Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][CH:9]1[CH2:23][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]2[CH2:10]1)C1C=CC=CC=1.CC(O)=O>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:23][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:15][CH:11]2[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(NCc3ccccc3)CC2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of tert-butyl 5-(benzylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (6.50 g, 20.5 mmol) and AcOH (1.23 g, 20.5 mmol) in MeOH (150 mL) was added Pd(OH)2/C (10% wt, 1.00 g), and the suspension was stirred at 40° C. under H2 atmosphere overnight. The mixture was filtered through a pad of Celite and then concentrated in vacuo. The residue was dissolved in saturated NaHCO3 solution (70 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give the title compound as a yellow solid (4.00 g, 86.2%).
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:21]=[CH:20][C:15]([NH:16]C(=O)C)=[N:14][C:12]2=[O:13])[CH2:8][CH2:7]1)(=O)C.CO.C(N(CC)CC)C>O>[C@@H:9]1([N:11]2[CH:21]=[CH:20][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[O:10][C@H:6]([CH2:5][OH:4])[CH2:7][CH2:8]1
Reactant: CC(=O)Nc1ccn([C@H]2CC[C@@H](COC(C)=O)O2)c(=O)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Temperature: 10 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A 22.0 L three-necked, round-bottomed flask equipped with mechanical stirrer, a thermometer and a condenser was placed in a large heating bath and charged with 1.55 kg (5.25 moles) of N-acetyl 2',3'-dideoxycytidine 5'-acetate 10.6 L of methanol, 3.1 L of triethylamine, and 1.56 L of deionized water. The heating bath was filled with hot water and the temperature was raised to 60°-65°. The flask contents were stirred at 55°-60° for 3 hr, then at ambient temperature for 12. The reaction mixture was concentrated in vacuo at 70°-80° (70 mm) on a large rotary evaporator to a volume of 2.5 L to induce crystallization. To the white semi-solid was added 1.5 L of absolute ethanol and again the mixture was concentrated in vacuo to 2.5 L volume to remove residual solvents. The white semi-solid was cooled to 10° C. for 0.5 hr and was collected by filtration and washed with 1.5 L of absolute ethanol. The damp white solid was recrystallized from 50.0 L of absolute ethanol at reflux and filtered through a sintered glass funnel to remove any particulate matter. The filtrate was concentrated in vacuo at 70°-80° (70 mm) on a rotary evaporator to a volume of 3.0 L. The semi-solid was then heated for 10 minutes without vacuum at reflux in the rotary evaporator. The mixture was cooled to 10° C. for 2 hr to effect crystallization and the white solid was collected by filtration, and washed with 2×1.0 L=2.0 L of absolute ethanol. The solid was dried in a vacuum oven at 85° C. and 1 mm overnight to yield 1.02 kg (92%) of 2',3'-dideoxycytidine as a white solid, m.p. 225°-228° C; [α]S25 +76.9° (c 0.56, H2O); [α]D25 +105.0° (c 0.50, CH3OH); lit. m.p. 215°-217°; [α]D25 +81° (c 0.635, H2O) [J. P. Horowitz, J. Chua, M. Noel, and J. T. Donatti, J. Org. Chem., 32, 817 (1967)]. The mother liquors from three batches were pooled and concentrated to a volume of 1.0 L to effect recrystallization. This solid was recrystallized from 5.0 L of absolute ethanol which was concentrated to a volume of 1.0 L to yield 2-4% additional 2',3'-dideoxycytidine. The second crop mother liquors were combined and purified by column chromatography on 70-230 mesh silica gel 60 using 65:1 methylene chloride-methanol-water as eluant. In this manner, cytosine, 5,6-dihydro-2',3'-deoxyuridine and 5,6-dihydrouracil were also isolated and characterized.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][O:14][C:15]2[N:16]([CH3:28])[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)[CH:19]=2)[CH3:11])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][O:14][C:15]2[N:16]([CH3:28])[N:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[CH:19]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(OCCN(C)CCc3ccc(Cl)cc3)n(C)n2)cc1
Agent: BrB(Br)Br
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: ClCCl
Solvent: O
Product: CN(CCOc1cc(-c2ccc(O)cc2)nn1C)CCc1ccc(Cl)cc1
Reaction time: 12 h
Yield: 66.2 %

Procedure:
1.8 g of 3-(2-[N-(2-(4-chlorophenyl)-ethyl)-N-methylamino]-ethyloxy}-5-(-4-methoxyphenyl)-2-methylpyrazole (see Example 24) were dissolved in 100 ml of dichloromethane. 10 ml of a 1 molar solution of boron tribromide in dichloromethane were added to the solution. The reaction mixture was allowed to stand for 12 hours and then placed in water and extracted with dichloromethane. The aqueous phase was separated, rendered alkaline and extracted three times with a mixture of dichloromethane and methanol, and the combined organic phases were dried and concentrated. The crude title compound obtained as an oil was purified by chromatography on silica gel using dichloromethane/methanol. The purified title compound was reacted in accordance with the method described in Example 4C) with an equimolar quantity of L-(+)-tartaric acid to form a salt, and the resulting salt was crystallized from a mixture of diethyl ether and isopropanol. 1.15 g of 3-{2-[N-(2-(4-chlorophenyl)-ethyl)-N-methylamino]-ethyloxy}-5-(4-hydroxyphenyl)-2-methylpyrazole x 1.3 hydrogen tartrate were obtained having a melting point of 90° to 91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[CH3:17][CH:18]([CH3:24])/[CH:19]=[CH:20]/[C:21](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:48]([OH:53])(=[O:52])[C:49]([OH:51])=[O:50]>C(OCC)(=O)C>[C:48]([OH:53])(=[O:52])[C:49]([OH:51])=[O:50].[CH3:17][CH:18]([CH3:24])/[CH:19]=[CH:20]/[C:21]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]2[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:16]=1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Reactant: CC(C)/C=C/C(=O)Cl
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/C(C)C)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-4-methyl-2-pentenoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 383.41; mp: 140.0-141.0° C.; 1H-NMR (DMSO) δ: 8.71 (1H, d, J=3.7 Hz), 8.16-8.10 (1H, m), 7.64-7.56 (2H, m), 7.28 (1H, d, J=9.2 Hz), 7.19 (1H, d, J=2.2 Hz), 6.99-6.83 (2H, m), 6.37 (1H, d, J=15.8 Hz), 3.80 (3H, s), 2.52-2.42 (1H, m), 1.02 (6H, d, J=6.6 Hz).
Reaction SMILES: [C:1]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]=1[CH2:22][O:23][CH3:24])=[CH:18][C:17]([OH:25])=[CH:16][CH:15]=3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1.C(O)(=O)C>CS(C)=O.C(OCC)(=O)C>[C:1]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]=1[CH2:22][O:23][CH3:24])=[CH:18][C:17]([O:25][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1)=[CH:16][CH:15]=3)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3ccc(O)cc3c12
Reactant: Brc1ccc(Br)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3ccc(Oc4ccc(Br)cn4)cc3c12

Procedure:
332 mg of 3-benzoyl-6-hydroxy-4-methoxymethyl-beta-carboline and 130 mg of potassium hydroxide powder were mixed in 3 ml of dimethyl sulfoxide under argon with 285 mg of 2,5-dibromopyridine in 1 ml of dimethyl sulfoxide and heated for 1 hour to 90°-95° C. The reaction mixture was poured on ice water, acidified with 1N-acetic acid to pH 5 and shaken out with ethyl acetate. The ethyl acetate phase was washed with saturated common salt solution, dried on magnesium sulfate and concentrated by evaporation. After chromatography on silica gel with dichloromethane/ethyl acetate 1:1 as eluant and recrystallization from the main fraction from ethyl acetate/petroleum ether, the title compound with melting point 193°-194° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[Br:18][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:9][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1
Reactant: Cc1ccc(Cl)c(OC(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(Oc1cc(CBr)ccc1Cl)c1ccccc1

Procedure:
A mixture of benzoic acid 2-chloro-5-methyl-phenyl ester (CAB02124, 2.47 g, 10.0 mmol), N-bromo-succinimide (1.96 g, 11.0 mmol) and dibenzoyl peroxide (10 mg) in carbon tetrachloride (25 mL) was heated to reflux for 1 hour (TLC-control). After cooling to room temperature water (50 mL) and diethyl ether (100 mL) were added. The organic layer was separated, washed with brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:hexane, 1:40, Rf: 0.21). Yield: 2.012 g (62%) colourless oil, which solidified after a few hours (contains ca. 10% benzoic acid 5-dibromomethyl-2-chloro-phenyl ester).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:24])[C:8]([CH2:22][CH3:23])=[C:9]([C:20]#[N:21])[C:10]=1B1OC(C)(C)C(C)(C)O1)=[O:5])[CH3:2].Br[C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH3:42])[CH2:33][CH2:34][NH:35][S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:24])[C:8]([CH2:22][CH3:23])=[C:9]([C:20]#[N:21])[C:10]=1[C:26]1[CH:27]=[CH:28][C:29]([N:32]([CH3:42])[CH2:33][CH2:34][NH:35][S:36]([CH:39]([CH3:40])[CH3:41])(=[O:37])=[O:38])=[CH:30][CH:31]=1)=[O:5])[CH3:2]
Reactant: CC(C)S(=O)(=O)NCCN(C)c1ccc(Br)cc1
Reactant: CCOC(=O)c1c(B2OC(C)(C)C(C)(C)O2)c(C#N)c(CC)n1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(N(C)CCNS(=O)(=O)C(C)C)cc2)c(C#N)c(CC)n1C
Yield: 55 %

Procedure:
Prepare the title compound in a manner analogous to the procedure set forth in Example E-281, using 4-cyano-5-ethyl-1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (817 mg, 2-4 mmol, prepared in preparation 50), propane-2-sulfonic acid {2-[(4-bromo-phenyl)-methyl-amino]-ethyl}-amide (550 mg, 1.6 mmol, prepared in preparation 81), aqueous sodium carbonate (4.0 mL, 8.0 mmol, 2N), and [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II) complex with methylene chloride (1:1) (39 mg, 0.05 mmol) to give 404 mg (55%) of the title compound. Mass spectrum (ES+)=461.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCC1CCN(Cc2ccccc2)CC1)c1ccccc1
Yield: 53.4 %

Procedure:
0.248 g (0.00121 mol) of 1-benzyl-4-hydroxymethyl-piperidine was dissolved in 5 ml of toluene and treated with 0.2 ml (0.00145 mol) of triethylamine and 0.155 ml (0.00133 mol) of benzoyl chloride. The mixture was boiled at reflux for 18 hrs., the solvent was distilled off and the residue was taken up in ether. The organic phase was washed with water and saturated sodium chloride solution and dried over magnesium sulfate. It was concentrated and the residue was chromato-graphed on silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.2 g (53%) of 1-benzylpiperidin-4-ylmethyl benzoate was obtained as a yellow oil. MS: me/e (% basic peak)=309 (C20H23NO2+, 18), 308 (17), 232 (14), 204 (41), 159 (18.6), 105 (25.5), 91 (100).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]1[O:30][C:29](=[O:31])[C:28]([CH3:32])=[C:27]([OH:33])[C:26]=1[CH3:34].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]1[O:30][C:29](=[O:31])[C:28]([CH3:32])=[C:27]([O:33][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:26]=1[CH3:34]
Reactant: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Pyridine (64 μl) and benzoyl chloride (45 μl) were added to a suspension of 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg) in CH2Cl2 (5 ml), and the mixture was stirred at room temperature for 50 minutes. The reaction solution was poured into a KHSO4 aqueous solution and extracted with AcOEt, and the organic layer was rinsed with saturated saline and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→4/1) to obtain 6-(benzofuran-2-yl)-4-benzoyloxy-3,5-dimethyl-2H-pyran-2-one.
Reaction SMILES: C[N:2]1[CH2:12][CH:11](C2C=CC=C(N=C=S)C=2)[C:10]2[CH:9]=[C:8]([OH:22])[C:7](Cl)=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:24]([OH:30])(C(F)(F)F)=[O:25]>O.C(#N)C>[CH2:4]([O:22][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:2]([C@H:3]([CH3:4])[C:24]([OH:30])=[O:25])[CH:12]=[CH:11]2)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2cccc(N=C=S)c2)C1
Solvent: O
Solvent: CC#N
Product: C[C@H](C(=O)O)n1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.12 h

Procedure:
Reverse Phase HPLC conditions: Column: YMC-Pack ProC18 (AS-300), 50×4.6 mm (I.D.), S-5 μm, 12 nm (No. 040506614); Mobile Phase: A: 0.1% TFA in water; B: 0.1% TFA in acetonitrile; Gradient: 90-5% A (10-95% B) in 7 min.; Flow rate: 4.0 mL/min; Detector (UV): 220 nm. Retention time of title compound: 3.53 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.Br[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6]2
Reactant: BrCCCc1ccccc1
Reactant: COc1ccc2c(c1)CCNC2=O
Product: COc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O

Procedure:
6-Methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (example 1) is condensed with 1-bromo-3-phenylpropane under N-alkylation conditions described in example 1 to yield 6-methoxy-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[CH:21]=[C:22]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][C:34]([NH2:36])=[O:35])[CH:31]=3)[CH:23]=[C:24]([CH3:26])[CH:25]=2)[N:14]=1)(C(C)(C)C)(C)C>C1COCC1.O>[OH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[CH:21]=[C:22]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][C:34]([NH2:36])=[O:35])[CH:31]=3)[CH:23]=[C:24]([CH3:26])[CH:25]=2)[N:14]=1
Reactant: Cc1cc(Nc2nccc(OCCO[Si](C)(C)C(C)(C)C)n2)cc(-c2cnn(CCC(N)=O)c2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2nccc(OCCO)n2)cc(-c2cnn(CCC(N)=O)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HCl (550 μL, 0.55 mmol) was added to a solution of 3-[4-(3-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]propanamide (91 mg, 0.18 mmol) in THF (1000 μL). The reaction mixture was stirred for 18 h at room temperature then diluted with water and extracted with EtOAc (2×) and chloroform:IPA (3:1). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, triturated with dichloromethane:hexanes (1:1) and then purified by reverse phase HPLC (ACN/water with 0.1% formic acid modifier) to afford 3-[4-(3-{[4-(2-hydroxyethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]propanamide as a white solid. MS ESI calcd. for C19H23N6O3 [M+H]+ 382. found 382.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[N:5][CH:4]=1.Cl.[F:19][C:20]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:21]=1[CH2:22][C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:19][C:20]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:21]=1[CH2:22][C:23]1([OH:29])[CH2:28][CH2:27][N:26]([C:11]([C:10]2[C:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][N:5]=3)=[N:17][CH:16]=[CH:15][CH:14]=2)=[O:13])[CH2:25][CH2:24]1
Reactant: O=C(O)c1cccnc1-c1ccncn1
Reactant: OC1(Cc2ccc(F)cc2F)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1-c1ccncn1)N1CCC(O)(Cc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A suspension of 2-(pyrimidin-4-yl)nicotinic acid dihydrochloride (0.36 g), 4-(2,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride (0.42 g), HATU (0.75 g) and triethylamine (1.1 mL) in DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3)c3cc(Br)cnc32)cc1
Yield: 111.5 %

Procedure:
5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (70 mg, 0.147 mmol), 4-fluorophenylboronic acid (25 mg, 0.176 mmol) and dichlorobis(triphenylphosphine)palladium (II) (10 mg, 0.015 mmol) were combined in CH3CN (2 ml) and 1 M Na2CO3 (2 ml) and stirred at 60° C. for 3 hrs. EtOAc was added and the mixture was washed with water, dried and evaporated to yield 73 mg (112%) of the title compound. MS ESI (m/z): 445.1/447.2 (M+1)+, calc. 444/446.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12](O)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Si:19]([O:26][CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Si:19]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:12](=[O:13])[C@H:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=2[CH3:18])[C@@H:15]([OH:17])[CH3:16])([C:32]([NH:34][NH2:35])=[O:33])[CH2:36][CH:37]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)C2(C(=O)NN)C=CC(CO[Si](C)(C)C(C)(C)C)=CC2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (3 g, 11.16 mmol), 4-((tert-butyldimethylsilyloxy)methyl)benzohydrazide (3.44 g, 12.28 mmol) and anhydrous THF (250 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (1.51 g, 11.16 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (3.21 g, 16.74 mmol) at −15° C. followed by triethylamine (2.33 mL, 16.74 mmol). The reaction mixture was maintained at −15° C. and stirred for 1 h after which, stirring continued overnight while the mixture slowly warmed to room temperature. After 19 h, the mixture was filtered under vacuum and the residue washed with THF (70 mL). The THF solution was concentrated to ca. 20 mL, whereupon EtOAc (100 mL) was added followed by water (50 mL). The phases were partitioned and the organic phase washed with water (30 mL), brine (30 mL) dried (Na2SO4), filtered and concentrated to furnish a light brown solid (5.82 g). This crude product was not chromatographed. 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.82 (d, J=9 Hz, 2H), 7.42 (d, J=8 Hz, 1H), 7.38 (d, J=8 Hz, 2H), 6.58 (d, J=8 Hz, 1H), 5.42 (d, J=8 Hz, 1H), 4.75 (s, 3H), 4.31-4.22 (m, 1H), 3.99-3.97 (m, 1H), 2.24 (s, 3H), 0.82 (s, 9H) and 0.01 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:31])=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][CH:19]([CH2:21][O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][C:17]=3[CH:30]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:32](OCC)(=O)[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:23]([O:22][CH2:21][CH:19]1[CH2:18][C:17]2[CH:30]=[C:13]([C:11]([NH:10][C:6]3[C:5]4[O:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:2][C:1](=[O:3])[C:4]=4[CH:9]=[CH:8][CH:7]=3)=[O:12])[CH:14]=[CH:15][C:16]=2[O:20]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:1]([OH:3])[CH3:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(NC(=O)c2ccc3c(c2)CC(COCc2ccccc2)O3)c1O
Product: CCO
Product: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc4c(c3)CC(COCc3ccccc3)O4)c2o1
Yield: 73 %

Procedure:
Following the process described in example 1 (point A), starting from N-(3-acetyl-2-hydroxyphenyl)-2-benzyloxymethyl-2,3-dihydrobenzofuran-5-carboxamide and diethyl oxalate, the title compound was prepared as a yellow solid with melting point 166-168° C. and purified by crystallization in ethanol (73% yield).
Reaction SMILES: ClC1C=C(F)C=CC=1CN[C:11](=[O:20])[C@H:12]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]1[CH2:18][CH3:19].[F:21][C:22]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[CH2:18]([N:13]1[C:14](=[O:17])[CH2:15][CH2:16][C@H:12]1[C:11]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([F:31])([F:32])[F:33])[C:22]=1[F:21])=[O:20])[CH3:19]
Reactant: NCc1cccc(C(F)(F)F)c1F
Reactant: CCN1C(=O)CC[C@@H]1C(=O)NCc1ccc(F)cc1Cl
Product: CCN1C(=O)CC[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1F

Procedure:
1-ethyl-N-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-5-oxoprolinamide was prepared in a manner analogous to that described above (see example 70) for N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-5-oxo-D-prolinamide but using 2-fluoro-3-trifluoromethylbenzylamine in the place of 2-chloro-4-fluorobenzylamine.