mg), tetrakistriphenylphosphine palladium (50 mg) and dioxane (15 ml) was refluxedfor2hours. The reaction solutionwas concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give colorless solid of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(5-vinyl-2-thiophenesulfonyl)-2-piperazinone (209 mg).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:49](O)=[O:50])=[C:46]([CH3:48])[N:47]=3)[C:39]2=[O:52])=[CH:28]1.[N:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][NH2:60])[CH:54]=1>>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:49]([NH:60][CH2:59][C:55]4[CH:54]=[N:53][CH:58]=[CH:57][CH:56]=4)=[O:50])=[C:46]([CH3:48])[N:47]=3)[C:39]2=[O:52])=[CH:28]1
Reactant: Cc1nc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)sc1C(=O)NCc1cccnc1
Yield: 36 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(2-(1H-indol-3-yl)ethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 36% yield: mp 198-201° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.60-8.52 (m, 2H), 8.27 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.31-7.06 (m, 5H), 6.26-6.23 (m, 1H), 4.56 (d, J=5.4 Hz, 2H), 3.99 (t, J=7.8 Hz, 2H), 3.67 (t, J=6.8 Hz, 2H), 3.48 (t, J=7.8 Hz, 2H), 3.05 (t, J=6.9 Hz, 2H), 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.7, 155.4, 153.7, 149.0, 148.9, 148.6, 136.3, 135.9, 127.2, 122.2, 121.9, 119.5, 118.4, 116.6, 112.3, 111.3, 44.2, 42.5, 42.1, 41.3, 23.5, 17.3; MS (ES+) m/z 341.2 (M+1); MS (ES+) m/z 461.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][CH3:11])[C:6]=2[C:12]=1[N+:13]([O-])=O>[Pt]=O>[NH2:13][C:12]1[C:6]2[N:7]([CH2:10][CH3:11])[CH:8]=[N:9][C:5]=2[CH:4]=[C:3]([C:16]([F:18])([F:19])[F:17])[C:2]=1[Cl:1]
Reactant: CCn1cnc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c21
Agent: O=[Pt]
Product: CCn1cnc2cc(C(F)(F)F)c(Cl)c(N)c21

Procedure:
6-Chloro-1-ethyl-7-nitro-5-trifluoromethylbenzimidazole (3.54g.; 0.012 mole; m.p. 126.5°-128°C.) was hydrogenated in the presence of platinum oxide catalyst in accordance with the procedure of Example IV. The product was obtained as a white crystalline solid (1.54g.; 48.9%) which, after recrystallization from a CCl4 --CHCl3 mixture, melts at 191.5°-193°C.
Reaction SMILES: C[CH:2]([N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[CH:4]=1.[C:23](OCC)(=O)C>>[NH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[CH3:23])[CH2:2][N:12]1[C:13](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21]
Reactant: CC(c1cccc([N+](=O)[O-])c1)N1C(=O)c2ccccc2C1=O
Reactant: CCOC(C)=O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1N
Reaction time: 12 h

Procedure:
2-(Methyl-3-nitro-benzyl)-isoindole-1,3-dione (0.45 g, 1.52 mmol) was taken up in ethyl acetate in a Paar vessel and flushed with argon. Palladium on carbon (100 mg) was added and the argon atmosphere was replaced with hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen was then replaced with argon and the catalyst was removed by filtration through celite. The solvent was removed under reduced pressure to yield 0.40 g of the desired amine. C16H14N2O2 MS m/e=267.3 (M+H).
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[C:12]([C:15]1[CH:27]=[CH:26][C:18]2[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:17]=2[CH:16]=1)(=[O:14])[CH3:13].[N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=1.C(=O)=O.Cl>CO>[NH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]1[CH2:13][C:12]([C:15]1[CH:27]=[CH:26][C:18]2[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:17]=2[CH:16]=1)=[O:14]
Reactant: C1=NCCCC1
Reactant: CC(=O)c1ccc2oc3ccccc3c2c1
Agent: COC(=O)[O-]
Agent: Cl
Agent: O=C=O
Solvent: CO
Product: O=C(CC1CCCCN1)c1ccc2oc3ccccc3c2c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
Magnesium methyl carbonate (0.6 mole, 2.5 N in dimethylformamide) is heated to 120°C. under an atmosphere of carbon dioxide. The compound 2-acetyldibenzofuran, 31.5 g (0.15 mole) is added and the mixture is stirred at 120°C. for a period of 4 hours under a stream of nitrogen to form the chelate, allowing the methyl alcohol that forms to escape. The mixture is cooled to room temperature under an atmosphere of carbon dioxide and 15.2 g (0.18 mole) of 2,3,4,5-tetrahydropyridine (as α-tripiperidine) is added and the mixture stirred at room temperature for a period of 40 hours in an atmosphere of carbon dioxide. The resulting mixture is poured into 200 ml of concentrated HCl on 600 g of ice. After standing for 48 hours the precipitate which forms is filtered and washed with ethyl ether. The 2-dibenzofuranyl-2-piperidylmethyl ketone so prepared is twice recrystallized from isopropyl alcohol as the hydrochloride salt and is obtained in 32% yield (16.0 g) and has a M.P. of 218-20°C. (dec.)
Reaction SMILES: [C:1]([C:4](=[N:9][O:10][CH2:11][CH3:12])[C:5]([O:7][CH3:8])=[O:6])(=O)[NH2:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OC(C)C)(C)C.Cl>N1C=CC=CC=1.O>[C:1]([C:4](=[N:9][O:10][CH2:11][CH3:12])[C:5]([O:7][CH3:8])=[O:6])#[N:2]
Reactant: CCON=C(C(N)=O)C(=O)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCON=C(C#N)C(=O)OC
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of methyl 2-carbamoyl-2-ethoxyiminoacetate (syn isomer) (5.22 g) in pyridine (50 ml) was dropwise added trifluoroacetic anhydride (15.7 g) below 25° C. under cooling in an ice-bath and stirring, which was continued for 30 minutes. The reaction mixture was poured into water (200 ml), followed by an addition of diisopropyl ether (200 ml). The mixture was adjusted to pH 2 with 6 N hydrochloric acid (80 ml) at 15° to 20° C. and the organic layer was separated out, washed with water, dried over magnesium sulfate and evaporated to give methyl 2-cyano-2-ethoxyiminoacetate (syn isomer) (4.23 g) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+]>CO>[C:11]([CH2:10][C:7]1[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)([OH:13])=[O:12]
Reactant: COC(=O)Cc1ccc(C(=O)OC)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-methoxycarbonylmethyl-furan-2-carboxylic acid methyl ester (250 mg, 1.26 mmol) in methanol (5 mL) is added 1N NaOH (2.78 mL, 2.78 mmol) and the mixture is stirred at room temperature for 18 hrs. The solvent is removed under reduced pressure and 2.78 mL of 1N HCl is added to the residue. The resulting solution is lyophilized to give the product which is used as is in subsequent reactions.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[C:8]([C:11]#[N:12])[C:7]([F:13])=[C:6]([F:14])[C:3]=1[C:4]#[N:5].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>CC(C)=O.O>[C:4]([C:3]1[C:6]([F:14])=[C:7]([F:13])[C:8]([C:11]#[N:12])=[C:9]([F:10])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1)#[N:5]
Reactant: N#Cc1c(F)c(F)c(C#N)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)c(C#N)c(F)c(F)c2C#N)CC1
Temperature: 55 °C
Yield: 51.2 %

Procedure:
2,3,5,6-tetrafluoroterephthalonitrile (1 g, 5 mmol) was dissolved in acetone (15 mL) in a 2-necked flask under Nitrogen. A solution of tert-butyl piperazine-1-carboxylate (1.39 g, 7.5 mmol) in water (3 mL) was then added followed by triethylamine (1.01 g, 10 mmol). The solution was heated to 55° C. for 8 h then cooled to rt. The resulting solid was filtered then washed with acetone. The filtrate was concentrated under vacuum and the residue was dissolved again in DCM (30 mL) and washed once with 1M HCl (30 mL) and once with brine (30 mL). The organics were dried over Na2SO4, filtered and the solvent removed in vacuo to give tert-butyl 4-(2,5-dicyano-3,4,6-trifluorophenyl)piperazine-1-carboxylate as a bright yellow solid (0.938 g, 51% yield).