Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(C2C3C(=CC=CC=3)N(C(C)C)C=2)=CC=1.P(Cl)(Cl)(Cl)=O.CO/C=C/C#N.C(=O)([O-])O.[Na+].[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH:52]([CH3:54])[CH3:53])[C:44]=2[CH:55]=[CH:56][C:57]#[N:58])=[CH:39][CH:38]=1>ClCCl>[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH:52]([CH3:53])[CH3:54])[C:44]=2/[CH:55]=[CH:56]/[C:57]#[N:58])=[CH:39][CH:38]=1
Reactant: CC(C)n1c(C=CC#N)c(-c2ccc(F)cc2)c2ccccc21
Agent: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Agent: CO/C=C/C#N
Agent: O=C([O-])O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)n1c(/C=C/C#N)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Into a solution prepared by dissolving 0.63 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole in 3 mL of dichloromethane was added dropwise 0.77 g of phosphorus oxychloride at an inner temperature of 0 to 10° C., then, 0.92 g of trans-3-methoxyacrylonitrile was added dropwise. Then, the mixture was stirred overnight at room temperature to cause a reaction, further, the mixture was reacted for 6 hours at the reflux temperature. After completion of the reaction, the reaction liquid was added into 100 mL of 5 wt % aqueous sodium hydrogen carbonate, and extracted with ethyl acetate three times. The resulting organic layers were combined and washed with water, then, dried with anhydrous magnesium sulfate. The magnesium sulfate was filtrated off, and the resulting filtrate was concentrated to obtain a concentrated residue containing 3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylonitrile (trans-cis isomer mixture containing mainly trans isomer). The resulting concentrated residue was purified by silica gel column chromatography (developing liquid: n-heptane/ethyl acetate: 10/1 to 5/1) to obtain 0.34 g of trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylonitrile (yellow solid). Yield: 45%
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[F:26])=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:27]I>ClCCl.C(Cl)(Cl)Cl>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[CH:2]([CH2:3][I:27])[CH2:1][C:4]3[C:5]4[C:6]2=[N:7][CH:8]=[N:9][C:10]=4[CH:11]=[C:12]([O:16][CH3:17])[C:13]=3[O:14][CH3:15])=[C:20]([F:26])[CH:21]=1
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12
Reactant: II
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-bromo-2-fluoro-phenyl)-amine (0.236 g, 0.564 mmol) (from Example 19, Step E, supra) in dichloromethane (30 mL) was added I2 (1.43 g, 5.64 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with chloroform (100 mL), and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated to give the desired 4-(4-bromo-2-fluoro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene as an off white oil. (Yield 0.034 g, 11%).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1.[NH2:20][CH2:21][CH2:22][NH:23][C:24]([NH:26][CH3:27])=[O:25]>C(O)(C)C>[OH:16][CH:14]([CH2:13][O:12][C:11]1[CH:17]=[CH:18][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH:2]([CH3:19])[CH3:1])=[CH:9][CH:10]=1)[CH2:15][NH:20][CH2:21][CH2:22][NH:23][C:24]([NH:26][CH3:27])=[O:25]
Reactant: CC(C)COCCOc1ccc(OCC2CO2)cc1
Reactant: CNC(=O)NCCN
Solvent: CC(C)O
Product: CNC(=O)NCCNCC(O)COc1ccc(OCCOCC(C)C)cc1

Procedure:
10.6 g of 3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)-1,2-epoxypropane and 14 g of N-2-aminoethyl-N'-methyl-urea was refluxed 40 h in isopropanol. The product crystallized when the heating was stopped. Recrystallized from isopropanol. Yield 8 g. M.p. 121° C. (base). The structure was determined using NMR.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)=[O:4].[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 2.9 %

Procedure:
A solution of 1H-[1,2,4]triazole-3-carboxylic acid methyl ester (3.0 g, 0.23 mol) in N,N-dimethylformamide (76 mL) at 25° C. was treated with triphenylmethylchloride (7.2 g, 0.23 mol) and triethylamine (6.41 mL, 0.23 mol). The reaction mixture was stirred at 25° C. for 4 days and then diluted with ethyl acetate. The mixture was then washed with a dilute aqueous hydrochloric acid solution. At this time, methanol was added to the organic layer. A precipitate formed and was removed by filtration. The organics were further washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was triturated with diethyl ether. The solid was collected by filtration and washed again with diethyl ether to afford 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid methyl ester as a white solid (2.45 g, 84%) which was used without further purification: LR-FAB for C23H19N3O2 (M+) at m/z=369.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[N+:14]([C:17]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([O-:16])=[O:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.COCCOC.O>[N+:14]([C:17]1[CH:29]=[C:28]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([O-:16])=[O:15]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccn2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Water (3 mL), sodium carbonate (0.76 g), 2-bromopyridine (0.42 mL), and tetrakis(triphenylphosphine)palladium(0) (0.17 g) were added to an ethylene glycol dimethyl ether (10 mL) solution of tert-butyl 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.0 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 90-85% hexane/ethyl acetate] to obtain 0.32 g of tert-butyl 2-nitro-4-(pyridin-2-yl)benzoate as a light yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:32]1[CH:46]=[CH:45][C:35]2[C:36]([CH:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[N:37][O:38][C:34]=2[CH:33]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:32]1[CH:46]=[CH:45][C:35]2[C:36]([CH:39]3[CH2:40][CH2:41][NH:42][CH2:43][CH2:44]3)=[N:37][O:38][C:34]=2[CH:33]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(C3CCNCC3)noc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc2c(C3CCNCC3)noc2c1
Yield: 60.5 %

Procedure:
N-[4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 15, 50 mg), DMF (1.5 ml), aqueous sodium carbonate (1M, 0.75 ml), tetrakis (triphenylphosphine) palladium (7.5 mg) and 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole (41 mg) were heated together at 80° C. under nitrogen for 18 h. The solvent was evaporated, and the residue was purified by column chromatography on silica (10 g ) eluting with dichloromethane:ethanol:ammonia (100:8:1) to give the title compound (36.8 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.C([N-]C(C)C)(C)C.[Li+].[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]([N+:35]#[C-:36])[CH2:33][CH3:34].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([S:49][CH2:50][CH2:51]Cl)[CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46]>O1CCCC1.CCOCC.C(O)(=O)C>[CH2:33]([C:32]([N+:35]#[C-:36])([C:28]1[S:27][CH:31]=[CH:30][CH:29]=1)[CH2:51][CH2:50][S:49][C:41]1[CH:40]=[C:39]([O:38][CH3:37])[C:44]([O:45][CH3:46])=[C:43]([O:47][CH3:48])[CH:42]=1)[CH3:34]
Reactant: COc1cc(SCCCl)cc(OC)c1OC
Reactant: [C-]#[N+]C(CC)c1cccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: [C-]#[N+]C(CC)(CCSc1cc(OC)c(OC)c(OC)c1)c1cccs1
Yield: 74.4 %

Procedure:
A solution of diisopropylamine (2.65 g) in tetrahydrofuran is cooled to -60° C. and 1.6M n-butyl lithium/hexane solution (14 ml) is added dropwise thereto in nitrogen atmosphere. The mixture is stirred at the same temperature, whereby the solution containing lithium diisopropylamide is obtained. A solution of 1-(2-thienyl)propyl isocyanide (2.8 g) in tetrahydrofuran is added dropwise to the solution obtained above at -60° C. and the mixture is stirred at the same temperature for 20 minutes. A solution of 2-(3,4,5-trimethoxyphenylthio)ethyl chloride (5.9 g) in tetrahydrofuran is added dropwise to the mixture at -60° C. and the mixture is stirred at -30° C. in nitrogen atmosphere for 2 hours. Acetic acid is added to the mixture to cease the reaction and ether is added to the reaction mixture. The mixture is washed, dried and concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography, whereby 1-ethyl-3-(3,4,5-trimethoxyphenylthio)-1-(2-thienyl)propyl isocyanide (5.2 g) is obtained as red oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:9]2[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:12][N:13]=2)[S:6][C:7]=1I)#[N:2].C[Sn](C)(C)[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]([CH:40]2[CH2:42][CH2:41]2)=[O:39])[CH:32]=1.[Cl-].[Li+].O1CCOCC1>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:9]2[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:12][N:13]=2)[S:6][C:7]=1[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]([CH:40]2[CH2:41][CH2:42]2)=[O:39])[CH:32]=1)#[N:2]
Reactant: C[Sn](C)(C)c1ccnc(NC(=O)C2CC2)c1
Reactant: CC(C)(C)OC(=O)N1CCN=C1c1sc(I)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN=C1c1sc(-c2ccnc(NC(=O)C3CC3)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Yield: 59.3 %

Procedure:
tert-butyl 2-[4-cyano-3-(2,4-dichlorophenyl)-5-iodo-2-thienyl]-4,5-dihydro-1H-imidazole-1-carboxylate (0.500 g, 0.912 mmol), N-[4-(trimethylstannyl)pyridin-2-yl]cyclopropanecarboxamide (0.445 g, 1.37 mmol), Lithium chloride (0.116 g, 2.74 mmol), Copper(I) iodide (0.0521 g, 0.274 mmol) and Tetrakis(triphenylphosphine)palladium(0) (0.105 g, 0.0912 mmol) were combined in a 100 mL round-bottom flask under an atmosphere of argon and 1,4-Dioxane (45.3 mL, 0.580 mol) was added. The solution was heated to reflux for 2 hours. The reaction was concentrated in vacuo and the residue was purified using ISCO chromatography on silica gel, elution 10 to 70% ethyl acetate in hexanes to afford the product (0.315 g, 59%). LCMS: (FA) ES+, 582, 584. 1H NMR (400 MHz, d1-chloroform) δ: 8.62-8.58 (m, 1H) 8.41-8.38 (m, 1H), 8.26 (s, 1H), 7.54-7.50 (m, 1H), 7.50-7.48 (m, 1H), 7.40-7.37 (m, 1H), 7.33-7.29 (m, 1H), 3.96-3.73 (m, 4H), 1.56-1.54 (m, 1H), 1.32 (s, 9H), 1.17-1.11 (m, 2H), 0.95-0.88 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([OH:13])(=O)=[O:11].CN(C=O)C.C(Cl)(=O)C([Cl:22])=O.CCOC(C)=O.CCCCCC>C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([Cl:22])(=[O:13])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=S(=O)(O)Cc1cccc(Cl)c1Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)Cc1cccc(Cl)c1Cl
Temperature: 0 °C
Yield: 54.7 %

Procedure:
(2,3-dichlorophenyl)-methanesulfonic acid (260 mg, 1.0 mmole) was dissolved in 5 mL dry THF and cooled to 0° C. A catalytic drop of DMF was added followed by oxalyl chloride (0.44 mL, 5.0 mmole). The reaction mixture was allowed to warm to room temperature over 90 minutes and then filtered through Celite®, rinsing the Celite® with an additional 15 mL dry THF. The filtrate was evaporated to a volume of ca. 5 mL and then 5 mL water was added in small portions, cooling the vessel in a water bath. The mixture was extracted with 2×25 mL EtOAc and the combined organics were washed with saturated sodium bicarbonate, brine, and dried (MgSO4). Filtration and evaporation gives the crude product as a yellow oil. Chromatography on silica gel using a gradient of 5% EtOAc/Hexane to 30% EtOAc/Hexane gives 142 mg (2,3-dichlorophenyl)-methanesulfonyl chloride as a white solid.1H NMR (400 MHz, CHLOROFORM-D) δ ppm 5.09 (s, 2 H) 7.25 (t, J=7.96 Hz, 1 H) 7.45 (m, 1 H) 7.53 (dd, J=8.08, 1.52 Hz, 1 H)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[NH:7][CH3:8].N1C=CC=CC=1.[CH3:21][CH:22]([CH2:26][S:27][CH3:28])[C:23](Cl)=[O:24]>ClC(Cl)C.O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[N:7]([CH3:8])[C:23](=[O:24])[CH:22]([CH3:21])[CH2:26][S:27][CH3:28]
Reactant: CSCC(C)C(=O)Cl
Reactant: CNc1sc(-c2cccnc2)nc1Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC(Cl)Cl
Product: CSCC(C)C(=O)N(C)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
To a solution of (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-methylamine (200 mg, 0.88 mmol) in dichloroethane (2 mL) was added pyridine (83 mg, 1.05 mmol), N,N-dimethylaminopyridine (54 mg, 0.44 mmol) followed by 2-methyl-3-methylsulfanyl-propionyl chloride (160 mg, 1.05 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction was diluted with water and the mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a light yellow solid (250 mg, 84%): mp 70-73° C.; 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.75 (d, J=3.8 Hz, 1H), 8.28-8.15 (m, 1H), 7.45 (dd, J=8.0, 4.9 Hz, 1H), 3.32 (s, 3H), 2.99-2.72 (m, 2H), 2.50 (d, J=7.5 Hz, 1H), 2.06 (d, J=2.5 Hz, 3H), 1.31-1.14 (m, 3H); ESIMS m/z 342 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@H:9]1[C:24](OCC)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].Cl.[Cl-].[Na+]>C(OCC)(=O)C.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:10][C@H:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1CO
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
Under nitrogen atmosphere, to a solution of (2S)-2-ethoxycarbonylpiperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (9.35 g) was added portionwise lithium borohydride (1.82 g), and the reaction mixture was stirred for 90 minutes. After methanol (2.32 ml) was added dropwise to the solution under ice-cooling, the mixture was stirred at room temperature for 17 hours. 1N Hydrochloric acid (80 ml) was added dropwise under ice-cooling, and ethyl acetate (100 ml) and sodium chloride (6 g) was added to it. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give colorless oil. The oil was purified by column chromatography on silica gel (90 g) using a mixed solvent of hexane and ethyl acetate (3:2). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (8.40 g) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH:34]=[O:35])[CH2:24][C:23]2=[O:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].P([O-])([O-])(O)=[O:38].[Na+].[Na+].OO.Cl[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>O.C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([OH:38])=[O:35])[CH2:24][C:23]2=[O:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=P([O-])([O-])O
Reactant: O=Cc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(=O)C1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: OO
Solvent: CC#N
Solvent: O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3C(=O)O)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 192.2 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-formylphenyl)piperidin-3-one (300 mg, 0.62 mmol) obtained in Example 15 and sodium hydrogen phosphate (22 mg, NaH3PO4) in the mixed solvent of 1 ml of acetonitrile and 0.5 ml of water, was added 35%-hydrogen peroxide solution (0.1 ml) and 3 ml of sodium hypochlorite solution (NaClO4; 78 mg) at 10° C. The reaction mixture was stirred for about 1 hour at room temperature. Sodium sulfite (1.0 g) was added to the reaction mixture, which was then acidified with 10%-hydrochloride solution. The resulting solid was filtered and dried to give 150 mg of the titled compound.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:20])=O>C(OCC)(=O)C.CN(C=O)C>[Cl:20][C:9]([CH:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)C(CC1CCCCC1)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CCCCC1)C(=O)Cl
Temperature: 0 °C

Procedure:
A solution comprised of 3-cyclohexyl-2-ethoxycarbonylpropionic acid (8.52 g, 37 mmol) in ethyl acetate (80 mL) was cooled to 0° C. was treated sequentially with 2 drops of DMF and oxalyl chloride (3.93 mL) added dropwise over five minutes. The mixture was allowed to warm slowly and after approximately 2 hours concentrated to provide ethyl 2-chlorocarbonyl-3-cyclohexylpropionate.
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([CH3:18])=[CH:16][C:15](=[O:19])[NH:14]1)=[O:12].Cl[Si](C)(C)C.C(Br)C=C>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17](=[CH2:18])[CH:16]([CH2:3][CH:1]=[CH2:2])[C:15](=[O:19])[NH:14]1)=[O:12]
Reactant: COC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC(=O)C=C1C
Reactant: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1C(=C)C(C(=O)OC)(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
Lithium diisopropylamide solution (0.695 M solution in tetrahydrofuran, 5.66 ml, 3.93 mmol, 1.0 equiv) was added dropwise via syringe to a stirred solution of 2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (1.5 g, 3.93 mmol, 1.0 equiv) in tetrahydrofuran (45 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Chlorotrimethylsilane (0.5 ml, 427 mg, 3.93 mmol, 1.0 equiv) was added and the resultant solution was stirred at −78° C. for 3 h. Another equiv of lithium diisopropylamide solution (0.695 M solution in tetrahydrofuran, 5.66 ml, 3.93 mmol, 1.0 equiv) was added dropwise at −78° C. The reaction mixture was stirred −78° C. for 30 min. Allyl bromide (0.68 ml, 0.951 g, 7.86 mmol, 2.0 equiv) was added dropwise via syringe at −78° C. The reaction mixture was stirred at −78° C. for 2 h. A buffer solution (pH=7, 100 ml) was added at −78° C. The mixture was extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over sodium sulfate and the solids were filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (10% ethyl acetate-hexanes initially, grading to 20% ethyl acetate-hexanes) to furnish 4-allyl-2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-3-methylene-5-oxo-pyrrolidine-2-carboxylic acid methyl ester (0.757 g, 46%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2cnc(N)nc2)cc1F
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc(Nc3ccccc3)nc2)cc1F
Temperature: 200 °C

Procedure:
A mixture of 5-(3-fluoro-4-methoxyphenyl)pyrimidin-2-amine (Step 1, 0.44 g, 2.0 mmol) and bromobenzene (0.60 g, 4.0 mmol) in N,N′-dimethylacetamide (1.0 mL) and toluene (1.0 mL) was placed in a microwave tube and was treated with Pd(OAc)2 (0.024 g, 0.1 mmol), 2-biscyclohexyl 1,1-biphenyl phosphine (Strem Chemical, 0.070 g, 0.20 mmol), and KOtBu (0.44 g, 4.0 mmol). The mixture was degassed with N2 (2×) and was subject to microwave heating at 200° C. for a total of 20 min. After the mixture was cooled to RT, it was filtered through a pad of Celite®. The solid was washed with EtOAc (3×10 mL), and the combined organic phase was washed with H2O, NH4Cl (sat.), dried with Na2SO4, and concentrated to an oil. Purification on silica using hexanes-EtOAc (3:1) resulted the desired compound as a yellow solid. MS (ESI pos. ion) m/z: 296. Calc'd for C17H14FN3O: 295.11.