Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N=C=N.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:34]([F:37])([F:36])[F:35])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.[F:38][C:39]([F:43])([F:42])[CH2:40][NH2:41]>ClCCl>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:34]([F:36])([F:37])[F:35])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([NH:29][CH2:30][C:31](=[O:32])[NH:41][CH2:40][C:39]([F:43])([F:42])[F:38])=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: NCC(F)(F)F
Agent: N=C=N
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
PS-Carbodiimide (0.53 g, 123 mmol/g, Argonaut Technologies, Inc.) was added to a stirred mixture of N-[[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine (i.e. the product of Step D, 510 mg) and 2,2,2-trifluoroethylamine (0.072 mL) in dichloromethane (3 mL) at room temperature. The mixture was stirred at room temperature for 5 h, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound (99 mg), a compound of this invention, as a white solid. 1H NMR (CDCl3): δ 8.82 (d, 1H), 8.26 (d, 1H), 7.46-7.67 (m, 7H), 7.09 (m, 2H), 4.28 (d, 2H), 4.25 (d, 1H), 3.96 (m, 2H), 3.88 (d, 1H).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:15][CH:14]=2)=[N:8][CH:9]=1)[CH3:3].[C:27]([OH:36])(=[O:35])[C@@H:28]([C@H:30]([C:32]([OH:34])=[O:33])[OH:31])[OH:29].O>CO>[C:32]([C@@H:30]([C@H:28]([C:27]([OH:36])=[O:35])[OH:29])[OH:31])([OH:34])=[O:33].[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][C@H:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:15][CH:14]=2)=[N:8][CH:9]=1)[CH3:3]
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Agent: Cl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Solvent: CO
Product: CCc1ccc(CCOc2ccc(C[C@H]3SC(=O)NC3=O)cc2)nc1
Reaction time: 96 h

Procedure:
5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione hydrochloride (100 mg) in MeOH (2 mL) was stirred for 5 min. using brief sonication to give a clear solution. L-tartaric acid (38 mg, 1 eq) was added followed by dropwise addition of water until a haziness persisted (up to 2 mL used). The reaction was stirred in closed vial for 96 h, the precipitated solid was collected on a filter cup and washed with H2O-MeOH (2:1, 3 ml) and then dried under vacuum (42 mg). (Method 13) 48.30%, Rt 9.62 min.; 51.60%, Rt 14.30 min.; d.e. 3.3%. 1H NMR (400 MHz, DMSO-d6): δ 8.34-8.29 (1H, d, J 1.9), 7.55-7.49 (1 H, dd, J 2.2, 7.9), 7.24-7.20 (1 H, d, J 7.8), 7.12-7.05 (2 H, d, J 8.6), 6.84-6.77 (2 H, d, J 8.6), 4.78-4.71 (1 H, dd, J 4.3, 9.1), 4.30-4.19 (1 H, d, J 4.3), 3.24-3.18 (2 H, d), 3.11-3.03 (2 H, t, J 6.6), 3.00-2.92 (1 H, dd, J 9.2, 14.2), 2.59-2.50 (2 H, q, J 7.6), 1.17-1.09 (3 H, t, J 7.7).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][C:3]1=[O:8].CC(C)([O-])C.[K+].[N:15](OCC(C)C)=[O:16].Cl>O1CCCC1.C(O)C>[N:15](=[C:4]1[C:3](=[O:8])[N:2]([CH3:1])[CH2:7][CH2:6][O:5]1)[OH:16]
Reactant: CN1CCOCC1=O
Reactant: CC(C)CON=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCOC(=NO)C1=O

Procedure:
While maintaining the temperature near -55°, a solution of 11.5 grams of 4-methyltetrahydro-1,4-oxazin-3-one dissolved in 100 ml of anhydrous tetrahydrofuran was added over a period of twenty minutes to a slurry of 14.6 grams of potassium t-butoxide in 100 ml of tetrahydrofuran vigorously stirring under a nitrogen atmosphere. After equilibrating the resultant mixture for 30 minutes at -60°, a solution of 11.4 grams of isobutyl nitrite in 50 ml of tetrahydrofuran was added over 15 minutes while maintaining the temperature at -60° with external cooling. After a 15-minute equilibration at -60°, the reaction mixture was brought to 25° and stirred for 3 hours. The solution was then cooled to 0° and neutralized to pH 5 with 65 ml of a solution of 18 ml of conc. hydrochloric acid diluted to 100 mls. with absolute ethanol. After a 15-minute equilibration, potassium chloride was filtered off and the solvent removed in vacuuo. The resulting oil was triturated with 50 ml of ethyl acetate and the resulting solid was collected and then recrystallized from 150 ml. of acetonitrile yielding 5.07 g of the oxime product, mp. 199°-201°.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N[C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[C:21]([C:1]([NH2:8])=[O:2])[CH:22]=1.[C:1]([NH:8][C@@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: Nc1cnc2ccccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-Boc-D-phenylalanine (1.25 g, 4.7 mmol) in ethyl acetate (40 mL) was treated sequentially with 3-aminoquinoline (1.4 g, 9.4 mmol) and dicyclohexylcarbodiimide (1.02 g, 4.9 mmol). The reaction mixture was stirred at 25° C. for 16 hr, filtered and the filtrate washed with 1M hydrochloric acid (2×25 mL), saturated sodium bicarbonate (1×25 mL), and brine (1×25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford titled compound (950 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH2:7]O)[CH:6]=1.S(Cl)([Cl:15])=O>ClCCl>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH2:7][Cl:15])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCn1cc(Br)c(C(F)(F)F)n1
Solvent: ClCCl
Product: FC(F)(F)c1nn(CCl)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.28 g of 4-bromo-3-(trifluoromethyl)-1H-pyrazole-1-ylmethanol was dissolved to 40 ml of dichloromethane. 2.9 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure. The obtained solid was washed with the mixture of hexane and chloroform to obtain 3.33 g of 4-bromo-1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
4'-Hydroxyacetophenone (10 g, 73.4 mmole) was suspended in 200 ml dichloromethane in a 500 ml one neck round bottom flask under nitrogen at 0° C. The suspension was treated with diisopropylethylamine (14.7 ml, 84.5 mmole) followed by acetyl chloride (6.0 ml, 84.5 mmole) in 1×50 ml dichloromethane slowly dropwise. The reaction mixture was stirred 30 minutes at 0° C. and then for 1 hour at room temperature. The mixture was washed with 1×100 ml 10% hydrochloric acid and the organics were dried over magnesium sulfate. The dried organics were conentrated in vacuo to a yellow oil. The oil was distilled via kugelrohr (high vacuum, 165° C.) to give 12.25 g (94%) of 4'-acetoxy-acetophenone as a white solid. Melting Point: 47°-49° C. 4'-Acetoxy-acetophenone (10 g, 56.2 mmole) was dissolved in acetic anhydride (10.6 ml, 112.2 mmole) in an oven dried 50 ml two neck round bottom flask under nitrogen. The solution was cooled to 0° C. and boron trilfuoride gas was bubbled into the reaction mixture until it was saturated. The reaction was stirred 1 hour at room temperature and was poured into 600 ml diethyl ether. The orange precipitate was collected, washed with fresh diethyl ether, and was dried to afford 6.6 g (43%) of a boron difluoride complex. Melting Point: 130°-132° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][C:4](=[O:19])[CH2:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].Cl.CN>>[CH3:23][N:24]1[CH:26]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C:6](=[O:18])[C:5]([C:4](=[O:19])[CH2:3][CH:2]([CH3:20])[CH3:1])=[CH:25]1
Reactant: COC(OC)N(C)C
Reactant: CC(C)CC(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Agent: CN
Agent: Cl
Product: CC(C)CC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A 3.9 g. portion of impure 6-methyl-1-(3-trifluoromethylphenyl)-2,4-heptanedione was reacted with 50 ml. of N,N-dimethylformamide dimethyl acetal, and then with 5 g. of methylamine hydrochloride as described in the examples above. The product was purified as described in Example 13 to obtain 0.22 g. of the desired product, m.p. 110°-112°. Nmr analysis is DMSOd6 showed peaks at δ7.6-8.3 (m, 6H, atomatic); 3.8 (s, 3H, N--CH3); 2.9-3.1 (d, 2H, COCH2); 1.8-2.4 (m, 1H, CH2CH); 0.8-1.0 (d, 6H, CH(CH3)2).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[C:11](I)[CH:10]=[CH:9][N:8]=1.[B:14](OCCCC)([O:20]CCCC)[O:15]CCCC.[OH-].[Na+]>C(OCC)C.O>[F:6][C:7]1[CH:12]=[C:11]([B:14]([OH:20])[OH:15])[CH:10]=[CH:9][N:8]=1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Fc1cc(I)ccn1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: OB(O)c1ccnc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of n-butyl lithium (3.2 mL 2.5M, 8.0 mmol) in dry diethyl ether (20 mL) at −78° C. was added a solution of 2-fluoro-4-iodopyridine (1.5 g, 6.7 mmol) in dry ether (10 mL) and the reaction mixture was stirred at −78° C. for 10 minutes. Tributyl borate (2.4 mL, 2.01 g, 8.7 mmol) was added and the reaction mixture was allowed to warm to room temperature over 2 hours. Water (5 mL) was added followed by 2N aqueous sodium hydroxide solution (10 mL) to dissolve the solids. The organic phase was separated. The aqueous phase was acidified to pH 3 using 6N hydrochloric acid and the resulting white solid was collected by filtration and dried under vacuum to give the title compound, 0.74 g (78%). 1H NMR (DMSO-d6) δ 8.65 (broad s, 2H), 8.21 (d, 1H), 7.59 (t, 1H), 7.37 (d, 1H).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl.Cl[CH2:21][N:22]1[CH:26]=[CH:25][CH:24]=[N:23]1>O1CCCC1>[C:8]1([P:7]([CH2:21][N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: ClCn1cccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(P(Cn2cccn2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
Diphenylphosphine (2.642 g, 14.2 mmol) is placed into a Schlenk flask with degassed tetrahydrofuran (50 ml). The solution is cooled to −78° C. and n-butyllithium (8.4 ml, 1.6 M in hexanes, 15.0 mmol) is added dropwise. The red solution is stirred at −78° C. for an additional 1 hour then the cooling bath is removed and the solution is stirred for 3 hours. The red solution is cooled to 0° C. and 1-(chloromethyl)pyrazole hydrochloride (0.698 g, 4.56 mmol) is added at once. The ice bath is removed and the reaction is stirred for 11 hours before adding degassed methanol (25 ml) and water (20 ml). The organic phase is separated and the aqueous phase is extracted with diethyl ether (3×10 ml). The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude material is purified by chromatography (SiO2, 10% ethyl acetate/petroleum ether) to give 1-(diphenylphosphinomethyl)pyrazole as a white solid in 47% yield (0.574 g, 2.16 mmol). This material is characterized as follows: 1H NMR (CDCl3, 500 MHz) δ 7.49 (dd. J=2.0, 0.5 Hz, 1 H), 7.45-7.40 (m, 4 H), 7.40-7.35 (m, 6 H), 7.25 (dd, J=2.5, 0.5 Hz, 1 H), 6.19 (dd, J=2.5, 2.0 Hz, 1 H), 4,91 (d, J=4.5 Hz, 2 R); 13C{1H} NMR (CDCl3, 125 MHz) δ 139.50, 136.04 (d, J=13.4 Hz), 133.18 (d, J=19.3 Hz), 129.34, 129.49, 128.95 (d, J=6.4 Hz), 106.11, 53.01 (d, J=16.0 Hz); 13P{1H} NMR (CDCl3, 80 MHz) δ−14.98.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[NH2:33])[C:28]#[N:29].C1N2CCN(CC2)C1>CN1C(=O)CCC1.CCOC(C)=O>[C:28]([C:27]1[CH:30]=[CH:31][C:32]2[NH:33][C:2]([CH2:3][C:4]3[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]4[C:5]=3[CH:6]=[CH:7][N:8]4[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:24][C:25]=2[CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=C(Br)Br
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 4-(2,2-dibromovinyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.3 g, 2.92 mmol), 3,4-diaminobenzonitrile (700 mg, 5.26 mmol) and DABCO (819 mg, 7.30 mmol) in NMP (12 mL) was stirred at 110° C. for overnight. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified using FCC eluting with heptane/EtOAc(60-80%) to provide the title compound. MS (ESI+) m/z 417.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:27][CH2:28][CH2:29][CH3:30])[NH:11][C:5]=2[N:4]([CH2:31][CH2:32][CH3:33])[C:3]1=[O:34].[CH:35](=O)[CH2:36][CH3:37].[Na]>CO.C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:26][CH2:25][N:24]([CH2:35][CH2:36][CH3:37])[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:27][CH2:28][CH2:29][CH3:30])[NH:11][C:5]=2[N:4]([CH2:31][CH2:32][CH3:33])[C:3]1=[O:34]
Reactant: CCC=O
Reactant: CCCOc1ccc(S(=O)(=O)N2CCNCC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CCC)CC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
A mixture of the title compound of example 87 (50 mg, 0.1 mmol), propanal (0.073 mL, 1 mmol) and 3 Å molecular sieves (300 mg) in methanol (2 mL) and acetic acid (0.1 mL), was stirred at room temperature for 4 hours. Then sodium cianoborohydride (32 mg, 0.51 mmol) was slowly added and the mixture was stirred at room temperature overnight. The reaction mixture was purified by solid phase extraction using a Varian Bond Elut SCX cartridge (methanol for washing, methanol-ammonia for elution) to yield the title compound (40 mg, 72%).
Reaction SMILES: CC1C=CC(S([CH2:11][C@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](=[O:24])[CH2:14][CH2:13]2)(=O)=O)=CC=1.[I-:25].[Na+].CC(C)=O>C1CCCCC1>[I:25][CH2:11][C@H:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:24])[CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2Cc2ccccc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: O=C1CC[C@@H](CI)N1Cc1ccccc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of (S)-5-[[(4-methylphenyl)sulfonyl]methyl]-1-(phenylmethyl)-2-pyrrolidinone (244.5 g, 0.68 mol), sodium iodide (305 g, 2.03 mol), and 3 L of acetone was refluxed and stirred overnight. The suspension was cooled to 10° C. and was filtered. The salts were rinsed with three 250-mL portions of acetone, and the acetone washes and filtrate were concentrated on a rotary evaporator to a thick slurry. Methylene chloride (1.5 L) was added and the white precipitate was filtered off and washed with methylene chloride. The filtrate was dried over magnesium sulfate (MgSO4), filtered through a pad of silica gel, and concentrated on a rotary evaporator to give 196.8 g (92% yield) of (S)-5-iodomethyl-1-(phenylmethyl)-2-pyrrolidinone as an off-white solid, mp 92°-94° C. (cyclohexane). 1 h NMR (CDCl3) δ 1.7-2.75 (m, 4 H, CH2), 3.18-3.28 (m, 2 H, CH2I), 3.42 (m, 1 H, NCH), 3.98 and 4.05 (AB, 2 H, Jgem =15 Hz, CH2Ph), 7.20 (m, 5 H, phenyl). [α]25D =+12.11 (c 0.35, methanol). Anal. Calcd for C12H14NOI: C, 45.73; H, 4.48; N, 4.44. Found: C, 45.58; H, 4.35; N, 4.22.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.BrC1C=C(O)C=CC=1.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][N:27]1[C:35]2[CH:34]=[C:33]3[O:36][CH2:37][CH2:38][O:39][C:32]3=[CH:31][C:30]=2[C:29](=[O:40])[C:28]1=[O:41].FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:40][C:29]1([C:9]2[C:8]([OH:11])=[CH:7][C:3]3[O:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)[C:30]2[CH:31]=[C:32]3[O:39][CH2:38][CH2:37][O:36][C:33]3=[CH:34][C:35]=2[N:27]([CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH3:20])[C:28]1=[O:41]
Reactant: COCCOCCN1C(=O)C(=O)c2cc3c(cc21)OCCO3
Reactant: Oc1ccc2c(c1)OCCO2
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: COCCOCCN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3-bromophenol, and 6-[2-(2-methoxyethoxy)ethyl]-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one was obtained (19%): MS (ES+) m/z 441.9 (M−17).
Reaction SMILES: [N:1]([C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH2:20][CH2:21][CH3:22])[CH2:15]1)[CH2:5][O:6]CC1C=CC=CC=1)=[N+]=[N-].[ClH:23].O1CCOCC1.[H][H]>C(O)C.[C].[Pd]>[ClH:23].[NH2:1][C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH2:20][CH2:21][CH3:22])[CH2:15]1)[CH2:5][OH:6]
Reactant: [H][H]
Reactant: CCC[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCC[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A suspension of 23.0 g of (3R,5S)-5-[(S)-1-azido-2-benzyloxyethyl]-3-propyldihydrofuran-2-one obtained in Example (116e) (75.9 mmol), 40.0 ml of a solution of 4 N hydrochloric acid in dioxane (160 mmol) and 5.20 g of 10% palladium-carbon (50% wet) in ethanol (400 ml) was stirred under a hydrogen atmosphere at room temperature for seven hours. Hydrogen in the reaction vessel was replaced by nitrogen, and then the reaction mixture was diluted with 200 ml of ethanol. Palladium-carbon was separated by filtration and washed with ethanol. The solvent was evaporated from the filtrate under reduced pressure to obtain crude (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-propyldihydrofuran-2-one hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[O:8][C:7]([CH3:17])([CH3:16])[CH2:6][C:5]2=[O:18].S(Cl)([Cl:22])(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:22])[C:11]=1[O:12][CH:13]([CH3:14])[CH3:15])[O:8][C:7]([CH3:16])([CH3:17])[CH2:6][C:5]2=[O:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)Oc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Solvent: ClCCl
Product: CC(C)Oc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O

Procedure:
Following General Procedure B, 6-bromo-7-isopropoxy-2,2-dimethyl-chroman-4-one, (Compound 6, 2.2 g, 7.0 mmol) and sulfuryl chloride (0.84 mL, 10.5 mmol) in dichloromethane were reacted to yield the title compound as white trapezoidal plates after recrystallization from hexanes.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>C(O)C>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:9]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:17][CH:16]=1
Reactant: COCCNCCCNCCOC
Reactant: Fc1ccc(CCl)cc1
Solvent: CCO
Product: COCCNCCCN(CCOC)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.4 %

Procedure:
To a solution of N,N'-bis(methoxyethyl)-1,3-propanediamine (4.5 g, 23.9 mmol) in ethanol (100 ml) was added under ice-cooling a solution of p-fluorobenzyl chloride (2.8 g, 19.1 mmol) in ethanol (50 ml) and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure and the resulting white oily substance was subjected to silica gel chromatography to obtain 2.3 g of the title compound as a colorless oily substance from the fraction from methylene chloride-methanol-aqueous ammonia. Yield=40%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[CH:16][CH:15]=1>>[C:2]1([N:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2ccccc12
Reactant: CNc1ccc(OC)cc1
Product: COc1ccc(N(C)c2nccc3ccccc23)cc1
Temperature: 140 °C
Yield: 54.8 %

Procedure:
A mixture of 1-chloroisoquinoline (50 mg, 0.31 mmol) and (4-methoxy-phenyl)-methyl amine (300 mg, 2.2 mmol) was heated in a sealed tube at 140° C. overnight. The crude product was purified by chromatography (5-6% ethyl acetate/hexanes) on silica gel to give the title compound (46 mg, 0.17 mmol, 57%). 1H NMR (CDCl3): 8.22 (d, 1H, 5.7), 7.68 (d, 1H, J=8.1), 7.62 (d, 1H, J=8.7), 7.47 (ddd, 1H, J=0.9, 6.9, 8.1), 7.24 (d, 1H, J=6.0), 7.19 (ddd, 1H, J=1.5, 6.9, 8.7), 6.94 (m, 2H), 6.79 (m, 2H), 3.76 (s, 3H), 3.52 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@H:7]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:23])=[CH:17][N:18]=[C:19]2[Cl:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:38]1C2C(=CC=C(S(Cl)(=O)=O)C=2)C(Cl)=CN=1.Cl.C(OC(=O)[C@H](CCCCN)NC(OC(C)(C)C)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[O:5]([CH:1]([CH3:3])[CH3:4])[CH:6]([CH3:7])[CH3:38].[C:1]([O:5][C:6](=[O:36])[C@H:7]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:23])=[CH:17][N:18]=[C:19]2[Cl:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: CC(C)(C)OC(=O)NCCCC[C@H](NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(C)C

Procedure:
Nα-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-Nε-tert-butyloxycarbonyl-L-lysine tert-butyl ester ##STR190## A solution of 1,4-dichloro-7-isoquinolinylsulphonyl chloride (250 mg, 0.84 mmol), Ne-tert-butyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (286 mg, 0.84 mmol) and triethylamine (235 μl, 1.69 mmol) in CH2Cl2 (25 ml) was stirred at 23° C. for 3h. The reaction mixture was washed with water (2×20 ml), dried (MgSO4) and concentrated in vacuo to a residue which upon trituration with hexane and then i-Pr2O gave Nα-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-Nε-tert-butyloxycarbonyl-L-lysine tert-butyl ester as a white powder (270 mg, 0.48 mmol).