Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].CCN(CC)CC>CC(N(C)C)=O>[C:29]([O:28][C:27]([NH:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1)=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COC(=O)c1c(C)nc(Cl)nc1-c1cnn(C)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Temperature: 90 °C
Yield: 44.9 %

Procedure:
To a mixture of methyl 2-chloro-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (0.227 g, 0.851 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.182 g, 0.851 mmol) in DMA (3 mL) was added Et3N (0.356 mL, 2.55 mmol). The reaction mixture was heated at 90° C. for 4 h. The reaction mixture was cooled to RT and poured onto ice. The solid was filtered and dried under high vacuum to yield the title compound as an off-white foam (170 mg). [M+H] calc'd for C22H32N6O4, 445. found, 445.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:18](C(OC(C)(C)C)=O)[C:9]2=[N:10][C:11]([Cl:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH2:2]([O:3][C:4]([C:6]1[NH:18][C:9]2=[N:10][C:11]([Cl:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(OCC)c(Cl)nc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2cc(OCC)c(Cl)nc2[nH]1

Procedure:
A solution of 1.0 g (2.71 mmol) 6-chloro-5-ethoxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 20 mL dichloromethane was cooled to 0° C., 10 mL (14.9 g, 0.13 mol) trifluoroacetic acid was added and then the cooling bath was removed. After 1 h the volatile components were removed and the residue was poured into 10% aqueous sodium bicarbonate solution and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The resulting white solid (100%) was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(CO)cc2n1Cc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C=O)cc2n1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-(hydroxymethyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 52, 340 mg, 0.759 mmol) in CH2Cl2 (10 ml) at 25° C. under argon was added molecular sieve powder (300 mg), NMO (267 mg, 2.28 mmol), TPAP (26 mg, 0.08 mmol). The reaction was stirred for 10 minutes, then concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound as a light yellow solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Al](C)C.N#N.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[CH3:23][C:21]1[N:10]([C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH:8]=2)[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1cccc(N2CCOCC2)c1
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2cccc(N3CCOCC3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.3 %

Procedure:
To a solution of 3-morpholinylaniline (3.42 g, 19.20 mmol) in CH2Cl2 (100 mL) was added trimethylaluminum (96 mL, 96 mmol, 1 M in toluene) carefully under N2. The reaction mixture was stirred at rt for 30 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (3.29 g, 19.20 mmol) in anhydrous CH2Cl2 (50 mL). The reaction mixture was stirred at rt overnight, then quenched with saturated NH4Cl aqueous solution (200 mL) and extracted with CH2Cl2 (200 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (0.73 g, 13%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(Cl)Cl.Br[C:5]1[CH:6]=[C:7]([N+:17]([O-:19])=[O:18])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][CH:10]=1.[F:20][C:21]1[N:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I.O>[F:20][C:21]1[N:26]=[CH:25][C:24]([C:5]2[CH:10]=[N:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:7]([N+:17]([O-:19])=[O:18])[CH:6]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: O=[N+]([O-])c1cc(Br)cnc1-c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(-c2ccc(F)nc2)cnc1-c1ccccc1
Temperature: 25 °C
Yield: 57 %

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocnee]dichloropalladium(II), w/DCM (7.32 mg, 8.96 μmol) was added to a solution containing 5-bromo-3-nitro-2-phenylpyridine (0.05 g, 0.179 mmol), (6-fluoropyridin-3-yl)boronic acid (0.025 g, 0.179 mmol), Copper(I) iodide (3.41 mg, 0.018 mmol) and Potassium carbonate (0.134 ml, 0.269 mmol) in DMF (Volume: 0.597 ml). Heated the reaction in a microwave at 110° C. for 15 minutes. Let the reaction cool to room temperature. Diluted reaction with water, dried, filtered, concentrated and purified with Combiflash using 0% to 25% ethyl acetate in hexanes to afford 6′-fluoro-5-nitro-6-phenyl-3,3′-bipyridine (0.03 g, 0.102 mmol, 56.7% yield).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@H](OCCCCCCCCC)[C@H]2[OH:42])=C(N)N=1.CS(C)=O.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH2:14]([O:13][C@@H:12]1[C@H:23]([OH:24])[C@@H:25]([CH2:27][OH:28])[O:26][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:42])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)nc(N)nc32)O[C@@H]1CO
Reactant: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
A mixture of 2,6-diamino-9-(2'-O-nonyl-β-D-ribofuranosyl)purine and 2,6-diamino-9-(3'-O-nonyl-β-D-ribofuranosyl)purine (≈80:20 mixture, 29 g) in 0.1 M sodium phosphate buffer (50 ml, pH 7.4), 0.1 M tris buffer (1800 ml, pH 7.4) and DMSO (1080 ml) was treated with adenosine deaminase (1.6 g) as per the procedure of Example 3 to yield 60 g of product as an oil. An analytical product was purified by silica gel chromatography and recrystallized from EtOAc. m.p. 258-259° C. 1H NMR (DMSO-d6) δ 0.96 (t, 3, CH3, J=7 Hz); 1.17 [m, 12, O--CH2 --CH2 --(CH2)6 ]; 1.42 [m, 2, O--CH2CH2 (CH2)6 ]; 3.27-3.61 (m, 4, H-5', O--CH2 (CH2)7 ]; 3.95 (m, 1, H-4'), 4.10-4.13 (m, 2, H-2', H-3'); 5.13-6.06 (m, 2, 3'-OH5'-OH); 5.80 (d, 1, H-1', J=6.4 Hz); 6.47 (s, 2, 2-NH2); 7.98 (s, 1, 8-H) and 10.64 (s, 1, N1 amide). Anal. Calcd. for C19H31N5O5 : C, 55.73; H, 7.63; N, 17.10. Found: C, 55.67; H, 7.66; N, 17.02.
Reaction SMILES: BrC1C=CC(C(CCCCl)C(O)=O)=NC=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20](I)=[N:21][CH:22]=1.[CH2:24]([O:26][C:27](=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:25]>[Cu]>[CH2:24]([O:26][C:27](=[O:34])[CH:28]([C:20]1[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][N:21]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:25]
Reactant: Brc1ccc(I)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]
Agent: O=C(O)C(CCCCl)c1ccc(Br)cn1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cn1

Procedure:
Key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII) can be prepared according to Scheme 8. Starting with commercially available 5-bromo-2-iodo-pyridine (XXXV), copper-catalyzed reaction with malonic acid diethyl ester furnishes 2-(5-bromo-pyridin-2-yl)-malonic acid diethyl ester (XXXVI). Hydrolysis and decarboxylation under basic conditions gives (5-bromo-pyridin-2-yl)-acetic acid (XXXVII), which subsequently can undergo nucleophilic acyl substitution with thionyl chloride in methanol to provide (5-bromo-pyridin-2-yl)-acetic acid methyl ester (XXXVIII). Deprotonation of XXXVIII with strong base followed by alkylation with 1-bromo-3-chloropropane gives 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid methyl ester (XXXIX), which can then be hydrolyzed under aqueous basic conditions to furnish key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(CC)CC.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of 4-fluoro-3-nitroaniline (2.00 g, 12.8 mmol) and Et3N (1.98 mL, 14.1 mmol) in THF (40 mL) was added benzoyl chloride (1.58 ml, 13.5 mmol) dropwise at 5° C. The mixture was stirred at 5° C. for 1 hour, warmed to room temperature, and then evaporated. The residue was suspended in H2O (100 ml), adjusted to pH 2, and then extracted with EtOAc. The extract was washed with H2O, 10% NaHCO3 and brine, dried over MgSO4, and concentrated under vacuum to give the crude product, which was purified by washing with i-Pr2O to give the title compound as pale brown crystal (2.70 g, 81%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:11](=[O:38])[NH:12][C@@H:13]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][O:22][CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=[O:15])[CH3:10])C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:32]1([C@H:13]([NH:12][C:11](=[O:38])[C@@H:9]([NH:7][CH3:6])[CH3:10])[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[CH2:21][O:22][CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:15])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1CCC[C@H]1COC1Cc2ccccc2C1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1CCC[C@H]1COC1Cc2ccccc2C1)C1CCCCC1
Yield: 21.7 %

Procedure:
((S)-1-{(S)-1-Cyclohexyl-2-[(S)-2-(indan-2-yloxymethyl)-pyrrolidin-1-yl]-2-oxo-ethylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (Q) (0.54 g, 1 mmol) is dissolved in DCM (8 mL) and treated with trifluoroacetic acid (4 mL) for 45 minutes. The reaction mixture is concentrated in vacuo, purified by preparative reverse-phase hplc to give 0.096 g of the methylamine (34) as a clear gum: LCMS (ES) 442.26 (MH+).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH:40]=1)[O:9][CH:10](OS(C1C=CC=CC=1S(N(C)C1CCN(C)CC1)(=O)=O)(=O)=O)[CH2:11][CH2:12][O:13][NH:14][C:15](=[NH:17])[NH2:16].CC1C=CC([O:64][S:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[S:74]([N:77]([CH3:85])[CH:78]2[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]2)(=[O:76])=[O:75])(=[O:67])=[O:66])=C(C=1)OCCCOC1C=CC=C2C(NC(=O)C=12)=O.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:64][S:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[S:74]([N:77]([CH3:85])[CH:78]2[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]2)(=[O:75])=[O:76])(=[O:67])=[O:66])[CH:7]=[C:8]([CH:40]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: Cc1cccc(OC(CCONC(=N)N)OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c1
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c(OCCCOc2cccc3c2C(=O)NC3=O)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c1
Yield: 76 %

Procedure:
N-{3-[5-Methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl) phenylsulfonyloxy]phenoxy propoxy}guanidine dihydrochloride: The title compound was prepared in 76% yield from N-{3-[5-methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl) aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 8.25 (d, J=7.9 Hz, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.02 (t, J=7.6 Hz, 1H), 7.89 (t, J=7.7 Hz, 1H), 7.37 (br s, 4H), 6.75 (s, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 4.07 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.22 (m, 2H), 3.17 (s, 3H), 2.79 (s, 3H), 2.72 (t, J=12.0 Hz, 2H), 2.22 (s, 3H), 1.99 (pentet, J=6.3 Hz, 4H), 1.60 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C24H35N5O7S2: 570.2 (M+H), 592.2 (M+Na). Found: 570.1, 592.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[C:26]([CH:27]=[CH:28][C:29]([O:31]CC)=[O:30])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[C:26]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C=Cc1cccnc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C=CC(=O)O)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a mixture of ethyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]propenoate (2.00 g), tetrahydrofuran (10 mL) and ethanol (10 mL) was added a 1N aqueous sodium hydroxide solution (7 mL) and the mixture was stirred at 70° C. for 3 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (1.77 g, yield 94%) of 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]propenoic acid. Recrystallization from tetrahydrofuran-diisopropyl ether gave colorless prism crystals. melting point: 174-175° C.
Reaction SMILES: Cl[C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:24])=[N:17][C:18]([O:22][CH3:23])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([O:30][CH:31]([F:33])[F:32])[C:26]([F:29])([F:28])[F:27])=[CH:4][CH:3]=1>C(O)(=O)C.[Pd]>[F:33][CH:31]([F:32])[O:30][CH:25]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[C:20]([CH3:21])=[N:19][C:18]([O:22][CH3:23])=[N:17][C:16]=4[CH3:24])[C:8]3=[N:9][C:10]=2[CH:2]=[CH:3][CH:4]=1)[C:26]([F:29])([F:28])[F:27]
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1nc(C)c(N2CCCn3c2nc2cccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
To a solution of 9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (783 mg, 1.59 mmol) in acetic acid (8.0 mL) was added 10% palladium on carbon (50% wet, 78.3 mg), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 2 days. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 75-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless powder (507 mg, 1.11 mmol, 70%)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.Br[C:25]1[CH:53]=[CH:52][C:28]([C:29]([NH:31][CH2:32][C:33]2[C:42](=[O:43])[C:41]3[C:36](=[CH:37][C:38]([Cl:44])=[CH:39][CH:40]=3)[N:35]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])[CH:34]=2)=[O:30])=[CH:27][N:26]=1.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:44][C:38]1[CH:37]=[C:36]2[C:41]([C:42](=[O:43])[C:33]([CH2:32][NH:31][C:29](=[O:30])[C:28]3[CH:52]=[CH:53][C:25]([C:9]4[CH:13]=[N:12][NH:11][CH:10]=4)=[N:26][CH:27]=3)=[CH:34][N:35]2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[Cl:51])=[CH:40][CH:39]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C(NCc1cn(-c2ccccc2Cl)c2cc(Cl)ccc2c1=O)c1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1cn(-c2ccccc2Cl)c2cc(Cl)ccc2c1=O)c1ccc(-c2cn[nH]c2)nc1
Temperature: 120 °C
Yield: 7.6 %

Procedure:
While purging with argon, a small microwave tube was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30.0 mg, 0.155 mmol), K3PO4.H2O (53 mg, 0.230 mmol), and PdCl2(dppf) (9.3 mg, 0.013 mmol). 6-Bromo-N-[7-chloro-1-(2-chloro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-yl-methyl]-nicotinamide (Example I-101) (50 mg, 0.099 mmol) in DMF (0.50 mL) was added followed by water (0.05 mL). The reaction mixture was heated at 120° C. via microwave irradiation for 15 min. HPLC showed one or two new peaks forming; LC/MS showed one of the new peaks with the product mass. The reaction mixture was heated at 120° C. for another 40 min. After this time, most of the starting material was consumed, as observed by HPLC. The reaction mixture was diluted with H2O, then extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with brine. The organic phase was dried over Na2CO3, filtered, and concentrated. The crude product was purified using flash chromatography (12 g silica gel column eluting with 100% methylene chloride ramped to 0% methanol in methylene chloride). N-[7-Chloro-1-(2-chloro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-6-(1H-pyrazol-4-yl)-nicotin-amide (3.7 mg, 7%) was obtained as a light brown solid at 90% purity by reverse-phase HPLC. MS calcd. for C25H17Cl2N5O2 [(M+H)+] 491.0, obsd. 489.9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:26]([F:27])=[C:25](F)[C:11]([C:12]([C:14](=[CH:20][NH:21][CH:22]2[CH2:24][CH2:23]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[C:10]([F:29])[C:9]=1[F:30].O>CN(C)C=O>[Br:7][C:8]1[C:26]([F:27])=[C:25]2[C:11]([C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][N:21]2[CH:22]2[CH2:24][CH2:23]2)=[C:10]([F:29])[C:9]=1[F:30]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)c(Br)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(Br)c(F)c(F)c2c1=O
Temperature: 150 °C
Yield: 64.1 %

Procedure:
Potassium carbonate (30 g) was added to a stirred solution/suspension of 31.65 g ethyl 2-(4-bromo-2,3,5,6-tetrafluorobenzoyl)-3-cyclopropylaminopropenoate in 300 ml dimethylformamide. The mixture was heated at 150° C. for 1.5 hours, then cooled, poured into water and extracted with methylene dichloride. The extract was washed with water and sodium chloride solution, dried (magnesium sulfate) and concentrated. The residue was recrystallized from acetonitrile to give 19.3 g (64%) ethyl 7-bromo-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, m.p. 187°-189° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[N:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:38]=[C:37]([CH3:39])[C:31]3[N:32]([CH3:36])[C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:36][N:32]1[C:31]2[C:37]([CH3:39])=[CH:38][C:28]([C:26]([C:22]3[CH:21]=[C:20]([N:15]4[CH2:14][CH2:13][CH:12]([N:10]5[C:9](=[O:18])[NH:8][C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)=[N:11]5)[CH2:17][CH2:16]4)[N:25]=[CH:24][N:23]=3)=[O:27])=[CH:29][C:30]=2[O:34][C:33]1=[O:35]
Reactant: O=c1[nH]c(-c2ccccc2)nn1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C(=O)c2cc(N3CCC(n4nc(-c5ccccc5)[nH]c4=O)CC3)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
98 mg (0.40 mmol) 5-phenyl-2-piperidin-4-yl-2,4-dihydro-[1,2,4]triazol-3-one, 0.12 g (0.40 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.14 mL (0.80 mmol) DIPEA were combined in 3 mL DMF and stirred for 48 h at RT. The mixture was diluted with MeOH, suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5](OCC)[O:6]CC.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]=[O:6]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCOC(OCC)/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C(C=O)=C\COc1ccc(Cl)cc1Cl
Reaction time: 5 h
Yield: 87.2 %

Procedure:
In 100 ml dimethylformamide there is combined 34.9 g (E)-4-bromo-1,1-diethoxy-2-methyl-2-butene, 24.0 g 2,4-dichlorophenol, 40.5 g potassium carbonate and 2.37 g potassium iodide and stirred under nitrogen for about five hours. The resulting solution is poured into 500 ml deionized water and the solution extracted with two 200 ml portions diethylether which are then combined and washed first with 300 ml 10% aqueous potassium carbonate solution and then with three 400 ml portions of deionized water. The ether solution is treated with magnesium sulfate and activated charcoal then filtered. The filtrate is evaporated to dryness and the yellow-brown oil is taken up in a mixture of 120 ml acetone and 20 ml water and stirred under nitrogen as 3.0 g p-toluenesulfonic acid is added. Thirty minutes after the addition, the solution is evaporated to dryness and the residue taken up in 200 ml diethylether and this solution washed with two 200 ml portions deionized water. The ether solution is treated with magnesium sulfate and activated carbon and then filtered. The filtrate is evaporated to dryness to yield 31.47 g purple oil which is purified by chromatography on a Waters Prep. 500 LC using a silica gel cartridge yielding 25.31 g of a yellow oil. The oil is recrystallized from diethylether-hexane yielding 18.22 g solid product, m.p. 58.5°-59.5° C. Elemental Analysis. Calculated: C,53.90; H,4.11; Cl,20.93. Found: C,53.86; H,4.00; Cl,28.78.