Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[O:19])[C:13]1=[O:38])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[O:19])[C:13]1=[O:38]
Reactant: COc1ccc(NP(=O)(Nc2ccc(OC)cc2)N2CCC[C@H](NC(=O)OCc3ccccc3)C2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(NP(=O)(Nc2ccc(OC)cc2)N2CCC[C@H](N)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Palladium black (30 mg) was added to a solution of (3S)-3-benzyloxycarbonylamino-1-bis(4-methoxyphenylamino)phosphinyl-2-piperidone (150.2 mg, 0.2789 mmol) in methanol (5 mL), and the resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][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)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]3[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=3)=[CH:31][C:26]=2[N:25]=[CH:24]1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=4)=[CH:31][C:26]=3[N:25]=[CH:24]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: NCCCn1cnc2cc(C3=NNC(=O)CC3)ccc21
Product: CC(C)COCCc1ccc(OCC(O)CNCCCn2cnc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(3-aminopropyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1]I.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[O:22][CH3:23])=[CH:16][CH:15]=1.[H-].[Na+].O>CN(C)C=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:1])[C:21](=[O:24])[O:22][CH3:23])=[CH:16][CH:15]=1
Reactant: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N(C)c1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
0.27 ml of methyl iodide were added to a solution of 138.6 mg of methyl N-[4-(benzothiazol-2-ylmethoxy)phenyl]carbamate (prepared as described in Example 11) in 5 ml of dimethylformamide cooled in an ice-water bath and then 19.4 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to the resulting mixture. The reaction mixture was stirred at the same temperature for 10 minutes, the temperature of the mixture was then elevated to room temperature and the mixture was stirred for a further 30 minutes. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate to give 126.7 mg (yield 87%) of the title compound as a solid having a melting point of 85°-87° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[C:17](=[CH:18][CH2:19][S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:16][CH:15]2[N:12]1[C:13](=[O:28])[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([CH:11]1[C:17](=[CH:18][CH2:19][S:20]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:37])[O:16][CH:15]2[N:12]1[C:13](=[O:28])[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)C1C(=CCSCc2ccccc2)OC2CC(=O)N21
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1C(=CCS(=O)Cc2ccccc2)OC2CC(=O)N21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzyl3-(2-benzylthioethylidene)-7-oxo-4-oxa-1-azabicyclo [3,2,0]heptane-2-carboxylate (39.5 mg) was dissolved in methylene chloride (5 ml) and treated with m-chloroperbenzoic acid (19 mg) at 0° C. The solution was stirred at 0° C. for 1/2 hour and washed with 3% bicarbonate solution (3×5 ml). The solvent was evaporated and the gum chromatographed to yield the title product as a mixture of R and S sulphoxides (30 mg; 73%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.[I:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[CH3:30])[NH2:26].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.C(Cl)Cl>[I:22][C:23]1[CH:24]=[C:25]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([CH2:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
To a flask containing 1.0 g (2.67 mmol) of 4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)-benzoic acid (CAS #859027-02-4; prepared according to Asaki, T. et al. Bioorg. Med. Chem. Lett. (2006), 16, 1421-1425), 0.62 g (2.67 mmol) of 3-Iodo-4-methylaniline, 0.77 g (4.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC), and 0.43 g (3.2 mmol) of N-hydroxybenzotriazole monohydrate (HOBt.H2O) was added 5 mL of DCM and 5 mL of triethylamine. The solution was stirred at ambient temperature under an atmosphere of N2 for 3 days, concentrated, and the crude product purified by silica gel chromatography (eluted with 100% EtOAc then 10% MeOH/EtOAc), to provide 0.69 g of product as a white solid.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10]O.C=O>CO.O>[NH:1]1[C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:8][O:9][CH2:10]1
Reactant: CO
Reactant: NC1(CO)CCCCC1
Agent: C=O
Solvent: O
Product: C1CCC2(CC1)COCN2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a 500 mL flask containing 1-amino-cyclohexylmethanol (135 g, 1.05 mol) and methanol (50 mL) is added methyl formcel (53 mL of 55% formaldehyde in methanol/water, 1.06 mol) dropwise over a 1 hour period. During the addition, the stirred solution is warmed gently from room temperature to 37° C. After the addition is completed, the mixture is allowed to stir overnight at room temperature. The clear, colorless reaction mixture is stripped on a rotary evaporator (50° C./29″ vacuum). The resulting oil is distilled under vacuum giving a clear, colorless, mobile liquid with a boiling point of 43° C./0.8 torr. A total of 123.4 g is collected (83% yield). A GC analysis indicates 95.6% purity.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1.CI>CN(C)C=O>[CH3:1][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([F:7])=[N:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A round bottom flask was charged with K2CO3 (191 g, 1380 mmol), 6-fluoronicotinic acid (77.8 g, 551 mmol) and dimethylformamide (551 mL). Methyl iodide (51.5 mL, 827 mmol) was then added in one portion at room temperature and mixture stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed three times with water and once with brine, and then dried over Na2SO4. Purification by silica gel flash chromatography (ethyl acetate/dichloromethane) gave 6-fluoro-nicotinic acid methyl ester (71.8 g, 84%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 3.96 (s, 3H) 7.01 (dd, J=8.58, 2.93 Hz, 1H) 8.41 (ddd, J=8.49, 7.61, 2.44 Hz, 1H) 8.89 (d, J=2.34 Hz, 1H); MS (M+1): 156.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][CH:19]=1)=[O:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:16][CH:15]=1)=[O:13])(=[O:4])=[O:3]
Reactant: Nc1cccc(CNC(=O)c2cnc(-c3ccccc3)nc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(CNC(=O)c2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
Methanesulfonyl chloride (0.553 mmol) is added to a stirred solution of 2-phenyl-pyrimidine-5-carboxylic acid 3-amino-benzylamide (Example 115, 0.526 mmol) and triethylamine (1.05 mmol) in DCM (20 mL) at 0° C. The mixture is stirred at room temperature for an hour. The reaction mixture is quenched with 5% HCl and extracted with DCM (20 mL). The organic layer is separated, washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 0-5% MeOH in DCM to afford 2-(phenyl)-pyrimidine-5-carboxylic acid 3-methanesulfonylamino-benzylamide (200 mg) as a solid. MS: 383 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.41 (s, 3H), 4.76-4.72 (m, 2H), 7.00 (bs, N—H), 7.05-7.23 (m, 2H), 7.27-7.60 (m, 5H), 8.40-8.53 (m, 2H), 9.16 (s, 2H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[NH:14][CH:13]=[N:12]1.I[CH3:18].[NH4+].[Cl-]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:18])[CH:13]=[N:12]1
Reactant: CI
Reactant: O=c1[nH]cnn1-c1cc(F)ccc1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1cnn(-c2cc(F)ccc2Br)c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66.4 %

Procedure:
To a stirred suspension of sodium hydride (0.124 g of a 60% dispersion in mineral oil, 3.09 mmol) in DMF (5 mL) was added a solution of 1-(2-bromo-5-fluorophenyl)-1H-1,2,4-triazol-5(4H)-one (0.725 g, 2.81 mmol) in DMF (5 mL) at 0° C. The resulting mixture was stirred 45 min at room temperature followed by the addition of iodomethane (0.23 mL, 3.65 mmol). The mixture was stirred at room temperature for 2 h and then poured onto saturated aqueous NH4Cl. The product was extracted with EtOAc, washed with water (3×), brine, dried over Na2SO4 and filtered. The residue was purified with a Biotage column chromatography system on silica gel with hexanes:ethyl acetate (3:7) gradient as the eluent to afford the title compound as a white solid (0.508 g, 66% yield): 1H NMR (400 MHz, CDCl3) δ 7.65 (1H, dd, J=9.0, 5.4 Hz), 7.56 (1H, s), 7.20 (1H, dd, J=8.6, 3.0 Hz), 7.04 (1H, ddd, J=8.9, 7.6, 2.9 Hz), 3.39 (3H, s); LCMS (ESI, M+H+) m/z 272-274.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][N+:15]([O-:17])=[O:16])[CH2:5][CH3:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][N:26]=1.CS(C)=O>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[N:26][CH:27]=2)[C:10]1=[N:14][N+:15]([O-:17])=[O:16])[CH2:5][CH3:6])[CH3:2]
Reactant: CCOC(CC)OCN1CCNC1=N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(CC)OCN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Yield: 20.8 %

Procedure:
15.0 g of 1-(1-ethoxy-1-propoxy)methyl-2-nitroiminoimidazolidine, 11.6 g of anhydrous potassium carbonate, 11.3 g of 2-chloro-5-chloromethylpyridine and 60 ml of dimethyl sulfoxide were agitated at 75° C. for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. After washing with water, the extract was dried with anhydrous sodium sulfate, after which the solvent was distilled off under reduced pressure. The resultant oily residue was purified by column chromatography [silica gel, eluant hexane/ethyl acetate (1:2)] to give 4.7 g of 1-(1-ethoxy-1-propoxy)methyl-2-nitroimino-3-(2-chloropyridin-5-ylmethyl)imidazolidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[NH:14][C:15](=[O:22])[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=3[CH:11]=[C:10]([C:23](O)=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][C:28]1[N:32]=[C:31]([C@H:33]([NH2:35])[CH3:34])[O:30][N:29]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[NH:14][C:15](=[O:22])[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=3[CH:11]=[C:10]([C:23]([NH:35][C@@H:33]([C:31]3[O:30][N:29]=[C:28]([CH3:27])[N:32]=3)[CH3:34])=[O:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: CC(C)(O)Cn1c(=O)[nH]c2c(-c3ccc(F)cc3)cc(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3)c3[nH]c(=O)n(CC(C)(C)O)c3c2)n1
Temperature: 50 °C
Yield: 39.9 %

Procedure:
To a mixture of 7-(4-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (40 mg, 0.069 mmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (13.6 mg, 0.083 mmol), 1-hydroxy-7-azabenzotriazol (1.88 mg, 0.014 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (23.2 mg, 0.121 mmol) was added N,N-dimethylformamide (0.138 mL) followed by triethylamine (0.048 mL, 0.346 mmol). Reaction heated at 50° C. for 1.5 h. Reaction cooled and filtered. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TPA) gave the title compound (12.5 mg): LC-MS [M+1]=454.4; HRMS [M+1] found=454.1884; 1H NMR (500 MHz, CHCl3-d): δ 7.65 (1H, s), 7.51-7.47 (3H, m), 7.22-7.15 (2H, m), 6.97 (1H, d, J=7.81 Hz), 5.60-5.52 (1H, m), 3.85 (2H, s), 3.12 (1H, s), 2.35 (3H, s), 1.69 (3H, d, J=7.10 Hz), 1.29 (6H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([OH:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:24])=[N-]>COCCOC.CCOCC>[CH3:24][O:19][C:18](=[O:20])[CH2:17][C@@H:16]([OH:21])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: COCCOC
Product: COC(=O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 450 mg (1.52 mmoles) of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoic acid in 1,2-dimethoxyethane, while being cooled in ice, was added dropwise 7 ml (4.56 mmoles) of a solution of diazomethane in ether. The mixture was stirred for 30 minutes. The reaction mixture was evaporated to dryness to yield 461 mg (98% yield) of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoic acid methyl ester; [α]D21 +1°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=2[F:26])[C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[F:22])=[O:13])[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:35]2[NH:39][CH:38]=[C:37]([C:40]([O:42][CH3:43])=[O:41])[CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O.O1CCOCC1>[F:26][C:25]1[CH:24]=[CH:23][C:11]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[F:22])=[O:13])=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:35]2[NH:39][CH:38]=[C:37]([C:40]([O:42][CH3:43])=[O:41])[CH:36]=2)[CH:7]=1
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(Cl)c3)c2)c1
Reactant: COC(=O)c1c[nH]c(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 100 °C

Procedure:
A mixture of 3-(2-Chloropyridin-4-yloxy)-4-fluoro-N-(2-fluoro-5-methylphenyl)benzamide (1.217 g, 3.25 mmol), methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (1.63 g, 6.50 mmol) and potassium carbonate (0.67 g, 4.87 mmol) in water (2.5 mL) and dioxane (15 mL) was purged with nitrogen for several minutes. To the mixture was added tetrakis-triphenylphosphine palladium(0) (0.18 g, (0.16 mmol). The reaction was sealed under nitrogen and heated at 100° C. for 15 h. The cooled reaction was mixed with dichloromethane and filtered through Celite. The red solution was evaporated. The resulting oil was dissolved in dichloromethane, put on a column of silica gel (80 g) and eluted with hexane/EtOAc (1:1) to afford methyl 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate as white solid. Yield: 1.162 g, 77%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: OCCc1cccc(O)c1
Reactant: COC(=O)c1ccccc1CBr
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1cccc(CCO)c1
Reaction time: 8 h
Yield: 96 %

Procedure:
3-(2-Hydroxyethyl)phenol (1.0 g, 7.24 mmol) and methyl 2-(bromomethyl)benzoate (1.74 g, 7.6 mmol) was dissolved in acetonitrile (10 ml). Potassium carbonate anhydrous (2.0 g, 14.48 mmol) was added. After stirring at 60° C. for three hours PS-trisamine was added (0.3 eq) and was stirred overnight. The PS-trisamine was filtered off and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic layer was washed with 3 portions of water (3×10 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 1.99 g of methyl 2-{[3-(2-hydroxyethyl)phenoxy]methyl}benzoate (yield 90%).
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>ClCCl>[C:15]([O:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: ON1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)ON1CCCCC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
A few of the inventive 1-hydroxypiperidine (0.96 g, 9.49 mmol) and triethylamine (1.50 mL, 10.8 mmol) were dissolved in anhydrous dichloromethane (40 mL) and cooled to 0° C. Methacryloyl chloride (1 mL, 10.2 mmol) was then added slowly, dropwise. The reaction was then slowly warmed to room temperature. After 2.5 h, the reaction mixture was washed with deionized water (40 mL), 1 M NaOH (20 mL), deionized water (20 mL), 5% citric acid (20 mL), and brine (20 mL). After drying over sodium sulfate and filtering, the product was concentrated by rotary evaporation and dried in vacuo to give and amber liquid. Flash chromatography on silica gel, eluting with dichloromethane, followed by 1-5% methanol:dichloromethane afforded piperidin-1-yl methacrylate as an amber liquid (1.23 g, 76%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][CH:19]([CH3:21])[CH3:20])[N:11]=2)[CH2:3]1.[OH-:22].[Na+].OO>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]([NH2:17])=[O:22])=[CH:14][N:13]=[C:12]([NH:18][CH:19]([CH3:21])[CH3:20])[N:11]=2)[CH2:3]1
Reactant: CC(C)Nc1ncc(C#N)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)Nc1ncc(C(N)=O)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
4-((1R,3R,4R)-3-Hydroxy-4-methylcyclohexylamino)-2-(isopropylamino)pyrimidine-5-carbonitrile (0.38 g, 1.313 mmol) was dissolved in DMSO (5 mL). To this solution was added a 50% aqueous sodium hydroxide solution (0.103 ml, 1.970 mmol) and a 30% aqueous hydrogen peroxide solution (0.101 ml, 0.985 mmol) at room temperature. Then the reaction mixture was stirred at 50° C. for 1 h. After that, the reaction mixture was poured into ice water (15 mL) and the resulting mixture was stirred for 1 h. The resulting precipitate was filtered and washed with water to afford 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(isopropylamino)pyrimidine-5-carboxamide (0.210 g, 0.683 mmol, 52% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 0.94 (d, J=6.40 Hz, 4H) 1.12 (d, J=5.91 Hz, 9H) 1.65 (dd, J=13.29, 2.95 Hz, 1H) 1.92 (br. s., 1H) 2.15 (br. s., 1H) 2.97 (br. s., 1H) 3.81-4.14 (m, 2H) 4.55 (d, J==5.41 Hz, 1H) 6.70-7.02 (m, 1H) 8.34 (br. s., 1H) 8.92 (br. s., 1H); MS (ESI) m/z 308.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[ClH:23]>ClCCl.O1CCOCC1>[ClH:23].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1ccc(OCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a cooled solution of tert-butyl 4-[(4-fluorophenoxy)methyl]piperidine-1-carboxylate (538 mg, 1.74 mmol; which may be prepared as described in Step 1) in dichloromethane (11.5 mL) was added dropwise HCl 4N in dioxane (8.5 mL). The solution was warmed to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure to give the title compound (416 mg, 97%) as a white solid.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:23]#[N:24]>ClCCl.CN(C=O)C.CO.ClC(Cl)C.N(CC)(CCC)CCC>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:20]([NH:19][C:10]([C:3]2[N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1][CH:2]=2)=[O:12])[CH:21]=1)#[N:24]
Reactant: Cc1ccc(C#N)cc1N
Reactant: O=C(O)c1cnc2ccccn12
Agent: CCCN(CC)CCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C#N)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Yield: 35.5 %

Procedure:
To a suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (16.6 g, 102 mmol) in dichloromethane (300 mL) and DMF (0.5 mL) at 0° C. was added oxalyl chloride (45 mL, 510 mmol) dropwise over 10 minutes. The reaction was slowly warmed to room temperature and stirred until complete conversion was detected by LCMS in MeOH. The reaction was subsequently reduced to dryness and suspended in dichloroethane (100 mL) and was added to a solution of 3-amino-4-methylbenzonitrile (7) (15 g, 113 mmol) in dichloroethane (200 mL) and Pr2NEt (55 mL) at 0° C. After the addition, the cold bath was removed and contents were stirred at room temperature for 1 hour and then heated to 50° C. for another 2 hours. After the completion of the reaction, the mixture was cooled and a white precipitate formed. The mixture was filtered and the solid was washed with cold dichloromethane. About 10 g of the desired N-(5-cyano-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (8) was obtained. The filtrate was washed with saturated NH4Cl, saturated NaHCO3, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude solid was triturated with diethyl ether to remove excess aniline and filtered to afford another crop of N-(5-cyano-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (8) as a white solid. MS m/z 277.1 (M+1).