Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:74][C@H:75]1[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:74][C@H:75]4[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76]4)=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)C1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (50 mg, 0.098 mmol), PyBOP® (28 mg, 0.054 mmol), DIEA (17 μL, 0.098 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (16 mg, 0.084 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalent of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalent of (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo to afford the crude (3S)-tert-butyl 3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrolidine-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:33]B1OB(C)OB(C)O1>C1COCC1.CCOC(C)=O>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:24]=[C:2]([CH3:33])[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([CH3:23])=[N:18]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Reactant: CB1OB(C)OB(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)-c1nc(-c3nc(C)nn3C(C)C)cn1CCO2
Temperature: 140 °C

Procedure:
A microwave vial was charged with a suspension of 10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.200 mg, 0.515 mmol) in 2.0 ml THF/0.400 mL water. To this suspension was added potassium phosphate (330 mg, 0.0015 mol) and trimethylboroxine (0.14 ml, 1.00 mmol). The reaction suspension was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and Bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (18 mg, 0.02 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 140° C. for 40 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water ×1, saline ×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 481. MS: (ESI+)=324.1
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[O:21])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=2)[C:5]1=[O:36])(=[O:3])[CH3:2].[CH3:37]I>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][N:29]=4)[CH2:26][CH2:27]3)=[O:21])=[C:13]([N:15]([CH3:37])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=2)[C:5]1=[O:36])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(NS(C)(=O)=O)c2)C1=O
Reactant: CI
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(N(C)S(C)(=O)=O)c2)C1=O

Procedure:
Using N-{5-(3-acetyl-2-oxoimidazolidin-1-yl)-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (93 mg) described in Example 596 and methyl iodide (12.3 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (15 mg) was obtained.
Reaction SMILES: [C:1]([O:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1)=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl.C(Cl)(Cl)Cl>[C:30]([N:15]1[CH2:16][CH2:17][N:12]([C:10]([O:9][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:11])[CH2:13][CH:14]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1CN(C(=O)OC(=O)c2ccccc2)CCN1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of rac-ethyl 4-benzoyloxycarbonylpiperazine-2-carboxylate (4 g) and triethylamine (5.1 ml) in dichloromethane (50 ml) was added acetic anhydride (1.72 ml) at 0° C. The mixture was stirred at ambient temperature for 3 hours, diluted with chloroform and washed with 1N hydrochloric acid, water, saturated aqueous solution of sodium hydrogen carbonate, water, brine, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography eluting with a mixture of ethyl acetate and n-hexane (2:1) to give rac-ethyl 1-acetyl-4-benzyloxycarbonylpiperazine-2-carboxylate (4.63 g).
Reaction SMILES: [CH:1]([C:4]1([CH3:17])[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:6][C:5]1=[O:16])([CH3:3])[CH3:2].C([Li])CCC.C[O:24][C:25](=O)[C:26]([N:28]([CH3:30])[CH3:29])=[O:27].O>O1CCCC1>[CH3:29][N:28]([C:26](=[O:27])[C:25]([C:14]1[C:9]([C:7]2[NH:6][C:5](=[O:16])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:17])[N:8]=2)=[N:10][CH:11]=[C:12]([CH3:15])[CH:13]=1)=[O:24])[CH3:30]
Reactant: Cc1ccc(C2=NC(=O)C(C)(C(C)C)N2)nc1
Reactant: COC(=O)C(=O)N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)C(=O)N(C)C)c1
Temperature: -70 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a stirred solution of 2.5 g (0.011 mole) of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2 -yl)-5-methyl pyridine in 100 ml of dry tetrahydrofuran cooled to -70° C. under the presence of nitrogen was added dropwise a 9.68 ml of 2.5 molar n-butyllithium, thereby temperature was maintained below -65° C. The solution was stirred at -70° C. for 3 hours and a solution 1.96 g of N,N-dimethyl oxamic acid methyl ester(0.015 mole) in 10 ml of anhydrous tetrahydrofuran was added dropwise while maintaining the temperature below -65° C. After stirring another hour at -70° C., the solution was poured into water and extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate, and evaporated under reduced pressure. Trituration of the residue with diethyl ether affored a crude solid which was recrystallized from a mixture of diethyl ether and methylene chloride to yield 1.67 g of a white solid (m.p=180°-182° C.).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C@H:11]1[CH2:13][C@@H:12]1[CH2:14][C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:9][CH2:10][C@H:11]1[CH2:13][C@@H:12]1[CH2:14][C:15]([O:17][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: O=C(O)C[C@H]1C[C@@H]1CO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C[C@H]1C[C@@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.1 %

Procedure:
Benzyl bromide (539 μL, 4.53 mmol) was added to a mixture of 2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetic acid (536 mg, 4.12 mmol), potassium carbonate (626 mg, 4.53 mmol) and DMF (8 mL) at room temperature, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water (80 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 33→53% ethyl acetate/hexane) to give benzyl 2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetate (718 mg, 3.26 mmol, 79%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@@H:17]3[C@H:21]([CH2:22][CH2:23][N:24]4[C:32](=[O:33])[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]4=[O:34])[C@H:20]([OH:35])[C@H:19]([OH:36])[O:18]3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.I([O-])(=O)(=O)=O.[Na+]>CO>[CH:19]([O:18][C@H:17]([CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)=[CH:14][CH:13]=1)[C@@H:21]([CH:20]=[O:35])[CH2:22][CH2:23][N:24]1[C:25](=[O:34])[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]1=[O:33])=[O:36]
Reactant: O=C1c2ccccc2C(=O)N1CC[C@@H]1[C@H](O)[C@H](O)O[C@@H]1CCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Product: O=CO[C@H](CCc1ccc(-c2cc(F)cc(F)c2)cc1)[C@@H](C=O)CCN1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
To a solution of the compound obtained from step c above (0.15 g) in methanol (6 mL) at 0° C., a solution of sodium metaperiodate (0.15 g in 1 mL of water) was added. The reaction mixture was stirred for 2 hours at the same temperature. After stirring the reaction mixture for an additional 1 hour at room temperature, the reaction mixture was evaporated on a rotary evaporator. The residue was taken into water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain the title compound (0.12 g).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:10][N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([NH2:21])=[N:15][C:16]=2[Cl:20])[CH2:5][C:6](OC)=[O:7].[BH4-].[Li+].O>C(O)(C)(C)C>[NH2:21][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[CH2:10][CH:4]([CH2:5][CH2:6][OH:7])[CH2:3][OH:2])=[C:16]([Cl:20])[N:15]=1
Reactant: COC(=O)CC(Cn1cnc2c(Cl)nc(N)nc21)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1nc(Cl)c2ncn(CC(CO)CCO)c2n1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (-)-dimethyl-2-(2-amino-6-chloropurin-9-ylmethyl)succinate (enantiomeric excess 85%; 19.9 mg, 0.0607 mmol), dissolved in tert. butanol (2.0 ml) at 40° C., was added lithiumborohydride (30 mg, 1.38 mmol) in portions with stirring. After 1 hr at ambient temperature, water (0.3 ml) was added slowly and stirring continued over night. Inorganic salts were filtered, washed carefully with tert. butanol and the solution was evaporated to dryness. Preparative thin-layer chromatography (PSC-Fertigplatten, Merck) with chloroform+methanol (5+1) as mobile phase afforded 16.5 mg (theoretical yield) of (-)-2-(2-amino-6-chloropurin-9-ylmethyl)-1,4-butanediol. [α]D20 °-5.20°, [α]54620 -5.92° (c 0.625, ethanol). TLC on silica (chloroform+methanol 5+1): Rf 0.40, identical to that of the racemate.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.Cl.[CH2:5]1[CH2:9]O[CH2:7][CH2:6]1>>[CH:6]([C:5]1[CH:9]=[CH:7][C:6]([CH2:2][CH2:1][OH:3])=[CH:5][CH:9]=1)=[CH2:7]
Reactant: C1CO1
Reactant: C1CCOC1
Agent: Cl
Product: C=Cc1ccc(CCO)cc1
Temperature: 0 °C

Procedure:
To a VP-MgCl solution as prepared in Example 12 of this section was added a solution of 4.84 g ethylene oxide (0.11 mol) in 50 ml THF. The solution was added via additional funnel over one hour, maintaining the reaction mixture at 0° C. Keep stir at 0° C. for one more hour after the addition was finished. The reaction was then stirred for an additional 1 h at 0° C. 60 ml of 2 M aqueous hydrochloric acid (HCl) solution was added via the addition funnel, maintaining the temperature below 20° C. The reaction was filtered and extracted two times with 100 mL of diethyl ether. The organic phases were combined, dried over MgSO4 and filtered. The diethyl ether was removed by vacuum evaporation at room temperature. 11.2 g white waxy solid, 75.7%). 1H NMR (DMSO-d6): δ 7.20-δ 7.40 (m, 4H, aromatic), δ 6.72 (m, 1H, vinyl), δ 5.75 (d, 1H, vinyl), δ 5.23 (d, 1H, vinyl), δ 4.70 (t, 1H, OH), δ 3.65 (t, 2H, CH2—O), δ 2.72 (t, 2H, CH2—C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](OC)=[O:33].[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH:23]([OH:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]
Reactant: COC(=O)CCCCCCCCC(=O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(O)CCCCCCCCCO)c2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 12.9 %

Procedure:
Methyl 10-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-10-oxo-decanoate (40 mg) was dissolved in tetrahydrofuran (3 ml), 0.93 M diisobutylaluminum hydride (1 ml) was added to the solution at 0° C., and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (4.9 mg, yield 13%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=1)=O.N(O)=O.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19].[OH-].[Li+]>CC(O)CC>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:31]=2)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]
Reactant: CN(C)C=CC(=O)c1cccnc1Cl
Reactant: CCOC(=O)c1cccc(NC(=N)N)c1
Agent: O=NO
Agent: [Li+]
Agent: [OH-]
Solvent: CCC(C)O
Product: CCOC(=O)c1cccc(Nc2nccc(-c3cccnc3Cl)n2)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 3-dimethylamino-1-(2-chloro-3-pyridyl)-2-propen-1-one (810 mg, 3.86 mmol), 3-ethoxycarbonyl-phenyl-guanidine nitrite (1.07 g, 3.96 mmol), lithium hydroxide (105 mg, 4.38 mmol) in 2-butanol (20 mL) is heated to reflux overnight. The reaction mixture is cooled to room temperature, the solvent is removed and water (40 mL) is added. The solid is collected by filtration and washed with water, isopropanol and dried to give N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro-3-pyridyl)-2-pyrimidineamine (1.15 g); ESI-MS (m/z): 355.1 (M++H).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[O:3][C:4]1[CH:45]=[CH:44][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[C:25](Cl)=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[O:11])=[CH:6][CH:5]=1.C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[F:47][C:2]([F:1])([F:46])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[O:11])=[CH:44][CH:45]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a mixture of the compound (0.99 g) obtained in Step 3 and ammonium formate (0.86 g) in ethanol (10 ml) was added 10% palladium carbon (0.50 g) at 80° C. After stirring at 80° C. for 30 min, ammonium formate (0.43 g) and 10% palladium carbon (0.50 g) were added. After stirring at 80° C. for 30 min, ammonium formate (0.43 g) and 10% palladium carbon (0.50 g) were added. After stirring at 80° C. for 30 min, the reaction mixture was allowed to return to room temperature, and the reaction mixture was diluted with ethyl acetate. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=7:3-8:2) to give the title compound (0.71 g).
Reaction SMILES: Br.[OH:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[C:5]([CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6]>Cl>[OH:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:5][CH2:4][CH2:3][OH:2])[CH2:9][CH2:8]1)=[O:6]
Reactant: O=C(c1ccccc1O)C1CCNCC1
Agent: Br
Agent: Cl
Product: O=C(c1ccccc1O)C1CCN(CCCO)CC1

Procedure:
4-(2-Hydroxybenzoyl)piperidine hydrobromide. An solution of 4-(2- and 4-hydroxybenzoyl)-1-acetyl piperidine (2.30 g, 9.30 mmol) in 6 N HCl (20 mL) was refluxed for 2 h. The cooled solution was extracted with ether (2×30 mL), made basic (NaOH) and was extracted with EtOAc (2×30 mL). An insoluble solid formed which was removed. The EtOAc portion was dried and was concentrated under reduced pressure. The free amine was dissolved in HBr (saturated solution in methanol, 5 mL) and the precipitated hydrobromide salt was collected, washed with ether (2×4 mL) and was dried in vacuo to afford the title compound as a colorless solid (0.26 g): mp 253° C. (dec); 1H NMR (DMSO-d6) d 1.60-1.83 (m, 2H), 1.94 (bd, J=12.9 Hz, 2H), 2.90-3.10 (m, 2H), 3.30 (bd, J=12.3 Hz, 2H), 3.65-3.90 (m, 1H), 6.94 (t, J=8.7 Hz, 2H), 7.50 (t, J =7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 8.33 (bs, 1H), 8.58 (bs, 1H), 11.63 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[C:34]([O:38][C:39](=[O:53])[CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47](O)=[O:48])([CH3:37])([CH3:36])[CH3:35].CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:47]([C:46]2[CH:45]=[C:44]([CH:52]=[CH:51][CH:50]=2)[CH2:43][S:42][CH2:41][CH2:40][C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:53])=[O:48])[CH:10]=1)=[O:28]
Reactant: Nc1ccc(N2CCOCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-morpholinophenyl)isonicotinamide (200 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid 1.1c (200 mg, 0.68 mmol, 1.50 equiv), EDC.HCl (160 mg, 0.84 mmol, 2.00 equiv), and 4-dimethylaminopyridine (60 mg, 0.49 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. After a conventional aqueous/organic workup, the resulting mixture was concentrated under vacuum to yield 100 mg of crude product as a yellow oil.
Reaction SMILES: C1C=CC=CC=1.[H-].[Na+].[OH:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.Cl[CH2:17][C:18]([OH:20])=[O:19]>O>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[CH2:10][O:9][CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)CCl
Reactant: OCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)COCc1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a stirred benzene suspension of NaH (0.39 g, 32.2 mmol) was added a benzene solution of 2-hydroxymethylthiophene (2.0 g, 15.1 mmol). The reaction was stirred 3 h and a benzene solution (10 mL) of chloroacetic acid (1.56 g, 16.6 mmol) was added. The reaction was heated to reflux for 15 h then cooled to room temperature and a small amount of water was cautiously added. The aqueous layer was diluted, separated, acidified and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over MgSO4. Evaporation afforded thien-2-ylmethoxyacetic acid as a tan oil (66%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:26][C:24]1[CH:23]=[C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:29][CH2:28]2)[CH:21]=[C:20]([Cl:19])[CH:25]=1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(F)cc21
Product: CCC1(CCCCN2CCN(c3cc(Cl)cc(Cl)c3)CC2)C(=O)Nc2ccc(F)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 3-(4-chlorobutyl)-3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-(3,5-dichlorophenyl)-piperazine.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:35][CH2:36]OC.O.B1(C=C)OB(C=C)OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.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>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:35]=[CH2:36])[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOC
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
Intermediate (15a) (11.0 g, 21.8 mmol) was dissolved in 1,2-dimethoxyethane (100 mL, 1 mol). Tetrakis(triphenylphosphine)palladium(0) (252 mg, 218 μmol) was added and the mixture was stirred under nitrogen for 20 minutes. Water (48 mL, 2.6 mol), 2,4,6-trivinylcyclotriboroxane pyridine complex (2.1 g, 8.7 mmol) and potassium carbonate (3.0 g, 21.8 mmol) were then added and the mixture was heated at 90° C. under nitrogen. After 2 hours, the mixture was cooled to room temperature, diluted with EtOAc, washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (0-50% EtOAc:hexanes) to yield intermediate (15b) (9.8 g). MS m/z: [M+H+] calcd for C26H27FN2O4, 451.2; found 451.0. 1H-NMR (CDCl3): 8.17 (1H, s), 7.79 (1H, d), 7.48 (1H, t), 7.40 (1H, t), 7.28 (1H, s), 7.01 (2H, m), 6.86 (1H, t), 6.67 (1H, m), 5.95 (1H, d), 5.41 (2H, s), 5.27 (1H, d), 4.48 (2H, q), 1.38 (3H, t), 1.25 (9H, s).