Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[N:21]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.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.O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:4]2[CH:3]=[C:2]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:21]=[CH:22][CH:23]=[CH:24]4)[N:7]=[C:6]([O:8][CH3:9])[N:5]=2)=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc2ncccc2c1
Reactant: COc1ccc(CCNc2cc(Cl)nc(OC)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CCNc2cc(-c3ccc4ncccc4c3)nc(OC)n2)cc1
Yield: 71 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine (150 mg, 0.51 mmol, Intermediate (8) prepared as described in Example 2 step 1), quinoline-6-boronic acid [176 mg, 1.02 mmol, Intermediate (22)], Cs2CO3 (590 mg, 1.81 mmol) tetrakis(triphenylphosphine)palladium (0) (59 mg, 0.051 mmol), ethylene glycol dimethyl ether (4 mL) and water (1 mL) is placed in a microwave tube, sealed and evacuated and flushed with argon three times and irradiated in a microwave oven at 140° C. for 10 minutes. The reaction mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residual solid is subjected to flash column chromatography on silica gel eluting with a mixture of EtOAc and heptane. The material is recrystallized from MeOH to afford [2-(4-methoxy-phenyl)-ethyl]-(2-methoxy-6-quinolin-6-yl-pyrimidin-4-yl)-amine [140 mg, 71%, Example 10(a)] LCMS: RT=5.97 minutes, MS: 387 (M+H). IC50=0.6 nM
Reaction SMILES: C([Li])CCC.[CH:6]1[N:7]=[CH:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=12.[CH2:15]=[O:16].Cl>CCOCC>[OH:16][CH2:15][C:8]1[N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[CH:6][N:7]=1
Reactant: c1ncn2c1CCCC2
Reactant: C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: OCc1ncc2n1CCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.58 molar n-butyl lithium in N-hexane (49 ml.) was added over 0.5 hour to a stirred solution of 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (8.9 g.) in dry ether at -60° under nitrogen. After 3 hours, gaseous formaldehyde generated by the thermal condensation of paraformaldehyde (6.9 g.) was passed into the red solution. The mixture was allowed to warm to room temperature overnight, acidified with hydrochloric acid and extracted with chloroform. The aqueous layer was basified with an excess of saturated sodium carbonate solution and extracted with chloroform. Concentration and recrystallisation of the residue from ethanol-ethyl acetate-petroleum ether afforded 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (7.7 g.), m.p. 188°-199°.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Br:9][C:10]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:13]([CH:14]=[O:15])=[C:12](F)[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(OC)(C)C>C(#N)C>[Br:9][C:10]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([N:4]2[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]2)[CH:11]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=Cc1cc([N+](=O)[O-])c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CC1CN(c2cc(Br)c([N+](=O)[O-])cc2C=O)CC(C)O1
Temperature: 25 °C
Reaction time: 63 h
Yield: 63.6 %

Procedure:
A solution of cis-2,6-dimethylmorpholine (1.06 g, 9.20 mmol) in acetonitrile (40 mL) is added to a flask containing 4-bromo-2-fluoro-5-nitrobenzaldehyde (from Step 1) (2.0 g, 8.06 mmol) and potassium carbonate (3.92 g, 28.4 mmol). The resulting slurry is stirred at room temperature for 63 hours. The mixture is poured into MTBE (100 mL) and is washed with water (100 mL) followed by brine (100 mL). The organics are filtered through silica gel and concentrated to give 1.76 g of bright yellow solid. 1H NMR (DMSO-d6) δ 9.93, 8.44, 7.53, 3.74–3.81, 3.48, 2.78, 1.12.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([CH2:26][CH2:27][CH3:28])=[N:18][C:19]3[N:20]([N:23]=[CH:24][CH:25]=3)[C:21]=2O)=[CH:11][CH:10]=1)#[N:2].O=P(Cl)(Cl)[Cl:31]>ClCCl>[Cl:31][C:21]1[N:20]2[N:23]=[CH:24][CH:25]=[C:19]2[N:18]=[C:17]([CH2:26][CH2:27][CH3:28])[C:16]=1[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:10][CH:11]=1
Reactant: CCCc1nc2ccnn2c(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCc1nc2ccnn2c(Cl)c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
27 g of 6-[(2'-cyanobiphenyl-4-yl)methyl]-7-hydroxy-5-propylpyrazolo[1,5-a]pyrimidine, prepared in Example 18, are added in portions to 540 ml of POCl3. The mixture is refluxed for 3 h. It is concentrated under vacuum. The oil obtained is taken up in dichloromethane and washed twice with a solution of water and ice. The organic phase is decanted, dried and concentrated. The yellow oil is taken up in ether to give 25.6 g of crystals of 7-chloro-6-[(2'-cyanobiphenyl-4-yl)methyl]-5-propylpyrazolo[1,5-a]pyrimidine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:26][O:27][CH2:28][C:29]1[C:30]([NH:44][CH3:45])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[CH:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:33]5[CH:32]=[N:31][C:30]([NH:44][CH3:45])=[C:29]([CH2:28][O:27][CH3:26])[CH:34]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:25])[C:13]2=[O:24])[C:16]([CH3:23])=[N:17]1)([CH3:22])[CH3:21]
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1COC
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C(C)C)nc2C)c(=O)n4C)cc1COC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G) and [3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine (Stage 248.1.1) to give the title compound as a yellowish foam. (HPLC: tR 2.24 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.20 (s, 1H), 8.15-8.13 (m, 1H), 8.05-8.02 (m, 1H), 7.85-7.81 (m, 1H), 7.48-7.45 (m, 1H), 7.43-7.41 (m, 1H), 6.13 (q, 1H), 4.55 (hp, 1H), 4.30 (s, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 2.86 (d, 3H), 1.96 (s, 3H), 1.49-1.45 (m, 6H))
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:17])[N:10]([C@@H:18]3[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]3[O:20][C:21](=[O:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:8]([CH2:7][C:5]1[S:6][C:2]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[CH:3][CH:4]=1)=[CH:9][N:10]2[C@@H:18]1[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]1[O:20][C:21](=[O:23])[CH3:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cu]I
Agent: [Pd]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(-c4ccccn4)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A mixture of 3-(5-bromothiophen-2-yl-methyl)-4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 45-(3) (345 mg), 2-(tri-n-butylstannyl)pyridine (997 mg), copper(I) iodide (20 mg) and tetrakis(triphenylphosphine)-palladium(0) (63 mg) in toluene (10 ml) was refluxed for 3 hours under argon atmosphere. The reaction mixture was diluted with ethyl acetate, and thereto was added a 10% aqueous potassium fluoride solution. The resultant mixture was stirred vigorously, and the insoluble materials were filtered off. The filtrate was separated, and the organic layer was washed with brine and dried over sodium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate=90:10-50:50) to give 4-methyl-3-(5-(2-pyridyl)thiophen-2-yl-methyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole (122 mg) as a pale yellow solid. APCI-Mass m/Z 635 (M+H).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[NH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.C>O1CCOCC1>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([NH:20][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]2=3)=[O:3])[CH2:22][CH2:23]1
Reactant: CN1CCN(N)CC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Solvent: C1COCCO1
Product: CN1CCN(NC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1

Procedure:
A mixture of 5.5 gm (0.0202 mol) of 5-chlorocarbonyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 8.6 gm (0.075 mol) of 1-amino-4-methylpiperazine, and 200 ml of anhydrous dioxane was heated for 30 minutes over a steam bath. Then, 2 gm of active charcoal were added to the resulting cloudy reaction mixture while it was still hot, the mixture was filtered, and the filtrate obtained was concentrated by evaporation in vacuo. The residue was purified by column chromatography on 300 gm of silica gel [eluant: dichloromethane/methanol/conc. aqueous ammonia mixture (volume ratio of 800:200:5)]. The residue remaining after the eluates had been concentrated was taken up in 500 ml of ethyl acetate, 1 gm of active charcoal was added, and the resulting mixture was boiled, filtered, and concentrated by evaporation. Then, 300 ml of methanol were added, and the resulting mixture was filtered while hot and evaporated to dryness. After recrystallization from ethanol, 1.8 gm (25% of theory) of colorless crystals were obtained, m.p.: 213°-214° C. (D).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:10][CH2:11][CH3:12])[NH:6][C:7]=1[CH:8]=[O:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C>[F:19][C:20]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:6]1[C:7]([CH:8]=[O:9])=[C:3]([CH2:1][CH3:2])[N:4]=[C:5]1[CH2:10][CH2:11][CH3:12]
Reactant: Fc1cc(I)ccc1CBr
Reactant: CCCc1nc(CC)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc(CC)c(C=O)n1Cc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
4-Ethyl-2-propyl-1H-imidazole-5-carboxaldehyde (6.32 g, 38.0 mmol), potassium carbonate (10.57 g, 76.5 mmol), and 2-fluoro-4-iodobenzyl bromide (13.90 g of 86%, 38.0 mmol) were added together with 50 mL of DMF. The reaction mixture was stirred at room temperature overnight under N2. The solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic mixture was washed with H2O and brine, dried over MgSO4 and concentrated. The crude product mixture was purified by flash chromatography (silica gel, 30-50% EtOAc/hexane) to yield 10.63 g orange oil (70%). MS m/e 401.0, [M+H]+ ; 1H NMR (300 MHz, CDCl3): δ 0.95 (t, 3H, CH3), 1.32 (t, 3H, CH3), 1.70 (m, 2H, CH2), 2.60 (m, 2H, CH2), 2.82 (q, 2H, CH2), 5.52 (s, 2H, CH2Ar), 6.42 (t, 1H, ArH), 7.38 (d, 1H, ArH), 7.42 (d, 1H, ArH), 9.73 (s, 1H, CHO). ##STR62##
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([C:22](=[O:23])[NH:21][C:20](=[O:24])[NH:19]2)[C:11]1=[O:25]>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([N+:1]([O-:4])=[O:2])=[CH:16][CH:17]=2)[C:12]2([C:22](=[O:23])[NH:21][C:20](=[O:24])[NH:19]2)[C:11]1=[O:25]
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Fuming nitric acid (0.2 ml.) was added during 10 minutes to a stirred solution of 1'-(3,4-dichlorobenzyl)spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.79 g.) in concentrated sulphuric acid (1.5 ml.). maintained at a temperature of 0°-5° C. The reaction mixture was then stirred at 0°-5° C. for 1 hour and finally at 5°-20° C. for a further 1 hour. The solution was then poured onto crushed ice (300 g.) and the mixture which formed was extracted with ethyl acetate. The combined extracts were washed with water (3×150 ml.) then with brine (100 ml.) and dried (MgSO4). The extracts were evaporated and the residual oil was redissolved in ethyl acetate (20 ml.). The solution was evaporated on to chromatographic silica gel and the solid residue added to the top of a column of the same silica gel made up in toluene. The column was eluted with increasing concentrations of ethyl acetate in toluene (up to 1:1 v/v). The fractions containing the major component [TLC: Rf~0.6 on SiO2 : eluant 1:1 v/v EtOAc/toluene] were combined and evaporated. The residue was recrystallised from a mixture of toluene, ethyl acetate and petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-5'-nitrospiro[imidazolidine-4,3'-indoline]-2,2',5-trione (Example 35) (0.46 g.), m.p. 249°-251° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[N:12]2[C:26](=[O:45])[C@@H:27]([CH2:33][N:34]([CH:43]=[O:44])[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:10])=[N:6][CH:7]=1.ClC1C=C(C(OO)=[O:54])C=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[N:12]2[C:26](=[O:45])[C@@H:27]([CH2:33][N:34]([CH:43]=[O:44])[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:10])=[N+:6]([O-:54])[CH:7]=1
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccc(F)cn2)CCN1C(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccc(F)c[n+]2[O-])CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
To a solution of phenylmethyl (3S)-3-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-pyrazolidinecarboxylate (130 mg, 0.210 mmol) in dichloromethane (DCM) (4 mL) under nitrogen at 0° C. was added 3-chlorobenzenecarboperoxoic acid (141 mg, 0.629 mmol) in one portion. The reaction mixture was stirred at 0° C. for 10 min, then warmed up to room temperature and stirred overnight. The reaction was quenched by addition of sat. aq. NaHCO3 and extracted with DCM twice. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford the crude product as a white semi-solid. The crude product was purified by RP-HPLC to provide phenylmethyl (3S)-3-{[(5-fluoro-1-oxido-2-pyridinyl)amino]carbonyl}-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-pyrazolidinecarboxylate (103 mg, 77%). LCMS: (M+H)+: 636.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2C)[CH:5]=[C:4]([C:15]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])[N:3]=1.O.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(COC)OC.C(O)C>[CH3:16][C:15]([C:4]1[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=[C:2]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[CH:35][CH:36]=2)[N:3]=1)([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:21]
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nc(N3CCOCC3)cc(C(C)(C)S(C)(=O)=O)n2)cc1
Temperature: 90 °C
Yield: 99.7 %

Procedure:
(3S)-4-{2-Chloro-6-[1-methyl-1-(methylsulfonyl)ethyl]pyrimidin-4-yl}-3-methylmorpholine (1.75 g, 5.47 mmol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 dimethoxyethane:water:ethanol (18 mL). Tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (2.62 g, 8.2 mmol), 2M sodium carbonate solution (8 mL) and dichlorobis(triphenylphosphine) palladium catalyst (192 mg, 0.27 mmol) were then added and the reaction refluxed at 90° C. for 2 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temp then partitioned between ethyl acetate (20 mL) and water (20 mL). The organics were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude solid was chromatographed on silica, eluting with 0-30% ethyl acetate in DCM to give the desired material as a white solid (2.6 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:21])=[C:16](B(O)O)[CH:17]=1)[CH3:10]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:13]=[C:12]([O:11][CH2:9][CH3:10])[CH:17]=[CH:16][C:15]=2[F:21])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOc1ccc(F)c(B(O)O)c1
Product: CCOc1ccc(F)c(-c2ccc(Br)cn2)c1
Yield: 47 %

Procedure:
Obtained (1.18 g, yield 47%) following the procedure described in Intermediate 27, starting with 2,5-dibromopyridine (8.44 mmol, 2.0 g), 5-ethoxy-2-fluorophenylboronic acid (8.43 mmol, 1.55 g).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:4]=1[CH2:5][N:6]1[CH2:9][CH:8]([NH2:10])[CH2:7]1.[Cl:18][C:19]1[N:28]=[C:27](Cl)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.CCN(CC)CC>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[N:28]=[C:27]([NH:10][CH:8]2[CH2:9][N:6]([CH2:5][C:4]3[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:3]=3[N:2]([CH3:17])[CH3:1])[CH2:7]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COc1cccc(N(C)C)c1CN1CC(N)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(N(C)C)c1CN1CC(Nc2nc(Cl)nc3ccccc23)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Compound 168 (0.22 g, 0.92 mmol) in THF (10.0 mL) at 0° C. was added 2,4-dichloroquinazoline (0.22 g, 1.10 mmol), followed by Et3N (0.65 mL, 4.60 mmol) and DMAP (catalytic amount), and the reaction was allowed to warm up slowly to ambient temperature and stirred for 18 h, then quenched with 7N NH3 in MeOH. The solvent was removed, and the residue was purified by preparative thin layer chromatography with 7N NH3 in MeOH (2%), hexanes (8%) and CH2Cl2 (90%) to afford the compound EE as a yellow solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+].O.NN>C(O)CO>[C:8]1([C:3]2([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CCC1(c2ccccc2)CCCCC1=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C(O)CCC1(c2ccccc2)CCCCC1
Temperature: 130 °C

Procedure:
A mixture of 3-(2-oxo-1-phenylcyclohexyl)propanoic acid (1 g, 4.06 mmol), potassium hydroxide (0.770 g, 13.72 mmol), hydrazine monohydrate (0.348 mL, 6.09 mmol) and ethylene glycol (5 mL) was heated to 130° C. for 1.5 h. The condenser was removed and the mixture was heated to 200° C. for 30 min. The reaction mixture was then heated under reflux with a reflux condenser for additional 1.5 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl to a total reaction volume of 25 mL. The precipitated product was collected by filtration, washed several times with water, and dried in vacuo to obtain 3-(1-phenylcyclohexyl)propanoic acid as a white solid (1C, 923 mg, 93% yield). HPLC: tR=3.7 min, Chromolith SpeedRod 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.2% H3PO4; Final solvent: 90% aq. MeOH—0.2% H3PO4. LC/MS: m/e 215.19 (M+H−H2O)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:15]>CN(C=O)C>[Br:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc2nccc(O)c2c1
Solvent: CN(C)C=O
Product: COc1ccc2nccc(Br)c2c1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-hydroxy-6-methoxyquinoline (1.20 g, 70.5 mmole) in DMF (60 mL) at RT was added PBr3 (8.0 mL, 84.6 mmole) dropwise. After 2 h, the reaction contents were poured onto H2O (300 mL) and the product filtered and washed with H2O to give, after drying under high vacuum, the title compound (14.3 g, 87%) as a light yellow solid: LC-MS (ES) m/e 233 (M+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Clc1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 4-chlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 336.0 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.59 (s, 1H); 8.43 (d, J=4.6 Hz, 1H); 8.02 (br s, 1H); 7.86 (m, 1H); 6.86 (d, J=5.5 Hz, 1H); 5.79 (br s, 1H ); 4.73 (d, J=5.9 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([CH3:23])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[F:20])[N:16]([CH3:21])[C:15](=[O:22])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[Cl:24][C:25]1[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[F:20][C:19]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:22])[N:16]2[CH3:21])=[CH:11][C:10]=1[C:6]1[C:5]([CH3:23])=[C:4]([CH2:3][NH:2][C:31]([C:26]2[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:32])[CH:9]=[N:8][CH:7]=1
Reactant: Cc1c(CN)cncc1-c1cc2c(cc1F)N(C)C(=O)CC2
Reactant: O=C(O)c1ncccc1Cl
Agent: Cl
Product: Cc1c(CNC(=O)c2ncccc2Cl)cncc1-c1cc2c(cc1F)N(C)C(=O)CC2

Procedure:
In analogy to the procedure described for the preparation of example 75, 6-(5-aminomethyl-4-methyl-pyridin-3-yl)-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 226) has been coupled with 3-chloro-pyridine-2-carboxylic acid to give the title compound as a colorless solid. MS: 439.4 (M+H+).