Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:21])[CH2:6][CH2:5]2.I.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](SC)=[NH:29]>C(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[N:15]1([CH2:14][CH2:13][CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:1][C:28]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)=[NH:29])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C:7]2=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N=C(Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCCC1)c1cccs1
Reaction time: 64 h

Procedure:
A solution of 6-amino-1-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (0.065 g, 0.226 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.129 g, 0.452 mmol) at room temperature and the resulting mixture was stirred for 64 hours. The reaction was transferred to a separatory funnel and diluted with ethyl acetate (30 mL) and saturated sodium hydrogen carbonate (20 mL). The aqueous was partitioned twice more with ethyl acetate (2×20 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 0-1:10-9). The product was dried under high vacuum. Yield: 46 mg of yellow solid (51%). 1H NMR (DMSO-d6) δ: 8.02 (d, J=3.9 Hz, 1H), 7.99 (d, J=3 Hz, 1H), 7.32 (d, J =4.8 Hz, 1H), 7.28 (d, J=6.3 Hz, 1H), 7.20 (s, 1H), 7.17 (s, 1H), 4.32 (br s, 2H), 3.98−3.93 (m, 2H), 3.45-3.40 (m, 4H), 3.16-3.10 (m, 4H), 2.95-2.90 (m, 4H), 2.61-2.56(m, 2H), 2.01-1.90 (m, 2H). MS (ESI): 397.2 (M+1). ESI-HRMS calculated for C22H29N4SO (MH+): 397.2056, Observed: 397.2073.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCCl>[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][C:13]([Cl:3])=[O:15])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1cccnc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(Cl)CCc1cccnc1
Temperature: 25 °C

Procedure:
Add thionyl chloride (0.05 mL, 0.53 mmol) to a stirred suspension of 3-(3-pyridyl)propionic acid (80.2 mg, 0.53 mmol) and benzyltriethylammonium chloride (1 mg, 0.004 mmol) in 1,2-dichloroethane (20 mL) and heat to reflux for 2.5 hours. Cool the reaction mixture to room temperature and concentrate in vacuo. Azeotrope the residue with CCl4 and place under vacuum. Use the resulting acid chloride without further purification.
Reaction SMILES: [CH3:1]C1(C)CCCNC1=O.[CH3:10][C:11]1([CH3:18])[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].CI>C1COCC1>[CH3:1][N:16]1[C:11]([CH3:18])([CH3:10])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: CC1(C)CCCC(=O)N1
Reactant: CC1(C)CCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)CCCC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of a 3 to 1 mixture of 3,3-dimethylpiperidin-2-one and 6,6-dimethylpiperidin-2-one (4.72 g, 37.1 mmol) in 60 ml of THF was added 60% sodium hydride suspension (1.93 g, 48.2 mmol). The grey reaction mixture was stirred at room temperature for 30 minutes. Then methyl iodide (3.02 ml, 48.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, and worked up with ethyl acetate/water. The orange oil was chromatographed over a prepacked 70 g silica column After elution with a 50% to 100% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 2.46 g (47%) of the title compound as a light yellow solid; and 0.91 g (17%) of isomeric 1,3,3-trimethyl-piperidin-2-one as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:13]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)C.C(OCC)(=O)C>[CH3:16][C:13]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:23][CH:24]=1)([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccnc1NCc1ccc(C(C)(C)C)cc1
Temperature: 160 °C

Procedure:
A solution of ethyl 2-chloro-3-pyridinecarboxylate (0.610 g, 3.29 mmol) in ethanol (10.0 mL) was treated with 4-tert-butylbenzylamine (0.580 mL, 3.29 mmol). The mixture was heated to 160° C. for 1 h in a Biotage Initiator microwave synthesizer. The solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (20-60% ethyl acetate in hexanes) afforded the title compound clear yellow oil (0.461 g, 45%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.34 (dd, J=4.8, 1.8 Hz, 1H), 8.18 (dd, J=7.8, 2.0 Hz, 1H), 7.30-7.42 (m, 4H), 6.58 (dd, J=7.6, 4.8 Hz, 1H), 4.75 (d, J=5.6 Hz, 2H), 4.34 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.34 (s, 9H). MS(ES+) m/e 313 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=O)=[C:5]([CH3:10])[O:4][N:3]=1.N1CC[CH2:14][CH2:13][CH2:12]1.C(=O)CC>CCO>[CH3:1][C:2]1[C:6]2=[N+:7]([O-:9])[C:13]([CH3:14])=[CH:12][CH:10]=[C:5]2[O:4][N:3]=1
Reactant: C1CCNCC1
Reactant: Cc1noc(C)c1[N+](=O)[O-]
Solvent: CCC=O
Solvent: CCO
Product: Cc1noc2ccc(C)[n+]([O-])c12
Temperature: 90 °C
Yield: 225 %

Procedure:
3,5-dimethyl-4-nitroisoxazole (2.50 g, 17.6 mmol) in 25 mL EtOH was dissolved. Piperidine (0.174 mL, 1.76 mmol) was added followed by propionaldehyde (1.52 mL, 21.1 mmol). The solution was heated at 90° C. overnight. The solution was concentrated and chromatographed using EtOAc to obtain the title compound (0.650 g, 22.5% yield).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]([NH2:24])[C:17]2[C:22]([Cl:23])=[N:21][CH:20]=[CH:19][N:18]=2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2[NH:24][C:30](=[O:31])[N:18]3[CH:19]=[CH:20][N:21]=[C:22]([Cl:23])[C:17]=23)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Temperature: 80 °C

Procedure:
A solution C-(3-benzyloxy-phenyl)-C-(3-chloro-pyrazin-2-yl)-methylamine hydrochloride (5 g, 13.8 mmol) and CDI (2.46 g, 15.19 mmol) in anhydrous THF (70 mL) was charged with DIEA (2.40 mL, 13.8 mmol) and heated to 80° C. for 1 h and then concentrated in vacuo. The crude material was partitioned between EtOAc and H2O and separated. The aqueous layer was washed with EtOAc (3×) and the combined organic layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by chromatography on silica gel [eluting with 5% MeOH in DCM], to yield the desired product as a yellow solid; 1H NMR (DMSO-d6, 400 MHz) δ 5.17 (s, 2H), 6.86 (d, J=5.2 Hz, 1H), 7.10-7.16 (m, 2H), 7.22-7.23 (m, 1H), 7.34-7.48 (m, 6H), 7.50 (d, J=7.9 Hz, 1H); MS (ES+): m/z=352.15 (100) [MH+], HPLC: tR=3.19 min (MicromassZQ, polar—5 min)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])=[C:4]([F:22])[CH:3]=1.[N:23]1([CH2:28][CH2:29][O:30][C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35]([CH:40]=O)=[CH:34]3)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3=[CH:40][C:35]2[NH:36][C:37]3[C:33]([CH:34]=2)=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:39][CH:38]=3)(=[O:11])=[O:10])=[C:4]([F:22])[CH:3]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3ccc(Cl)cc3F)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2ccc(S(=O)(=O)Nc3ccc(Cl)cc3F)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (4-chloro-2-fluoro-phenyl)-amide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:31]6[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=6)=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(-c6cnn(C)c6)n5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 77 mg, 0.189 mmol) was dissolved in DME (0.629 mL) with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (39.2 mg, 0.189 mmol), 2 M Na2CO3 solution (0.339 mL, 0.679 mmol) and tetrakis(triphenylphosphine)palladium (10.9 mg, 0.009 mmol). The RM was heated at 150° C. 5 min under microwave irradiations. It was taken up with EtOAc and washed with 10% Na2CO3 solution and brine. Then it was dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and passed through an SPE cartridge of PL-Thiol MP to remove the palladium. Then the filtrate was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered to afford after evaporation of the solvent the title compound as a white solid (tR 0.7 min (conditions 2), MH+=410).
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][N:9]1[CH2:22][CH2:21][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]=2[CH2:10]1.Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1>O>[F:36][C:33]([F:34])([F:35])[C:30]1[N:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][N:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]3[CH2:10][N:9]([CH3:8])[CH2:22][CH2:21][C:12]2=3)=[CH:28][CH:29]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: FC(F)(F)c1ccc(CCCBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCCc2ccc(C(F)(F)F)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
To a suspension of DMF (5 mL) and sodium hydride (0.024 g, 0.0006 mol) at 0° C., 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.0005 mol) was added and stirred for 2 h at room temperature, Reaction mix was cooled to −20° C. and 5-(3-Bromo-propyl)-2-trifluoromethyl-pyridine (0.2 g, 0.00075 mol) was added, stirred for 1 h at 15° C. After completion (TLC), reaction mass was cooled to 0° C. and water (10 mL) was added, and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (3-4% methanol:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide desired compound as brown oil (0.04 g, 20% yield). 2,8-Dimethyl-5-[3-(6-trifluoromethyl-pyridin-3-yl)-propyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.04 g, 0.000103 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.0000952 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.030 g, 61% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)[O:10][N:9]=2)=[C:4]([CH3:27])[CH:3]=1.[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC.[F-].[Cs+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:28]=[CH2:29])=[CH:3][C:4]=3[CH3:27])[N:12]=2)=[CH:14][C:15]=1[C:23]([F:26])([F:25])[F:24])([CH3:22])[CH3:21]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(Br)ccc1-c1noc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2noc(-c3ccc(OC(C)C)c(C(F)(F)F)c3)n2)c(C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of 1.12 g (2.54 mmol) of 3-(4-bromo-2-methylphenyl)-5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (EXAMPLE 12), 816 μL (2.79 mmol) of tributyl(vinyl)tin, and 848 mg (5.58 mmol) of cesium fluoride in 20 mL of 1,4-dioxane was added 32 mg (0.06 mmol) of bis(tri-tert-butylphosphine)palladium(0). After stirring at 100° C. for 2 h, the mixture was filtered through a cake of Celite and concentrated. Chromatography on Biotage 40M cartridge using 1:19 v/v EtOAc/hexanes as the eluant afforded 873 mg of the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:12]([F:13])=[C:11]([O:14][CH3:15])[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=C.CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:13][C:12]1[C:3]([CH:1]=[O:30])=[C:4]([CH:9]=[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)[C:11]=1[O:14][CH3:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(OC)c1F
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(OC)c(F)c1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-ethenyl-3-fluoro-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate (0.12 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00 mL)-water (2.00 mL) were added osmium oxide (fixed catalyst I) (0.04 g) and sodium periodate (0.35 g), and the mixture was stirred at room temperature for 3 hr under argon atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give methyl 3-fluoro-2-formyl-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate as a crude product. The obtained crude product (20% v/v) was dissolved in THF (2.00 mL), (tetrahydrofuran-2-yl)methanamine (0.006 g) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was diluted with acetic acid (1.00 mL). Sodium triacetoxyborohydride (0.03 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by HPLC (water/acetonitrile, containing 0.1% TFA). The fractions were combined, saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.90 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][N:51]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc([N+](=O)[O-])cn1)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
A solution of triphenylphosphine (393 mg, 1.5 mmol) in methylene chloride (10.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (303 mg, 1.7 mmol). After stirring at 0° C. for 10 min, the reaction mixture was treated with 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 87, 304 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for 20 min and at 25° C. for 30 min. At this time, the reaction mixture was treated with 2-amino-5-nitropyridine (290 mg, 1.5 mmol) and pyridine (0.14 mL, 1.8 mmol). The resulting reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 200-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide (425 mg, 60%) as a white solid: mp 121-122° C.; EI-HRMS m/e calcd for C20H19F4N3O3 (M+) 425.1363, found 425.1363.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:13])=[O:9].[CH2:27]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)[CH3:28].C(O)(=O)C>CO>[NH2:5][C:6]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([O:29][CH2:27][CH3:28])=[CH:31][CH:32]=2)[CH2:20][CH2:21]1)=[O:13])=[O:9]
Reactant: CCOc1ccc(C=O)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(Cl)ccc3N)CC2)cc1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
Sodium cyanoborohydride (140 mmol) in methanol (0.4 mL) was added to a mixture of 4-[{N -(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]piperidine (0.10 mmol), 4-ethoxybenzaldehyde (0.10 mmol), acetic acid (0.050 mL), and methanol (1.6 mL). The reaction mixture was stirred at 60° C. for 14 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH3OH (20 mL). Product was eluted using 2 N NH3 in CH3OH (6 mL) and concentrated. Preparative TLC (SiO2, AcOEt/CH3OH 5:1) afforded 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]-1-(4-ethoxybenzyl)piperidine (Compound No. 1429) and 1-(4-ethoxybenzyl)-4-[{N-(2-(4-ethoxybenzyl)amino-5-chlorobenzoyl)glycyl}aminomethyl]piperidine (Compound No. 1433).
Reaction SMILES: C(O[C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:32])=[N:18][C:19]=3[NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[O:7][C@@H:6]1[CH2:33][O:34]C(=O)C)(=O)C.[CH3:38]O>C[O-].[Na+]>[Cl:32][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@H:8]2[C@@H:9]3[O:10][C:11]([CH3:12])([CH3:38])[O:13][C@@H:5]3[C@@H:6]([CH2:33][OH:34])[O:7]2)=[C:19]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[N:18]=1
Reactant: CO
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(Nc3ccc(Cl)cc3F)nc(Cl)nc21
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3-yl acetate (400 mg) in methanol (7 ml), sodium methoxide, 25% in methanol, (3 drops) was added. On stirring for 15 min at 20° C. the reaction mixture went clear. On stirring at 20° C. for a further 90 min a precipitate formed. The precipitate was collected by filtration and dried in vacuo for 16 hours. This was dissolved in a mixture of acetone (15 ml) and 2-2-dimethoxypropane (3 ml), and para-toluene sulphonic acid (193 mg) added. The mixture was stirred at 20° C. for 3 hours. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (50 ml), washed with water (50 ml) and brine (30 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with cyclohexane:ethyl acetate (1:1) gave the title compound as a white foam (240 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: OB(O)c1ccc(F)c(F)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(F)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3,4-difluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.24 (s, 1H), 7.28 (q, J=9.2 Hz, 1H), 7.11 (dd, J=8.7, 2.4 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 6.90 (m, 2H), 6.74 (m, 1H), 3.26 (s, 3H), 1.97 (m, 4H), 0.81 (t, J=7.3 Hz, 6H). MS (ESI) m/z [M+H]+ (347); MS (ESI) m/z [M−H]−(345); Anal. calcd for C19H20F2N2O2: C, 65.88; H, 5.82; N, 8.09. Found: C, 65.30; H, 5.71; N, 7.79.