Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[C:3]1([P:9](=S)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[OH:24].[Na+].Cl[O-].[Na+]>O>[C:3]1([P:9](=[O:24])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: S=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Solvent: O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of methanol (125 ml), triphenylphosphine sulfide (7.5 g) and aqueous 2.5% sodium hydrogen carbonate (25 ml) is added aqueous 14.3% sodium hypochlorite (125 ml) at 10° C. to 15° C., and the mixture is stirred for 1 hour at the same temperature. The reaction mixture is diluted with water (500 ml), and the separated crystals are collected by filtration, washed with water and dried to give triphenylphosphine oxide (6.5 g). m.p. 154°-157° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.[Li]CCCC.C1C[O:22][CH2:21]C1>>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[F:13])[CH:21]=[O:22]
Reactant: C1CCOC1
Reactant: Fc1ccc(Br)cc1C1OCCO1
Agent: [Li]CCCC
Product: O=Cc1ccc(F)c(C2OCCO2)c1
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a −78° C. solution of 2-(5-bromo-2-fluoro-phenyl)-[1,3]dioxolane (1.024 g, 4.047 mmol) in THF (40 mL) was added 2.5 M n-BuLi (1.80 mL, 4.45 mmol). After 20 min, the reaction was quenched with DMF (1.60 mL). After stirring for 1 h, the mixture was diluted with DCM, washed with a satd. aq. NaHCO3, dried (MgSO4), and concentrated. Purification by FCC (EtOAc/hexanes) gave the desired product (406.5 mg, 87%) as a white solid. 1H NMR (acetone-d6): 10.05 (s, 1H), 8.17-8.09 (m, 1H), 8.06-7.97 (m, 1H), 7.43-7.33 (m, 1H), 6.10-6.04 (m, 1H), 4.19-4.11 (m, 2H), 4.08-4.00 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](Br)[CH:8]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)O1>>[NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH:6]=[N:5][CH:4]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC(=O)N3)OC1(C)C
Reactant: NCc1cncc(Br)c1
Product: NCc1cncc(-c2ccc3c(c2)CCC(=O)N3)c1

Procedure:
In analogy to the procedure described for the preparation of example 45, reaction of 3-aminomethyl-5-bromopyridine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-34) gave the title compound as a light yellow amorphous solid. MS: 254.4 (M+H+).
Reaction SMILES: Cl[C:2]1([NH2:20])[N:19]=[CH:18][N:17]=[C:16]2[C:3]1=[N:4][CH2:5][N:6]2[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH:21]1(N)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)C>CO>[CH:21]1([NH:20][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:16]=3[N:17]=[CH:18][N:19]=2)[C@@H:7]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCC1
Reactant: NC1(Cl)N=CN=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A solution of 6-chloroadenosine (43 g) and cyclopentylamine (5 eq.) in ethanol (50 eq.) was heated at reflux for 3 hours then cooled to room temperature. The resultant reaction mixture was concentrated in vacuo and the resultant residue was diluted with water (400 ml) and ethyl acetate (400 ml). The organic layer was separated and the aqueous layer was extracted into ethyl acetate (2×400 ml). The combined organic layers were washed with water (2×200 ml), dried over sodium sulfate, concentrated in vacuo and dried under vacuum to provide a solid which was suspended in MeOH (400 mL), filtered and dried to provide N6-cyclopentyladenosine (43.8 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:33]([O:35]C)=[O:34])=[CH:29][C:30]([Cl:32])=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>[OH-].[Na+].CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:33]([OH:35])=[O:34])=[CH:29][C:30]([Cl:32])=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(Cl)cc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2cc(Cl)cc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 73.5 %

Procedure:
A solution of methyl 2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazol-7carboxylate (0.28 g) in 1N NaOH (2 ml) and methanol (4 ml) was stirred for 16 hours at room temperature. The reaction mixture was concentrated, and the concentrate was dissolved in water (10 ml), which was made acidic with 1N-HCl. Crystals thus separated were collected by filtration, recrystallized from methanol-chloroform to afford colorless crystals (0.2 g, 72%), m.p. 232°-234° C.
Reaction SMILES: C.[C:2]([O:6][C:7]([C@@H:9]1[CH2:13][S:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[N:10]1[C:21](=[O:45])[CH2:22][NH:23][C:24](=[O:44])[NH:25][C:26]1[CH:27]=[C:28]([CH:32]([CH3:43])[C:33]([O:35]CC2C=CC=CC=2)=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3]>C(OCC)(=O)C.[OH-].[Na+]>[C:2]([O:6][C:7]([C@@H:9]1[CH2:13][S:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[N:10]1[C:21](=[O:45])[CH2:22][NH:23][C:24](=[O:44])[NH:25][C:26]1[CH:27]=[C:28]([CH:32]([CH3:43])[C:33]([OH:35])=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:8])([CH3:4])([CH3:3])[CH3:5]
Reactant: CC(C(=O)OCc1ccccc1)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.1 %

Procedure:
0.1 g of 10% palladinised charcoal is added to a solution of 0.35 g of benzyl 2-{3-{3-{2-[(2R,4R)-4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenyl}propionate (B form) in 40 cm3 of ethyl acetate. The suspension is stirred for 48 hours at a temperature in the vicinity of 25° C. under a hydrogen atmosphere (100 kPa). The catalyst is then separated by filtration and the filtrate is concentrated to dryness under reduced pressure at 40° C. The residue obtained is dissolved in 10 cm3 of 0.1N aqueous sodium hydroxide solution and washed with 2 times 10 cm3 of ethyl ether. The aqueous phase is brought to a pH of 2 by addition of a 1N aqueous sulphuric acid solution. The product precipitated is separated by filtration, is washed with 2 times 10 cm3 of water and dried in air. 0.12 g of 2-{3-{3-{2-[(2R,4R)-4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}-phenyl}propionic acid (B form), melting at 126° C., is thus obtained.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[O:16][CH2:15][CH2:14][O:13]2)=[CH:8][C:7]=1[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:4].[N-:32]=[N+:33]=[N-:34].[Na+]>CO>[N:32]([CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[O:16][CH2:15][CH2:14][O:13]2)=[CH:8][C:7]=1[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:4])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCC(=O)Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of intermediate (25) (0.105 mol) and sodium azide (6.84 g) in methanol (160 ml) was stirred and refluxed for 6 h. The mixture was cooled, poured into ice water and extracted with DCM. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The product was used without further purification, yielding 2-azido-N-[2-benzoyl-4-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]phenyl]acetamide (intermediate 26).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][C:4]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[OH:1][CH:2]1[CH2:5][C:4]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
To a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (600 mg, 2.5 mmol, 1.0 equiv) in MeOH (6.0 mL) was added sodium borohydride (190 mg, 5.0 mmol, 2.0 equiv) in portions at 0° C. under nitrogen. The mixture was stirred at room temperature for 2.0 hrs. The solution was concentrated by evaporator to give the white solid. Saturated NaHCO3 solution (40 mL) was added. The aqueous phase was extracted with DCM (4×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated to give the crude which was purified by CombiFlash (24 g silica gel column, EtOAc/Hexane=0-60%) to afford 334 mg (yield 57%) of tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:21])[F:22])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnc(O[C@@H](C)C(F)(F)F)c(-c2ccc(Cl)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Oc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of 0.860 g (5)-methyl 5-(4-chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinate in 9 mL tetrahydrofuran was added 3 mL of a 1M solution of lithium hydroxide in water and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was acidified by addition of 1M hydrochloric acid till pH=2. Ethyl acetate was added and the phases were separated. The organic phase was dried over MgSO4 and the solvent was removed to yield 830 mg (100%) of the title compound as light yellow solid; MS (ESI) 344.1 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:20]=[C:19]([F:29])[CH:18]=3)[CH:12]=[CH:11][C:10]=2[CH3:31])[CH:5]=[CH:4][N:3]=1.[OH-:32].[NH4+]>C(O)=O>[F:29][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=1)[C:16]([NH:15][C:13]1[CH:12]=[CH:11][C:10]([CH3:31])=[C:9]([CH:14]=1)[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([OH:32])[N:7]=1)=[O:30]
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Reactant: [OH-]
Agent: [NH4+]
Solvent: O=CO
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1ccnc(O)n1
Temperature: 65 °C

Procedure:
A mixture of 2-chloro-4-[5-(3-fluoro-5-morpholinobenzamido)-2-methylanilino]pyrimidine (0.1 g) and formic acid (1.0 ml) was stirred and heated to 65° C. for 16 hours. The mixture was allowed to cool to ambient temperature and was poured into a dilute aqueous ammonium hydroxide solution. The resultant precipitate was isolated and washed with anhydrous diethyl ether. There was thus obtained the title compound (0.09 g); NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 3.2 (m, 4H), 3.73 (m, 4H), 5.70 (br m, 1H), 6.95 (m, 1H), 7.09 (m, 1H), 7.19 (m, 1H), 7.25 (s, 1H), 7.4 (m, 1H), 7.5 (m, 1H), 7.68 (m, 1H), 10.14 (s, 1H), 10.5 (broad s, 1H); Mass Spectrum: M+H+ 424.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: NCc1ccccn1
Solvent: O
Product: Cc1cc(O)cc(=O)n1Cc1ccccn1
Yield: 91.8 %

Procedure:
To a suspension of 12.6 g (0.1 mol) of 4-hydroxy-6-methyl-2-pyrone in 50 ml water was added 2-(aminomethyl)pyridine (10.3 ml, 0.1 mol) and the mixture heated to reflux for 2.5 hours. The resulting light yellow compound was filtered from the cooled mixture. Concentration of the filtrate and trituration of the resulting gum with dichloromethane afforded a second crop of the title compound (19.85 g, 92%). 1H NMR (DMSO-d6, ppm): 10.5 (s, 1H), 8.5 (d, 1H), 7.7-7.8 (t, 1H), 7.2 (t, 1H), 7.1 (d, 1H), 5.8 (s, 1H), 5.5 (s, 1H), 5.2 (s, 2H), 2.2 (s, 3H). FIA: m/z−215.1 ES−/217.1 ES+
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[CH3:15])[CH:7]([C:16](O)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH3:15][C:12]1[C:13]2[C:14]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH:7]([CH2:16][OH:17])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc2c1-c1c(C)cccc1C2C(=O)O
Solvent: C1CCOC1
Product: Cc1cccc2c1-c1c(C)cccc1C2CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A solution of 4,5-dimethyl-9-fluorenecarboxylic acid (4.2 g, 17.8 mmol) in 100 mL of THF was Charged with IM THF solution of BH3 -THF complex (25.0 mL, 25.0 mmol) at 0° C. The reaction mixture was stirred overnight at room temperature then quenched with water (100 mL) and HCl (3 mL). After addition of ethyl acetate (50 mL) the organic layer was separated and washed with 10% potassium carbonate solution, water, brine, dried dried over magnesium sulfate and evaporated to afford 4.5-dimethyl-9-fluorenemethanol (3.0 g, 75.3%).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6](C(CN)O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[CH:18](O)([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.[Pd]>[CH3:19][C:18]1([CH3:20])[C:7]2([CH3:6])[CH:8]3[CH2:9][CH:10]1[CH2:11][CH:12]23
Reactant: NCC(O)Cc1ccccc1
Reactant: CC(C)O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C2CC3C(C2)C31C
Temperature: 20 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
53 ml of concentrated sulfuric acid is added to a solution of 95 ml of benzylethanolamine in 690 ml of toluene. The suspension that is produced is heated to boiling for 2 hours. The water that is produced in this case (14 ml) is separated with the aid of a water separator. After cooling to 20° C., the reaction mixture is mixed with 1300 ml of water and absorptively precipitated for 10 minutes, and the organic phase is separated. Then, the aqueous phase is quickly added to a solution of 92.2 g of NaOH in 95 ml of water that is introduced in a second reaction vessel. The reaction mixture is heated to boiling. 880 g of water-N-benzylaziridine emulsion in a third reaction vessel is distilled off through a distillation bridge. The emulsion is mixed with 880 ml of ethanol and heated to 60° C. To this end, a solution of 38.0 g of p-TsOH in 19 ml of water is added within 8 hours via a metering pump. After the addition is completed, it is refluxed for two hours. Then, the reaction mixture is mixed with a solution of 12.0 g of NaOH in 20 ml of water. The precipitated product is filtered and recrystallized from 600 mlof 2:1 ethanol-THF mixture. The tetrabenzylcyclene (53 g) thus obtained is dissolved in 500 ml of isopropanol and hydrogenated with 10 g of Pd/C (10%) at 80° C. and 20 bar of H2 pressure. After the catalyst is filtered off, the reaction solution is concentrated by evaporation, andthe product is recrystallized from toluene. 15.9 g (55% of theory) of cyclene is obtained as colorless crystals. Melting point 110°-112° C.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.Cl.Cl.[C:18]1([CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33][NH2:34])[CH2:28]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.P(C#N)(OCC)(OCC)=O.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:18]1([CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33][NH:34][C:13]([C:5]3[S:6][C:7]4[N:12]5[C:3](=[CH:2][N:1]=[C:11]5[CH:10]=[CH:9][CH:8]=4)[CH:4]=3)=[O:15])[CH2:28]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCC1CCCN(CCCc2ccccc2)C1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCC1CCCN(CCCc2ccccc2)C1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 8 h

Procedure:
To a solution of 0.406 g (1.860 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid, 0.62 g (2.05 mM) of 1-(3-phenylpropan-1-yl)piperidin-3-ylmethylamine dihydrochloride, and 1.04 ml (7.44 mM) of triethylamine in 10 ml of N,N-dimethylformamide was added 0.34 ml (2.23 mM) of diethyl cyanophosphate at room temperature and the mixture was stirred at the prevailing temperature overnight. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=4/1 to 2/1) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([O:26][CH3:27])=[CH:24][N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:34][CH2:35][CH2:36][CH2:37][C:38](Cl)=[O:39]>CC(C)=O>[Cl:34][CH2:35][CH2:36][CH2:37][C:38]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([O:26][CH3:27])=[CH:24][N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:39]
Reactant: O=C(Cl)CCCCl
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(N)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(NC(=O)CCCCl)cc23)CC1
Temperature: 0 °C
Reaction time: 19 h
Yield: 66.7 %

Procedure:
To a mixture of 1-[3-[5-amino-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (2.3g, 6.3 mmol), and sodium carbonate (0.67 g, 6.3 mmol) in 25 mL of acetone, cooled to 0° C., was added dropwise 4-chlorobutyryl chloride (0.89 g, 6.3 mmol). Additional acetone (10 mL) was added and the suspension was stirred for 19 h at 23° C. The insoluble material was separated by filtration and the acetone was removed in vacuo. The crude material was dissolved in EtOAc, and the solution was washed with water, dried (brine, MgSO4), filtered, and concentrated in vacuo to give crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.98 g, 4.2 mmol, 67%) as a gum. Sodium ethoxide (0.67 mL, 2.1 mmol, 21% in ethanol) was added dropwise to a solution of crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.0 g, 2.1 mmol) in ethanol (5 mL). After the addition, the reaction mixture was heated at 78° C. for 90 min and then cooled to room temperature. The insoluble solid was separated and the filtrate was concentrated in vacuo. Silica gel column chromatography (95:5:0.5 CH2Cl2 -MeOH-30% NH4OH) afforded 1-[3-[5-[2-pyrrolidinone-1-yl]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (0.33 g, 0.76 mmol, 36%). The free base (0.25 g, 0.58 mmol) was dissolved in a minimum volume of acetonitrile. A concentrated solution of oxalic acid (0.052 g, 0.58 mmol) in CH3CN was added with stirring. The precipitate was separated by filtration, washed sparingly with CH3CN, and dried at 70° C. in vacuo overnight to give the title compound (0.17 g, 56%): mp 100°-101° C. Anal. Calcd for C24H30N6O2.1.0 C2H2O4.1.15 H2O: C, 57.26; H, 6.34; N, 15.41. Found: C, 56.90; H, 5.96; N, 15.51.
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+].O>O1CCOCC1>[OH:1][CH:2]([C:7]([O:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(O)C(OCCc1ccc(OC)c(OC)c1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CCOC(c2ccccc2)(c2ccccc2)C(O)C(=O)O)cc1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
12 g (27.5 mmol) of methyl 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate were dissolved in 110 ml of dioxane, and 55 ml of 1 N NaOH solution were added. The mixture was stirred at 80° C. for 2 hours. Water was added to the mixture, and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous HCl and extracted with ether, the organic phase was dried over magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from ether/n-hexane, and 10.2 g (87%) of colorless crystals were isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:12]CC[O:9]1.[NH:13]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:14][C:15]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])=[O:16].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[NH:13]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[CH2:14][C:15]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])=[O:16].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:12])[OH:9]
Reactant: Nc1ccccc1B1OCCO1
Agent: CCOP(=O)(C#N)OCC
Agent: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccccc1B(O)O

Procedure:
To a solution of o-aminophenylboronic acid (13.7 g, 100 mmoles) in dichloromethane (200 ml) is added ethylene glycol (6.30 g, 102 mmoles). The solution is shaken for 20 minutes, and then stirred over solid sodium sulfate. Removal of the volatiles affords ethylene o-aminophenylboronate. To a flame dried three neck round bottom flask equipped with septum, stopper and gas inlet, is added ethylene o-aminophenylboronate (0.36 g, 2.20 mmoles) in dry dimethylformamide (10 ml). To this solution is added Z-Gly-Ala (0.62 g, 2.21 mmoles), triethylamine (0.62 ml, 4.45 mmoles), and finally diethyl cyanophosphonate (0.37 ml, 2.44 mmoles). After stirring the reaction at room temperature for 17 hours, the DMF is removed under reduced pressure. The remaining residue is dissolved in ethyl acetate, and washed sequentially with 10% HCl, saturated sodium bicarbonate, and brine. After drying the organic phase over magnesium sulfate, the salts are removed by filtration and filtrate concentrated in vacuum to leave (0.63 g) of Z-Gly-Ala-o- aminophenylboronic acid. This compound can be used "as is" in the present invention, or the benzyloxycarbonyl (Z) group can be removed by hydrogenolysis (see first step of Example 4).