Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[C:5]([NH:8][C:21](=[O:23])[CH3:22])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc(Br)nc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.3 %

Procedure:
To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (5.0 g, 19 mmol) and pyridine (3.8 mL, 46 mmol) in anhydrous THF (75 mL) was added acetyl chloride (1.6 mL, 23 mmol) in a drop-wise manner. After stirring for 48 hr at rt, additional acetyl chloride (0.4 mL, 6 mmol) was added and the mixture was stirred for an additional 48 hr at rt. The solvent was removed in vacuo, and the residue was diluted with 30% EtOAc in hexanes. The mixture was filtered, and the filtrate was purified via silica gel chromatography eluting with 30% EtOAc in hexanes to give a yellow-brown solid (1.8 g, 31%). 1H NMR (CDCl3, 300 MHz): δ 8.34 (s, 1H), 8.08 (s, 1 H), 2.46 (s, 3 H), 0.32 (s, 9H). HPLC retention time: 2.29 minutes. MS ESI (m/z): 312.2, 314.2 (M+H)+, calc. 311.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:10][CH:11]([CH3:13])[CH3:12])[CH:4]=1.[H][H]>CO.O1CCCC1.[Pd]>[CH3:23][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:4]=1
Reactant: CC(C)C=C(c1cccc(N(C)C)c1)c1cc2cccnc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(c1cccc(N(C)C)c1)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A solution of N,N-dimethyl-3-(3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)benzenamine (1.6 g, 5.2 mmol) in methanol (40 mL) and tetrahydrofuran (40 mL) was treated with 10% palladium on carbon (320 mg). The reaction was stirred for 16 h at 25° C. under a balloon filled with hydrogen gas. At this time, the reaction mixture was filtered through a pad of celite and washed with tetrahydrofuran (2×20 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (30 g, petroleum ether/ethyl acetate 8:1) afforded N,N-dimethyl-3-(3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)butyl)benzeneamine (1.2 g, 75%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 9.54 (br. s., 1H), 8.14 (d, 1H, J=4.5 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.15 (t, 1H, J=7.2 Hz), 7.03 (dd, 1H, J1=7.8 Hz, J2=4.8 Hz), 6.64-6.57 (m, 3H), 6.30 (s, 1H), 4.12 (t, 1H, J=8.1 Hz), 2.89 (s, 6H), 2.09-1.81 (m, 2H), 1.61-1.52 (m, 1H), 0.96 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[Br:17][C:18]1[CH:19]=[N:20][C:21](Cl)=[N:22][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1)[CH2:6][NH:7][C:21]1[N:22]=[CH:23][C:18]([Br:17])=[CH:19][N:20]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(CNc2ncc(Br)cn2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
3,5-Bis-trifluoromethyl-benzylamine (10 g) and 5-bromo-2-chloro-pyrimidine (12 g) are dissolved in 1,4-dioxane (50 ml) and thereto is added N,N-diisopropylethylamine (10.7 ml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (10.1 g). MS (m/z): 713 [M+H]+
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:33])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C)C.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.O>[Cl-].[Na+].O>[CH:38]1([NH:41][C:2]2[C:3]3[C:10]([C:11]([C:13]4[C:14]([F:33])=[C:15]([NH:20][S:21]([C:24]5[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][CH3:32])=[CH:28][CH:29]=5)(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=4[F:19])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:40][CH2:39]1
Reactant: NC1CC1
Reactant: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(Cl)c34)c2F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(NC5CC5)c34)c2F)cc1
Temperature: 80 °C
Yield: 101.7 %

Procedure:
To N-[3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide (P-1034, 50 mg, 0.10 mmol), 0.702 mL of isopropyl alcohol is added, followed by cyclopropylamine (79, 0.0357 mL, 70% aqueous solution, 0.509 mmol). The reaction is heated at 80° C. in an oil bath for 17 hours, then poured into water and brine and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (P-1040, 52 mg). MS (ESI) [M+H+]+=512.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1>>[NH2:37][C:32]1[CH:31]=[C:30]([CH3:29])[CH:35]=[CH:34][C:33]=1[NH:36][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: Cc1ccc(N)c(N)c1
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccc(C)cc5N)cccc4c3)c2cc1OC
Yield: 82 %

Procedure:
The title compound (39.4 mg, 82% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-methyl-o-phenylenediamine (14.6 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) (isomer ratio 0.77/0.23) δ 2.21 (s, 1H, Ar—CH3), 4.01 (s, 6H, 2×OCH3), 4.77 (s, 0.23×2H, benzene-NH2), 4.89 (s, 0.77×2H, benzene-NH2), 6.46 (d, J=7.6 Hz, 0.77×1H, Ar—H), 6.64 (s, 0.77×1H, Ar—H), 6.73 (d, J=7.9 Hz, 0.23×1H, Ar—H), 6.81 (s, 0.23×1H, Ar—H), 7.24 (d, J=8.1 Hz, 1H, Ar—H), 7.41 (s, 1H, Ar—H), 7.58-7.66 (m, 3H, Ar—H), 7.85 (d, J=6.7 Hz, 1H, Ar—H), 7.97 (s, 1H, Ar—H), 8.08 (d, J=7.9 Hz, 1H, Ar—H), 8.38 (d, J=9.0 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.77 (s, 1H, benzene-NH). LC-MS (m/z) 481 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24](Cl)=[O:25])[C@H:20]([CH2:27][CH3:28])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][O:5][C:24]([N:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:17])[CH2:19][C@H:20]1[CH2:27][CH3:28])=[O:25]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: OCc1cc(I)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.2 %

Procedure:
A mixture of 2-fluoro-5-iodo-benzylalcohol (5.0 g, 19.8 mM) and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester (5.5 g, 19.8 mM) in dimethylformamide (70 mL) was added slowly to a suspension of sodium hydride (1.3 g, 55%, 1.89 mM) in dimethylformamide (30 mL). The mixture was stirred at room temperature for 5 h and partitioned between water and diethylether. Organic phases were pooled, washed with brine and dried with Na2SO4 to yield after evaporation a yellow oil (11.2 g). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate 3:1) to yield 9.4 g (97%) of the product as a yellowish oil. MS (ISP): 510.3 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.I[CH2:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]1
Reactant: FC(F)(F)c1ccc(Cl)c(N2CCNCC2)c1
Reactant: CCCI
Product: CCCN1CCN(c2cc(C(F)(F)F)ccc2Cl)CC1

Procedure:
Beginning with 1-(2-Chloro-5-trifluoromethyl-phenyl)-piperazine and 1-iodopropane, the title compound was recovered by the procedure described in Example 2. m.p. 234° C. (HCl), MS m/z (rel. intensity, 70 eV) 306 (M+, 20), 279 (34), 277 (bp), 70 (99), 56 (48).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=O)=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:24])=O.O.[OH-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:19]#[N:21])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6]([Cl:24])[N:7]=1
Reactant: CC(C)n1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2nc(C#N)c(N)nc2Cl)ccc1=O
Temperature: -30 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide (29.1 g) was dissolved in DMF (290 ml). The solution was cooled to −30° C. To the cooled solution was added phosphoryl chloride (46.3 g) dropwise at −30˜−40° C. After addition of phosphoryl chloride, the temperature of the reaction mixture was raised to 40-45° C. The mixture was stirred at 40-45° C. for 1 hour. To the reaction mixture was added water (1160 ml). The suspension was stirred at 30-35° C. for 15 hours. The pH of the suspension was adjusted to 7 with 12% aq. NaOH (400 ml). The suspension was cooled to 0-5° C. and stirred at the same temperature for 2 hours. The precipitate was collected by filtration and washed with water, and dried in vacuo at 40-50° C., to give 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile (17.2 g).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6](Cl)(Cl)=[S:7].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=1[Cl:22].Cl>C(Cl)Cl.O.C(Cl)Cl>[Cl:22][C:12]1[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][C:11]=1[N:10]=[C:6]=[S:7]
Reactant: S=C(Cl)Cl
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(N=C=S)c(Cl)c1
Temperature: 0 °C
Yield: 107.9 %

Procedure:
Calcium carbonate (626 mg, 6.25 mmol) and thiophosgene (191 μl, 2.51 mmol) were suspended in methylene chloride-water (10 ml, 1:1, v/v). To the resulting suspension was added a solution of methyl 4-amino-3-chlorophenylacetate (500 mg, 2.50 mmol) in methylene chloride (5 ml) under stirring at 0° C. The temperature of the reaction mixture was raised from 0° C. to room temperature over 1.5 hours. The reaction mixture was acidified with 1N HCl, followed by extraction with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to give methyl 3-chloro-4-isothiocyanatophenylacetate (652 mg, 100%) as a yellow oil.
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[S:6])[CH2:3][CH2:2]1.[C:7]([O:11][C:12](=[O:25])[N:13]([C@@H:15]([CH2:23][NH2:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:14])([CH3:10])([CH3:9])[CH3:8]>ClCCl>[C:7]([O:11][C:12](=[O:25])[N:13]([C@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:23][NH:24][C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[S:6])[CH3:14])([CH3:10])([CH3:8])[CH3:9]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CN)Cc1ccccc1
Reactant: S=C=NC1CC1
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At 0° C., cyclopropylisothiocyanate (0.32 ml) was added to a solution of N-((1R)-1-aminomethyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester (410 mg, 1.6 mmol) in dichloromethane (4 ml). The reaction mixture was first stirred at 0° C. for 10 min, and successively for 2.5 h at room temperature. The solvent were removed in vacuo. The crude product was purified by flash chromatography on silica (50 g) using ethyl acetate/heptane as eluent to give 492 mg of N-((1R)1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[N:14]1([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]3)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:17]1[CH2:18][CH2:19][N:14]([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]3)=[O:21])[CH2:15][CH2:16]1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC

Procedure:
1.8 Grams of 3,4-dimethoxybenzoic acid and 2.75 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril were added to a mixed solvent of 20 ml of dioxane with 20 ml of methylene chloride. Under the condition that the outside of reaction vessel was ince-cooled with stirring, a solution of 2.1 g of N,N-dicyclohexylcarbodiimide being dissolved in 5 ml of methylene chloride by keeping its temperature to 10°-20° C. was added dropwise thereto and stirred at the same temperature for 3.5 hours. The crystals formed in the reaction mixture were removed by filtration, and the mother liquor was concentrated under a reduced pressure. The residue thus obtained was dissolved in 100 ml of methylene chloride and the organic layer was washed with 5%-hydrochloric acid aqueous solution, 5%-sodium hydrogen-carbonate aqueous solution and water in this order, then the organic layer was dried with anhydrous sodium sulfate. The solvent was removed by distillation under a reduced pressure and the residue thus obtained was recrystallized from chloroform-ethanol to obtain 0.9 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=3)=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OCc2ccc(-c3cc(C(N)=O)on3)cc2)cc1
Temperature: 85 °C
Yield: 34.6 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 4-methoxyphenol (24 mg, 0.22 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 85° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(4-methoxy-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (12 mg, 35%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.00 (br. s., 1H), 7.90 (d, J=8.4 Hz, 2H), 7.52-7.64 (m, 3H), 6.90-7.00 (m, 1H), 6.81-6.89 (m, 1H), 5.11 (s, 1H), 3.26-3.34 (m, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl>[C:38]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:12][CH2:13][N:14]([S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:18])=[O:19])[CH2:15][CH2:16]2)=[O:10])[CH2:5][CH2:4]1)(=[O:40])[CH3:39]
Reactant: N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(trans-4-aminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (50 mg) and triethylamine (30 mg) in dichloromethane (10 ml) was added acetic anhydride (50 mg), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (41 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][O:28][CH3:29])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:30]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH2:27][O:28][CH3:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(COC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 32 %

Procedure:
A solution of 4′-{[4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (4.5 g), benzyl bromide (1.5 mL) and cesium carbonate (4.2 g) in N,N-dimethylacetamide (45 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.8 g, 32%) as a colorless liquid.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]2[CH2:14][C:15]([CH3:18])([CH3:17])[CH2:16][C:5]1=2)#[N:2].[ClH:19].C(OCC)(=O)C>[Pd].C(O)C>[ClH:19].[NH2:2][CH2:1][CH2:3][N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]2[CH2:14][C:15]([CH3:17])([CH3:18])[CH2:16][C:5]1=2
Reactant: CCOC(=O)c1cc2c(n1CC#N)CC(C)(C)C2
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2c(n1CCN)CC(C)(C)C2
Reaction time: 6 h

Procedure:
A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 2.0 g dry weight), 167c (4.5 g, 18 mmol), 12% hydrochloric acid (9.2 mL, 37 mmol), ethyl acetate (80 mL) and ethanol (52 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 6 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (10.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×50 mL), and the combined filtrates were concentrated to dryness under reduced pressure. The crude residue 167d was carried onto the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][C:24]([OH:26])=O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:52]([O:59][NH2:60])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>O1CCCC1>[C:53]1([CH2:52][O:59][NH:60][C:24](=[O:26])[CH2:23][NH:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:12][CH2:11]3)=[CH:18][CH:17]=2)(=[O:20])=[O:21])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1)NOCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In a separate flask containing a cool (5° C.), stirred solution of [4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetic acid (0.2307 g, 0.0006161 mol) and 1-hydroxy-benzo-1,2,3-triazole (0.0842 g, 0.000623 mol) in anhydrous tetrahydrofuran (10 mL) was added in one portion 1,3-dicyclohexyl-carbodiimide (0.1449 g, 0.000702 mol). The mixture was stirred for 30 minutes at 5° C. then allowed to warm to room temperature. After 3 hours at room temperature, the mixture was added in one portion to the filtrate containing O-benzylhydroxylamine. The mixture was stirred at room temperature for 16 hours, then refluxed (74° C.) for 1 hour. The volatiles were rotary evaporated off, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 0.1 M NaOH, water, 0.1 M HCl, water, and saturated sodium chloride. The organic layer was dried (MgSO4) and rotary evaporated. The residue was dissolved in chloroform, and chromatographed on silica gel (34 g, 230-400 mesh) eluting with dichloromethane-acetone (9:1, 10×30 mL). Fractions containing product were rotary evaporated to give a white solid. The solid was dried in vacuo; yield 0.1448 g (49%), mp=163-165° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(N(CC)CC)C.[CH2:22]([O:29][C:30](ON1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:23]1([CH2:22][O:29][C:30]([NH:1][CH2:2][C@@H:3]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of (S)-3-(aminomethyl)-1-N-Boc-pyrrolidine (3.0 g, 14.98 mmole) in DMF (40 mL) was added triethylamine (2.5 mL, 17.94 mmole) and N-(benzyloxycarbonyloxy)succinimide (4.46 g, 17.90 mmole). After 18 hours, the reaction solution was concentrated under vacuum and redissolved in diethyl ether (250 mL). The organic solution was washed with H2O (2×150 mL), brine (100 mL) and dried over Na2SO4 and concentrated. The remaining residue was purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to give the title compound (4.46 g, 91%) as a light yellow oil: LC-MS (ES) m/e 335 (M+H)+.