Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([NH:20][C@H:21]([C:23]([OH:25])=O)[CH3:22])=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.[CH3:27][O:28][NH:29][CH3:30]>ClCCl.C(N(CC)CC)C>[CH3:27][O:28][N:29]([CH3:30])[C:23](=[O:25])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[CH3:22]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
CDI (185.6 g) was added to a dichloromethane (2000 ml) solution containing N-(tert-butoxycarbonyl)-L-alanine (200 g) at 5° C. or less, followed by stirring for 1 hour. Subsequently, triethylamine (115.8 g) and N-methoxy-N-methylamine hydrochloride (111.7 g) were added to the solution, followed by stirring at 15° C. or less for 1.5 hours. Dichloromethane (230 ml) was added to the reaction solution. The organic layers were washed with a 20% sodium hydroxide aqueous solution and the solvent was distilled away under reduced pressure. Heptane was added to the obtained residue for suspension and a solid was collected by filtration. A white solid of (S)-tert-butyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (237.8 g) was thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[S:39][CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:38]2[S:39][CH:40]=[C:36]([F:35])[CH:37]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CC1(C)OB(c2cc(F)cs2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc(F)cs2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
To a 30 mL sealed cap glass vessel containing tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.401 mmol) and 2-(4-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137 mg, 0.601 mmol) dissolved in DME and water (4:1) was added tetrakis(triphenylphosphine)palladium(0) (105 mg, 0.401 mmol) and potassium phosphate, tribasic (212 mg, 1 mmol). The cap was sealed, and the reaction mixture was heated at 85° C. for 4 hours and then cooled to room temperature. The mixture was diluted with water and extracted with EtOAc (2×25 mL). The organic layers were combined, dried over sodium sulfate, and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(4-fluorothiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and stirred at room temperature for 2 hours. The mixture was evaporated and purified by preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (112 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.54 (m, 2H), 1.60 (d, J=12.88 Hz, 2H), 1.66-1.81 (m, 2H), 1.83-1.99 (m, 2H), 3.81 (br s, 1H), 4.24 (br s, 1H), 4.45 (d, J=2.27 Hz, 2H), 7.14 (d, J=5.31 Hz, 1H), 7.31 (t, J=1.39 Hz, 1H), 7.79 (br s, 3H), 8.62 (s, 1H), 8.97 (d, J=1.77 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C17H18F2N4OS, 365. found, 365.
Reaction SMILES: CN1CCCC1=[O:7].Cl.BrC1[CH:11]=[C:12]([CH:15]=[CH:16]C=1)[CH2:13]N.C(N(C(C)C)CC)(C)C.[BH-](OC(C)=O)(OC(C)=O)[O:28][C:29](C)=[O:30].[Na+]>C(O)(=O)C>[CH3:16][CH:15]([OH:7])[C:12]([C:29]([OH:30])=[O:28])([CH3:13])[CH3:11]
Reactant: NCc1cccc(Br)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN1CCCC1=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 250 mL shaker vessel was added 2,6-dimethoxy-4-polystyrenebenzyloxy-benzaldehyde (DMHB resin) (10 g, 1.5 mmol/g, 15 mmol) and 150 mL of 1-methyl-2-pyrrolidinone (NMP). 3-Bromo-benzylamine HCl salt (17 g, 75 mmol), diisopropylethylamine (DIEA) (13 mL, 75 mmol), acetic acid (HOAc) (15 mL), and Na(OAc)3BH (19.1 g, 90 mmol) were then added. The resulting mixture was shaken at rt for overnight, and was then washed with NMP (150 mL×2), dichloromethane (DCM) (150 mL×2), MeOH (150 mL×2) and DCM (150 mL×2). The resulting resin was dried in vacuum oven at 35° C. for overnight to yield DMHB resin-bound 3-bromo-benzylamine (15 mmol).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([NH:24][CH2:25][CH2:26][NH2:27])=[N:16][CH:15]=1.O>CN(C)C=O>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:27][CH2:26][CH2:25][NH:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:13][CH3:12])=[CH:15][N:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: COc1cnc(NCCN)c2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(NCCNCC(O)COc2ccccc2)c2ccccc12
Reaction time: 72 h

Procedure:
5.2 g. Phenyl glycidyl ether and 15 g. 4-methoxy-1-(2-aminoethylamino)-isoquinoline are dissolved in dimethylformamide and left to stand for 72 hours at ambient temperature. The reaction mixture is then poured into water, extracted with methylene chloride, dried and purified chromatographically on a silica gel column using, as elution agent, methylene chloride-methanol-triethylamine (8:1:0.05 v/v/v). By evaporation of the pure fractions, there are obtained 5.5 g. (44% of theory) of an oil. By the addition of 1.7 g. fumaric acid to a solution of this oil in ethyl acetate-ethanol, a hydrogen fumarate is precipitated out and this is then recrystallized from isopropyl alcohol. The desired product is obtained in the form of colorless crystals; m.p. 152°-153° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([OH:18])=O.[CH3:19][CH:20]([CH3:44])[CH2:21][NH:22][C@H:23]1[CH2:28][C@@H:27]([C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])[CH2:26][N:25]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:24]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>ClCCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:22]([CH2:21][CH:20]([CH3:44])[CH3:19])[C@H:23]1[CH2:28][C@@H:27]([C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])[CH2:26][N:25]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:24]1)=[O:18]
Reactant: COCCCCn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
1-(4-Methoxybutyl)-1H-indole-2-carboxylic acid (210 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (270 mg) and N,N-diisopropylethylamine (5601) were dissolved in 1,2-dichloroethane (10 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (360 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (0:10-10:0) was concentrated under reduced pressure to give the object product (83 mg).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[C:16]([Br:21])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[S:10])[CH3:8].Cl>CO>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]2[C:9](=[S:10])[N:7]([CH3:8])[CH2:6][C:5]([OH:22])=[O:4]
Reactant: COC(=O)CN(C)C(=S)c1cccc2c(Br)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC(=O)O)C(=S)c1cccc2c(Br)cccc12
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A 1 N aqueous NaOH solution (25 ml) was added to a suspension of N-[(5-bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester (7.3 g, 20.7 mmoles; described in Example 3) in methanol (75 ml). The mixture was stirred at 20° to 22° C. for 21/2 hr, neutralized to pH 7 with aqueous HCl and concentrated under reduced pressure to remove methanol. The residual solution was rendered acidic (pH=2) with the addition of aqueous HCl solution and extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated to dryness. The residue was crystallized from ethyl acetate-hexane to give 5.3 g of the title compound; mp 181° C.; NMR (DMSO-d6) δ2.95 (s, 3H), 4.65 & 5.2 (2d, J=16.8, 2H), 7.85 (m, 6H), UVλmax (EtOH) 285 nm (ε12,300), 280 (12,400), 221 (42,600); IR (Nujol™) 2900, 1720 cm-1 ; Anal Calcd: C, 49.72% H, 3.58% N, 4.14%; Found: C, 49.63% H, 3.63% N, 4.18%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]1[S:27][C:26]([CH2:28][OH:29])=[CH:25][CH:24]=1.CC(C)([O-])C.[K+]>COCCOC>[CH:17]1([C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:29][CH2:28][C:26]5[S:27][C:23]([F:22])=[CH:24][CH:25]=5)=[CH:3][C:4]4=[O:21])=[CH:13][N:12]3[C:14]=2[CH3:20])[CH2:19][CH2:18]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Reactant: OCc1ccc(F)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)s4)cc3=O)cn12
Temperature: 120 °C
Yield: 36.8 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (285 mg), (5-fluorothiophen-2-yl)methanol (109 mg), potassium tert-butoxide (93 mg) and DME (5 ml) was heated at 120° C. for 30 min under microwave irradiation. Additional potassium tert-butoxide (93 mg) and (5-fluorothiophen-2-yl)methanol (109 mg) in DME (0.5 ml) were added to the reaction mixture, and the resulting mixture was heated at 120° C. for further 30 min under microwave irradiation. The mixture was quenched with water and extracted with EtOAc/MeOH. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOH-IPA to give the title compound (120 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][O:5][CH2:6][C:7]#[CH:8].C([Li])CCC.[CH2:15]1[O:25][C:24]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=2[O:16]1.[Cl-].[NH4+]>O1CCCC1>[OH:21][CH:20]([C:19]1[CH:22]=[CH:23][C:24]2[O:25][CH2:15][O:16][C:17]=2[CH:18]=1)[C:8]#[C:7][CH2:6][O:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C#CCOCC=C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)=CCOCC#CC(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g (161 mmol) of 1-[(3-methyl-2-butenyl)oxy)-2-propyne in 200 ml of tetrahydrofuran was treated at -78° under argon with 111 ml of n-butyllithium (1.6M in hexane). The mixture was left to stir at -40° for 30 minutes, again cooled to -78° and a solution of 26.6 g (177 mmol) of 3,4-methylenedioxybenzaldehyde in 150 ml of tetrahydrofuran was then added within 40 minutes. The reaction mixture was stirred at -78° for a further 1 hour, then warmed to room temperature and subsequently treated with 150 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 1-hydroxy-4-[(3-methyl-2-butenyl)oxy]-1-[3,4-(methylenedioxy)phenyl]-2-butyne as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH3:22])[CH3:2].[CH2:27]([NH2:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:1]([C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:33][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:18])=[CH:20][CH:21]=2)[N:9]=[C:8]1[CH3:22])[CH3:2]
Reactant: CCc1ccccc1NC=C1C(=O)N(c2ccc(C(=O)O)cc2)N=C1C
Reactant: CCCCCCN
Product: CCCCCCNC(=O)c1ccc(N2N=C(C)C(=CNc3ccccc3CC)C2=O)cc1

Procedure:
From the reaction of 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzoic acid and hexylamine, 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-N-hexylbenzamide is obtained, Mp 62.1° C.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:38])[C@@H:3]1[OH:39].Cl.I[CH2:42][CH2:43][O:44][CH2:45][CH2:46]I.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([N:38]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C@@H:3]1[OH:39]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: ICCOCCI
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N2CCOCC2)[C@H](O)[C@H](C)O1
Reaction time: 36 h
Yield: 62.3 %

Procedure:
To a solution of adriamycin hydrochloride (20 mg; 0.034 mmoles) in 1 ml of DMF were added 200 mg (0.614 mmoles) of bis(2-iodoethyl)ether and 0.014 ml (0.104 mmoles) of triethylamine, and the reaction was carried out for 36 hours at room temperature. The product was worked up in the same way as in the purification procedure of Example 1 to give 13 mg (yield 61%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:12]12[CH:11]([N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:10]1[CH2:9][NH:8][CH2:13]2
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2N(Cc1ccccc1)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CN(Cc2ccccc2)C2C3CNCC32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-dibenzylamino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.800 g, 2.10 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (2.5 mL). The resulting mixture was stirred at ambient temperature for 3 hours and then quenched with saturated aqueous solution of Na2CO3 (10 mL). The organic phase was separated, washed with water, saturated NaCl, dried over MgSO4 and then concentrated in vacuo. The obtained crude product, (3-azabicyclo[3.1.0]hex-6-yl)dibenzylamine, was used without further purification.
Reaction SMILES: I[C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].C(N(CC)CC)C.[CH2:26]([NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[C:27]#[CH:28]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:32][C:31]([F:34])([F:33])[C:30]([NH:29][CH2:26][C:27]#[C:28][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])=[O:35]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1I
Reactant: C#CCNC(=O)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCC#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O)C(F)(F)F
Temperature: 45 °C
Reaction time: 3.5 h
Yield: 95 %

Procedure:
This compound was prepared similarly. 5-Iodouridine (1.35 mmol, 500 mg) was dissolved in dry DMF (12 mL) and Ar was bubbled through the solution for 10 min. Then, (Ph3P)4Pd (0.1 equiv., 0.1351 mmol, 156 mg) was added and Ar was bubbled through the solution for another 5 min. Triethylamine (2.0 equiv., 2.703 mmol, 273 mg, 0.376 mL) was added via syringe followed by addition of N-propargyltrifluoroacetamide (2.5 equiv., 3.38 mmol, 510 mg and CuI (0.2 equiv., 0.27 mmol, 51.5 mg). The mixture was stirred at 45° C. for 3.5 h, then the solvent was evaporated, and the residue dissolved in MeOH/methylene chloride 1:1 (10 mL). Ion exchange resin (Bio-Rad AG1 X8, HCO3-form, 1.5 g) was added to remove Et3N.HI, and the mixture stirred at room temperature for 20 min. The mixture was then filtered through Celite, the solid washed with MeOH/methylene chloride 1:1 (10 mL) and the solvents removed by rotary evaporation. The residue was purified by column chromatography (chloroform/MeOH 8.25:1.75) to yield 5-(3-trifluoroacetamidopropyn-1-yl)-uridine (ca. 95%) as a yellow foam contaminated with some Et3N.HI. Rf:0.43 (chloroform/MeOH 8.25:1.75). 1H-NMR (DMSO-d6): 3.61 (m, 2H, 5′), 3.86 (m, 1H, 4′), 3.93-4.08 (m, 2H, 2′, 3′), 4.23 (m, 2H, H-9), 5.08 (d, 1H, OH), 5.19 (t, 1H, OH), 5.41 (d, 1H, OH), 5.75 (d, 1H, 1′), 8.48 (s, 1H, H-6), 10.10 (t, 1H, NH chain), 11.64 (s, 1H, NH cycl.). 13C-NMR (DMSO-d6): 29.5 (C-9), 60.5 (5′), 69.6 (3′), 73.8 (2′), 75.3 (C-8), 85.0 (4′), 87.6, (C-7), 88.3 (1′), 97.8 (C-5), 113.9, 117.7 (q, CF3, J=288.48 Hz), 144.4 (C-6), 149.7 (C-2), 155.9, 156.4 (q, COCF3, J=36.80 Hz), 161.6 (C-4).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11]>C(OCC)C>[CH3:1][N:2]([CH3:3])[S:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][Cl:4])(=[O:12])=[O:11]
Reactant: CNC
Reactant: O=S(=O)(Cl)CCCCCCl
Solvent: CCOCC
Product: CN(C)S(=O)(=O)CCCCCCl
Yield: 95.1 %

Procedure:
A 50% aqueous solution of dimethylamine (5.95 g, 66 mmol) was added dropwise to a solution of diethyl ether (60 ml) and 5-chloropentanesulfonyl chloride (6.15 g, 30 mmol) with stirring under ice-cooling. Thereafter, the mixture was stirred at the same temperature for 20 minutes. The reaction solution was washed twice with water (10 ml) and then with brine (10 ml), and thereafter dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The crude product was purified by column chromatography on silica gel with ethyl acetate-n-hexane (1:4), to give N,N-dimethyl-5-chloropentanesulfonamide (6.10 g) as a pale yellow oil.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:36])[C:15]2[N:16]=[CH:17][N:18]([C:34]=2[N:35]=1)[C@@H:19]1[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[C@H:20]1[O:21][CH2:22][O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:43][O:44][C:45]1[CH:66]=[CH:65][C:48]([C:49](Cl)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)=[CH:47][CH:46]=1>CO>[O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:36])[C:15]2[N:16]=[CH:17][N:18]([C:34]=2[N:35]=1)[C@@H:19]1[O:33][C@H:30]([CH2:31][O:32][C:49]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C:48]2[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:66][CH:65]=2)[C@@H:28]([OH:29])[C@H:20]1[O:21][CH2:22][O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCOCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)COc3ccccc3)nc21
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
N2-Phenoxyacetyl-2′-O-(2-cyanoethoxymethyl)guanosine (660 mg, 1.32 mmol) was subjected to azeotropic distillation with pyridine, and then was dried with a vacuum pump for 30 minutes. The residue was dissolved in 9 mL of THF, and 2.1 g of pyridine (26.4 mmol) and 600 mg of molecular sieve 4 A were added under an argon atmosphere, and the reaction solution was stirred for 10 minutes. To the solution was added 540 mg of 4,4′-dimethoxytritylchloride (1.58 mmol) by 3 portions every 1 hour, and the reaction solution was further stirred for 1 hour. After 2 mL of methanol was added and the reaction solution was stirred for 2 minutes, the reaction solution was filtrated with a celite, and was washed with ethyl acetate. After concentrating the filtrate with evaporation, the residue was dissolved in ethyl acetate, and was separated with a saturated aqueous sodium bicarbonate solution. After the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was purified by silica gel chromatography to obtain the objective compound (800 mg, yield 75%).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.O.[NH2:24][NH2:25]>>[N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:21])[NH:24][N:25]=3)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(-n2cnc3ccccc32)cc1
Solvent: O
Product: O=C1CCC(c2ccc(-n3cnc4ccccc43)cc2)=NN1

Procedure:
Similarly, the reaction of 4-(1H-benzimidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(1H-benzimidazol-1-yl)phenyl]-3(2H)-pyridazinone (3i), mp 262°-264° C.