Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Cl:7][C:8]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]=[C:30]([Cl:32])[Cl:31])[CH:24]=[C:23]([Cl:33])[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]=[C:30]([Cl:32])[Cl:31])[CH:24]=[C:23]([Cl:33])[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(F)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
84 mg of potassium tert-butylate and 236 mg of methyltriphenylphosphonium bromide are stirred in 6 ml of toluene for 3 hours at 80° C. 200 mg of 4-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-1-(4-fluoro-phenyl)-butan-1-one in 2 ml of toluene are then added and the mixture is stirred for a further 2 hours at 80° C. The reaction mixture is cooled and filtered and the filtrate is concentrated. After purification over silica gel, the title compound is obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:22][CH2:23][CH2:24][OH:25])[C:5]2[O:9][C:8]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)=[N:7][C:6]=2[CH:21]=1.C(N(CC)CC)C>C1COCC1.[Pd]>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH2:10][C:8]1[O:9][C:5]2[C:4]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:3][CH:2]=[CH:21][C:6]=2[N:7]=1
Reactant: COc1ccc(Cc2nc3cc(Cl)cc(CCCO)c3o2)cc1OC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cc2nc3cccc(CCCO)c3o2)cc1OC
Reaction time: 2.5 h
Yield: 51.9 %

Procedure:
A solution of 2.89 g (8.0 mmol) of 5-chloro-2-(3,4-dimethoxybenzyl)-7-(3-hydroxy-propyl)-benzoxazole in 50 ml of THF and 1.23 ml (8.8 mmol) of triethylamine and with 0.58 g of 10% Pd-C was hydrogenated in an autoclave at about 1100 psi. After 2.5 hour, the catalyst was filtered off and the solvents evaporated in vacuo. The residue was dissolved in dichloromethane and filtered through 6.3 g of silica gel in a column. The recovered material (2.53 g) was crystallized from di-isopropyl ether to give the title compound (1.36 g, 51.9%), mp 95-7° C. A second crop of 0.94 g (35.9%) was also obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][C:59](C)(C)C)=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[F:65]C1C=CC=CC=1C(NC(OC)=O)C(O)=O>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=6[F:65])[NH:55][C:56]([O:58][CH3:59])=[O:57])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1F
Yield: 8 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid (0.061 g, 0.269 mmol) to provide {1-[2-(5-{6-[4-(2-{1-[2-(2-Fluoro-phenyl)-2-methoxycarbonylamino-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.012 g, 8%) as a white solid. LCMS-ESI+: calc'd for C47H49FN8O6: 840.38 (M+); Found: 841.86 (M+H+).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1[N:24]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])(=[O:3])[CH3:2].C[O-].[Na+]>CO.C[O-].[Na+].CO>[C:1]([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@@H:9]([OH:15])[C@@H:8]([CH2:19][OH:20])[O:7][C@@H:6]1[N:24]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1N(C(=O)CCCCCN)C(=O)OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1N(C(=O)CCCCCN)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Compound 49 (1.4 g) was dissolved in methanol to which sodium methoxide-methanol solution was added dropwise to pH 11.0 and stirred at room temperature. The pH was adjusted to 11.0 with fresh sodium methoxide solution several times until the pH was stable (approximately 1 hr). The reaction mixture was acidified with Dowex-H type resin and the resin was removed from the solution by filtration. The solvent was removed from the filtrate under vacuum to give 2-acetamido-1-(N-CBZ-6-aminohexanamido)-1,2-dideoxy-a-D-galactopyranose, 50, as a gum (630 mg). 1H NMR (CDCl3): 1H NMR (CD3OD): 7.35-7.40, s, 5H, C6H5CH2—; 5.78-5.8,m, 1H; 5.12, s, 2H, C6H5CH2; 4.45-3.8, m, 6H; 3.65-3.6, m, 1H; 2.22,s, 3H; NHCOCH3; 1.5-1.7, m, 10H.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][N:4]=1)#[N:2].S(=O)(=O)(O)[OH:19].[Na]>>[CH2:13]([O:12][P:10]([CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:19])[CH:8]=1)([O:15][CH2:16][CH3:17])=[O:11])[CH3:14]
Reactant: CCOP(=O)(Cc1ccnc(C#N)c1)OCC
Reactant: O=S(=O)(O)O
Agent: [Na]
Product: CCOP(=O)(Cc1ccnc(C(N)=O)c1)OCC

Procedure:
A mixture of 1.10 g of 2-cyano-4-(diethylphosphonomethyl)pyridine and 4.5 ml of concentrated sulfuric acid is heated at 90° for 5 minutes. The reaction mixture is poured onto ice and neutralized with 10% sodium hdroxide. The resulting precipitate is collected to afford 4-(diethylphosphonomethyl)-2-pyridinecarboxamide melting at 140°-142°.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[CH:12][C:5]=1[NH:6][C@@H:7]([CH3:11])[C:8]([O-])=[O:9].CO.O>C(Cl)Cl>[F:3][C:4]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[CH:12][C:5]=1[NH:6][C@@H:7]([CH3:11])[CH2:8][OH:9]
Reactant: C[C@H](Nc1ccc(F)c(F)c1F)C(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in methylene chloride (0.2 ml). Then a solution (0.8 ml) of methyl. (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in metylene chloride was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 159.8 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N=[C:25]=[O:26])CCCCC.N12CCN(CC1)CC2.ClC(OC(Cl)(Cl)Cl)=O>C1(C)C(C)=CC=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:25]=[O:26])(=[O:15])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCN=C=O
Reactant: NS(=O)(=O)c1ccccc1Oc1ccccc1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1ccccc1Oc1ccccc1
Yield: 82.6 %

Procedure:
25.0 g of 2-phenoxyphenylsulfonamide, 14.0 g of n-hexyl isocyanate, a catalytic amount of 1,4-diazabicyclo[2,2,2]-octane and 150 ml xylene were refluxed with stirring for an hour. Thereafter, the mixture was reacted with a solution of 11.9 g of trichloromethyl chloroformate in 30 ml of xylene in a manner similar to that of Example (1). At the end of the reaction, the xylene and n-hexyl isocyanate were distilled off, to obtain 22.8 g of 2-phenoxyphenylsulfonylisocyanate. B.p. 146°-150° C./0.7 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)[CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1
Reactant: CN1CCNc2ccc(Br)cc2C1
Reactant: Clc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(Cl)cc2)c2ccc(Br)cc2C1
Yield: 21.2 %

Procedure:
A mixture of 7-bromo-4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (2.25 g, 9.33 mmol), 1-chloro-4-iodobenzene (3.10 g, 12.1 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-isopropyl-1,1′-biphenyl (444 mg, 0.933 mmol), and cesium carbonate (6.1 g, 18.7 mmol) in toluene (60 mL) was purged with argon for 10 minutes before palladium(II) acetate (210 mg, 0.993 mmol) was added. After purging with argon for 5 minutes, the reaction mixture was heated at reflux overnight. The mixture was cooled, partitioned with water (100 mL) and ethyl acetate (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 10:1 methylene chloride/methanol followed by rechromatography eluting with 3:1 methylene chloride/ethyl acetate to yield 7-bromo-1-(4-chlorophenyl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (694 mg, 21%) as a brown foam: 1H NMR (CDCl3, 500 MHz) δ 7.45 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.12 (d, J=6.8 Hz, 2H), 7.01 (d, J=8.4 Hz, 1H), 6.62 (d, J=6.9 Hz, 2H), 3.71-3.67 (m, 2H), 3.60 (s, 2H), 2.88-2.85 (m, 2H), 2.36 (s, 3H); ESI MS m/z 351, 353 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[NH:16]([C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1)[NH2:17]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(NN)nc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
18.0 g (84.2 mmol) of tert-butyl 6-chloropyridine-3-carboxylate are initially charged in 85 ml of ethanol. 42.2 g (842.0 mmol) of hydrazine hydrate are added, and the mixture is stirred at 100° C. for 2 h. The mixture is then concentrated, and the residue is taken up in a mixture of ethyl acetate and water. The phases are separated, and the organic phase is washed once with water and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated again. The residue is triturated with petroleum ether, and the solid formed is filtered off and dried under high vacuum.
Reaction SMILES: [CH:1]([C:3]12[CH2:10][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)=O.[C:19]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-].C([O-])(O)=O.[Na+]>CO.C(OCC)(=O)C>[C:1]([C:3]12[CH2:10][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)#[CH:19]
Reactant: CC(C)(C)OC(=O)NC12CCCC(C=O)(CC1)C2
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CC12CCCC(NC(=O)OC(C)(C)C)(CC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a solution of tert-butyl 5-formylbicyclo[3.2.1]octan-1-ylcarbamate (6.4 g, 25.3 mmol) and K2CO3 (7.1 g, 50.6 mmol) in methanol (200 mL) under N2 was added dimethyl 1-diazo-2-oxopropylphosphonate (6.0 g, 30.3 mmol). After stirring at room temperature for three hours, the reaction mixture became a clear solution. Ethyl acetate (300 mL) and 5% NaHCO3 (300 mL) were added. Aqueous layer was extracted with ethyl acetate (2×200 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give 5.8 g (90%) the crude title compound, tert-butyl 5-ethynylbicyclo[3.2.1]octan-1-ylcarbamate, as colorless oil. ESI-MS m/z: 194 (M-55)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[OH:1][C:2]1[C:11]([O:12][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(O)c1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1cccc(OC(=O)c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
A solution of methyl 2,3-dihydroxybenzoate (27 g, 160 mmol) in dichloromethane (300 mL) was cooled to 0° C. and powdered potassium carbonate (23.3 g, 169 mmol) was added. The reaction mixture was then added benzoyl chloride (19.6 mL, 169 mmol) and the mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned with ethyl acetate and 0.3M aqueous hydrochloric acid. The organic layer was washed with brine, dried over anhydrous magnesium sulfate. Filtration and concentration afforded 42.1 g (97%) of crude methyl 2-hydroxy-3-[(phenylcarbonyl)oxy]benzoate as an orange oil: 1H NMR (400 MHz, d4-MeOH): 8.17 (dd, J=1.6, 12.5 Hz, 2H), 7.80 (dd, J=1.6, 8.0 Hz, 1H), 7.71-7.67 (m, 1H), 7.57-7.53 (m, 2H), 7.41 (dd, J=1.8, 8.0 Hz, 1H), 6.97 (t, J=8.6 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>C(#N)C>[Cl:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=2)[N:24]=1
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Reactant: Clc1ncnc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reaction time: 16 h
Yield: 70.5 %

Procedure:
To a dry flask containing a magnetic stir bar and a nitrogen atmosphere was added 0.247 g (1.33 mmol) of 3-[(methylsulfonyl)methyl]aniline, 2 mL dry acetonitrile and 0.23 mL (1.3 mmol) of diisopropylethyl amine and resultant mixture cooled in an ice bath. To the cold solution was added a solution of 0.2 g (1.33 mmol) of 2,4-dichloro-1,3,5-triazine in 2.4 mL of dry acetonitrile over 1 min. The reaction mixture was stirred for ca. 16 hrs and 1 gram of silica gel was added. The mixture was concentrated in vacuo to dryness and applied to the top of column of silica gel and eluted with a 15-50% ethyl acetate/dichloromethane gradient. The proper fractions were combined and concentrated in vacuo to give 0.28 g (70%) of 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine as a white solid. HNMR: δ 10.83 (s, 1H), 8.64 (s, 1H), 7.63 (m, 2H), 7.4 (t, 1H), 7.25 (d, 1H), 4.48 (s, 2H), 2.94 (s, 3H); MS (ES+, m/z) 299, 301 (M+H).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[Cl:24])=O>>[Cl:24][C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: O=C(CBr)c1cnccc1Cl
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3cnccc3Cl)cs2)c(C)s1
Yield: 80.4 %

Procedure:
240 mg (0.970 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-1-(4-chloro(3-pyridyl))ethan-1-one (1.06 mmol; 250 mg) in a manner similar to Example 22, step (a) to afford 286 mg (77% yield) of methyl 4-[4-(4-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [BH4-].[Na+].C(N)CN.[CH3:7][O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1[CH2:23][OH:24].[H][H]>C(O)C.[Ni](Cl)Cl>[CH3:7][O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1[CH2:23][OH:24]
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1CO
Reactant: [H][H]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: NCCN
Product: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1CO
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
95% Ethanol (0.5 mL) was added to a mixture of nickel (II) chloride (105 mg, 0.81 mmol) and sodium borohydride (15 mg, 0.40 mmol). The mixture immediately turned black. After 15 min at rt, ethylene diamine (86 μL, 1.29 mmol) was added. After 15 min at rt, a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (from Example 1, step 3, 43.3 mg, 0.16 mmol) in 95% ethanol (1.0 mL) was added via cannula. A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 16.7 mg (38%) of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=2[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:11]([Cl:34])[CH:10]=1)=O)(C)(C)C.C(OC(=O)C)C.Cl>C(OCC)(=O)C>[NH2:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=2[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:11]([Cl:34])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of N-[4-(tert-butoxycarbonyl)amino-2-chlorobenzyl]-2-(cyclopentylamino)-5-nitrobenzamide (141 mg) in anhydrous ethyl acetate (2 mL) was added 4N-hydrochloric acid ethyl acetate solution. (4 mL). After stirring for 2 hours at ambient temperature, the mixture was partitioned between 1N-sodium hydroxide solution and chloroform. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give N-(4-amino-2-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide as yellow powders (102 mg).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=1)=[O:19].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:3]#[C:2][C:1]([NH2:5])=[O:4])[CH:24]=[CH:25][CH:26]=1)=[O:19]
Reactant: C#CC(N)=O
Reactant: O=C(Nc1cccc(I)c1)Nc1cc(C(F)(F)F)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C#Cc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.5 %

Procedure:
To a mixture of propynoic acid amide (41.4 mg, 0.60 mmol), 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(3-iodophenyl)urea (169.7 mg, 0.40 mmol), triethylamine (0.167 mL, 1.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (22.5 mg, 0.032 mmol), and triphenylphosphine (5.2 mg, 0.020 mmol) in 3.0 mL DMF (degassed) was added copper(I)iodide (7.6 mg, 0.04 mmol) and the reaction stirred at rt for 15 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed 3 times with H2O/brine mixture, then brine, dried with anhydrous Na2SO4 and rotary evaporated to a solid. The solid was triturated with hot MeOH and then triturated with hot EtOAc to give the title compound as a light tan solid (107.4 mg, 74%). 1H NMR (DSMO-d6) δ: 9.33 (s, 1H), 8.95 (d, J=2.1 Hz, 1H), 8.60 (dd, J=7.3, 2.1 Hz, 1H), 8.17 (br. s., 1H), 7.87 (s, 1H), 7.67 (br. s., 1H), 7.37-7.55 (m, 4H), 7.17-7.25 (m, 1H)
Reaction SMILES: C(OCC1C(N2CCN3C4CCCCC=4C=C3C2=O)=NC=CC=1C1C=C(NC2C=CC(N3CCN(C4COC4)C[C@@H]3CC)=CN=2)C(=O)N(C)C=1)(=O)C.[C:53]([O:56][CH2:57][C:58]1[C:59]([N:73]2[CH2:85][CH2:84][N:76]3[C:77]4[CH2:78][CH2:79][CH2:80][CH2:81][C:82]=4[CH:83]=[C:75]3[C:74]2=[O:86])=[N:60][CH:61]=[CH:62][C:63]=1B1OC(C)(C)C(C)(C)O1)(=[O:55])[CH3:54].Cl[C:88]1[CH:89]=[C:90]([NH:96][C:97]2[CH:105]=[C:100]3[CH2:101][O:102][CH2:103][CH2:104][N:99]3[N:98]=2)[C:91](=[O:95])[N:92]([CH3:94])[N:93]=1>>[C:53]([O:56][CH2:57][C:58]1[C:59]([N:73]2[CH2:85][CH2:84][N:76]3[C:77]4[CH2:78][CH2:79][CH2:80][CH2:81][C:82]=4[CH:83]=[C:75]3[C:74]2=[O:86])=[N:60][CH:61]=[CH:62][C:63]=1[C:88]1[CH:89]=[C:90]([NH:96][C:97]2[CH:105]=[C:100]3[CH2:101][O:102][CH2:103][CH2:104][N:99]3[N:98]=2)[C:91](=[O:95])[N:92]([CH3:94])[N:93]=1)(=[O:55])[CH3:54]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1nc(Cl)cc(Nc2cc3n(n2)CCOC3)c1=O
Agent: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 55.9 %

Procedure:
Following the procedures as described for compound 131a and starting with 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (200 mg, 0.52 mmol) and 132a (153 mg, 0.52 mmol) afforded 132b as a yellow solid (170 mg, 55%). LCMS: [M+H]+ 598
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:4][C:3]1=[O:18].S(Cl)([Cl:22])(=O)=O.N>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]2[S:8][C:9]([Cl:22])=[CH:10][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:4][C:3]1=[O:18]
Reactant: Cn1c(=O)nc(-c2ccccc2Cl)c2ccsc21
Reactant: O=S(=O)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)nc(-c2ccccc2Cl)c2cc(Cl)sc21
Temperature: 50 °C
Reaction time: 7 h

Procedure:
To a solution of 450 mg of 1-methyl-4-(o-chlorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 11 ml of chloroform is added dropwise 0.66 g of sulfuryl chloride. After stirring the reaction mixture for 7 hours at 50°C, the reaction mixture is neutralized with aqueous ammonia, then extracted with chloroform. The chloroform extracts are washed with water, dried and evaporated under reduced pressure to a residue to give crystals, which are recrystallized from ethanol-ether to give 1-methyl-4-(o-chlorophenyl)-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 164° - 166°C.