Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:4]([CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])=[C:4]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27]
Reactant: CCOC(=O)C(O)c1c(C)c(Br)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)c(Br)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A solution of ethyl 2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (crude, 1.22 g, ˜2.60 mmol) in DCM (60 mL) was treated with Dess-Martin periodinane (1.32 g, 3.12 mmol) at 23° C. After 30 min, 10% Na2S2O3 (30 mL) was added at 23° C. The system was diluted with H2O (20 mL) and extracted with DCM (3×30 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was treated with benzene, filtered, and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (1.18 g, 98% yield over 2 steps from ethyl 2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=8.6 Hz, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.77 (dd, J=8.6, 8.2 Hz, 1H), 7.71 (dd, J=8.6, 8.6 Hz, 1H), 4.42 (q, J=7.0 Hz, 2H), 2.57 (s, 3H), 1.39 (t, J=7.0 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−73.3 (s).
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.Br[CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18]>C(Br)C.O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccsc1-c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: CCBr
Solvent: C1CCOC1
Product: Cc1ccsc1-c1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
To a mixture of 1.2 g (0.05 mole) of magnesium turnings and 50 ml of anhydrous tetrahydrofuran was added under a nitrogen stream one drop of ethyl bromide, followed by adding 10 g (0.0395 mole) of 4-(3-methyl-2-thienyl)-1-bromobenzene (boiling point 171°-175° C./16-17 mmHg). After refluxing for 30 minutes, the mixture was cooled. To the mixture was added a solution of 2.8 g (0.0205 mole) of anhydrous zinc chloride in 50 ml of anhydrous tetrahydrofuran, and the mixture was stirred at room temperature for 3 hours. To the mixture was added 7.2 g (0.0398 mole) of ethyl 2-bromopropionate. After having been stirred at 50° to 60° C. for one hour, the mixture was freed from the solvent by distillation under reduced pressure. The residue was mixed with 50 ml of 2 N hydrochloric acid and 50 ml of benzene. The organic layer was separated, washed with water, and freed from the solvent by distillation under reduced pressure. The residue was mixed with 50 ml of an ethanol solution containing 2.3 g of sodium hydroxide, heated under reflux for 3 hours, and then freed from the ethanol by distillation. The residue was mixed with 100 ml of water and 50 ml of benzene. The aqueous layer was separated, neutralized with hydrochloric acid, and the liberated oily substance was extracted with cyclohexane. The extract solution was dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: cyclohexane) to obtain 3.2 g (32.9% yield) of intended 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)(=O)=O.[CH3:18][NH:19][CH3:20]>CO.O1CCCC1>[CH3:18][N:19]([CH2:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CC1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Yield: 79.9 %

Procedure:
To a solution of tert-butyl 3-[(methanesulfonyloxy)methyl]azetidine-1-carboxylate (1.05 g) in methanol (20 ml) was added a 2M solution of dimethylamine in tetrahydrofuran (20 ml), followed by heating in a sealed tube at 70° C. for 40 hr. The reaction mixture was allowed to cool down to room temperature. The reaction mixture was concentrated, and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed to provide the titled compound as a yellow oil (678 mg, 79.9%).
Reaction SMILES: CN(C=O)C.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[I:12][C:13]1[CH:22]=CC2[C:15](=[CH:16][NH:17][C:18](=O)[N:19]=2)[CH:14]=1>ClCCCl>[I:12][C:13]1[CH:22]=[C:7]2[C:16](=[CH:15][CH:14]=1)[N:17]=[CH:18][N:19]=[C:6]2[Cl:11]
Reactant: O=c1nc2ccc(I)cc2c[nH]1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C

Procedure:
To a stirred solution of DMF (6.3 mL) in DCE (20 mL) cooled to 0° C. was added dropwise a solution of oxalyl chloride (60 mL of a 2M solution in DCE). After addition was complete, the cooling bath was removed and 6-iodo-3H-quinazolinone (10 g, 36.8 mmol) was added as a solid. The resulting mixture was heated to reflux under nitrogen for 3 hours. Upon cooling to room temperature, the reaction was quenched cautiously with H20. CH2Cl2 was added and the bilayer transferred to a separatory funnel. The aqueous layer was extracted with CH2Cl2 (2×50 mL) and the combined organic layers dried (Na2SO4). The solvent was removed in vacuo to provide a yellow solid which was triturated with diethyl ether to remove any remaining impurities. The resulting yellow solid obtained by filtration was shown to be pure by NMR. 1HNMR (CDCl3, 400 MHz): δ: 9.05 (s, 1H), 8.65 (d, 1H), 8.21 (dd, 1H), 7.78 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]3=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([NH:29][NH2:30])(=O)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]4[C:21]([C:22]5[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=5)=[N:29][N:30]=[C:15]34)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccncc1
Reactant: O=C1NCCCC1Cc1noc(-c2cccc(Cl)c2)n1
Solvent: ClCCl
Product: Clc1cccc(-c2nc(CC3CCCn4c(-c5ccncc5)nnc43)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
37 mg (0.25 mmol) Me3OBF4 was added to a solution of 60 mg (0.21 mmol) 3-[5-(3-chloro -phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one in 2 ml CH2Cl2. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with CH2Cl2, washed with NaHCO3 (sat), dried and concentrated. The residue was dissolved in 3 ml EtOH and 22 mg (0.16 mmol) isonicotinic hydrazide was added. The solution was heated with microwaves at 120° C. for 10 min. The reaction mixture was cooled and the volatiles were removed under reduced pressure. The crude product was purified by preparative HPLC to afford 17 mg (20%) of the desired product. 1H NMR (CDCl3):d ppm 1.75 (m, 1 H) 1.99 (m, 1 H) 2.21 (m, 2 H) 3.16 (dd, 1 H) 3.73 (m, 1 H) 3.85 (dd, 1 H) 4.07 (m, 1 H) 4.19 (m, 1 H) 7.47 (t, 1 H) 7.56 (m, 1 H) 7.67 (m, 2 H) 8.01 (m, 1 H) 8.11 m, 1 H) 8.76 (d, 2H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:22]=[C:23]4[N:29]=[C:28]([CH3:30])[N:27](COCC[Si](C)(C)C)[C:24]4=[N:25][CH:26]=3)[CH:19]=2)[N:14]=[CH:13][N:12]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:22]=[C:23]4[N:29]=[C:28]([CH3:30])[NH:27][C:24]4=[N:25][CH:26]=3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: Cc1nc2cc(-c3ccc4ncnc(N5CCc6ccccc6C5)c4c3)cnc2n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cc(-c3ccc4ncnc(N5CCc6ccccc6C5)c4c3)cnc2[nH]1
Yield: 36.2 %

Procedure:
0.70 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazoline and 825 μl of trifluoroacetic acid in 8 ml of dichloromethane are stirred at 25° C. in a flask until the reaction is complete (HPLC check, about 120 hours). The cooled reaction solution is diluted with dichloromethane and washed with sodium hydrogencarbonate solution. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient EA: methanol 0-30% in 13 min), giving 0.19 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline (“A4”) as white solid (yield 36%, content 97%); MS-FAB (M+H+)=393.1; Rf (polar method): 1.39 min;
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:22])=O.O>C(#N)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:22])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2ccccc2c1O
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)c1nc(Br)c2ccccc2c1O
Temperature: 80 °C
Reaction time: 64 h
Yield: 3.9 %

Procedure:
2 g (7.7 mmol) of 1,4-Dihydroxy-isoquinoline-3-carboxylic acid butyl ester (from Example D-20b) dissolved in 100 ml of acetonitrile. 15.4 g (53.6 mmol) of phosphorous oxybromide added to solution and mixture stirred at 80° C. for 64 h. 100 ml of water was added to mixture, and mixture was removed from heat. Mixture was partitioned between ethyl acetate and water. Two phases were separated and the aqueous layer was extracted with ethyl acetate. Organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, and evaporated. Residue was purified by silica gel flash chromatography to give 0.1 g (0.3 mmol) of product. 1H NMR (200 MHz, CDCl3) δ 11.89 (s, 1H), 8.41 (m, 1H), 8.25 (m, 1H), 7.84 (m, 2H), 4.49 (t, J=7.0 Hz, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 1.00 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:30][C:31]1[N:36]=[C:35]([C:37]#[C:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:34]([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:47])=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([O:10][C:8](=[O:9])[N:2]([CH3:1])[CH:3]([CH3:7])[C:4]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:47])=[C:35]([C:37]#[C:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:36]=1)=[O:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (34 mg, 0.17 mmol) and N,N′-dicyclohexylcarbodiimide (17 mg, 0.08 mmol) in DCM (1 ml) is stirred at RT for 20 minutes. This mixture is added to N-[6-amino-2-(2-phenylethynyl)pyridin-3-yl]oxane-4-carboxamide D5b (28 mg, 0.09 mmol) and DIPEA (17 μl; 0.10 mmol) in DCM (1 ml). After stirring for 6 days at 40° C. the reaction mixture is diluted with DCM and extracted with water. The combined organic layers are dried over MgSO4 to and concentrated in vacuo. The crude product (70 mg) is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33])[N:13]=1
Reactant: NC(CO)CO
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Product: O=c1ccc2c(-c3ccccc3Cl)nc(NC(CO)CO)nc2n1-c1ccccc1Cl

Procedure:
The product of Example 47, and serinol were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.44 (m, 1H), 3.68 (m, 4H), 6.30 (br s, 1H), 6.48 (d, 1H, J=9.7 Hz), 7.24-7.65 (m, 9H). LC MS (m/e)=457 (MH+).
Reaction SMILES: Cl/[C:2](/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]/[O-].[K+].S(=O)(=O)(O)O.O.[CH:17]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH2:35])[CH:30]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]>CCOCC>[CH:17]([N:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]3[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:35]=[C:31]3[CH:30]=2)[CH2:24][CH2:25]1)([CH3:19])[CH3:18]
Reactant: CCOC(=O)/C(Cl)=C\[O-]
Reactant: CC(C)N1CCN(CCOc2ccnc(N)c2)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cnc2cc(OCCN3CCN(C(C)C)CC3)ccn12
Temperature: 65 °C
Yield: 59.4 %

Procedure:
Potassium (E)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (Preparation E; 41.32 g, 219.0 mmol) was suspended (through vigorous magnetic stirring) in anhydrous ether (365 mL) and 6N sulfuric acid (18.25 mL, 109.5 mmol) was added. Water (100 mL) was added to aid in phase separation. When the pH of the bottom (aqueous) phase, dropped below 3, the ether layer was separated. The aqueous phase was further extracted with ether (400 mL). The combined ether phases were dried over sodium sulfate and magnesium sulfate for 10 minutes. The solution was filtered and concentrated under reduced pressure, with the temperature of the water bath not exceeding 20° C. A residual oil was obtained, which crystallized upon drying under high vacuum overnight. This residue was dissolved in absolute EtOH (360 mL). 4-(2-(4-Isopropylpiperazin-1-yl)ethoxy)pyridin-2-amine (Preparation G; 28.95 g, 109.5 mmol) was added, and the mixture was heated under nitrogen at 65° C. for 18 hours. After allowing the mixture to cool, the resulting suspension was evaporated to dryness. The resulting solids were shaken with THF and collected by filtration, then dried under vacuum. This material (HCl salt) was mixed with water (400 mL) and ethanol (200 mL). Sodium bicarbonate (20 g) was added and the mixture was stirred for 16 hours (some effervescence occurred). The suspension was evaporated to dryness under vacuum. The solids were shaken in EtOAc/THF and filtered. These solids were washed with a large volume of ethyl acetate and THF. The organic solution was further dried with sodium sulfate and magnesium sulfate, filtered and evaporated under vacuum to give an amber gum. This material was triturated with 2:1 ether-hexanes, and the resulting solids were collected by filtration to afford ethyl 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (23.46 g, 59% yield) as beige solids.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]#[N:17])=[C:14]([CH2:18][CH3:19])[S:13][C:12]=2[C:20]([NH2:22])=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:25]([N:28]([CH3:30])[CH3:29])OC>>[CH3:25][N:28]([CH:30]=[N:22][C:20]([C:12]1[S:13][C:14]([CH2:18][CH3:19])=[C:15]([C:16]#[N:17])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=1)=[O:21])[CH3:29]
Reactant: COC(OC)N(C)C
Reactant: CCc1sc(C(N)=O)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Product: CCc1sc(C(=O)N=CN(C)C)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Prepare a solution of 3-(4-tert-butyl-phenyl)-4-cyano-5-ethyl-thiophene-2-carboxylic acid amide (270 mg, 0.86 mmol) in 4 mL of dry dimethoxymethyl-dimethyl-amine and heat to reflux under nitrogen. After 1 hour allow 1 mL of solvent to distill out of the reaction, then cool the mixture to room temperature. Dilute the slurry with 10 mL of hexanes, filter off the resulting yellow product and wash with 5 mL hexanes. Vacuum-dry the solid overnight to give 261 mg (82%) of the title compound. MS(ES+, m/e)=368 (M++1).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([N:17]([CH3:30])[CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[C:13](=[O:31])[CH2:12]1)=O)C1C=CC=CC=1.[ClH:32]>C(OCC)(=O)C.CO.[Pd]>[ClH:32].[ClH:32].[CH3:30][N:17]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:31]
Reactant: CN(C1CCN(c2ccncc2)CC1)N1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C1CCN(c2ccncc2)CC1)N1CCNCC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-benzyloxycarbonyl-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-2-piperazinone (2.22 g) and a 4N solution of hydrochloric acid in ethyl acetate (2.6 ml) in methanol (50 ml) was combined with 10% Pd/C (50% hydrated, 0.44 g) and stirred at room temperature for 5 hours under a hydrogen atmosphere. The catalyst was filtered off and the reaction mixture was concentrated to obtain the title compound. (2.13 g) as a yellow amorphous material.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[C:22]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:22][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:14])[F:15])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(O)cc(C)c2OC1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=Cc2cc(OC)cc(C)c2OC1C(F)(F)F
Temperature: 55 °C
Yield: 105.4 %

Procedure:
The ethyl 6-hydroxy-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.2 g, 0.66 mmole) and K2CO3 (0.48 g, 3.44 mmole) was suspended in acetone (7.5 mL). lodomethane (0.93 g, 6.60 mmole) was added and heated to 55° C. for 3 hrs. The contents were filtered through a plug of celite and washed with acetone. The solution was concentrated in vacuo to give a yellow solid (0.22 g, 98%). GCMS m/z 316.0 (M+). LCMS m/z 317.0 (M+H). 1H NMR (CDCl3/400 MHz) 7.64 (s, 1H), 6.72 (s, 1H), 6.55 (s, 1H), 5.65 (q, 1H, J=7.0 Hz), 4.28 (m, 2H), 3.73 (s, 3H), 2.20 (s, 3H), 1.32 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]C2C=CC=CC=2)=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][CH2:21][C:22]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[O:23])=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cc(N2CCN(C(=O)NCC(=O)O)CC2)c2ccc(Cl)cc2n1
Reactant: Fc1ccc(Nc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1cc(N2CCN(C(=O)NCC(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 171, [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid, 4-fluorophenylaniline, iPr2NE, HATU, are reacted to afford the product. LC-MS: 456 (M++1). 1H NMR (CDCl3): δ 3.05–3.3 (m, 4H), 3.6–3.8 (m, 4H), 4.0–4.2 (m, 2H), 4.65–4.9 (s, 2H), 6.1–6.2 (s, 1H), 7.0–7.1 (m, 2H), 7.2 (m, 1H), 7.3 (m, 2H), 7.6–7.7 (s, 1H), 7.7–7.8 (m, 1H), 8.6–8.7 (s, 1H).
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[S:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:33][CH2:34][CH2:35][O:36][CH3:37])[C@@H:21]1[OH:38])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>C1COCC1>[CH3:37][O:36][CH2:35][CH2:34][O:33][C@@H:22]1[C@H:21]([OH:38])[C@@H:20]([CH2:19][OH:18])[S:24][C@H:23]1[N:25]1[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S[C@H]1n1ccc(=O)[nH]c1=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO)S[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of Compound 114 (0.49 g, 0.88 mmol) in anhydrous THF (37 mL) 1M tetrabutylammonium fluoride in THF (1.8 mL) was added. Acetic acid (0.12 mL, 2.03 mmol) was added to this mixture and the resulting reaction mixture stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue obtained was purified by flash silica gel column chromatography and eluted with acetone to yield Compound 51 (0.23 g, 83%). 1H NMR (300 MHz, DMSO-d6): 11.2 (s, 1H), 8.04 (d, 1H,), 5.94 (d, 1H), 5.69 (d, 1H), 5.20 (d, 1H), 4.15 (t, 1H), 4.04 (m, 1H), 3.67-3.53 (m, 6H), 3.47-3.36 (m, 2H), 3.31 (s, 3H); MS (API-ES) m/z 341.0 [M+Na]+.
Reaction SMILES: Cl[C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH3:22][N:19]1[CH2:18][CH2:17][CH:16]([NH:15][C:3]2[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][N:6]=[C:5]([NH2:8])[CH:4]=2)[CH2:21][CH2:20]1
Reactant: OB(O)c1ccccc1
Reactant: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CCC(Nc2cc(N)ncc2-c2ccccc2)CC1
Temperature: 130 °C
Yield: 238.6 %

Procedure:
A solution of the N-(5-chloro-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (Synthesis 153-C) (0.187 g, 0.57 mmol), phenyl boronic acid (0.140 g, 1.15 mmol), sodium carbonate (0.153 g, 1.43 mmol) and Bedford catalyst (0.003 g, 0.005 mmol) in a mixture of acetonitrile/water (4/1, 3.1 mL) was heated under microwave irradiation for 30 min at 130° C. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (1 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was used without further purification. A solution of the protected amine in 6 M HCl (3 mL) was heated under microwave irradiation at 105° C. for 50 min. The solution was basified with Na2CO3 and extracted with ethyl acetate (3×10 mL). The crude mixture was purified by flash chromatography on silica, eluting with methanol and dichloromethane (1/9), to give the title compound as a colourless solid (0.384 g, 73%).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:6]=2[C:7]=1[CH3:8])[CH3:2].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:13][C:9]1[C:6]2[C:7]([CH3:8])=[C:3]([CH2:1][CH3:2])[O:4][C:5]=2[CH:12]=[CH:11][CH:10]=1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: CCc1oc2cccc(O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2oc(CC)c(C)c12
Yield: 118.3 %

Procedure:
A mixture of 2-ethyl-4-hydroxy-3-methylbenzofuran (760 mgs; 4.3 mmoles), allyl bromide (1.0 g; 8.6 mmoles), anhydrous potassium carbonate (1.1 g; 8.6 mmoles) and acetone (50 ml) was refluxed for 4 hours. The mixture was filtered, concentrated, and chromatographed to obtain 1.1 g of the title compound as an oil which was used as such in the next step.