Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:55])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]5[CH2:43][CH2:42][N:41]([C:44]([O:46][CH2:47][C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)=[O:45])[C@@H:40]([CH3:54])[CH2:39]5)[CH:32]=4)[CH:30]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)C.Cl>O1CCOCC1>[F:55][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:16]=2)=[O:22])=[CH:30][C:29]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:45])[C@@H:40]([CH3:54])[CH2:39]2)[CH:32]=1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCNCC5)c4)ccc3F)c2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of phenylmethyl (2S)-4-[(5′-{[({3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (673 mg, 0.90 mmol) in 5 mL of 1,4-dioxane was added 5 mL of 4M HCl in 1,4-dioxane. The mixture was stirred at room temperature for 30 min. After removal of the solvent, the crude was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (390 mg, 67%). LC/MS: m/z, 649 (M+H), 1.69 min.
Reaction SMILES: [F:1][C:2]([F:14])=[CH:3][C@H:4]1[C@H:6]([C:7]([O:9]CC)=[O:8])[C:5]1([CH3:13])[CH3:12].[OH-].[Na+].Cl>C(O)C>[F:1][C:2]([F:14])=[CH:3][C@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:12])[CH3:13]
Reactant: CCOC(=O)[C@H]1[C@H](C=C(F)F)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
A stirred solution of ethyl trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarboxylate (10.0 g; 0.049 mole) and 30 ml of an aqueous 10% sodium hydroxide solution in 60 ml of ethanol was heated at reflux for 1.25 hours, then stirred at room temperature for approximately 18 hours. The reaction mixture was heated at 70° C. for an additional 1.5 hours, then cooled to room temperature and poured into 150 ml of an aqueous 5% hydrochloric acid solution. The resultant mixture was extracted with three 50 ml portions of diethyl ether. The extracts were combined, washed twice with water (50 ml) and once with an aqueous saturated sodium chloride solution, then dried over anhydrous magnesium sulfate. The organic solution was filtered, and the filtrate evaporated under reduced pressure to yield 7.95 g of trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarboxylic acid as an oil.
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][CH2:20][C:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1.[Na].O>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][CH2:20][CH:21]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=3)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCCCC(=O)CCc1ccccc1OCc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)CCCCC(CCc1ccccc1OCc1ccc(C2CCCCC2)cc1)Nc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At 0° C., 217 mg (1.15 mmol) of TiCl4 (1 M in CH2Cl2) were added to a solution of 500 mg (1.15 mmol) of methyl 8-{2-[(4-cyclohexylbenzyl)oxy]phenyl}-6-oxo-octanoate XIV and 190 mg (1.26 mmol) of methyl 4-aminobenzoate in 12.5 ml of 1,2-dichloroethane. The mixture was stirred at room temperature for 20 min, and 383 mg (1.72 mmol) of sodium triacetoxyborhydride were then added. The progress of the reaction was monitored by thin-layer chromatography, and after the reaction had ended, water was added. The mixture was extracted with ethyl acetate and the combined organic phases were dried over Na2SO4. The product was purified chromatographically (silica gel, gradient cyclohexane/ethyl acetate 10:1 to 0:100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[CH:33]([N:36]=[C:37]=[O:38])([CH3:35])[CH3:34]>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:37]([NH:36][CH:33]([CH3:35])[CH3:34])=[O:38])[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: CC(C)N=C=O
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.4 %

Procedure:
To a solution of 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (0.06 g, 0.15 mmol, obtained in example 90) in DMF (1 mL), isopropylisocyanate (0.02 g, 0.18 mmol) was added under argon atmosphere. This was stirred at room temperature for 2 days. The solvent was concentrated again and diethyl ether was added to the residue obtained. The solvent was concentrated, to afford 38 mg of title compound in solid form (yield: 50%).
Reaction SMILES: [NH:1]1[C@H:9]([CH2:10][OH:11])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]([OH:4])[CH2:2]1.[CH:12]([CH:14]=[O:15])=[O:13]>>[OH:13][CH:12]1[O:11][CH2:10][C@@H:9]2[C@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]([OH:4])[CH2:2][N:1]2[CH:14]1[OH:15]
Reactant: OC[C@H]1NC[C@H](O)[C@@H](O)[C@H]1O
Reactant: O=CC=O
Product: OC1OC[C@@H]2[C@H](O)[C@H](O)[C@@H](O)CN2C1O

Procedure:
Preparation is carried out analogously to Example 1 from 1,5-didesoxy-l,5-imino-D-galactitol and corresponding molar ratios of 30% strength aqueous glyoxal.
Reaction SMILES: C([O:3][C:4](=[O:14])[C@@H:5]([N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[O:13])[CH3:6])C.C1COCC1.[OH-].[Na+]>O>[O:13]=[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]1[C@@H:5]([CH3:6])[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)[C@H](C)n1ccccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C(=O)O)n1ccccc1=O
Reaction time: 1 h
Yield: 26.9 %

Procedure:
A stirred mixture of (S)-2-(2-Oxo-2H-pyrid-1-yl)-propionic acid ethyl ester (364 mg, 1.87 mmol), THF (2 ml), water (1 ml) and sodium hydroxide (90 mg, 2.24 mmol) was kept at room temperature for 1 h, then concentrated under reduced pressure. The residue was dissolved in ether and the resulting solution washed with water. The organic layer was discarded and the aqueous layer was acidified with concentrated HCl then extracted several times with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was triturated with ether to afford the title compound as a colorless solid (84 mg, 27%): [α]31D=−50° (c=0.2, CH3OH); 1H NMR (400 MHz, DMSO) δ 1.5 (3H, d), 5.1 (1H, q), 6.2 (1H, t), 6.4 (1H, d), 7.4 (1H, m), 7.6 (1H, d).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][C:6]([OH:9])=[N:5]1)(=O)C.[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:9][C:6]1[CH:7]=[CH:8][NH:4][N:5]=1
Reactant: BrCc1ccccc1Br
Reactant: CC(=O)n1ccc(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Brc1ccccc1COc1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 1-acetyl-3-hydroxy-pyrazole (1.0 g, 7.9 mmol), 2-bromobenzyl bromide (2.0 g, 7.9 mmol) and K2CO3 (1.2 g, 8.4 mmol) in 20 mL of 2-butanone was heated to reflux for 90 min. After cooling to room temperature, the precipitated salts were filtered off and rinsed with tert-butyl methyl ether (TBME). The filtrate was then concentrated under reduced pressure (50 mbar) and redissolved in a mixture of tetrahydrofuran (THF) and methanol (MeOH) (3:2, 25 mL). 1 mL of a 10% NaOH solution was added and the solution was stirred 60 min at ambient temperature. Then, all volatiles were removed under reduced pressure (50 mL). The residue was diluted with 10 mL of H2O and 20 mL of ethyl acetate (EtOAc). The aqueous phase was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water and brine (both 20 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles and used in the next step without further purification (1.9 g, 7.5 mmol, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][OH:15])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:14][OH:15])[CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=[N+]([O-])c1cc(CO)ccc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1cc(CO)ccc1C(F)(F)F
Yield: 86.8 %

Procedure:
The product from Example 4A (3.6 g, 16.28 mmol) in methanol (100 mL) was hydrogenated in the presence of a catalytic amount of Pd /C for 4 hours. The catalyst was filtered off and the volatiles were evaporated to yield 2.7 g of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[C:3]#[C:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[BH4-].[Na+]>CO>[CH3:16][Si:2]([CH3:1])([CH3:15])[C:3]#[C:4][CH:5]([OH:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC(=O)C#C[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCC(O)C#C[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 200 ml of methanol was added 10 g (41.93 mmol) of the product of Example 5. The reaction mixture was cooled to 0° C. and 0.53 g (14 mmol) of NaBH4 was added portionwise over 5 minutes. After an additional 15 minutes, the reaction was quenched with acetone and the solvent removed under reduced pressure. The residue was partitioned between water and diethyl ether. The aqueous layer was extracted one additional time with diethyl ether and the combined organic extracts were washed 1× with brine and then dried (MgSO4). Thin layer chromatography indicated the crude product to contain both the titled product and its unsilylated analogue. This was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:16]C)=[N:5][C:6]([CH3:15])=[C:7]([C:9]2[N:10]([CH3:14])[N:11]=[CH:12][N:13]=2)[CH:8]=1)[CH3:2].[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[CH2:1]([C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[C:7]([C:9]2[N:10]([CH3:14])[N:11]=[CH:12][N:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2ncnn2C)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(-c2ncnn2C)c(C)[nH]c1=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 102 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-(2-methyl-2H-1,2,4-triazol-3-yl)-pyridine (76 mg, 0.328 mmol) and sodium iodide (148 mg, 0.987 mmol) under a nitrogen atmosphere is added anhydrous acetonitrile (5 mL) followed by drop-wise addition of chlorotrimethylsilane (123 μL, 0.979 mmol). The reaction mixture is stirred at 60° C. under nitrogen for 12 hr. The reaction mixture is allowed to cool and then quenched with water (0.75 mL). After stirring for 30 min, the mixture is partitioned between water and dichloromethane. The dichloromethane layer is separated and the aqueous layer is extracted with ten further portions of dichloromethane. The combined organic layer is dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (9:1). Fractions containing the product are combined and the solvent evaporated to give 3-ethyl-6-methyl-5-(2-methyl-2H-1,2,4-triazol-3-yl)-1H-pyridin-2-one (73 mg, 100% yield) as a cream solid. LC/MS: RT: 1.85 min, MS: m/e=219 (M+H); 1H NMR (400 MHz, d6-DMSO, δ, ppm): 11.92 (1H, s), 7.98 (1H, s), 3.74 (3H, s), 2.39 (2H, q), 1.09 (3H, t).
Reaction SMILES: Br.[OH:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([C:9](=O)[CH2:10][Br:11])[N:8]=1.C(=O)(O)[O-].[Na+].[C:18]([NH:21][C:22]([NH2:24])=[S:23])(=[NH:20])[NH2:19]>O.CC(C)=O>[BrH:11].[NH:21]([C:22]1[S:23][CH:10]=[C:9]([C:7]2[N:8]=[C:4]([CH2:3][OH:2])[NH:5][CH:6]=2)[N:24]=1)[C:18]([NH2:20])=[NH:19]
Reactant: O=C(CBr)c1c[nH]c(CO)n1
Reactant: N=C(N)NC(N)=S
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: N=C(N)Nc1nc(-c2c[nH]c(CO)n2)cs1
Yield: 87.6 %

Procedure:
1.78 g (0.0059 mol) of 2-hydroxymethyl-4-bromoacetylimidazole hydrobromide was dissolved in water and saturated sodium bicarbonate solution was added to precipitate the free base. This material was collected by filtration and dried and combined with 956 mg (0.0081 mol) of amidinothiourea in 60 ml acetone and heated to 70°. After 15 minutes heating a solid formed. The reaction mixture was cooled and the resultant solid was collected by filtration to give 1.65 g (87%) 2-guanidino-4-(2-hydroxymethyl-4-imidazolyl)thiazole hydrobromide, mp>310°. A sample was converted to the free base by dissolving in hot water and adding sodium bicarbonate solid to pH 10 to precipitate 2-guanidino-4-(2-hydroxymethyl-4-imidazolyl)thiazole free base. This material was dried over toluene at high vacuum to give a light tan solid, mp 208°-209° with decomposition. nmr (DMSO-d6) (δ): 7.16 (s, 1H); 6.83 (broad s, 4H) 6.68 (s, 1H); 4.45 (s, 2H); 3.46 (very broad s, 1H). High resolution mass spectrum, calcd for C8H10N6OS: 238.0638; found: 238.0654.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Br)[N:4]([CH3:8])[N:3]=1.C([Li])CCC.[CH:14](=[O:16])[CH3:15]>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5]([CH:14]([OH:16])[CH3:15])[N:4]([CH3:8])[N:3]=1
Reactant: CC=O
Reactant: Cn1nc(Br)nc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1nc(Br)nn1C
Temperature: -75 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a solution of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (2.634 g, 10.9 mmol, Eq: 1.00) in tetrahydrofuran (184 ml) was added dropwise at −78° C. under argon atmosphere n-butyllithium 1.6 M in hexanes (6.83 ml, 10.9 mmol, Eq: 1.00). The resulting mixture was stirred for 20 minutes at −75° C. then a solution of acetaldehyde (1.2 g, 1.54 ml, 27.3 mmol, Eq: 2.5) in tetrahydrofuran (36.9 ml) was added slowly and stirring at −75° C. was continued for further 1.5 hours. The mixture was quenched with sat. aq. NH4Cl solution and was warmed to 25° C. The mixture was diluted with ethyl acetate and washed 2 times with water. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 1-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-ethanol (1.639 g, 72.7%) as a light yellow oil. MS: m/z=206209 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[C:9](O)=O)[CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:20][C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][C:16]=3[N:21]=2)[OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)c1cccc(Br)c1
Reactant: Nc1ccc(F)cc1N
Agent: [Na+]
Agent: [OH-]
Product: OC(c1cccc(Br)c1)c1nc2cc(F)ccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of (3-bromophenyl)hydroxyacetic acid (3.7 g) and 4-fluoro-ortho-phenylenediamine (2 g) in 5N aqueous hydrochloric solution (3.2 mL) is heated under reflux for 15 h and cooled back to room temperature. The mixture is basified with concentrated sodium hydroxide and extracted with ethyl acetate. The organic phase is then dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 90/10/0.5) to afford the pure 3-bromophenyl(5-fluoro-1H-benzimidazol-2-yl)methanol.
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:55])[C@H:30]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[NH:31][C:32](=[O:45])[CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[C@H:20]1[OH:21])(=O)C1C=CC=CC=1.C(N)CCC>>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:55])[C@H:30]([CH2:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)[NH:31][C:32](=[O:45])[CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[C@H:20]1[OH:21]
Reactant: COc1ccc(C[C@H](NC(=O)CNC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2C(=O)O)cc1
Solvent: CCCCN
Product: COc1ccc(C[C@H](NC(=O)CNC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Yield: 37.3 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-3-[N-(N-benzyloxycarbonylglycyl)-O-methyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (242 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-3-[N-(N-benzyloxycarbonylglycyl)-O-methyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (752 mg) prepared in Example 15 with n-butylamine (4 ml) according to a similar manner to that of Example 23, mp. 118°-125° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18](Br)=[CH:19][N:20]=2)[N:17]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])[NH2:24].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl>O.COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:29]3[CH:30]=[CH:31][C:26]([C:23](=[O:25])[NH2:24])=[CH:27][CH:28]=3)=[CH:19][N:20]=2)[N:17]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCNc1ccc2ncc(Br)n2n1)C(=O)OC(C)(C)C
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCNc1ccc2ncc(-c3ccc(C(N)=O)cc3)n2n1)C(=O)OC(C)(C)C

Procedure:
{2-[3-(4-Carbamoyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-ethyl}-methyl-carbamic acid tert-butyl ester was prepared similarly to the procedure for example 5.6.60 from [2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-methyl-carbamic acid tert-butyl ester (367.4 mg, 1.0 mmol), (4-carbamoylphenyl)boronic acid [123088-59-5] (196.7 mg, 1.2 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (418.4 mg, 1.8 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (82.1 mg, 0.1 mmol) in 30% (v/v) water in 1,2-dimethoxyethane (25 mL) at 85° C. for 17 h. White powder from ethyl acetate/heptane, mp. 190-191° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ ppm (rotamers present) 1.15 (br. s., 5H) 1.28 (br. s., 1H) 1.38 (br. s., 3H) 2.85 (br. s., 3H) 3.32 (br. s., 1H) 3.54 (br. s., 1H) 6.73 (d, J=9.35 Hz, 1H) 7.27 (br. s., 1H) 7.34 (br. s., 1H) 7.79 (d, J=9.60 Hz, 1H) 7.94-8.03 (m, 4H) 8.28 (d, J=8.08 Hz, 2H). LRMS (ESI) m/z 411.2 [(M+H)]+, calc'd for C21H26N6O3: 410.48.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][CH2:13][C:14](Cl)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[Cl:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O

Procedure:
12.5 g (73 mmol) of 2-amino-5-chlorobenzoic acid are initially introduced into 500 ml of acetonitrile and treated with 9.0 g (80 mmol) of chloroacetyl chloride with stirring, the temperature being kept at 20°-25° C. (ice-bath). 22 g (0.16 mol) of finely pulverized potassium carbonate are then introduced and the mixture is stirred overnight at room temperature. The batch is adjusted to pH 2 with dilute hydrochloric acid and the acetonitrile is stripped off on a rotary evaporator. The precipitate is filtered off with suction and washed well with water. The crude product is treated with sodium bicarbonate solution and stirred. Insoluble matter is filtered off with suction and the filtrate acidified with dilute hydrochloric acid to pH 2. The precipitated product is filtered off with suction and dried. Yield: 7 g (77.3% of theory) M.p.: 188° C.
Reaction SMILES: [H-].[Na+].S(Cl)(=O)(=O)N.O.[S:9](=[O:13])(=[O:12])([OH:11])[NH2:10].O[CH2:15][C@:16]1([O:25][CH2:24][C@@H:22]([OH:23])[C@@H:20]([OH:21])[C@@H:18]1[OH:19])[OH:17]>CN(C=O)C>[CH3:15][C:16]1([CH3:18])[O:21][C@@H:20]2[C@@H:22]([CH2:24][O:25][C@@:16]3([CH2:15][O:12][S:9]([NH2:10])(=[O:11])=[O:13])[O:17][C:22]([CH3:24])([CH3:20])[O:19][C@H:18]32)[O:23]1
Reactant: NS(=O)(=O)O
Reactant: OC[C@@]1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O
Agent: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@@H]23)O1
Reaction time: 1.5 h

Procedure:
To a cold solution (-4° C.) of 2,3:4,5-di-O-isopropylidene-β-fructopyranose (75 g, 0.29 mol) in DMF (725 ml) was added 50% oily sodium hydride (16.34 g, 0.34 mol as NaH). After stirring for 90 min, sulfamoyl chloride (54.9 g, 0.48 mol) was added and the stirring continued for an additional 3.5 hr at that temperature. The reaction mixture was poured into cold water and extracted with toluene. The organic layer was dried (Na2SO4) and the solvents removed under vacuum to give a syrup which crystallized immediately. Recrystallization from ethylacetate/hexane gave pure 2,3:4,5-bis-O-methylethylidene)-β-D-fructopyranose sulfamate, mp 125°-126° C.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH:1]1([N:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:22]([CH3:21])(=[O:24])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cncc(CNC2CCCCC2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.85 g. portion of 3-cyclohexylaminomethylpyridine was dissolved in 15 ml. of dichloromethane, and 2.8 g. of potassium carbonate and 1.6 ml. of methanesulfonyl chloride were added. The mixture boiled vigorously for a short time, and was then stirred at ambient temperature overnight. The mixture was diluted with 25 ml. of additional dichloromethane, and was extracted with 20 ml. of water and dried over magnesium sulfate. The organic solution was reduced in volume and chromatographed over silica gel, eluting first with dichloromethane and then with 9:1 dichloromethane:ethyl acetate. The product-containing fractions were evaporated under vacuum, and the residue was triturated with petroleum ether and diethyl ether to obtain 0.8 g. of the desired product.