Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)(=[O:36])[CH3:35].O>ClCCl>[C:34]([C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:12]2[C:6]3[CH:7]=[N:8][C:9]4[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][C:4]=4[C:5]=3[N:14]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:19][CH:20]=3)[C:13]2=[O:26])(=[O:45])=[O:44])=[CH:41][CH:42]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(C)ccc4ncc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 3, 100 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in dichloromethane (6 ml) was added 4-acetylbenzene-1-sulfonyl chloride (103.75 mg, 0.44 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 50 mg (33%); 1H NMR (DMSO-d6, 300 MHz): δ 9.347 (s, 1H), 8.299-8.325 (d, 2H, J=7.8 Hz), 8.175-8.202 (d, 2H, J=8.1 Hz), 7.940-7.969 (d, 1H, J=8.7 Hz), 7.778-7.803 (d, 2H, J=7.5 Hz), 7.665-7.691 (d, 1H, J=7.8), 7.466-7.495 (d, 2H, J=8.7 Hz), 6.427 (s, 1H), 2.624 (s, 3H), 2.110 (s, 3H), 1.776 (s, 6H); MS: m/z 525 (M+).
Reaction SMILES: [C:1]([C:3]1[C:4](=[NH:19])[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].OC1C=CC=CC=1C(C1C=CC=CC=1)=O.C(#N)CC#N.N1CCCCC1>C(O)C>[NH2:19][C:4]1[O:5][C:6]2[C:11]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]=1[C:1]#[N:2])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: N#Cc1c(-c2ccccc2)c2ccccc2oc1=N
Agent: O=C(c1ccccc1)c1ccccc1O
Solvent: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC1=C(N)Oc2ccccc2C1c1ccccc1
Reaction time: 2 h
Yield: 8 %

Procedure:
3-Cyano-2-imino-4-phenyl-2H-chromene. To a mixture of 2-hydroxybenzophenone (2.0 g, 10 mmol) and malononitrile (661 mg, 10 mmol) in ethanol (15 mL) was added piperidine (0.5 mL, 5.0 mmol). The mixture was stirred under 0–5° C. for 2 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 1.2 g (8%) of the title compound. 1H NMR (CDCl3): 7.74–7.29 (m, 7H), 7.20–7.13 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:35]=[N+:36]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[N:10][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc(-c2ccc([N+](=O)[O-])cc2)c1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc(-c2ccc([N+](=O)[O-])cc2)c1N=[N+]=[N-]
Reaction time: 0.33 h
Yield: 25 %

Procedure:
A mixture of methyl 3-amino-2-(4-nitrophenyl)-6-(3-(trifluoromethyl)phenyl)isonicotinate (1 g, 2 4 mmol) in concentrated hydrochloric acid (20 mL, 37%) was cooled in an ice bath and a solution of sodium nitrite (0.99 g, 14.4 mmol) in water (0.5 ml) was added in small portions. The orange-red solution was stirred for 20 min and then a solution of sodium azide (0.94 g, 14.4 mmol) in water (0.5 mL) was added in portions. A precipitate formed and, after 30 min, the reaction was partitioned between DCM and water. The organic phase was washed with brine (2×50 mL), sat. aq. Na2CO3 solution, water, brine and then dried with sodium sulfate. Removal of the solvent followed by silica gel chromatography (elution with 40% EtOAc in hexane) afforded methyl 3-azido-2-(4-nitrophenyl)-6-(3-(trifluoromethyl)phenyl)-isonicotinate (1.0 g, 2 1 mmol, 89% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.40 (2H, d, J=9.2), 8.33 (s, 1H), 8.29 (d, 1H, J=8.3), 8.22 (s, 1H), 8.07 (d, 2H, J=8.9), 7.74 (d, 1H, J=7.3), 7.66 (t, 1H, J=7.6), 4.12 (3H, s).
Reaction SMILES: [C:1]1([C:7]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][C:14]3[C:10](=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:12][N:13]=3)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1.O>CN(C)C=O>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([N:13]2[C:14]3[C:10]([CH:9]=[CH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:15]=3)=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:12]2)=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: CCOC(=O)c1[nH]nc2c1C=CC(c1ccccc1)(c1ccccc1)C2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=C2C=CC(c3ccccc3)(c3ccccc3)C=C2N(c2ccc([N+](=O)[O-])cc2)N1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 1 g of ethyl 6,6-diphenyl-6,7-dihydro-2H-indazole-3-carboxylate in 5 cm3 of dimethylformamide is added dropwise to a suspension of 0.151 g of sodium hydride (at 60% in oil) in 4 cm3 of dimethylformamide. After stirring the mixture for one and a half hours in the region of 20° C., 0.46 cm3 of 1-fluoro-4-nitrobenzene is added and the reaction mixture is stirred in the region of 80° C. for about two hours. A further 0.26 cm3 of 1-fluoro-4-nitrobenzene is added to the mixture, cooled to the region of 20° C. After stirring for two hours in the region of 80° C., the mixture is slowly cooled to the region of 20° C. and 10 cm3 of water are added. The mixture is extracted three times with 75 cm3 of ethyl acetate, and the combined organic phases are washed with twice 75 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/ethyl acetate (90/10 by volume)], 0.34 g of ethyl 1-(4-nitrophenyl)-6,6-diphenyl-1H-indazole-3-carboxylate is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:21]1(=[O:26])[CH2:25][CH2:24][CH:23]=[CH:22]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:22]2[C:21](=[O:26])[CH2:25][CH2:24][CH:23]=2)=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][N:9]=1
Reactant: O=Cc1cc(-c2ccccc2)cnc1Cl
Reactant: O=C1C=CCC1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: O=C1CCC=C1C(O)c1cc(-c2ccccc2)cnc1Cl
Yield: 95 %

Procedure:
The clear solution of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 95% yield (2.84 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH3:12])(=[O:11])[O:6][CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].N.[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([CH3:12])(=[O:11])[O:6][CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: [H][H]
Reactant: CC(C)COP(C)(=O)CCC#N
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)COP(C)(=O)CCCN

Procedure:
A solution of 20.0 g of isobutyl P-(2-cyanoethyl)-P-methyl-phosphinate in 200 ml of ethanol is added to 230.0 g of an 8% solution of ammonia in ethanol. To this are added 15 ml of Raney nickel slurry and the resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate is concentrated under reduced pressure. The crude product is distilled under reduced pressure to give isobutyl P-(3-aminopropyl)-P-methyl-phosphinate, b.p. 130°/0.01 mbar, 31P-NMR spectrum: δ=+57.6 ppm (CDCl3).
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[C:17](/[CH:18]=[N:7]/[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a mixture of (R)-2-methylpropane-2-sulfinamide (2.4326 g, 20.07 mmol) and Cs2CO3 (9.81 g, 30.1 mmol) in DCM (50 mL) was added dropwise a solution of 3-bromobenzaldehyde (4.08 g, 22.08 mmol) in DCM (50 mL) over 10 min and the mixture stirred at ambient temperature for overnight. The reaction mixture was filtered through celite and the filter pad washed with DCM then with EtOAc. Filtrate was dried over MgSO4 and concentrated to give an oil which was purified by silica gel chromatography to give 2A (4.7626 g, 16.53 mmol, 82% yield) as an faint yellow colored oil. 1H NMR (500 MHz, CDCl3) δ 8.55 (s, 1H), 8.05 (t, J=1.8 Hz, 1H), 7.76 (dt, J=7.7, 1.2 Hz, 1H), 7.68-7.65 (m, 1H), 7.41-7.36 (m, 1H), 1.31-1.29 (m, 9H).
Reaction SMILES: [CH2:1]([C:16]([OH:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.O.C1CCC(N=C=NC2CCCCC2)CC1.[K+].[Br-]>C1COCC1.CC(C)=O>[CH2:12]1[C:13](=[O:15])[O:18][C:16](=[O:17])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(O)CCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCCCCCCCCCCCC(=O)O1
Reaction time: 0.12 h

Procedure:
A flame dried 500 ml round bottom flask was allowed to cool before 8 g (0.031 mole) of solid 1,12-dodecanedicarboxylic acid was added. Dry THF (~100 ml) was added to suspend the diacid. After stirring for 5-10 minutes the mixture was warmed with tap water to about 40° to effect dissolution of the diacid. A few particles were usually visible in the reaction flask at this point DCC was weighed in a flame dried beaker. DCC (6.4 gm, 0.031 mole) was dissolved in 20 ml of THF. The concentrated DCC solution was transferred to the reaction vessel using a disposable pipette. Throughout all procedures the reaction vessel was purged with nitrogen. The reaction was sealed under nitrogen pressure and allowed to stir at room temperature for 15 hours. After 15 hours a thick, white paste formed and stopped the stirring bar. (Ideally, sufficient THF should be added initially to the reaction to prevent paste formation.) After 15 hours, 500 ml of reagent grade acetone was added followed by filtration through a scintered glass funnel (medium, 300 ml capacity). The filtrate was stored in the refrigerator overnight to crystallize the product. The cyclic anhydride was collected by filtration through a medium scintered glass funnel. The product was rinsed with reagent grade acetone and dried under vacuum, room temperature, overnight. Typical yields are 50-70% based only on the first crop of crystals. Reactions were monitored by FTIR using KBr pellets prepared from aliquots of the reaction mixture taken to dryness by rotoevaporation. See FIG. 6.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[ClH:13].[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:17]=[CH:16][N:15]=[C:14]2[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: COCCOCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOc1cc2ncnc(C3C(=O)Nc4ccccc43)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
A solution of oxindole (153 mg, 1.15 mmol) in DMF (3 ml) was added to a suspension of sodium hydride (46 mg, 1.15 mmol, prewashed with hexane) in DMF (1 ml) and the mixture was stirred for 30 minutes at ambient temperature. 4-Chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (120 mg, 0.38 mmol) was added as a solid and the mixture was stirred for 10 minutes at ambient temperature and then for 45 minutes at 50° C. The mixture was allowed to cool and was partitioned between ether and water. The aqueous layer was separated and adjusted to pH7.5 with 1M hydrochloric acid. The resulting precipitate was collected by filtration washed with water followed by ether and dried over phosphorus pentoxide. The solid was dissolved in methylene chloride/methanol and 2.8M ethereal hydrogen chloride (1 ml) was added. The volatiles were removed by evaporation, the solid residue was triturated with ether, collected by filtration and dried under vacuum to give 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(oxindol-3-yl)quinazoline hydrochloride (124 mg, 73%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([CH:16]([NH2:20])[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>CC#N>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:20][CH:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Reactant: CCCC(N)CCC
Solvent: CC#N
Product: CCCC(CCC)Nc1cc(C)[nH]c(=O)c1[N+](=O)[O-]
Yield: 89.9 %

Procedure:
4-Chloro-6-methyl-3-nitropyridone (2.9 g, 15.40 mmol) was treated with 1-propylbutylamine (4 mL, 26.8 mmol) in CH3CN (30 mL) at 25° C. for 64 h and at reflux for 2 h. The reaction mixture was partitioned between EtOAc (200 mL) and water (50 mL). The EtOAc was washed with water (2×50 mL), brine, dried (MgSO4) and stripped in vacuo. The residue was washed with 20% EtOAc/hexanes (2×20 mL) to give the product (3.7 g).
Reaction SMILES: C[CH2:2][N:3]=[C:4]=[N:5][CH2:6]CCN(C)C.Cl.O[N:14]1C(=O)CCC1=O.[CH2:21]([N:23]([CH2:26]C)[CH2:24]C)C>ClCCl>[CH2:21]1[N:5]2[CH2:6][N:14]3[CH2:2][N:3]([CH2:4]2)[CH2:24][N:23]1[CH2:26]3
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C1CCC(=O)N1O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: C1N2CN3CN1CN(C2)C3
Reaction time: 8 h
Yield: 895.8 %

Procedure:
C4 (197 mg, 0.201 mmol), EDC hydrochloride (77 mg, 0.401 mmol) and N-hydroxysuccinimide (35 mg, 0.301 mmol) were dissolved in anhydrous dichloromethane (30 ml) and activated ester formation left at room temperature for two hours under argon. To the solution was added E4 (300 mg, 0.211 mmol) and triethylamine (61 mg, 0.602 mmol) and the reaction left overnight at room temperature under argon. The solvents were removed, and the resulting residues purified by gradient silica column chromatography (3-7% methanol in dichloromethane) to yield the title compound as a colourless solid (378 mg, 78%). C119H209N11O37 requires 2384.5. Found ES+: MH22+, 1193.9, MH33+, 796.4. δH (CDCl3) 1.23 (46H, (CH2)19(CH2)2CO, (CH2)4CH), 1.44 (72H, br+m, (Me)3C, CH2CH2N, CH2CH2CO), 1.95 (1H, br, CH), 2.02-2.23 (30H, 10×s, MeCO), 2.17 (2H, t, (CH2)22CH2CO), 2.4-2.8 (4H, brm, CO(CH2)2CO), 2.83 (6H, s, MeN), 2.9-3.5 (32H, m, CH2N), 4.12 (2H, m, CH2OAc), 4.30 (2H, dt, CH2OAc), 5.20, 5.25 (2H, 2×d, CHOAcCO), 5.43, 5.60 (4H, 2×m, (CHOAc)2CHOAcCO), 5.71 (1H, br, (CH2)23CONH), 6.11 (1H, br, CO(CH2)2CONH), 7.18, 7.65 (2H, 2×t, N(CH2CH2NH)2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)=[C:4]([F:28])[CH:3]=1.[C:29](Cl)(Cl)=[O:30].C(N(CC)CC)C.Cl.[CH3:41][O:42][C:43](=[O:52])[C:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH2:51])=[CH:46][CH:45]=1>C(Cl)Cl>[CH3:41][O:42][C:43](=[O:52])[C:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH:51][C:29]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:28])=[O:30])=[CH:46][CH:45]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1CNC(c2ccc(Cl)cc2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2ccc(Cl)cc2F)cc1
Yield: 149.8 %

Procedure:
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2,3-bis(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (126.9 mg, 0.30 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 90 mg, 0.90 mmol) in CH2Cl2 (2 mL) followed by reacting with 4-aminomethyl-benzoic acid methyl ester hydrochloride (90.7 mg, 0.45 mmol) at rt for 30 min to give rac-4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl ester (110.5 mg, 60.9%) as a white amorphous solid.
Reaction SMILES: [CH2:1](/[C:3](/[C:20]1[S:24][CH:23]=[C:22]([CH:25]=[O:26])[CH:21]=1)=[CH:4]\[CH2:5][CH2:6][C:7]([CH2:18][CH3:19])([O:10][Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13])[CH2:8][CH3:9])[CH3:2].[BH4-].[Na+].O>C1COCC1.CO>[CH2:1](/[C:3](/[C:20]1[S:24][CH:23]=[C:22]([CH2:25][OH:26])[CH:21]=1)=[CH:4]\[CH2:5][CH2:6][C:7]([CH2:8][CH3:9])([O:10][Si:11]([CH2:16][CH3:17])([CH2:12][CH3:13])[CH2:14][CH3:15])[CH2:18][CH3:19])[CH3:2]
Reactant: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(C=O)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(CO)cs1
Reaction time: 1 h

Procedure:
4 g (9.9 mmol) of 5-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)thiophene-3-carbaldehyde are dissolved in 50 mL of THF and 50 mL of methanol. 1 g (26 mmol) of sodium borohydride is then added portionwise. The reaction medium is stirred for 1 hour and then poured into 100 mL of water. After purification by chromatography on silica gel, the desired product is obtained in the form of a colourless oil (m=4 g; Y=100%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([NH2:22])[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>O1CCCC1>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([NH:22][C:34](=[O:36])[CH3:35])[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3noc(C(C)N)n3)s2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NC(C)c1nc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)no1
Yield: 51.5 %

Procedure:
To a solution of Example 40D (265 mg, 0.76 mmol) in tetrahydrofuran (5 mL) at room temperature, was added diisopropylethyl amine (400 uL) followed by acetic anhydride (150 μL, 1.59 mmol). After an hour the reaction was quenched with methanol and stirred for additional hour. The solvent was removed under vacuum and the product was purified via silica-gel column chromatography using a gradient of 25 to 75% ethyl acetate in hexane to provide the title compound (152 mg). 1H NMR (300 MHz, CDCl3) δ ppm 7.90 (s, 1H) 7.17-7.25 (m, 2H) 6.89-6.99 (m, 2H) 6.09 (d, J=7.72 Hz, 1H) 5.33-5.53 (m, 1H) 4.54 (heptet, J=6.0 Hz, 1H) 2.08 (s, 3H) 1.62 (d, J=7.0 Hz, 3H) 1.36 (d, J=6.0 Hz, 6.0H).). MS (DCI): m/z 389 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[C:14](=[O:23])[C:15]([CH3:22])=[C:16]([CH3:21])[C:17](=[O:20])[C:18]=2[CH3:19])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:28](O)[CH3:29]>>[C:1]1([CH:7]([C:13]2[C:14](=[O:23])[C:15]([CH3:22])=[C:16]([CH3:21])[C:17](=[O:20])[C:18]=2[CH3:19])[CH2:8][CH2:9][C:10]([O:12][CH2:28][CH3:29])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CC1=C(C)C(=O)C(C(CCC(=O)O)c2ccccc2)=C(C)C1=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
4-Phenyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-butanoic acid (1.2 g) was dissolved in ethanol (50 ml), and thionyl chloride (0.4 ml) was added to the solution, followed by stirring at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in isopropyl ether, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and the object compound was eluted with isopropyl ether to give ethyl 4-phenyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)butanoate (1.1 g, 84%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this example, the Compound No. 42 was prepared.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]2[C:12]([C:13]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)=[C:14]([C:20]([OH:22])=[O:21])[O:15][C:16]2=O)=[CH:11][C:10]=1[O:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(Cl)(Cl)Cl.O>CN1CCN(C)C1=O>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]2[C:12]([C:13]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)=[C:14]([C:20]([OH:22])=[O:21])[N:37]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[C:16]2=[O:15])=[CH:11][C:10]=1[O:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN1CCOCC1
Reactant: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)oc(=O)c2cc1OCc1ccccc1
Solvent: O
Solvent: CN1CCN(C)C1=O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)n(N3CCOCC3)c(=O)c2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
7-Benzyloxy-6-methoxy-4-(3,4,5-trimethoxyphenyl)isocoumarin-3-carboxylic acid (5.0 g) and 4-aminomorpholine (6.2 g) are dissolved in 1,3-dimethyl-2-imidazolidinone (20 ml), and the mixture is heated at 100° C. with stirring overnight. To the reaction mixture are added chloroform and water. The chloroform layer is separated, washed, dried, and concentrated under reduced pressure to give 7-benzyloxy-3-carboxy-6-methoxy-2-morpholino-4-(3,4,5-trimethoxyphenyl)-1(2H)isoquinolinone. The product thus obtained is dissolved in dimethylformamide (15 ml), and thereto are added potassium carbonate (2.1 g) and methyl iodide (1.27 ml). The mixture is stirred at room temperature for 30 minutes, and thereto are added ethyl acetate and water. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 7-benzyloxy-6-methoxy-3-methoxycarbonyl-2-morpholino-4-(3,4,5-trimethoxyphenyl)-1(2H)isoquinolinone (3.4 g) as listed in Table 1.