Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27](=[O:30])[NH:26][CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl[CH2:33][C@@H:34]1[CH2:38][O:37]C(C)(C)[O:35]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH2:33][C@@H:34]([OH:35])[CH2:38][OH:37])[CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)[nH]c1
Reactant: CC1(C)OC[C@@H](CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(C[C@@H](O)CO)c1
Temperature: 100 °C
Yield: 26.9 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (0.15 g, 0.35 mmol), (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (0.27 g, 1.8 mmol), and potassium carbonate (0.5 g, 3.5 mmol) was added N,N-dimethylformamide and the reaction mixture was heated to 100° C. overnight. The reaction was diluted with dichloromethane (20 mL) and washed with 1N hydrochloric acid (10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL). The organics were dried over sodium sulfate and evaporated. The crude residue was purified by silica gel chromatography (eluting with 0-10% methanol in dichloromethane) to yield the product (47 mg, 27%). ESI-MS m/z calc. 499.16. found 500.2 (M+1)+. Retention time 1.53 minutes.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].I[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])(=O)C.[Na+]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CI
Reactant: Nc1ccc2ccccc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCOC(=O)CNc1ccc2ccccc2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
A mixture of 2-napthylamine (compound I, FIG. 3B) (1.43 g, 10 mmol), ethyl iodoacetate (2.14 g, 10 mmol), and sodium acetate (1.64 g, 20 mmol, dissolved in 2 ml of water) was stirred at 90° C. for 3 hours. The solid material obtained upon cooling was filtered and recrystallized from hexane to yield 1.5 g ethyl N-(2-naphthalenyl)glycinate (compound II, FIG. 3B) (yield, 65%, mp 83-84° C.) (Ramamurthy and Bhatt, J. Med. Chem. 32:2421-2426, 1989). A solution of above product (2.29 g, 10 mmol) in ethanol (10 ml) was refluxed with hydrazine hydrate (0.6 g, 12 mmol) for 10 hours. Solvent and excess reagent were distilled under vacuum. The product was recrystallized from ethanol to yield 1.8 g of N-(2-naphthalenyl)glycine hydrazide (compound III, FIG. 3B) (yield 82%, mp 147-148° C.). A mixture of compound III (2.15 g, 10 mmol) and 3,5-dibromo-2,4-dihydroxybenzaldehyde (3 g, 10 mmol) in ethanol (5 ml) was refluxed for 3 hours. The hydrazone that crystallized upon cooling was filtered, washed with ethanol, and recrystallized from ethanol to give 3.8 g (78%) of GlyH-101. Melting point (mp)>300° C., ms (ES−): M/Z 492 (M−); 1H nmr (DMSO-d6): δ 4.1 (s, 2H, CH2), 6.5-7.5 (m, 9H, aromatic, NH), 8.5 (s, 1H, CH═N), 10.4 (s, 1H, NH—CO), 11.9 (s, 1H, OH), 12.7 (s, 1H, OH). Compounds GlyH-102-109, GlyH-114-127 and AceH401-404 were synthesized similarly by condensing appropriate hydrazides with substituted benzaldehydes.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH2:22][CH3:23])[C:9]2[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CN(C)C=O>[ClH:1].[CH3:25][O:24][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=1)[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]1[CH2:22][CH3:23]
Reactant: CCC1c2ccccc2CCN1c1nc(Cl)nc2c(OC)cccc12
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: CCC1c2ccccc2CCN1c1nc(Nc2ccc(F)cc2)nc2c(OC)cccc12
Product: Cl
Yield: 56 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 1.50 g of the compound (4.63 mM) prepared in Example 10 and 15 ml of dimethyl-formamide, 0.65 ml of 4-fluoroaniline(6.95 mM) was added, 1.20 g of the title compound was prepared.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:5][C:4]=1[C:26]1[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=1)[CH3:2].C(N(C(C)C)CC)(C)C.[C:41]([Cl:45])(=[O:44])[CH:42]=[CH2:43].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[ClH:45].[C:41]([N:29]1[CH2:28][CH:27]=[C:26]([C:4]2[N:5]=[C:6]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[CH:15][CH:14]=3)[C:7]([C:9]([NH2:11])=[O:10])=[N:8][C:3]=2[CH2:1][CH3:2])[CH2:31][CH2:30]1)(=[O:44])[CH:42]=[CH2:43]
Reactant: C=CC(=O)Cl
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1C1=CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CC=C(c2nc(Nc3ccc(N4CCN(C)CC4)cc3)c(C(N)=O)nc2CC)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-carboxamide (40 mg), diisopropylethylamine (75 μL), and chloroform (4 mL) was added under ice-cooling acryloyl chloride (25 μL), followed by stirring at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1). To an ethyl acetate solution of the obtained oily substance was added 4 M hydrogen chloride ethyl acetate solution, followed by stirring for 5 hours. The solvent was evaporated under reduced pressure and the obtained solid was washed with diisopropyl ether to obtain 5-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide monohydrochloride (21 mg) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1cc(C(=O)OC)ccc1-c1ccccc1F
Reaction time: 3 h

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate (10 g, 38.6 mmol) in toluene (80 mL) and water (20 mL) under nitrogen was added 2-fluorophenylboronic acid (7.0 g, 50.2 mmol), followed by potassium carbonate (16 g, 115.8 mmol) and Pd(PPh3)4 (2.23 g, 1.9 mmol). After 3 hours at 100° C., the reaction mixture was diluted with EtOAc (200 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL), water (2×100 mL) and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (silica, pet ether/EtOAc) to afford of the title compound as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.26 (1H, s), 8.04 (1H, d), 7.42 (1H, m), 7.35 (1H, d), 7.14-7.27 (3H, m), 4.34 (2H, s), 3.95 (3H, s), 3.30 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=1.CI.[C:15](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:15])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(Br)ccc(F)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1c(Br)ccc(F)c1F
Yield: 100 %

Procedure:
A solution of 6-bromo-2,3-difluorobenzoic acid (7.66 g, 32.3 mmol), methyl iodide (10 mL, 160 mmol) and potassium carbonate (5.36 g, 38.8 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 1 hour. The solution was poured into water, and organic matter was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (8.11 g, 100% yield).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1>>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH:7]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCNCC1
Reactant: Clc1cccnc1Cl
Product: CC(=O)NC1CCNC(c2ncccc2Cl)C1
Yield: 70 %

Procedure:
Following the modus operandi described in Example 1, by reaction of 4-acetamidopiperidine with 2,3-dichloropyridine, 4-acetamido-2-(3-chloropyridyl)piperidine is obtained, with a yield of 70%, which, after crystallization in ethyl acetate, melts at 118° to 120° C. By hydrolysis of the product thus obtained with 6 N hydrochloride acid, the monohydrochloride of 4-amino-1-(3-chloropyridyl)piperidine (CM 57375) is obtained which is crystallised in 90% ethanol; m.p. 258° to 260° C. with decomposition.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[C:5]=1[F:13].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22]O)[CH:16]=1.Cl.C[O:27][C:28]([C:30]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29]>>[F:13][C:5]1[C:6]([O:12][CH2:22][CH2:21][C:17]2[CH:16]=[C:15]([CH3:24])[CH:20]=[CH:19][CH:18]=2)=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([NH:37][C:30]1([C:28]([OH:29])=[O:27])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:14]
Reactant: COC(=O)c1ccc(OC)c(O)c1F
Reactant: Cc1cccc(CCO)c1
Reactant: COC(=O)C1(N)CCCCCC1
Agent: Cl
Product: COc1ccc(C(=O)NC2(C(=O)O)CCCCCC2)c(F)c1OCCc1cccc(C)c1

Procedure:
2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester was coupled to 2-m-tolylethanol, the intermediate hydrolyzed, coupled to 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride and the obtained ester hydrolyzed in analogy to steps 1 to 4 of example 1 to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14](O)=[O:15])=[N:10][N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][OH:15])=[N:10][N:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc(-n2nc(C(=O)O)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Nc1cccc(-n2nc(CO)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Reaction time: 1 h
Yield: 8.7 %

Procedure:
According to Scheme 7 Step 5: To a solution of 11(D) (380 mg, 0.92 mmol),) and diisopropylethylamine (189 μL, 1.1 mmol) in THF (10 mL) at 0° C. under nitrogen atmosphere was added ethyl chloroformate (101 μL, 1.06 mmol) dropwise. The reaction mixture was stirred for 1 h then treated dropwise with a solution of sodium borohydride (90 mg, 2.38 mmol) in water (2 mL). The mixture was stirred overnight at room temperature and quenched slowly with a saturated solution of NaHCO3 (100 mL). The aqueous layer was extracted thrice with CH2Cl2 (100 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford a yellow solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 20 g SiO2) using CH2Cl2/MeOH 97/3 as eluant to afford N-(3-(4-(4-chlorobenzyl)-6-(hydroxymethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 11(E) (32 mg, 9%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[OH-].[K+].[F:12][C:13]([F:17])=[C:14]([F:16])[F:15].C1(O)C=CC=CC=1>O.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:9][C:14]([F:16])([F:15])[CH:13]([F:17])[F:12])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1ccc(O)cc1F
Reactant: FC(F)=C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: Nc1ccc(OC(F)(F)C(F)F)cc1F
Reaction time: 0.33 h
Yield: 80 %

Procedure:
0.70 Gram of 3-fluoro-4-aminophenol, 0.06 g of potassium hydroxide and 10 ml of dimethylformamide were added to a reactor and stirred for 20 minutes at an oil bath temperature of from 60° to 70° C. This solution was then violently stirred at the same temperature for 2 hours under the stream of a tetrafluoroethylene gas in excess of said phenol. The reaction solution was cooled and after adding water, extracted with two 150-ml portions of diethyl ether. The ether layers were combined, washed with water, dried and concentrated to obtain a crude product. This crude product was subjected to chromatography on silica gel to obtain 1.00 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)aniline.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH2:27][CH2:28][CH2:29]Cl)(=[O:26])=[O:25])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:29][CH2:28][CH2:27][S:24]4(=[O:26])=[O:25])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCC1CN(c2ccc(NS(=O)(=O)CCCCl)cc2)C(=O)O1)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCC1CN(c2ccc(N3CCCS3(=O)=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 100 °C

Procedure:
A mixture of 13.5 mg (0.027 mmol) of 5-chloro-N-{[3-(4-{[(3-chloropropyl)sulphonyl]amino }phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophene-carboxamide (from Example 159) and 7.6 mg (0.055 mmol) of potassium carbonate in 0.2 ml of DMF is heated at 100° C. for 2 h. After cooling, the mixture is diluted with dichloromethane and washed with water. The organic phase is dried and concentrated. The residue is purified by preparative thin-layer chromatography (silica gel, dichloromethane/methanol, 95:5). Yield: 1.8 mg (14.4% of theory),
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[CH:11]=1>COCCOC>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:10]2[CH:15]=[CH:14][C:13]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:12]([F:19])[CH:11]=2)=[C:12]([F:19])[CH:11]=1
Reactant: OB(O)c1ccc(Br)cc1F
Reactant: Nc1cnc(Br)cn1
Solvent: COCCOC
Product: Nc1cnc(-c2ccc(-c3ccc(Br)cc3F)cc2F)cn1
Temperature: 100 °C

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate D with DME as a solvent, heating at 100° Celsius for 16 hours and using 2-amino-5-bromopyrazine and 4-bromo-2-fluorobenzeneboronic acid. MS (ESI): mass calcd. for C16H10BrF2N3, 361.00; m/z found, 362.0, 364.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.30 (d, J=1.4, 1H), 8.12-8.02 (m, 1H), 7.49-7.32 (m, 5H), 6.37-5.94 (m, 1H), 6.15 (s, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[NH:13][C:12]3=[O:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[N:13]([CH2:23][CH:22]=[CH2:21])[C:12]3=[O:18])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C23CC2C(=O)NC3=O)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C2CC2(c2ccc(NC(C)=O)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.2 g of 1-(4-acetylaminophenyl)-3-azabicyclo[3.1.0]hexane-2,4dione are dissolved in 25 ml of dimethylformamide and to this solution are added 180 mg of sodium hydride under nitrogen. The mixture is stirred for 1 hour at room temperature. The clear, pale yellow solution is cooled in an ice-water bath and then a solution of 0.65 ml of allyl bromide in 5 ml of dimethylformamide is added dropwise. The reaction mixture is stirred overnight and then the solvent is stripped off. The residue is partitioned twice between ethyl acetate and water. The organic phases are dried over magnesium sulfate, filtered and concentrated, and the residue is crystallised from ethyl acetate/ether/petroleum ether. The title compound is obtained in the form of white crystals with a melting melting point of 113°-116° C. and with Rf=0.33 on thin-layer silica gel plates in the system methylene chloride/methanol (10:1).
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]1([CH3:32])[CH2:11][C:10]2[C:12]([CH3:31])=[C:13]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[C:14]([CH3:17])=[C:15]([OH:16])[C:9]=2[O:8]1.Br[CH2:34][CH2:35][O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:37][O:36][CH2:35][CH2:34][O:16][C:15]1[C:9]2[O:8][C:7]([CH3:32])([CH3:6])[CH2:11][C:10]=2[C:12]([CH3:31])=[C:13]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)[C:14]=1[CH3:17]
Reactant: Cc1ccc(N2CCN(c3c(C)c(O)c4c(c3C)CC(C)(C)O4)CC2)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1c(C)c(N2CCN(c3ccc(C)cc3)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 100 °C
Reaction time: 24 h
Yield: 14.5 %

Procedure:
To a solution of DMF (5 mL) containing 2,2,4,6-tetramethyl-5-[4-(4-methylphenyl)piperazin-1-yl]-2,3-dihydro-1-benzofuran-7-ol (200 mg, 0.546 mmol) synthesized in Example 72, 1-bromo-2-methoxyethane (382 mg, 2.75 mmol) and potassium carbonate (380 mg, 2.75 mmol) were added, and the mixture was stirred at 100° C. for 24 hours. After cooled to room temperature, water was added to the mixture, and extraction was performed using ethyl acetate. The extract was dried using anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0-90:10) to obtain 33.5 mg of the title compound (yield 14%). Melting point was 118 to 120° C. (hexane).
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH:3]([NH:6][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][OH:5].[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH3:20][C:19]([Si:16]([CH3:18])([CH3:17])[O:5][CH2:4][CH:3]([NH:6][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]([OH:1])[CH3:15])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCC(=O)NC(CO)C(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCC(=O)NC(CO[Si](C)(C)C(C)(C)C)C(C)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.5 %

Procedure:
A mixture of 11c, (1.945 g) of t-butyldimethylsilyl chloride, (1.4165 g) of triethylamine (951 mg, 1.31 mL), and 4-dimethylaminopyridine (42.76 mg) in 13 mL of methylene chloride is stirred under argon at room temperature for 18 h. The reaction mixture is diluted with methylene chloride and water added. The organic layer is separated, washed with water, dried and evaporated to give 3.25 g of a residual oil which is purified by chromatography by slution with 1:5 ethyl acetate/hexane to give 2.30 g of the desired product as an oil. NMR δ 0.08 (d, 6H), 0.89 (t, 3H), 0.90 (s, 9H), 1.16 (d, 3H), 1.65 (m, 2H), 2.24 (t, 2H), 3.47 (s, 1H), 3.84 (m, 1H), 3.85 (s, 2H), 4.28 (q, 1H), 6.13 (brd, 1H); MS (FAB) m/z=332 (M+H calc'd for C17H38NO3Si 332).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31](O)=[O:32])[CH2:26]3)[N:22]=1)=[CH:5]2.[CH3:34][NH:35][CH3:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:34][N:35]([CH3:36])[C:31]([CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C@@H:21]2[CH2:20][S:19][C:18]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:22]2)[CH2:26]1)=[O:32]
Reactant: CNC
Reactant: O=C(O)C1CCCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CCCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
The compound (84 mg, 0.18 mmol) prepared in Example 112 was dissolved in N,N-dimethylformamide (4 ml). Dimethylamine (0.13 ml, 2M in THF, 0.27 mmol), EDC (58 mg, 0.30 mmol) and HOBT (48 mg, 0.35 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (18 mg, Yield 20%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[C:9]([F:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:23][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][C:9]=1[F:17]
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1F
Reactant: NCc1cccc(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Cc1ccc(-c2ccccc2)cc1F)NCc1cccc(F)c1
Reaction time: 8 h

Procedure:
4-phenyl-2-fluorophenylacetic acid (0.2 gm, 0.9 mmole), 3-fluorobenzylamine (0.14 ml, 1.1 mmole), PyBOP (0.57 gm, 1.1 mmole), and DIEA (0.36 ml, 2.2 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol. (0.20 gm, 70%); H1-NMR INOVA-500 (DMSO d6) δ 3.612 (s, 2H), 4.318 (d, J=6 Hz, 2H), 7.064-7.117 (m, 3H), 7.345-7.503 (m, 7H), 7.695 (d, J=7.5 Hz, 2H), 8.660 (t, J=6 Hz, 1H). MS (m/z) 338.1 (M+H)+.