Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]1([CH2:15][C:16]#[N:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+].CCOC(C)=O>CN1C(=O)CCC1.O>[Br:8][C:7]1[C:2]([CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]#[N:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccnc1Br
Reactant: N#CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: N#CC(c1ccccc1)c1ncccc1Br

Procedure:
2,3-Dibromo-pyridine (1 eq., 0.5 g) and Phenyl-acetonitrile (4 eq., 0.97 mL) were mixed in NMP (3 mL). Potassium tert-butoxide (1.3 eq, 0.3 g) was added to the solution. The resulting mixture was heated in microwave at 110° C. for 40 min EtOAc and water were added to the reaction mixture. The aqueous layer was separated and extracted with EtOAc (×3). The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid. It was used in the next step without further purification
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]2[CH3:14].[OH-].[Na+].Cl[CH2:18][C:19]#[N:20]>C1(C)C=CC=CC=1>[C:19]([CH2:18][C:6]1([CH3:14])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH3:12])[C:7]1=[O:13])#[N:20]
Reactant: N#CCCl
Reactant: COc1ccc2c(c1)C(C)C(=O)N2C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(C)(CC#N)C(=O)N2C
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
To a mixture containing 50 g of 5-methoxy-l,3-dimethyloxindole, 10.57 g of Aliquat 366 in 375 ml of toluene and 100 ml of 50% NaOH was added dropwise under nitrogen, a solution containing 21.73 g of chloroacetonitrile in 125 ml of toluene over 30 min. A slightly exothermic reaction ensued (50° C.). The reaction mixture was stirred for another 10 minutes, and then cooled to 10° C. To this cooled reaction mixture was added 400 ml of ice-cold water. The reaction mixture was transferred to a separatory funnel. The layers were separated and the organic layer was extracted with 3N HCl (2×250 ml) and water (1×250 ml). The toluene extract was concentrated under reduced pressure and the resultant dark oil was filtered through silica gel (500 g) eluting with 3% methanol-methylene chloride mixture. The eluate (2 L) was concentrated to give the target compound as an oil (54.61 g; 91% yield) which slowly crystallized upon seeding. This material was sufficiently pure and was reduced to (±)-1,3-dimethyl-5-methoxy-oxindolylethylamine without further purification. A small sample of (±)-cyanomethyl-5-methoxy-1,3-dimethyloxindole was recrystallized from isopropyl ether, m.p.=75.5°-76° C. (lit: 75°-76° C.).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 104b, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-[4-(7-chloro-quinolin-4-ylamino)-phenyl]-propionic acid (prepared by reaction of 2-amino-3-(4-aminophenyl)-propionic acid with 4,7-dichloro-quinoline as in Example 104a) to provide the title compound in good yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([N:15]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14])[CH:3]=1.N1C=CC=CC=1.[Cl:58][C:59]1[C:64]([Cl:65])=[CH:63][C:62]([S:66](Cl)(=[O:68])=[O:67])=[CH:61][N:60]=1.S(Cl)(Cl)(=O)=O>O1CCCC1>[Cl:58][C:59]1[C:64]([Cl:65])=[CH:63][C:62]([S:66]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([N:15]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14])[CH:3]=2)(=[O:68])=[O:67])=[CH:61][N:60]=1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(N)c2ccccc2c1O
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Cl)c1
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2cnc(Cl)c(Cl)c2)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A solution of 22.5 g (0.0318 mole) 4-amino-1-hydroxy-N,N-dioctadecyl-2-naphthamide and 4.0 g (0.5 mole) pyridine in 300 ml tetrahydrofuran (THF) under nitrogen was stirred at room temperature and a solution of 9.0 g (0.036 mole) 2,3-dichloropyridine-5-sulfonyl chloride in 50 ml THF was added. The mixture was stirred 2 hours at room temperature. A thin-layer Chromogram on silica gel sheets indicated unreacted amine, so an additional 1.0 g of the sulfonyl chloride was added followed by 0.5 ml pyridine and stirring for an additional hour. Since a thin-layer chromotogram indicated no more amine, the mixture was concentrated to a small volume on a rotary evaporator, slurried in water several times with the water layer decanted off each time. The oil was dissolved in ether, water was separated, and the extract was dried with anhydrous Na2SO4. The ether layer was removed to leave a reddish oil which solidified on standing. The oil was extracted several times with boiling acetonitrile to leave a purplish black residue. The extracts were chilled and the precipitate was reextracted; chilling the extracts gave 25.7 g (88 percent) of product as a beige powder with a m.p. 88°-9° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH2:24])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29](Cl)=[O:30].[CH2:32](N(CC)CC)[CH3:33]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:33][CH2:32][CH2:28][C:29]5=[O:30])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CBr
Solvent: CC#N
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 72.5 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (370 mg) obtained in Example 322-3), bromoacetyl chloride (220 mg), triethylamine (140 mg) and acetonitrile (10 ml) were treated as in Example 373 to give the title compound (320 mg) as an oil (yield: 65%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:32][NH:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:42])[NH2:41])=[CH:36][CH:35]=1.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:32][NH:33][C:34]1[CH:35]=[CH:36][C:37]([C:40](=[NH:41])[NH:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:39]=1
Reactant: CCCOC(=O)CN(c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: O=C(Cl)c1ccccc1
Product: CCCOC(=O)CN(c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 31 from 1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-5-[N-(n-propyloxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and benzoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH:7]=[C:6]([C:26]([OH:28])=[O:27])[C:5]2=[O:29].[CH3:30]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:30])[CH2:14][CH2:13]1)[N:8]([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[CH:7]=[C:6]([C:26]([OH:28])=[O:27])[C:5]2=[O:29]
Reactant: O=C(O)c1cn(-c2ccc(O)cc2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reactant: CI
Solvent: CN(C)C=O
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(O)cc4)c3c2F)CC1
Yield: 39.3 %

Procedure:
To a solution of 6,8-Difluoro-1-(4-hydroxyphenyl)-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.18 g) in DMF (29 ml) is added a solution of methyl iodide (7.7 g) in DMF (20 ml). The mixture is heated in a stainless steel autoclave on an oil bath at 110°-120° C. for 5 hours. DMF is distilled off under reduced pressure, and to the residue is added 10% aqueous sodium hydroxide to regulate pH 13. The insoluble substance is filtered off, and the remaining mixture is regulated to pH 8 with acetic acid. The precipitated crystals are separated by filtration, washed with water, dried, and then recrystallized from DMF to give 6,8-difluoro-1-(4-hydroxyphenyl)-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.7 g) as pale yellowish white crystals, m.p. >300° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>CC(C)=O.C(Cl)Cl.CCOCC>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:7][CH:8]=1)=[O:1]
Reactant: NS(=O)(=O)c1ccc(CO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCOCC
Product: NS(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
To a solution of 4-(hydroxymethyl)benzenesulfonamide (Step 3) (3.75 g, 20 mmol) in a mixture of acetone (250 ml) and methylene chloride (250 ml), pyridinium chlorochromate (6.47 g, 30 mmol) was added. After stirring at room temperature for 5 hours, the reaction mixture was diluted with ether and filtered through a short silica gel column. The column was eluted with hexane/ethyl acetate, (1/1). The fractions containing the desired material were combined and concentrated to give a white solid (2.0 g, 53%): mp 104-106° C. Anal Calc'd. for C7H7NSO3 : C, 45.40; H, 3.81; N, 7.56; S, 17.31. Found: C, 45.61; H, 3.59; N, 7.18; S, 16.27.
Reaction SMILES: [CH:1]1([C@H:7]([NH2:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]1[C:12]([CH3:14])([CH3:13])[CH2:11]1>>[CH:1]1([C@H:7]([NH:9][CH2:11][C:12]([CH3:14])([CH3:13])[OH:10])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](N)C1CCCCC1
Reactant: CC1(C)CO1
Product: C[C@@H](NCC(C)(C)O)C1CCCCC1

Procedure:
(1R)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1R)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-((1R)-1-Cyclohexyl-1-ethyl)-N-(2,2dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-3-((1R)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:27][CH2:28][O:29][CH3:30])[CH:19]=3)[CH2:14][CH2:13]2)[CH:8]=[CH:7][C:6]=1[O:31][CH3:32])C.[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:32][O:31][C:6]1[CH:7]=[CH:8][C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:27][CH2:28][O:29][CH3:30])[CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][C:5]=1[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)c1cc(CN2CCC(c3cn(CCOC)c4ccccc34)CC2)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCn1cc(C2CCN(Cc3ccc(OC)c(C(=O)O)c3)CC2)c2ccccc21
Yield: 65.1 %

Procedure:
Over a solution of 0.9 g (0.002 mol) of 2-methoxy-5-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]piperidin-1-ylmethy}-benzoic acid ethyl ester in 9 ml of methanol and 5 ml of tetrahydrofuran, 5 ml of a 1N aqueous sodium hydroxide were added. The crude mixture was stirred at room temperature for 20 hours and then neutralised with 1 N aqueous HCl. The product precipitated from the mixture. The solid obtained was filtrated and washed with ethanol and ethyl ether. 0.55 g (65% of yield) of 2-methoxy-5-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]piperidin-1-ylmethyl}-benzoic acid were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH2:23][CH2:22][N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[CH:11]3[CH2:10]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:3][CH:2]=1.O.Cl.[H][H]>O=[Pt]=O.C(O)C>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:23][CH2:22][N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[CH:11]3[CH2:10]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1Nc2ccccc2N2CCN(CCc3ccncc3)CC12
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2N2CCN(CCC3CCNCC3)CC12

Procedure:
A solution of 2,3,4,4a-tetrahydro-3-[2-(4-pyridinyl)ethyl]-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one in 120 ml. water and 60 ml. ethanol containing 13 ml. conc. hydrochloric acid was placed in a Parr hydrogenation apparatus, with 1.2 g. PtO2, under 45 psi. of hydrogen and shaken till pressure drop ceased. After filtering off catalyst the solvents were removed under vacuum and the residue crystallized from hot ethanol. Product filtered off, washed (ethanol), and dried. Dissolved in hot methanol which was displaced by ethanol by boiling off lower boiling solvent. Yield: 4.0 g. of the title compound as the dihydrochloride salt, m.p. 238°-240° C.
Reaction SMILES: C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C.[CH2:18]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:50][CH3:51])=[C:27]([NH:29][C:30]2[O:31][C:32]([C:35]3[CH:36]=[C:37]([C:41]4[CH:46]=[CH:45][C:44]([C:47](O)=[O:48])=[CH:43][CH:42]=4)[CH:38]=[CH:39][CH:40]=3)=[CH:33][N:34]=2)[CH:28]=1)(=[O:22])=[O:21])[CH3:19].[CH2:52]1[N:57]([CH2:58][CH2:59][NH2:60])[CH2:56][CH2:55][O:54][CH2:53]1>CN(C=O)C>[CH2:18]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:50][CH3:51])=[C:27]([NH:29][C:30]2[O:31][C:32]([C:35]3[CH:36]=[C:37]([C:41]4[CH:42]=[CH:43][C:44]([C:47]([NH:60][CH2:59][CH2:58][N:57]5[CH2:52][CH2:53][O:54][CH2:55][CH2:56]5)=[O:48])=[CH:45][CH:46]=4)[CH:38]=[CH:39][CH:40]=3)=[CH:33][N:34]=2)[CH:28]=1)(=[O:22])=[O:21])[CH3:19]
Reactant: NCCN1CCOCC1
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(-c4ccc(C(=O)O)cc4)c3)o2)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(-c4ccc(C(=O)NCCN5CCOCC5)cc4)c3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
In succession, diethylcyanophosphonate (50.0 mg, 0.27 mmol) and triethylamine (65 mg, 0.65 mmol) were added to a solution of the title compound from Example 236 (104.0 mg, 0.22 mmol) and 2-(4-morpholino)ethylamine (54.0 mg, 0.42 mmol) in DMF (2 mL). After the reaction was allowed to stir for 1 h at RT, the reaction was quenched with water (10 mL). The resulting precipitate was filtered, washed with water (10 mL) and dried to afford the title compound (85 mg, 66%) as a tan solid. (In the event that a clean precipitate was not formed on quench, the aqueous solution was washed with 3:1 chloroform/i-propanol (3×20 mL). The combined organic layers were separated, dried by anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product purified by chromatography on silica gel using dichloromethane:methanol (up to 20% methanol gradient) as eluent to afford the title compound.) 1H NMR (400 MHz, d6-DMSO): δ 9.71 (bs, 1H), 8.74 (d, J=2.1, 1H), 8.45 (t, J=5.5, 1H), 7.88–7.93 (m, 3H), 7.78 (d, J=8.2, 2H), 7.58–7.64 (m, 3H), 7.52 (t, J=7.7, 1H), 7.44 (dd, J1=2.1, J1=8.5, 1H), 7.23 (d, J=8.6, 1H), 3.93 (s, 3H), 3.52 (t, J=4.5, 4H), 3.36 (q, J=6.4, 2H), 3.25 (s, 2H), 3.15 (q, J=7.3, 2H), 2.33–2.40 (m, 4H), 1.10 (t, J=7.3, 3H). MS (ES+, m/z)=591 (m+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[OH:12])[O:8][C:7](=[O:14])[C:6]([C:15]([O:17]CC)=[O:16])=[CH:5]2.[OH-].[K+].Cl>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[OH:12])[O:8][C:7](=[O:14])[C:6]([C:15]([OH:17])=[O:16])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)c(O)c(F)c2oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(F)c(O)c(F)c2oc1=O
Yield: 90.4 %

Procedure:
A solution of 14 (100 mg, 0.37 mmol) and KOH (70 mg, 85%, 1.1 mmol) in 7 mL of THF/MeOH/H2O (5:5:1) is heated at 60° C. for 2 hours. The reaction is poured into 50 mL 5% HCl and extracted with EtOAc (40 mL×2), washed with brine (30 mL), dried over anhydrous MgSO4, and concentrated in vacuo to yield 81 mg (94%) of Compound 15 as a green powder.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([O:35][C@H:36]1[C@@H:40]([O:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:39](OC(=O)C)[O:38][C@@H:37]1[C:54]([NH:56][CH2:57][CH3:58])=[O:55])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[C@H]1[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C)O[C@@H]1C(NCC)=O)(=O)C1C=CC=CC=1.II>>[C:27]([O:35][C@H:36]1[C@@H:40]([O:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:39]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([C:19]#[N:20])=[N:18][C:10]=3[NH:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:38][C@@H:37]1[C:54]([NH:56][CH2:57][CH3:58])=[O:55])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CCNC(=O)[C@H]1O[C@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: CCNC(=O)[C@H]1O[C@@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: II
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
A mixture of 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile (Preparation 24) (5.00 g, 14.7 mmol), (2S,3S,4R,5R)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate and (2S,3S,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (Preparation 18) (6.50 g, 14.7 mmol) and iodine (0.38 g, 15.0 mmol) were heated together at 150° C. under reduced pressure (7 kPa, 1 psi) for 2.5 hours. The reaction was then allowed to stand at room temperature for 18 hours. The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate: pentane (40:60 by volume) increasing in polarity to neat ethyl acetate to afford the title compound as a foam (4.95 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:17]2[CH2:18][C:19]3[C:24]([C:16]2=[N:15][N:14]=1)=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3.C(=O)([O-])[O-].[K+].[K+].ClC[C:34]1[CH:35]=[N:36][N:37]([CH3:39])N=1.[CH3:40][N:41](C=O)C>O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:17]2[CH2:18][C:19]3[C:24]([C:16]2=[N:15][N:14]=1)=[CH:23][C:22]([O:25][CH2:34][C:35]1[N:41]=[CH:40][N:37]([CH3:39])[N:36]=1)=[CH:21][CH:20]=3
Reactant: CN(C)C=O
Reactant: Cn1ncc(CCl)n1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(O)cc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(OCc3ncn(C)n3)cc1-2

Procedure:
3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ol (35 mg) and potassium carbonate (30 mg) and 5-(chloromethyl)-2-methyltriazole were heated together with DMF (1 ml) at 120° C. for 2 hours. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water (×5), dried and evaporated to yield an oil which was purified by column chromatography on silica using methanol/dichloromethane to yield the title compound (7.8 mg).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][O:15][C:14]2=[O:26])=[O:12])=CC=1)([O-])=O.[C:27]1([C:33]2([C:45]#[N:46])[CH2:38][CH2:37][CH:36]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCCCCC.CCOC(C)=O>C1COCC1>[F:25][C:20]1[CH:19]=[C:18]([CH:17]2[CH2:16][O:15][C:14](=[O:26])[N:13]2[C:11]([N:42]2[CH2:41][CH2:40][N:39]([CH:36]3[CH2:37][CH2:38][C:33]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)([C:45]#[N:46])[CH2:34][CH2:35]3)[CH2:44][CH2:43]2)=[O:12])[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: N#CC1(c2ccccc2)CCC(N2CCNCC2)CC1
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CC1(c2ccccc2)CCC(N2CCN(C(=O)N3C(=O)OCC3c3ccc(F)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
To a solution of 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid 4-nitrophenyl ester (80 mg, 0.21 mmol) in 5 ml of THF was added 1-phenyl-4-piperazin-1-yl-cyclohexanecarbonitrile (80 mg, 0.29 mmol) in a portion and the resulting solution was stirred for 12 h at 25° C. Reaction mixture was concentrated in vacuo yielding a yellow oil, which was subjected to column chromatography (50% Hexane/EtOAc) to provide 53 mg (51%) of the desired product as a colorless oil. The product obtained was converted to the HCl salt and recrystallized from EtOAc-Et2O to afford 43 mg of the product as white solid: mp 148-151° C.; Anal. Calc. For C27H28F2N4O3.1.0HCl requires C, 61.07; H, 5.50; N, 10.55. Found: C, 59.48; H, 5.41; N, 10.34.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[O:20][C:18](=[O:19])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([N-]C(C)C)(C)C.[Li+].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1(C)C=CC=CC=1.O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH2:29]([C@H:17]1[CH2:16][C@@H:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:14][CH:13]=2)[O:20][C:18]1=[O:19])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCBr
Reactant: CCCCCCCOc1ccc([C@@H]2CCC(=O)O2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCOc1ccc([C@@H]2C[C@H](CCCCCC)C(=O)O2)cc1
Temperature: -65 °C
Yield: 1.3 %

Procedure:
Rel-(S)-γ-(4-heptyloxyphenyl)-γ-butyrolactone (3.0 g) and anhydrous tetrahydrofuran (50 ml) were placed in a 200 ml three-necked flask, followed by cooling the mixture down to -65° C. with stirring, dropwise adding a tetrahydrofuran solution of lithium diisopropylamide (21.8 mmol) (hereinafter abbreviated to LDA) over 30 minutes, cooling down to -65° C. with stirring for one hour, dropwise adding a mixed solution of hexylbromide (2.71 g), hexamethylphosphoric triamide (hereinafter abbreviated to HMPA) (2.93 g) and anhydrous tetrahydrofuran (5 ml) over 20 minutes, gradually raising the temperature, agitating the mixture at room temperature overnight, adding ice water (50 ml) and toluene (200 ml), washing the resulting organic layer with 2N-hydrochloric acid, saturated NaHCOs aqueous solution and saturated NaCl aqueous solution in this order, drying the organic layer over anhydrous magnesium sulfate, removing magnesium sulfate, concentrating the organic layer under reduced pressure, separation-purifying according to chromatography and recrystallizing from ethanol, to obtain rel-(αS,γS)-α-hexyl-γ-(4-heptyloxyphenyl)-γ-butyrolactone (cis-form) (0.05 g). m.p.: 74.8°-75.8° C.