Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][N:6]=1)=O.[Mg+2].[Br-].[Br-].[CH3:18][NH:19][CH3:20].[OH-].[Na+]>C1COCC1.CO.O>[CH3:18][N:19]([CH3:20])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][N:6]=1)=[O:2]
Reactant: CNC
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Agent: [Br-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(C(=O)O)cn1
Temperature: 40 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a suspension of pyridine-2,5-dicarboxylic acid dimethyl ester (10.1 g, 51.6 mmol) and MgBr2 (4.75 g, 25.8 mmol) in THF (200 mL) was added drop-wise a solution of dimethylamine (51.6 mL, 103.2 mmol, 2N in THF) at room temperature under nitrogen over a period of 10 min. The reaction mixture was stirred overnight and quenched with 1N HCl (52 mL) and H2O (50 mL), extracted with EtOAc (200 mL×3). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was dissolved in a mixture of DMF (10 mL), AcOEt (50 mL), MeOH (20 mL) and DCM (50 mL), the formed solution was partially evaporated to produce a crystalline material, which was removed by filtration. The mother liquor was collected and evaporated to form a solid, which was dissolved in a mixture of THF (67 mL) and MeOH (67 mL). To this solution NaOH (2.95 g, 73.7 mmol) in H2O (33.5 mL) was added. The reaction mixture was heated at 40° C. for few hours, acidified (pH 3) to form a solid precipitate, which was collected by filtration and dried to afford the title compound 27 (4.937 g, 50% yield over two steps).
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[C:14]2[O:15][C:16]3([C:26]([CH3:28])([CH3:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[CH3:29])[CH:17]=[N:18][C:13]=2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=O.[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][C:36]#[N:37])=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[C:36]([C:35]([C:34]1[CH:38]=[CH:39][C:31]([CH3:30])=[CH:32][CH:33]=1)=[CH:3][C:5]1[C:14]2[O:15][C:16]3([C:26]([CH3:27])([CH3:28])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[CH3:29])[CH:17]=[N:18][C:13]=2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)#[N:37]
Reactant: Cc1ccc(CC#N)cc1
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(C#N)=Cc2cc3ccccc3c3c2OC2(C=N3)N(C)c3ccccc3C2(C)C)cc1
Reaction time: 2 h

Procedure:
5 ml of a 50% strength sodium hydroxide solution are added to a solution of 0.36 g (1 mmol) of the compound of Example 1, of 0.13 g (1 mmol) of 4-methylbenzyl cyanide and of 0.05 g of polyethylene glycol 400 in 15 ml of toluene. The mixture is left at ambient temperature for 2 hours. The organic phase is separated off, washed with water, dried and evaporated. The product is purified by chromatography on a silica column (CH2Cl2 eluent)
Reaction SMILES: [C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([O:20]C)=[O:19])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O>CO>[C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Yield: 77.6 %

Procedure:
Methyl 2-phenyl-4-quinolone-6-carboxylate (3.8 grams) obtained in Example 1 is refluxed for three hours in a mixture of 100 ml of methanol, 3 grams of sodium hydroxide and 15 ml of water. The mixture is evaporated to dryness in vacuo, 100 ml of water is added to the residue, filtered, acidified with 10% hydrochloric acid solution, and the crystals which separate out therefrom are collected by filtration. These are recrystallized from dimethyl formamide to give 2.8 grams of 2-phenyl-4-quinolone-6-carboxylic acid, colorless powder, melting at above 300° C.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C[O:15]S([O-])(=O)=O.CC1C=CC=C2C=1N=C1C(C=CC=C1)=[NH+]2.C(O)(=O)C.O.NN>O.[Ni]>[OH:15][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[OH:10])[CH2:3][C@@H:2]([C:11]([OH:13])=[O:12])[NH2:1]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: COS(=O)(=O)[O-]
Agent: [Ni]
Agent: Cc1cccc2[nH+]c3ccccc3nc12
Agent: NN
Solvent: O
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Yield: 1139.3 %

Procedure:
1.8 g of tyrosine, 0.15 g of 9-methylphenazinium methylsulphate are placed into a reactor, dissolved in 1,000 ml of water. The resulting solution is acidified with acetic acid to the reaction medium pH of 4.5 and added with 30 ml of hydrazine hydrate and 5 g of Raney nickel. After filtering-off nickel, the resulting reaction mixture is evaporated to dryness under the pressure of 20 mm Hg, the residue is dissolved in 20 ml of methanol and the mixture is chromatographically separated into alumina and the desired product by eluting with a mixture consisting of n-propanol and a 34% aqueous ammonia taken in the ratio of 70:3. 1.1 g of 3,4-dihydroxyphenylalanine is thus obtained; the yield is 61% as calculated for the starting compound, m.p. of the product is 271°-272° C. The composition, in percent, is as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:27]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:28])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2
Reactant: Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=379.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]([OH:20])[CH3:19])[CH:5]=[C:6]([F:17])[C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.CO.FC1C=C([C:31]2(O)CC[O:33][CH2:32]2)C=C(F)C=1>>[F:17][C:6]1[CH:5]=[C:4]([C:18]2([OH:20])[CH2:31][CH2:32][O:33][CH2:19]2)[CH:3]=[C:2]([F:1])[C:7]=1[B:8]1[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:15])([CH3:16])[O:9]1
Reactant: OC1(c2cc(F)cc(F)c2)CCOC1
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Solvent: CO
Product: CC1(C)OB(c2c(F)cc(C3(O)CCOC3)cc2F)OC1(C)C

Procedure:
Following the procedure of Intermediate 106, replacing 1-(3,5-difluorophenyl)ethanol with 3-(3,5-difluorophenyl)tetrahydrofuran-3-ol methanol (Intermediate 142) provided the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[C:44]1([CH2:54][C:55](O)=[O:56])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:55](=[O:56])[CH2:54][C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH:47]=[CH:46][CH:45]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1cccc2ccccc12)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 1-naphthylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-naphthalen-1-yl-acetamide (0.7 g, 74%) as a white solid: mp 187-189° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.70 min. (98%); 1H NMR (DMSO-d6) δ 1.98-2.06 (m, 1H), 2.54-2.63 (m, 2H), 2.83-2.96 (m, 1H), 4.03 (s, 2H), 4.74 (d, J=5.8 Hz, 2H), 5.11-5.17 (dd, J=5.2 and 12.8 Hz, 1H), 7.43-8.11 (m, 10H), 8.71 (t, J=4.6 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 37.89, 48.82, 121.86, 124.17, 125.52, 125.64, 125.95, 127.11, 127.15, 127.92, 128.37, 131.48, 131.90, 132.47, 133.23, 133.33, 134.56, 139.23, 166.89, 167.42, 169.77, 170.60, 172.72; Anal. Calcd. for C26H21N3O5: C, 68.56; H, 4.65; N, 9.23. Found: C, 68.24; H, 4.54; N, 9.19.
Reaction SMILES: [C:1]1([P:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:9]2[C:17]([CH3:18])=[C:16]3[C:12]([CH2:13][CH2:14][CH2:15]3)=[C:11]([CH3:19])[C:10]=2[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][C:21]=2[O:30][CH3:31])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C1C2C(=CC=CC=2)C=CC=1.Cl[SiH](Cl)Cl.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1.C(OCC)C>[C:32]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[C:17]([CH3:18])=[C:16]3[C:12]([CH2:13][CH2:14][CH2:15]3)=[C:11]([CH3:19])[C:10]=2[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][C:21]=2[O:30][CH3:31])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc2ccccc2c1-c1c(C)c2c(c(C)c1P(=O)(c1ccccc1)c1ccccc1)CCC2
Agent: Cl[SiH](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccc2ccccc2c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc2ccccc2c1-c1c(C)c2c(c(C)c1P(c1ccccc1)c1ccccc1)CCC2
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
(−)-1-[6-(Diphenylphosphinoyl)-4,7-dimethylindan-5-yl]-2-methoxynaphthalene (800 mg, 1.59 mmol, 97% ee) was placed into a flask and the atmosphere in the flask was replaced with nitrogen. Triethylamine (4.4 mL, 31.8 mmol) was added to a solution of this naphthalene compound in xylene (40 mL), and cooled to 4° C. Further, trichlorosilane (800 μL, 7.95 mmol) was added dropwise, and the mixture was stirred for 30 minutes and then stirred at room temperature for 15 minutes. Further, the reaction mixture was heated to 110° C. and stirred for 3 hours. After the resulting reaction mixture was cooled to room temperature, diethyl ether (60 mL) and saturated aq. sodium bicarbonate (800 μL) were added, and the mixture was stirred for 30 minutes. The reaction mixture was filtered through Celite, and the filtrate was dried with sodium sulfate. After silica gel was added, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the titled compound (744 mg, 96%, 97% ee).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1>Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)[C@@H](Cc3ccc(Cl)c(Cl)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Product: O=C(O[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCN(C2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 30 mg (0.04 mmol) of (R)-1-(3,4-dichloro-benzyl)-2-[4-(1-tert-butoxycarbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 25) in 5 mL 4 M HCl was stirred overnight at RT. The reaction mixture was lyophilised, and the product was obtained as the HCl salt.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]([OH:17])([C:10]#[C:11][C:12]([CH3:16])(O)[CH2:13][CH3:14])[CH2:8][CH3:9]>C([O-])(=O)C.[Hg+2].C([O-])(=O)C.O>[CH2:8]([C:7]1([CH3:6])[C:10](=[O:2])[CH2:11][C:12]([CH2:13][CH3:14])([CH3:16])[O:17]1)[CH3:9]
Reactant: CCC(C)(O)C#CC(C)(O)CC
Reactant: O=S(=O)(O)O
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: O
Product: CCC1(C)CC(=O)C(C)(CC)O1
Temperature: 80 °C
Yield: 435.1 %

Procedure:
A mixture of mercury (II) acetate (2.7 g, 0.0084 mol), sulfuric acid (2.7 ml, 0.027 mol), water (270 ml) and 3,6-dimethyl-oct-4-yne-3,6-diol (27.0 g, 0.159 mol) is heated at 80° C. The reaction mixture is maintained at 80° C. for 4 hours and allowed to cool to ambient temperature. The mixture is extracted with diethyl ether (3×150 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 2,5-diethyl-2,5-di-methyldihydrofuran-3-one (20 g) as a colourless oil.
Reaction SMILES: N(CC[O:6]CCOCCOCCN)=[N+]=[N-].[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)CC[C@H](NC(C1C=CC(NCC2N=C3C(N=C(NC3=O)N)=NC=2)=CC=1)=O)C(O)=O>CS(C)=O.N1C=CC=CC=1>[C:23]([NH:22][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:6]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-(2-(2-Azidoethoxy)ethoxy)ethoxy)ethanamine (0.3 ml, 1.2, equiv.) (commercially available or prepared as described by Schwabacher et al., J. Org. Chem. 1998, 63: 1727) and dicyclohexylcarbodiimide (DCC) (650 mg, 2.5 equiv.) were added to a solution of folic acid dehydrate (600 mg, 1.26 mmol) in DMSO (20 ml) and pyridine (10 ml). The reaction mixture was stirred overnight, in darkness, at ambient temperature, giving rise to the formation of a precipitate of dicyclohexylurea (DCU). After removal of the precipitate, filtrate was poured into a solution of anhydrous ether (400 ml) cooled to 0° C. The yellow precipitate thus obtained was recovered by filtration, then washed with Et2O to remove traces of DMSO. An HPLC analysis of the precipitate (Method 1) showed that the two isomers 6a and 6b were obtained in a ratio of 7/3. The solid (812 mg) was dissolved in a solution (8 ml) 8:2:0.3:0.3 H2O/ACN/DMSO/Et3N, and purified by reverse phase preparative HPLC (Method 2). The fraction containing the inseparable isomers 6a and 6b was concentrated under reduced pressure. The residue was then dissolved in methanol under reflux and poured into a solution of Et2O cooled to 0° C. The precipitate was recovered by filtration and washed with Et2O to yield a yellow powder (240 mg, 30%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]2C=CN=[C:43](S(C)=O)[N:42]=2)[CH2:37][CH2:36]1)=[O:33].Cl.NC1CCN(C2[S:59][C:60]([C:63]([NH2:65])=[O:64])=CN=2)CC1>CN(C=O)C>[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:36][CH2:37][N:38]([C:41]2[S:59][C:60]([C:63]([NH2:65])=[O:64])=[CH:43][N:42]=2)[CH2:39][CH2:40]1)=[O:33]
Reactant: NC(=O)c1cnc(N2CCC(N)CC2)s1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ccnc(S(C)=O)n3)CC2)c(Cl)c1Cl
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(N)=O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
Diisopropylethylamine (0.19 ml, 1.12 mmol), EDC (0.098 g, 0.51 mmol) and HOAT (0.070 g, 0.51 mmol) were added to a stirred solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3, 0.1 g, 0.51 mmol) in DMF (1.5 ml) at room temperature. The resultant solution was stirred for 30 mins and 2-(4-aminopiperidin-1-yl)-1,3-thiazole-5-carboxamide hydrochloride (Intermediate 81; 0.163 g, 0.62 mmol) was added. The reaction was stirred at room temperature overnight under nitrogen. The reaction was stirred overnight, then concentrated under vacuum and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with 1 N HCl, water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by reverse phase chromatography (water/acetonitrile gradient, 20-95%) to give the desired product as a white solid (50 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([I:11])[N:3]=1.[F:12][C@@H:13]1[C@H:17]([OH:18])[C@@H:16]([CH2:19][OH:20])[O:15][C@H:14]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[OH-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:14]2[O:15][C@H:16]([CH2:19][OH:20])[C@@H:17]([OH:18])[C@H:13]2[F:12])=[C:4]([I:11])[N:3]=1
Reactant: Nc1nc(I)c2[nH]cnc2n1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc(I)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1
Temperature: 37 °C

Procedure:
2-Amino-6-iodopurine (0.8 g, 3.1 mmoles) which may be prepared according to R. T. Koda et al. (J. Pharm. Sci. 57:2056, 1968) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.39 g, 1.6 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 20 ml of 10 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. The pH of the suspension was adjusted to 7.2 with KOH. Thymidine phosphorylase (2,000 I.U.) and purine nucleoside phosphorylase (3,250 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 37° C. On day 12, the pH of the reaction was adjusted to 6.8 with acetic acid, and 2,000 I.U. of thymidine phosphorylase and 3,250 I.U. of purine nucleoside phosphorylase were added. On day 26, the reaction was diluted to 500 ml with 5 mM potassium phosphate buffer, pH 7, which contained 0.04% (w/v) potassium azide, and 2,000 I.U. thymidine phosphorylase and 3,250 I.U. purine nucleoside phosphorylase were added. On day 40, the reaction was filtered. The filtrate was evaporated. The residue was suspended in water/n-propanol (7/3) and filtered. The filtrate was evaporated. The residue was suspended in methanol and then filtered. The product which was contained in the filtrate was purified by chromatography on a 5×90 cm column of Biogel P-2 (Bio-Rad) with water/n-propanol (7/3) as the solvent, followed by chromatography on a 5×90 cm column of Sephadex G-10 (Pharmacia LKB) whith water/n-propanol (7/3) as the solvent. After the solvent was removed under vacuum, the residue was suspended in water and lyophilized to obtain title compound that analyzed as a 0.6 hydrate.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14].[Br:20][C:21]1[CH:22]=[C:23]([C:27](F)=[CH:28][N:29]=1)[C:24]([OH:26])=[O:25]>C1COCC1.CCOC(C)=O>[Br:20][C:21]1[CH:22]=[C:23]([C:27]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([I:19])=[CH:18][C:12]=2[F:11])=[CH:28][N:29]=1)[C:24]([OH:26])=[O:25]
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1cc(Br)ncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Temperature: -78 °C
Yield: 59.3 %

Procedure:
Lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (11.9 ml, 1.00 M, 11.82 mmol) was added to a solution of 2-fluoro-4-iodoaniline (1.40 g, 5.91 mmol) at −78° C. The pale green colored solution was stirred for 1½ h at −78° C. Then, lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (5.45 ml, 1.00 M, 5.45 mmol) was added followed by 2-bromo-5-fluoroisonicotinic acid (1.00 g, 4.55 mmol) in THF (5 ml). The dark colored homogeneous mixture was warmed to room temperature and stirred overnight. The crude was diluted with EtOAc (300 ml). Then, it washed with dilute HCl solution (20 ml), H2O (20 ml), dried and purified on Flashmaster II using a 100 g cartridge to obtain 1.18 g (59%) of 2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid. LC/MS: 7.43 min, 438 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:21].[Na+]>CO.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=1)=[O:21]
Reactant: COC(=O)CCCCCSc1ccc(N(C)C)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCS(=O)c1ccc(N(C)C)cc1
Temperature: 60 °C
Yield: 80.7 %

Procedure:
To a solution of 6-(4-dimethylamino-phenylsulfanyl)-hexanoic acid methyl ester (1.4 g, 5.0 mmol) in methanol (60 mL) was added dropwise at 0° C. a solution of sodium metaperiodate (1.3 g, 6.0 mmol) in distilled water (20 mL). The mixture was heated at 60° C. for 1 hour. The solution was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (150 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (100 mL), distilled water (2×50 mL), and lastly with brine (2×50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (100:1 ethyl acetate:triethylamine) to give the title compound (1.2 g, 81%) as a colourless oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)cc1
Reactant: OB(O)c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccncc2)cc1
Yield: 78 %

Procedure:
By carrying out the operation analogously to example 3, starting from 4-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 4-pyridineboronic acid, the expected product is obtained in the form of a cream powder with a yield of 78%.