Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)=[CH:19][CH:18]=1)(=[O:16])=[O:15].[O:36]([CH2:48][C:49]([O:51]N1C(=O)CCC1=O)=O)[CH2:37][C:38]([O:40]N1C(=O)CCC1=O)=O.[CH2:59]([N:61]([CH2:64][CH3:65])[CH2:62][CH3:63])C>CN(C=O)C>[O:36]([CH2:48][C:49]([NH:1][CH2:2][CH2:3][O:51][CH2:49][CH2:48][O:36][CH2:37][CH2:38][O:40][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH:63]2[C:32]3[C:65](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:64][N:61]([CH3:59])[CH2:62]2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:51])[CH2:37][C:38]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:40]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)C1
Reactant: O=C(COCC(=O)ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)COCC(=O)NCCOCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 82) (200 mg, 0.37 mmol) in DMF (2 mL) was added bis(2,5-dioxopyrrolidin-1-yl) 2,2′-oxydiacetate (intermediate 178.1) (60 mg) and triethylamine (184 mg). The resulting solution was stirred for 2 h at room temperature at which point LCMS indicated complete conversion. The mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC with acetonitrile:water (0.05% CF3COOH)(25%-35%). This resulted in 79.6 mg (31%) of the title compound as a TFA salt. 1H-NMR (300 MHz, CD3OD, ppm): 7.94-7.91 (m, 4H), 7.58-7.57 (m, 2H), 7.51-7.48 (m, 4H), 6.88 (m, 2H), 4.82-4.74 (m, 4H), 4.52-4.47 (m, 2H), 4.06 (m, 4H), 3.90 (m, 2H), 3.64-3.42 (m, 34H), 3.15-3.13 (s, 6H), 3.11-3.09 (m, 4H). LC-MS (ES, m/z): 596 [(M+2H)/2]+.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[CH:4]/[C:5]([O:7][Si](C(C)(C)C)(C)C)=[CH2:6].[CH2:15]([C:19](=[O:23])C([O-])=O)[CH2:16][CH2:17]C.FC(F)(F)[C:26](O)=[O:27].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[O:7]=[C:5]1[CH:4]=[CH:3][O:2][CH:1]([C:26]([O:23][CH2:19][CH2:15][CH2:16][CH3:17])=[O:27])[CH2:6]1
Reactant: O=C(O)C(F)(F)F
Reactant: C=C(/C=C/OC)O[Si](C)(C)C(C)(C)C
Reactant: CCCCC(=O)C(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C1CC(=O)C=CO1
Reaction time: 2 h
Yield: 40 %

Procedure:
To 258 mg (1.2 mmol) of (E)-1-methoxy-3-tert-butyldimethylsilyloxy-1,3-butadiene and 130 mg (1 mmol) of n-butylglyoxylate was added at 0° C. the solution of the complex in toluene obtained above. After stirring for 2 hours, 0.1 ml of trifluoroacetic acid was added thereto. Next, the reaction mixture was stirred for 5 minutes, then poured into a saturated aqueous solution of sodium bicarbonate and filtered through celite. Then the filtrate was extracted with ether thrice and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1). Thus 79 mg of n-butyl 3,4-dihydro-4-oxo-2H-pyran-2-carboxylate was obtained (yield: 40%). When measured with CHIRALPAK AD column (manufactured by Daicel Chemical Industries) [hexane:i-PrOH=10:1, flow rate: 1.0 ml/min], the optical purity of this product was 50% e.e.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][CH:18]([F:24])/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:8]1[CH2:12][C@@H:20]([N+:21]([O-:23])=[O:22])[C@H:19]([CH:18]([F:24])[F:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/C(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])[C@@H]1CN(Cc2ccccc2)C[C@H]1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48780.8 %

Procedure:
To a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (56.6 g, 0.24 mol) in dry CH2Cl2 (160 ml) was added (E)-3,3-difluoro-1-nitroprop-1-ene (25 g, 0.2 mmol) and a few drops of TFA at 0° C. The resulting mixture was stirred at rt overnight. The mixture was concentrated and purified by flash column chromatography (petroleum ether:EtOAc=100:1 to 25:1) to give the title compound (25 g, 49% yield) as a yellow oil.
Reaction SMILES: [F:1][C:2]1(C(OCC)=O)[C:8](=[O:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.CS(C)=O.O.[Li+].[Cl-]>CCOC(C)=O>[F:1][CH:2]1[C:8](=[O:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)CC1
Temperature: 125 °C
Reaction time: 5 h
Yield: 55.8 %

Procedure:
To a 500 mL flask containing the product from Step A (23.5 g, 77.5 mmol) was added DMSO (160 mL) followed by H2O (6.98 mL, 387 mmol) and then LiCl (16.4 g, 387 mmol). The mixture was warmed to 125° C. and stirred for 5 hours. The resulting dark mixture was then cooled to ambient temperature and diluted with EtOAc (500 mL) and washed with a saturated aqueous NaHCO3:water (1:1, 3×250 mL). The combined aqueous phase was washed with EtOAc (100 mL) and the combined organic phases were washed with brine and dried over Na2SO4, filtered and concentrated. The crude oil was purified by column chromatography (10 to 30% EtOAc/hexanes) to provide 10.0 g (56%) of the desired product as a light golden oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@H:10]2[O:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([NH:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@H:10]2[O:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1)(=[O:25])=[O:24]
Reactant: Nc1cccc(OC[C@@H]2CO2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(OC[C@@H]2CO2)c1
Reaction time: 0.25 h
Yield: 45 %

Procedure:
Compound 16b-S (0.4 g, 2.4 mmol) dissolved in 20 ml anhydrous DCM, and N,N-diisopropyl-N-ethylamine (0.45 ml, 2.6 mmol) was added at 0° C. After stirring for 15 minutes, methanesulfonyl chloride (0.2 ml, 2.6 mmol) was added to the reaction mixture at 0° C. After stirring overnight, the reaction mixture was extracted with water and washed with brine. The organic phase was dried and evaporated. The residue was purified with flash chromatography using ethyl acetate:DCM (30:70) solvent to give a colorless oil (45% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[OH:15].O>CN(C)C=O>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([CH:14]([OH:15])[CH2:13][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:17][CH:18]=1)[CH3:23]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCc1ccc(C(O)CBr)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
Into a solution of 9.635 kg (72.99 mol) of 4-hydroxy benzaldehyde dissolved in 50 lit. dimethylformamide was added 5.675 kg (236.45 mol) of sodium hydride in 5 lit. dimethylformamide and stirred for 15 min. To this was added 15 Kg (65.22 mol) of 2-bromo-1-(5-ethyl pyridin-2-yl)-ethanol dissolved in 500 lit dimethylformamide and stirring was continued for 1 hr. at 25 to 30° C. Reaction mixture was heated at 80 to 90° C. for 14 hr., allowed to cool to 25° C. and excess of water was added into it. Product was extracted with diethyl ether. Organic layer was dried (magnesium sulfate) and concentrated to obtain crude product, which was purified in methyl tert-butyl ether as described in example 17 to obtain 12.195 Kg (69%) pure 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde. m.p. 83° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](O)=[O:10])=[N:6][CH:7]=1.B.O1CCCC1.O.C(O)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][OH:10])=[N:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cn1
Agent: B
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 19 h
Yield: 80.1 %

Procedure:
To a solution of (5-bromopyridin-2-yl)acetic acid (60.0 mg, 0.278 mmol) in dry tetrahydrofuran (1.4 mL) was added dropwise borane-tetrahydrofuran complex (1.06M in tetrahydrofuran, 0.34 mL, 0.361 mmol) under N2. The mixture was stirred at room temperature for 19 hours and water (5 mL)-acetic acid (5 mL) was added slowly. The mixture was concentrated under reduced pressure, the residue was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3→ethyl acetate) to give the title compound as a yellow oil (45 mg, yield 80%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][CH2:14][O:15][C:16]([CH3:18])=[O:17].[Cl:19][C:20]1[C:25]([CH:26]=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1>C1COCC1>[CH2:14]([O:15][C:16](=[O:17])[CH2:18][CH:26]([C:25]1[C:20]([Cl:19])=[N:21][CH:22]=[CH:23][CH:24]=1)[OH:27])[CH3:13]
Reactant: CCOC(C)=O
Reactant: O=Cc1cccnc1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 14.5 mL diisopropylamine in 336 mL THF was added 49 mL n-BuLi (2.5 M in hexanes) at 0° C. The mixture was stirred at 0° C. for 15 min, cooled to −78° C. before 10 mL EtOAc were dropwise added. After another 30 min, a solution of 2-chloro-3-pyridine carboxaldehyde (84.8 mmol), dissolved in 84 mL THF, was added. The mixture was stirred at −78° C. for 30 min and then allowed to warm to RT. After stirring for 1.5 h, the reaction was quenched with sat. aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept/EtOAc (10/1) to EtOAc gives the desired compound as yellow oil.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[N:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[CH:18][C:11]=1[C:12](N(OC)C)=[O:13].Cl>C1COCC1>[NH2:9][C:10]1[C:11]([C:12]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:13])=[CH:18][C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[CH:20][N:21]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1cc(-c2cc(C)cc(Cl)c2)cnc1N
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(-c2cnc(N)c(C(=O)c3ccccc3)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1M phenyl magnesium bromide in THF (0.79 ml, 0.79 mmol) is added dropwise to a solution of 2-amino-5-(3-chloro-5-methyl-phenyl)-N-methoxy-N-methyl-nicotinamide (intermediate GB) (0.08 g, 0.26 mmol) in THF (3 ml) at 0° C. The resulting solution is stirred at 0° C. for 30 minutes. 1M Phenyl magnesium bromide in THF (0.79 ml, 0.79 mmols) is added dropwise and the solution stirred for a further 30 minutes at 0° C. 2.5M HCl (10 ml) is added and the product extracted with EtOAc, and solvent removed in vacuo. Purification by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA) yields the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (1H, dd), 7.77 (2H, br s), 7.66-7.59 (4H, m), 7.55-7.51 (2H, m), 7.37 (1H, d), 7.29 (1H, dd), 7.23 (1H, d), 2.23 (3H, s); MS m/z 323 [M+H]+
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 246 mg of 2,3-dihydro-1,4-dioxino[2,3-c]pyridine-7-carbaldehyde, 100 mg of acetic acid was added, and stirred at room temperature for 2 hours. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 18 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 540 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-c]pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-quinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].ClC(F)C(N(CC)CC)(F)[F:17]>C(Cl)Cl>[F:1][C:2]1[C:7]([CH2:8][F:17])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13]
Reactant: CCN(CC)C(F)(F)C(F)Cl
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Product: FCc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of pentafluorobenzyl alcohol (3.0 g) and dry methylene dichloride (50 ml) was cooled to a temperature of 0° C. in an ice-bath and 2-chloro-1-diethylamino-1,1,2-trifluoroethane (4.3 g) was slowly added to the cooled, stirred mixture over a period of ten minutes. After standing for a period of 18 hr at 0° C. the reaction mixture was poured into ice and the organic layer was separated and washed with IM aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation and the product was distilled under reduced pressure to give pentafluorobenzyl fluoride, b.p. 51° C. at 30 mm Hg.
Reaction SMILES: N.C1(C[NH2:9])CCCCC1.[O:10]=[C:11]1[C:19]2([CH2:23][O:22][C:21]3[CH:24]=[C:25]4[C:29](=[CH:30][C:20]2=3)[CH2:28][CH2:27][O:26]4)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=O)=[CH:34][CH:33]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>ClCCl>[O:10]=[C:11]1[C:19]2([CH2:23][O:22][C:21]3[CH:24]=[C:25]4[C:29](=[CH:30][C:20]2=3)[CH2:28][CH2:27][O:26]4)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:9])=[O:38])=[CH:34][CH:33]=1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: N
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Solvent: ClCCl
Product: NC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using ammonia in dry dichloromethane to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (81%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.78 (d, J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.20-7.07 (m, 2H), 6.99 (t, J=7.4 Hz, 1H), 6.85 (s, 1H), 6.71 (d, J=7.6 Hz, 1H), 6.41 (br s, 1H), 6.35 (br s, 1H), 6.20 (s, 1H), 4.94 (ABq, 2H), 4.78 (ABq, 2H), 4.46 (t, J=8.5 Hz, 2H), 2.91 (t, J=8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.6, 168.7, 161.5, 160.9, 141.4, 139.3, 132.7, 132.1, 128.4, 127.8, 127.0, 123.6, 123.3, 119.6, 118.4, 108.8, 92.8, 80.2, 72.0, 57.3, 43.4, 28.6; MS (ES+) m/z 413.1 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Cl)[CH:8]=1>>[CH3:1][N:2]([CH2:13][C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: CNCCNC
Reactant: ClCc1cccnc1
Product: CNCCN(C)Cc1cccnc1
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To 7.50 gm of N,N'-dimethylethylenediamine which has been cooled in an ice-ethanol bath is added portionwise over a 30 minute period 1.40 gm of 3-picolyl chloride. After stirring cold for 1 hour after the addition is completed, the reaction mixture is concentrated in vacuo and the residue partitioned between 50 ml of ether and 10 ml of 5N NaOH solution. The organic layer is separated and the aqueous layer extracted 2 times with 50 ml of ether. The combined organic extracts are dried through sodium sulfate and concentrated in vacuo. Chromatography on 150 gm silica gel using CH2Cl2 /CH3OH/NH4OH (90/10/1) as eluent gives 0.930 g of N,N'-dimethyl-N-(3-pyridylmethyl)ethylenediamine.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH2:19][CH3:20])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.O>C1COCC1>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[F:25])[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1ccccc1F
Reactant: CCCc1c(OC)cc(CP(=O)(OCC)OCC)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OC)cc(C=Cc2ccccc2F)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl(3,5-dimethoxy-4-1-propylbenzyl)phosphonate (0.50 g, 1.5 mmol) in THF (10 mL) at 0° C. was added NaH (60% in mineral oil) (0.14 g, 3.5 mmol) under N2. After the addition was completed, the suspension was stirred at 0° C. for 1 h and then 2-fluorobenzaldehyde (0.2 mL, 1.9 mmol) in THF (10 mL) was added. The reaction was kept at 0° C. for 1 h and then at 50° C. for 5 h. The reaction was cooled to 0° C. Water (5 mL) was added slowly to quench the reaction followed by addition of 2N HCl (8 mL). The mixture was extracted with ether (3×20 mL). The extract was dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using 5% ethyl acetate in hexane as eluent afforded 2-(3,5-dimethoxy-4-1-propylphenyl)-1-(2-fluorophenyl)ethene (1). (0.31 g, 68%) as a yellow crystal. 1HNMR (CDCl3, ppm): δ 1.34 (d, J=7.1 Hz, 6H), 3.60 (qint. J=7.1 Hz, 1H), 3.89 (s, 6H), 6.74 (s, 2H), 7.0-7.2 (m, 5H), 7.4-7.6 (m, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(O)C.N1C=CC=CC=1.[OH:13][C:14]1[C:23]2[O:22][C@@H:21]([CH2:24][OH:25])[CH2:20][O:19][C:18]=2[CH:17]=[CH:16][C:15]=1[C:26](=O)[CH3:27]>C(O)C>[OH:13][C:14]1[C:23]2[O:22][CH:21]([CH2:24][OH:25])[CH2:20][O:19][C:18]=2[CH:17]=[CH:16][C:15]=1[C:26](=[N:2][OH:3])[CH3:27]
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1O)O[C@@H](CO)CO2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccc2c(c1O)OC(CO)CO2

Procedure:
A solution of hydroxylamine hydrochloride (2.38 g, 34.2 mmole) in 1:1 ethanol/pyridine (100 mL) was added to a solution of 1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone (1.92 g, 8.57 mmole) in ethanol (200 mL). It was then heated to reflux under nitrogen for 5 hours. Upon cooling, the solvent was removed and replaced with ethyl acetate. The solution was then washed with water (200 mL) and with aqueous 2N HCl (100 mL), dried over magnesium sulfate, filtered and evaporated in vacuum to give 1.89 g (93%) of the (S)-enantiomer of the title compound as a gray solid, m.p. 162 ° C. MS (ESI) m/z 240 (M+H)+.
Reaction SMILES: Cl.C([S:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[CH2:28][CH2:27]2)=[O:25])[CH2:7]1)(=O)C.C(OCC)(=O)C.CO>O1CCOCC1>[SH:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C@H:8]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:36])[CH2:30][CH2:31]2)=[O:25])[CH2:7]1
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
600 ml of a methanolic solution containing 10% w/v hydrogen chloride were added to a solution of 140 g of (2S,4S)-4-acetylthio-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl] -1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine dissolved in 150 ml of dioxane, and the resulting mixture was stirred at 50° C. for 1 hour. At the end of this time, the mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with 1500 ml of ethyl acetate, after which it was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The mixture was then washed with 300 ml of water and with 300 ml of an aqueous solution of sodium chloride, after which it was freed from the solvent by distillation under reduced pressure. The residue thus obtained was subjected to column chromatography through silica gel using mixtures of ethyl acetate and methanol ranging from 30:1 to 20:1 by volume as the eluent. Those fractions containing the desired compound were collected and concentrated to afford 96.44 g of the title compound as a colorless powder.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[C:17]([F:21])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[C:17]([F:21])=[CH:16][C:12]=1[C:13]([N:65]1[CH2:64][CH2:63][N:62]([C:45](=[O:44])[CH2:46][NH:47][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[O:49])[CH2:67][CH2:66]1)=[O:15]
Reactant: O=C(O)c1cc(F)c(Cl)cc1Cl
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)c(Cl)cc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2,4-dichloro-5-fluoro-benzoic acid (53.8 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 45 mg (33.9% yield) of biphenyl-4-carboxylicacid {2-[4-(2,4-dichloro-5-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 98.74%, 1H NMR: (DMSO) δ 8.7-8.62 (t, 1H), 8.02-7.92 (d, 3H), 7.82-7.7 (q, 4H), 7.7-7.64 (q, 1H), 7.52-7.45 (t, 2H), 7.45-7.36 (m, 1H), 4.26-4.12 (dd, 2H), 3.76-3.56 (m, 4H), 3.54-3.44 (m, 2H), 3.28-3.14 (m, 2H).