Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.C(N(CC)CC)C.[Br:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1>[Br:21][CH2:22][CH2:23][C:24]([N:9]1[CH2:8][C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)=[O:25]
Reactant: O=C(Cl)CCBr
Reactant: COc1ccc2c(c1)CNCCS2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C(=O)CCBr)CCS2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.250 g) and triethyl amine (0.53 g) in THF (10 ml) at 0° C. was added dropwise 3-bromopropionic chloride (0.444 g). The resulting mixture was stirred at 0° C. for 1 hour and at room temperature overnight. After dilution with ethyl acetate, the organic phase was washed with saturated NaHCO3/H2O and H2O. After drying over sodium sulfate and filtration, removal of solvent gave to the product.
Reaction SMILES: [C:1]1([C:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])([CH3:9])C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][C@H](N)CC1C=CC=CC=1>>[C:1]1([CH:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[CH2:9][CH3:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(Nc1nc(N)c2ncn([C@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Reactant: C[C@H](N)Cc1ccccc1
Product: CCC(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Yield: 74.8 %

Procedure:
Combine the acetonide (2) (638 mg, 1.87 mmol) with D-(+)-amphetamine (4.5 g) and heat to 130° C. for 5 hours under nitrogen with stirring. After cooling, purify by flash chromatography (3% to 5% to 10% methanol/chloroform) followed by radial chromatography four times (2% to 4% to 6% to 8% to 10% methanol/chloroform, 4 mm plate) to provide the secondary amine (3) (0.56 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:19])[C:12]2[S:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:9][C:8]=2[CH2:7][CH2:6][O:5]1.[CH3:20][NH2:21]>O1CCCC1>[CH3:20][NH:21][CH2:2][CH2:3][C:4]1([CH3:19])[C:12]2[S:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:9][C:8]=2[CH2:7][CH2:6][O:5]1
Reactant: CC1(CCBr)OCCc2nc(-c3ccccc3)sc21
Reactant: CN
Solvent: C1CCOC1
Product: CNCCC1(C)OCCc2nc(-c3ccccc3)sc21
Reaction time: 8 h

Procedure:
To a solution of 4-(2-bromoethyl)-6,7-dihydro-4-methyl-2-phenyl-4H-pyrano[ 4,3-d]thiazole (3.14 g, 9.28 mmoles, described above) in dry tetrahydrofuran (50 ml), methylamine gas is slowly added during one hr. After standing overnight additional methylamine gas is introduced and the solution is allowed to stand for 24 hr. After evaporation under reduced pressure the residue is taken up in aqueous sodium bicarbonate solution and extracted with chloroform. The organic extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in acetone-ether and the crystalline precipitate is removed by filtration. The filtrate is evaporated under reduced pressure to give the title compound, nmr (CDCl3) δ 1.57 (s, 3H), 2.07 (t, J= 5Hz), 2.44 (s, 3H), 2.60 (m, 2H), 2.94 (t, J= 5.5 Hz), 4.10 (t, J= 5.5 Hz), 7.5-8.0 (m, 5H), identical to the amine described in Example 31.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.[CH3:16][N:17]1[C:21]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=[N:18]1>>[I:1][C:20]1[CH:19]=[N:18][N:17]([CH3:16])[C:21]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][CH:25]=1
Reactant: Cn1nccc1CCc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(I)c1CCc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 101.7 %

Procedure:
N-iodosuccinimide (1.91 g) was added to a trifluoroacetic acid (15 mL) solution of 1-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethyl}-1H-pyrazole (1.96 g) at a room temperature, and the obtained solution was then stirred for 1 hour. Thereafter, the reaction solution was concentrated under a reduced pressure, and the residue was then diluted with chloroform. The resultant was washed with a saturated sodium hydrogencarbonate aqueous solution/a 30% sodium thiosulfate aqueous solution (1:1). The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=70:30 to 50:50), so as to obtain the title compound (2.98 g) in the form of a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[N:4][C:5]([CH3:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:11])=[N:4][C:3]=1[O:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:18]1
Reactant: Cc1nc(O[C@H]2CC[C@H](C(C)C)CC2)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1nc(O[C@H]2CC[C@H](C(C)C)CC2)c(Br)cc1N

Procedure:
To a stirred solution of 3-bromo-2-(trans-4-isopropylcyclohexoxy)-6-methyl-5-nitro-pyridine (0.917 g, 2.00 mmol) in EtOH/H2O (24 mL/6 mL, 4/1 v/v), ammonium chloride (0.109 g, 2.00 mmol, 1.0 eq) and iron powder (0.452 g, 8.00 mmol, 4 eq) were added at room temperature under inert atmosphere (Ar). The reaction mixture was stirred under heating to reflux for 3 h. At this point in time, TLC indicated that the starting material was consumed. Therefore, the reaction mixture was allowed to reach room temperature and was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue partitioned between a 2 molar aqueous NaOH solution (20 mL) and ethyl acetate (30 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to afford the title compound (0.658 g, 100%) as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:17]2[CH2:18][O:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC1CO1
Reactant: OCCCCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCCCCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 2 g of 7-phenylheptyl alcohol, 1.7 ml of epibromohydrin, 0.44 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 50 ml of anhydrous dimethylformamide were used, to give 1.15 g of the title compound having an Rf value of 0.49 (on silica gel thin layer chromatography, using a 1:6 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)c(F)c1-c1cccnc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 55.9 %

Procedure:
A mixture of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.1 g, 0.37 mmol), 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid (132 mg, 0.56 mmol) and 2 M Na2CO3 (0.56 ml) in 1,2-dimethoxyethane (2 ml) was degassed for 10 min with a stream of nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.022 g) was added and the mixture was stirred under nitrogen at 80° C. for 12 h. After allowing to cool to ambient temperature, the mixture was diluted with ethyl acetate then partitioned between water (100 ml) and ethyl acetate (100 ml). The organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 2.5% MeOH/CH2Cl2), to give 78 mg (55%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.17–7.22 (1H, m), 7.37–7.41 (1H, m), 7.80 (1H, d, J 8.4), 8.10–8.16 (1H, m), 8.56 (1H, d, J 2.6), 8.62 (1H, dd, J 4.6, 1.5), 8.72 (1H, 8.74 (1H, s); MS (ES+) m/z 378 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH2:21]Br.O>C(#N)C>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH2:21][N:4]1[C:3]([O:2][CH3:1])=[N:7][NH:6][C:5]1=[O:8]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: COc1n[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1n[nH]c(=O)n1Cc1cc(Br)ccc1F
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 24.1 %

Procedure:
To a solution of 5.75 g (50 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 30 ml of acetonitrile was added 6.21 g (45 mmol) of potassium carbonate. A solution of 13.54 g of crude 5-bromo-2-fluorobenzylbromide in 50 ml of acetonitrile was added dropwise at 55° C. thereto. After the mixture was stirred at 55° C. for 2.5 hours, 1.15 g of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one and 1.24 g of potassium carbonate were added thereto and then the mixture was stirred at 55° C. for 3 hours. Water was added to the reaction mixture and the mixture was extracted with a mixed solvent of ethyl acetate and tert-butyl methyl ether. The organic layer was washed with water, dried and concentrated. Then, to the semisolid residue (13.37 g) was added a mixture of equal amounts of tert-butyl methyl ether and hexane, then stirred for a while and cooled. The resultant solid was collected by filtration to obtain 3.64 g of 4-(5-bromo-2-fluorobenzyl)-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: [C:1]1([NH:11][C:12]([CH2:14][C:15]([O:17]CC)=O)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:20][OH:21].Cl.NO.[Na]>CO>[C:1]1([NH:11][C:12]([CH2:14][C:15]([NH:20][OH:21])=[O:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(=O)Nc1cccc2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: O=C(CC(=O)Nc1cccc2ccccc12)NO

Procedure:
19.3 g (0.075 mol) of ethyl α-naphthylcarbamoylacetate are treated with a solution of hydroxylamine, prepared from 5.6 g (0.08 mol) of hydroxylamine hydrochloride and 3.68 g of sodium in 250 ml of methanol. After leaving the reactants in contact for 5 hours, the mixture is evaporated to dryness in vacuo, the residue is taken up in 400 ml of cold water, the solution is filtered over charcoal, and the product is precipitated cold with 3N HCl, filtered off and washed with water. CRL 40,518 is obtained by recrystallisation from ethanol.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[C@H:16]([NH:18][C:19](=[O:21])[CH3:20])[CH3:17])[C:9]([O:11][CH3:12])=[O:10].N1C=CC=CC=1.[FH:28]>>[C:19]([NH:18][C@@H:16]([C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[F:28])[CH3:17])(=[O:21])[CH3:20]
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(N)c1
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium nitrite (640 mg) was added to a solution of methyl (R)-3-amino-4-(1-acetamidoethyl)benzoate (2 g) in hydrogen fluoride-pyridine (20 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to give 690 mg of methyl (R)-4-(1-acetamidoethyl)-3-fluorobenzoate.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[CH3:15][Li].[Cl-].[NH4+]>C(OCC)C>[C:12]([C:6]1[O:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)(=[O:14])[CH3:15]
Reactant: [Li]C
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)c1cc(C(C)C)c(C(C)C)o1
Reaction time: 0.75 h
Yield: 83.4 %

Procedure:
A solution of 4,5-diisopropylfuran-2-carboxylic acid (196 mg, 1.00 mmol) in diethyl ether (6 ml) was cooled to −18° C., and added dropwise with methyllithium (1.2 M in Et2O, 2.5 ml, 3 mmol), and the mixture was stirred for 45 minutes. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The reaction mixture was treated in a conventional manner, and then the resultant was purified by silica gel chromatography [hexane-ethyl acetate (7:1)] to obtain the title compound (162 mg, 84%) as colorless oil.
Reaction SMILES: Br[CH2:2][C:3](=[N:8][OH:9])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:10]([OH:14])[C:11](=[CH2:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:5][C:4]([C:3]1[CH2:2][CH2:12][C:11]([CH3:13])([CH2:10][OH:14])[O:9][N:8]=1)([CH3:7])[CH3:6]
Reactant: C=C(C)CO
Reactant: CC(C)(C)C(CBr)=NO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CO)CCC(C(C)(C)C)=NO1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of 1-bromo-3,3-dimethyl-2-butanone oxime (4.5 g) (J. Org. Chem., 1979, 44, 3861) in dichloromethane (150 mL) was added methallyl alcohol (22 mL) and sodium carbonate (16 g). The reaction mixture was stirred at room temperature for 40 h and then filtered through a pad of Celite. The solvent and excess alcohol were removed at reduced pressure. The residue was chromatographed on silica gel with 2:1 hexanes/ethyl acetate to give the title compound (3.2 g) as a low melting waxy solid. NMR (200 Mhz, CDCl3) 3.5 (m, 2H, CH2OH), 2.2-1.6 (m, 4H, ring CH2 's), 1.2 (s, 12H, t-Bu and Me). IR (Nujol) 3240 cm-1 (br, OH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1.[ClH:38].C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:38].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1cccnc1
Yield: 64 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 64% of theory, C28H31N7O3 (513.6); EKA mass spectrum: (M+H)+=514.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:5]([CH3:6])[CH:4]1[C:7]1[N:12]=[C:11]2[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]2=[CH:9][CH:8]=1.[O:23]1[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[N:24]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:19][C:17]([CH3:18])([CH3:20])[CH2:16][N:15]1[C:10]2[C:11](=[N:12][C:7]([CH:4]3[CH:5]([CH3:6])[CH:3]3[CH2:2][NH:1][C:28]([C:25]3[CH:26]=[CH:27][O:23][N:24]=3)=[O:29])=[CH:8][CH:9]=2)[N:13]([CH3:22])[C:14]1=[O:21]
Reactant: O=C(O)c1ccon1
Reactant: CC1C(CN)C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1C(CNC(=O)c2ccon2)C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-[2-(Aminomethyl)-3-methylcyclopropyl]-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (35-2, 35 mg, 0.11 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 14.3 mg, 0.12 mmol, 1.5 equiv), DIPEA (0.040 mL, 0.23 mmol, 2.0 equiv) and HATU (48.4 mg, 0.12 mmol, 1.1 equiv) were added to anhydrous acetonitrile (1 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 35-3 as a white solid. MS m/z (M+H): calculated=398.2188; observed=398.2195. 1H NMR δ (ppm)(CHCl3-d): 8.47 (1H, d, J=1.68 Hz), 7.04 (1H, d, J=7.90 Hz), 6.96 (1H, s), 6.83 (1H, d, J=1.67 Hz), 6.81 (1H, d, J=7.90 Hz), 3.76-3.65 (1H, m), 3.61 (2H, s), 3.60-3.52 (1H, m), 3.43 (3H, s), 1.82 (1H, dd, J=7.68, 3.43 Hz), 1.70-1.65 (1H, m), 1.64 (1H, dd, J=7.82, 0.02 Hz), 1.30 (3H, d, J=6.23 Hz), 1.02 (9H, s).
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][CH:9]([CH3:17])[CH2:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14].IC>O>[CH3:4][CH:12]([C:11](=[O:16])[CH2:10][CH:9]([CH3:17])[CH3:8])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)CC(=O)CC(C)C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)C(C)C(=O)CC(C)C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To 0.1 mol sodium hydride was added 100 ml anhydrous tetrahydrofuran, then added slowly dropwise 0.1 mol 6-methyl-2,4-heptandione at room temperature. The reaction was stirred for 0.5 hours, then 0.12 mol iodomethane was added dropwise and the reaction was stirred at room temperature for further 10 hours. Upon completing the reaction, 20 ml water was added. The mixture was extracted with ethyl acetate. After removing the solvent, distillation under reduced pressure gave a cut fraction 88-9° C./1 kPa (165-166° C. at atmosphere pressure), and the yield was 94%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:12])[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[Br:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:12][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([Br:20])=[CH:22][CH:23]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)nn1N
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C)nn1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-amino-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (310 mg, 1.83 mmol) in dichloromethane (4 ml) is added triethylamine (887 μl, 6.40 mmol). Then a solution of 4-bromobenzoyl chloride (803 mg, 3.66 mmol) in dichloromethane (2 ml) is added slowly. The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic layer is washed with 1 N HCl, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 2-(4-bromo-benzoylamino)-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester as brown oil; HPLC/MS 2.10 min (A), [M+H] 352/354.
Reaction SMILES: [F:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12](I)[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:12]([O:9][C:5]1[CH:6]=[C:7]([I:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11])[CH3:13]
Reactant: COc1cc(F)c(I)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cc(I)c(F)cc1OC
Temperature: 40 °C
Yield: 84.4 %

Procedure:
A mixture of 64C (580 mg, 2.16 mmol), ethyl iodide (0.23 mL, 2.92 mmol) and K2CO3 (598 mg, 4.32 mmol) in DMF (5.0 mL) was heated at 40° C. for 3.0 h. It was diluted with diethyl ether, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by silica gel chromatography (EtOAc:hexanes=1:5) to give 64D (540 mg, 85% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.03 Hz, 3H) 3.82 (s, 3H) 4.01 (q, J=7.03 Hz, 2H) 6.64 (d, J=9.23 Hz, 1H) 7.09 (d, J=6.15 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:14]1([CH2:20][C@H:21]([N:25]2[C:29](=[O:30])[C@H:28]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[NH:27][C:26]2=[O:38])[C:22](O)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:11]([O:10][C:8](=[O:9])[C:7]([C:5]1[N:6]=[C:2]([NH:1][C:22](=[O:23])[C@@H:21]([N:25]2[C:29](=[O:30])[C@H:28]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[NH:27][C:26]2=[O:38])[CH2:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[S:3][CH:4]=1)=[O:13])[CH3:12]
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)[C@H](CC2CCCCC2)N2C(=O)N[C@@H](CC3CCCCC3)C2=O)n1

Procedure:
By using the conditions described in Step (iv) of Example 17, ethyl 2-amino-4-thiazoleglyoxylate was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd. for C26H36N4O6S (M+) 533.2434, found 533.2431.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[NH2:12][C:13]1[CH:18]=[N:17][C:16](Br)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>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.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[N:17]=[CH:18][C:13]([NH2:12])=[N:14][CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cnc(N)cn2)c1
Temperature: 90 °C
Yield: 63 %

Procedure:
Nitrogen was bubbled through a solution of 3-methoxyphenyl boronic acid (393 mg, 2.59 mmol), 2-amino-5-bromopyrazine (300 mg, 1.72 mmol), sodium carbonate (603 mg, 5.69 mmol), dimethoxyethane (10 mL), and water (3 mL) for 15 min. After this time, the solution was treated with dichlorobis(triphenylphosphine)palladium(II) (121 mg, 0.17 mmol), and the resulting reaction mixture was heated at 90° C. for 2 d. The reaction was then poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 40/60 hexanes/ethyl acetate) afforded 5-(3-methoxy-phenyl)-pyrazin-2-ylamine (218 mg, 63%) as a light yellow solid: mp 113.2–115.5° C.; EI-HRMS m/e calcd for C11H11N3O (M+) 201.0902, found 201.0905.