Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)S(O[C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[C:21]([C:31](=[O:34])[NH:32][CH3:33])[C:20]=2[CH:35]=1)(=O)=O.[CH3:38][C:39]1[O:43][C:42]([C:44]2[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=2)=[N:41][N:40]=1.O1CCOCC1>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.O>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:22]2[O:23][C:19]3[CH:18]=[CH:17][C:16]([C:46]4[CH:47]=[CH:48][CH:49]=[C:44]([C:42]5[O:43][C:39]([CH3:38])=[N:40][N:41]=5)[CH:45]=4)=[CH:35][C:20]=3[C:21]=2[C:31]([NH:32][CH3:33])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1nnc(-c2cccc(B(O)O)c2)o1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnc(C)o4)c3)cc12
Temperature: 90 °C
Yield: 39 %

Procedure:
DIEA (50 μL, 0.288 mmol) was added to Pd(Ph3P)4 (6 mg, 4.79 μmol), -(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (40 mg, 0.096 mmol), 3-(5-methyl-1,3,4-oxadiazol-2-yl)phenylboronic acid (29 mg, 0.144 mmol). Dioxane (1 mL) and water (200 μL) was added at rt. The reaction was heated to 90° C. overnight. The mixture was cooled and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (16 mg, 37%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.56 (1H, m), 8.24 (1H, s), 7.98-8.05 (4H, m), 7.93 (1H, s), 7.79-7.83 (1H, m), 7.68-7.76 (2H, m), 7.41 (2H, t, J=8.70 Hz), 2.87 (3H, d, J=4.58 Hz), 2.62 (3H, s). LC-MS retention time: 1.41 min; m/z (MH−): 426. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=12.96 min, purity=95%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=11.53 min, purity=94%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.C(N(CC)CC)C.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][N:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccnnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccnnc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
A stirred suspension of 2.6 grams (0.027 mole) of 4-aminopyridazine (prepared as in Example 1, Step A) in 100 ml of tetrahydrofuran is cooled to 0° C. and 4.6 ml (0.033 mole) of triethylamine is added in one portion. A solution of 4.1 ml (0.033 mole) of phenyl chloroformate in tetrahydrofuran is added dropwise during a 30 minute period. Upon completion of addition the reaction mixture is allowed to warm to ambient temperature where it is stirred for three days. The reaction mixture is concentrated under reduced pressure to a residue. The residue is taken up in 500 ml of chloroform and filtered to collect 1.9 grams of phenyl N-(4-pyridazinyl)carbamate; m.p. 184°-185° C. The filtrate is washed with water, then dried with magnesium sulfate. The mixture is filtered and the filtrate placed on a column of silica gel. Further elution is accomplished using 10% methanol in methylene chloride. The appropriate fractions are combined and concentrated under reduced pressure to yield an additional 1.8 grams of phenyl N-(4-pyridazinyl)carbamate. The nmr spectra are consistent with the proposed structure. The reaction is repeated several times.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][O:31][CH3:32])[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].O>C1COCC1.CO>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][O:31][CH3:32])[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.3 %

Procedure:
A solution of methyl 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoate (16 g; 37 mmol) in THF (400 mL) and MeOH (400 mL) at RT was treated with NaOH (37 mL; 5 M; 184.99 mmol). The reaction mixture was stirred at RT for 12 hours. The reaction mixture was concentrated to give a yellow solid. Water (600 mL) was added and the aqueous phase was washed with EtOAc (250 mL). Then the aqueous phase was acidified with HCl cc until pH 2 and extracted with EtOAc (2×300 mL). Organics were washed with brine, dried over MgSO4 and concentrated affording the title compound as a beige solid (11.66 g, 75%). 1H NMR (DMSO, 400 MHz) δ 13.64 (br s, 1H), 8.33 (d, J=1.41 Hz, 1H), 8.17 (dd, J=7.92 Hz, 1.4 Hz, 1H), 8.13-8.03 (m, 2H), 7.96 (dd, J=11.10 Hz, 1.17 HZ, 1H), 7.43 (d, J=7.91 Hz, 1H), 7.37-7.27 (m, 3H), 7.15 (d, J=7.03 Hz, 1H), 4.25-4.14 (m, 2H), 3.25 (s, 3H), 2.04 (s, 3H). LC/MS (Method B): 419.1 (M+H)+; 417.2 (M−H)−. HPLC: Rt 5.19 min (Purity: 99.2%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].O>ClCCl>[S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)([O:7][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[Br:1])(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOc1ccccc1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOc2ccccc2Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(2-Bromophenoxy)ethanol (17.4 g) was dissolved in dichloromethane (250 ml) and cooled to 0° C. Triethylamine (9.7 g) was added along with tosyl chloride (18.3 g). The mixture was stirred for 2 h, then added to water (500 ml). The organics were washed twice with 2N hydrochloric acid and dried. Separation was achieved using silica chromatography eluting with hexane/ethyl acetate mixtures. This gave 2-(2-bromophenoxy)ethyl tosylate (14.4 g).
Reaction SMILES: [NH2:1][C:2]([CH2:26][CH2:27][O:28][CH3:29])([CH2:22][CH2:23][O:24][CH3:25])[CH2:3][NH:4][C:5](=[O:21])[O:6][CH2:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[CH:30](=O)[CH2:31][CH2:32][C:33]#[CH:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[CH3:29][O:28][CH2:27][CH2:26][C:2]([CH2:22][CH2:23][O:24][CH3:25])([NH:1][CH2:34][CH2:33][CH2:32][C:31]#[CH:30])[CH2:3][NH:4][C:5](=[O:21])[O:6][CH2:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: C#CCCC=O
Reactant: COCCC(N)(CCOC)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCCCNC(CCOC)(CCOC)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 3 h

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (2-amino-4-methoxy-2-(2-methoxyethyl)butyl)carbamate (G23, 186 mg) and 4-pentynal (42 mg) in methylene chloride (5 mL), sodium triacetoxyborohydride (247 mg) and acetic acid (26 μL) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 60 to 0% hexane in ethyl acetate) to obtain (9H-fluoren-9-yl)methyl (4-methoxy-2-(2-methoxyethyl)-2-((4-pentyn-1-yl)amino)butyl)carbamate (G24, 102 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:17]=[C:16]([N:18]=[O:19])[CH:15]=[C:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]=1[OH:24])([CH3:11])([CH3:10])[CH3:9].[CH3:25][S:26][C:27](=[N:29][O:30][C:31]([N:33]([S:35][N:36]([C:38](F)=[O:39])[CH3:37])[CH3:34])=[O:32])[CH3:28].O>CCOCC.CCCCCC>[CH3:25][S:26][C:27](=[N:29][O:30][C:31]([N:33]([S:35][N:36]([C:38]([O:19][N:18]=[C:16]1[CH:17]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:13](=[O:24])[C:14]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15]1)=[O:39])[CH3:37])[CH3:34])=[O:32])[CH3:28]
Reactant: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Reactant: CSC(C)=NOC(=O)N(C)SN(C)C(=O)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CSC(C)=NOC(=O)N(C)SN(C)C(=O)ON=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 84.4 %

Procedure:
A solution of 1.2 g of triethylamine in 10 ml of dry ether was added dropwise to a mixture of 2.4 g of 2,6-di-t-butyl-4-nitrosophenol and 2.7 g of N-[[[N-[[N-fluorocarbonyl-N-methylaminothio]]-N-methylaminocarbonyloxy]]]ethanimidothioic acid methyl ester suspended in 40 ml of dry ether at a temperature below 25°. The mixture was stirred at room temperature for 50 minutes. Then, water and hexane were added to the mixture. The product was collected by filtration, washed with water, hexane, and air-dried to give 4.1 g of N-[[[N-[[3,5-bis-(1,1-dimethylethyl)-4-oxo-2,5-cyclohexadien-1-yli-deneaminooxycarbonyl]-N-methylaminothio]]-N-methylaminocarbonyloxy]]ethanimidothioic acid methyl ester, m.p. 160°-161.6°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[Cl:18][C:19]1[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O.[Cl-].[Na+].O>[Cl:18][C:19]1[C:24]([O:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:12][CH:13]=2)=[N:23][CH:22]=[CH:21][N:20]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (3.1 g, 12.8 mmol) and 2,3-dichloropyrazine (2.29 g, 15.4 mmol) in DMSO (35 mL) was added cesium carbonate (5.0 g, 15.4 mmol). The reaction mixture was heated to 80° C. for 2 h. The mixture was cooled to RT, diluted with EtOAc and brine. The aqueous layer was extracted with EtOAc (2×) and the combined organics were dried over Na2SO4, filtered and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as light-tan solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:11]([F:22])[CH:10]=2)[CH:5]=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH3:31]>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:11]([F:22])[CH:10]=2)[CH:5]=[C:4]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH2:30][CH3:31])=[CH:34][CH:35]=2)[N:3]=1
Reactant: Nc1nc(Cl)cc(Nc2ccc(Sc3ccncc3)c(F)c2)n1
Reactant: CCOc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2cc(Nc3ccc(Sc4ccncc4)c(F)c3)nc(N)n2)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A solution of N-(2-amino-6-chloro-4-pyrimidinyl)-N-[3-fluoro-4-(4-pyridinylsulfanyl)phenyl]amine from step 1 in toluene (2 mL) in ethanol (1 mL) was treated with aqueous sodium carbonate solution (2M, 0.5 mL). The mixture was then treated with 4-ethoxyphenylboronic acid (0.36 mmol), tetrakis(triphenylphosphine)-palladium (0.009 mmol), and allowed to stir at 120° C. under argon overnight. At this time, the solvents were removed at reduced pressure and the residue was purified by preparative silica gel with 3% MeOH in CH2Cl2 to afford the desired product as a white solid (21 mg).
Reaction SMILES: [Na+].[Cl-].[CH:3]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[OH:4][CH2:3][C@@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C=O)Cc1ccc2c(c1)OCO2
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Product: CCOC(=O)[C@@H](CO)Cc1ccc2c(c1)OCO2
Temperature: 37 °C
Reaction time: 18 h

Procedure:
Recombinant Escherichia coli HB101 (PNTCRG) (Accession Number: FERM BP-6898) was inoculated in 50 ml of 2× YT medium (containing 1.6% of tripeptone, 1.0% of yeast extract, and 0.5% of NaCl, pH=7.0) sterilized in a 500-ml Sakaguchi Flask and incubated while shaking at 37° C. for 18 hours. To 550 ml of the resultant culture solution, 87 g of the ethyl 2-formyl-3-(3,4-methylenedioxyphenyl)-propionate obtained in Example 1, 27.5 mg of NADP, and 89 mg of glucose were added and the mixture was stirred at 30° C. for 24 hours. After completion of the reaction, the reaction solution was extracted with toluene and the extract was concentrated to obtain 84.1 g of a blown oily substance. The chemical purity and optical purity of the product were analyzed in the same manner as in Example 9. The chemical purity was 96.5% and the optical purity was 96.4% ee. The product had an (R) configuration.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH:17]1[C@H:21]([OH:22])[C@H:20]([OH:23])[C@@H:19]([CH2:24]Cl)[O:18]1.C(N(CC)CC)C.[H-].[Ca+2].[H-].[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[SH:43]>CN(C)C=O>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH:17]1[C@H:21]([OH:22])[C@H:20]([OH:23])[C@@H:19]([CH2:24][S:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[F:36])[O:18]1
Reactant: Fc1ccccc1S
Reactant: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Agent: [Ca+2]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O[C@@H]1[C@@H](CSc2ccccc2F)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.1 %

Procedure:
To a solution of 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]-purin-9-yl}(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol (166.5 g, 0.457 mol) and triethylamine distilled from calcium hydride (352 ml, 256 g, 2.53 mol, 4 equivalents) in degassed anhydrous N,N-dimethylformamide (1.8 liters) was added 2-fluorothiophenol (190 ml, 228 g, 1.78 mol, 4 equiv) in 38 5 ml portions every 2-3 hours. The mixture was stirred at room temperature for 4 days with continuous bubbling of nitrogen into the solution (the reaction was monitored by 1H NMR). After the reaction was complete, the reaction mixture was poured into 7 liters of ethyl acetate, which was washed with 3 liters of water. The aqueous layer extracted with ethyl acetate (2×500 ml), and the combined organic layers were washed with water (3×2 liters), then reduced to a volume of about 1.8 liters, providing a suspension of a white solid. The suspension was stirred for 9 hours at room temperature, and the white precipitate filtered off, washed with diethyl ether (3×200 ml), and dried for 24 hours under high vacuum to give 131 g (63% yield) of 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-[(2-fluorophenylthio)methyl]-oxolane-3,4-diol as a white powder (98.9% pure).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:23]O>>[CH3:23][O:5][C:4](=[O:6])[C:3]1[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1cccc(Oc2ccccc2)c1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)cccc1Oc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 2-methyl-6-phenoxy-benzoic acid (19.9 mmol, 4.54 g), methanol (20 mL), and concentrated sulfuric acid (1.5 mL) was refluxed with stirring for 18 h before it was concentrated in vacuo. To the residue was added water (50 mL) and the mixture was neutralized by adding small portions of NaHCO3 with stirring. Subsequently, the mixture was extracted with ethyl acetate (1×50 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes:ethyl acetate=7:3 as the eluent gave the title compound as a yellowish oil (2.16 g); MS-(+)-ion: M+1=242.8.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][C:13]1=[O:21]>>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH3:11])[C:13](=[O:21])[CH2:14]2)=[O:19])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: NCc1nccnc1Cl
Reactant: CN1CCC(C(=O)O)CC1=O
Agent: Cl
Product: CN1CCC(C(=O)NCc2nccnc2Cl)CC1=O
Yield: 62 %

Procedure:
2-Aminomethyl-3-chloropyrazine hydrochloride (content 77%; 5.36 mmol, 1.0 g) and 1-methyl-2-oxopiperidine-4-carboxylic acid (5.36 mmol, 0.843 g) were applied according to the procedure in example 13 step 13a and purified using column chromatography (silica gel; dichloromethane with 10% methanol) to give N-((3-chloropyrazin-2-yl)methyl)-1-methyl-2-oxopiperidine-4-carboxamide (940 mg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=3)[NH2:32])[CH2:23][CH2:22]2)[N:12]=1.CS([O:40][CH2:41][CH2:42][C:43]1C=CC=C(N2CCCC2=O)[CH:44]=1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([N:32]4[CH2:44][CH2:43][CH2:42][C:41]4=[O:40])[CH:33]=[CH:34][CH:35]=3)[CH2:25][CH2:26]2)[N:12]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CS(=O)(=O)OCCc1cccc(N2CCCC2=O)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCCC5=O)c4)CC3)cccc2n1
Temperature: 100 °C
Yield: 77 %

Procedure:
N,N-Diisopropylethylamine (0.23 mL) was added to a solution of 2-methyl-5-(1-piperazinyl)quinoline (D3) (0.05 g) and 2-[3-(2-oxo-1-pyrrolidinyl)phenyl]ethyl methanesulfonate (0.071 g) in dimethylformamide (1 mL) and the resulting mixture was heated to 100° C. for 18 hours, then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL), a mixture of water and brine (1:1, 2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with methanol-ethyl acetate (90:10) affording the title compound in 77% yield (0.07 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:4]2[CH:3]=1.[OH-].[K+].CCO.C(O)(=O)C>O>[I:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnn2ccc(I)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn2ccc(I)cc12
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A 22 L round bottom flask was charged with ethyl 5-iodopyrazolo[1,5-a]pyridine-3-carboxylate (I-41) (376 g, 1.19 mol), KOH (133.5 g), EtOH (3856 mL) and water (290 mL). The mixture was heated to 55° C. and stirred at 55° C. for 3 hours. A sample was taken for analysis and HPLC showed no (I-41) remaining. Water (2.5 L) was added to obtain a dark solution with some insoluble solids which were removed by filtration. To the filtrate was added acetic acid (150 g, 2.5 mol) until pH˜6 followed by water (4 L). The mixture was stirred at 15 to 20° C. over 30 minutes to form a slurry that was filtered and rinsed with EtOH/H2O (1:2 v/v) to yield 5-iodopyrazolo[1,5-a]pyridine-3-carboxylic acid (I-42) as a red solid. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (b, 1 H), 8.65 (d, 1 H), 8.44 (d, 1 H), 8.37 (s, 1 H), 7.37 (dd, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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]>[CH3:12][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[C:10]([C:17]2[CH:18]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:9]1
Reactant: Cn1cc(I)c2c(Cl)ncnc21
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(-c3ccccc3)c2)c2c(Cl)ncnc21
Yield: 27.6 %

Procedure:
A solution of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (10 mg, 0.034 mmol), 3-biphenyl-boronic acid (7.4 mg, 0.038 mmol), Na2CO3 (36.1 mg, 0.34 mmol) and PdCl2(dppf) (1.4 mg, 0.0017 mmol) in THF (10 mL) was heated to reflux overnight under an argon atmosphere. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield ZK103 (3 mg, 28% yield). ESI-MS (M+H)+ m/z calcd 320.1, found 320.0.