Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:6]1[CH:11]=[CH:10][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[S:8][CH:7]1[C:17]([O:19]CC)=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].C(O)C>>[CH2:1]([CH:6]1[CH:11]=[CH:10][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[S:8][CH:7]1[C:17]([OH:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1C=CC(CCCCC)C(C(=O)OCC)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC1C=CC(CCCCC)C(C(=O)O)S1

Procedure:
Part C. A solution of the ester compound from Part B above (4.53 g, 14.5 mmol) and sodium hydroxide (0.25N solution) in 95% ethanol (120 mL, 30.0 mmol NaOH) was stirred for 12 hours at ambient temperature. The reaction mixture was evaporated, and the residue acidified with hydrochloric acid (1N, 150 mL). This was saturated with sodium chloride and extracted with methylene chloride (2×200 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the product, 3,6-dipentyl-3,6-dihydro-2H-thiopyran-2-carboxylic acid, as an oily mixture of diastereomeric products (5:1 by NMR) (4.01 g, 14.1 mmol, 97%). 1H NMR (major isomer; CDCl3): δ 5.73 (2H, s); 3.48 (1H, br t, J=7 Hz); 3.40 (1H, d, J=3.7 Hz); 2.60-2.52 (1H, m); 1.71-1.24 (16H, m); 0.89 (6H, t, J=3.7 Hz). Mass spectrum (NH3 -CI/DDIP): m/z 287 (6%); 286 (18%); 285 (100%); 239 (25%); 211 (2%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][CH:17]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:11]2)=[CH:2]1.[F:28][C:29]1[CH:30]=[C:31]([CH:37]=[C:38]([F:41])[C:39]=1[F:40])/[CH:32]=[CH:33]/[C:34](O)=[O:35]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]([CH:22]3[CH2:23][CH2:24][N:25]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:31]4[CH:30]=[C:29]([F:28])[C:39]([F:40])=[C:38]([F:41])[CH:37]=4)[CH2:26][CH2:27]3)[C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: O=C(O)/C=C/c1cc(F)c(F)c(F)c1
Reactant: COC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Product: COC(=O)C(N[C@H]1CC[C@H](c2c[nH]c3ccccc32)CC1)C1CCN(C(=O)/C=C/c2cc(F)c(F)c(F)c2)CC1

Procedure:
The title compound was prepared from methyl 2-((4-(1H-indol-3-yl)cyclohexyl)amino)-2-(piperidin-4-yl)acetate (from Example 24, step A) and trans-3,4,5-trifluorocinnamic acid, by the method of Example 1, step K, and the mixture of product diastereomers was separated by flash chromatography giving a pale yellow solid for the more polar cyclohexyl diastereomer (trans, Example 49a), a tan solid for the less polar cyclohexyl diastereomer (cis, Example 49b). Mass spectrum (LCMS, APCI pos.) calcd. for C31H35F2N3O3: 536 (M+H). Found: 536.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[I:9][C:10]1[N:11]=[C:12]([CH:23]=O)[N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1.O.[OH-].[Na+]>CS(O)(=O)=O.C(Cl)(Cl)Cl>[I:9][C:10]1[N:11]=[C:12]2[N:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]2[O:1][CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[CH:14]=1
Reactant: CN1CCC(O)CC1
Reactant: O=Cc1nc(I)cn1CCc1ccccc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-N-methylpiperidine (223 mg, 2.02 mmoles) in methanesulfonic acid (3.4 mL) is added a solution of 4-Iodo-1-phenethyl-imidazole-2-carbaldehyde (example 2B) (220 mg, 0.675 mmoles) in chloroform (1 mL). The reaction mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the pH is adjusted to 9-10 by adding 12N NaOH dropwise. The aqueous phase is extracted three times with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (99:5:0.1) to (95:5:0.5) to give 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 126° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH2:23][NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:34]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:23][N:24]([C:25]([O:27][CH:28]([CH3:29])[CH3:30])=[O:26])[CH3:34])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(C)OC(=O)NCc1ccc(OCc2ccccc2)cc1CCC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N(C)Cc1ccc(O)cc1CCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.8 %

Procedure:
To a solution of 3-[5-benzyloxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (6.3 g, 0.015 mol) in DMF (100 mL) was added NaH (29.4 mmol, 60% oil dispersion). The reaction mixture was stirred at 0° C. for 15 min, treated with methyl iodide (4.18 g, 29.4 mmol), and stirred overnight under N2 at ambient temperature. The mixture was concentrated and triturated with hexanes (200 mL). The residue was diluted with EtOAc (200 mL), and the solution was washed with water (200 mL) and brine (200 mL), dried (Na2SO4), and concentrated to a yellow oil (5.2 g). The material was dissolved in EtOAc (100 mL), and 5% Pd/C (0.725 g) was added. The reaction mixture was shaken under a hydrogen atmosphere in a Parr apparatus at 60 psi overnight at 40° C. The mixture was filtered and concentrated to give the title compound (2.1 g). MS [ES] m/z 352 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>C(Cl)(Cl)Cl>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([N:1]2[CH2:3][CH2:2]2)(=[O:20])=[O:19])=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC2)cc1
Reaction time: 0.17 h

Procedure:
To a 25 mL round-bottom flask was added aziridine (10 mg, 234 μmol), sodium bicarbonate (20 mg, 234 μmol), 4-nitrobenzene-1-sulfonyl chloride (45 mg, 234 μmol) and 2 mL chloroform. After 10 minutes, LC-MS showed the desired product was formed. The reaction mixture was concentrated under reduced pressure to give the crude product of the title compound, that was used directly for the next step. MS m/z: 229 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1>>[C:1]([C:5]1[C:6]([NH:14][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)Cc2ccc(Cl)cc2)nn2cccnc12

Procedure:
The product from Example 105B and 4-chlorophenylacetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 3.64 (s, 2H), 7.00 (dd, J=7.1, 4.0 Hz, 1H), 7.37-7.41 (m, 4H), 8.48 (dd, J=4.0, 1.6 Hz, 1H), 8.92 (dd, J=7.1, 1.6 Hz, 1H), 9.98 (s, 1H); MS (DCI) m/z 343 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:19]N1C(=O)CCC1=O>CN(C)C=O>[C:1]1([C:7]2[C:12]([I:19])=[CH:11][CH:10]=[C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccc(N3CCOCC3)n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Ic1ccc(N2CCOCC2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A solution of 750 mg of 2-phenyl-6-morpholinopyridine and 5 ml of N,N-dimethylformamide was stirred in an ice bath, and to the mixture was added 740 mg of N-iodosuccinimide, followed by stirring at room temperature overnight. Further, 70 mg of N-iodosuccinimide was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was extracted by adding ethyl acetate, water and sodium sulfite thereto, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 5-10% ethyl acetate/hexane, to give 1.1 g of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16]3=[C:17]4[C:12](=[CH:11][CH:10]=[C:9]([C:20]5[S:19][C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=6[N:21]=5)[C:8]4=[CH:7][CH:6]=2)[CH:13]=[CH:14][C:15]=13
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: c1ccc2scnc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Brc1ccc2ccc3c(-c4nc5ccccc5s4)ccc4ccc1c2c43
Temperature: 130 °C
Reaction time: 6 h
Yield: 19.1 %

Procedure:
A mixed solution of 5 g of 1,6-dibromopyrene, 2.1 g of benzothiazole, 5 g of cesium carbonate, 0.31 g of cuprous iodide, 0.12 g of triphenylphosphine, 57 mg of palladium acetate and 50 ml of dimethylformamide was heated while stirred under nitrogen gas stream at a temperature of 130° C. for 6 hours. The mixed solution was cooled to room temperature, thereafter filtered and washed with 10 ml of dimethylformamide and 100 ml of dichloromethane. The filtrate was washed twice with 50 ml of water, dried by magnesium sulfate and thereafter evaporated. The filtrate was purified by silica gel column chromatography and vacuum dried to thereafter obtain 1.1 g of 6-bromo-1-(benzothiazole-2-yl)pyrene.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cnc2c(C(=O)N3CCOCC3)cnn2c1NCc1ccccc1)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
7-Benzylamino-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.08 g, 0.18 mmol) obtained in Example 1, step 5 was dissolved in DMF (1 mL), morpholine (0.02 mL, 0.21 mmol), 3-[(3-dimethylamino)propyl]-1-ethylcarbodiimide hydrochloride (0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol) were added, and the mixture was stirred at room temperature for 5 hr. 10% Aqueous citric acid solution (1 mL) and water (10 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, washed with water (20 mL), and purified by silica gel column chromatography (chloroform/methanol=90/10) to give compound a-11 (0.02 g, 18%).
Reaction SMILES: O[C:2]([CH3:16])([CH3:15])[C:3]#[C:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6].C(NCC)C.C([OH:24])C>>[CH3:15][C:2]1([CH3:16])[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:4][C:3]1=[O:24]
Reactant: CCO
Reactant: CC(C)(O)C#CC(=O)c1ccc(C#N)cc1
Solvent: CCNCC
Product: CC1(C)OC(c2ccc(C#N)cc2)=CC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of crude 4-(4-hydroxy-4-methylpent-2-ynoyl)benzonitrile (1.2 g, 5.60 mmol) in ethanol (12 mL), a solution of diethyl amine (0.58 mL, 5.60 mmol) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 1 h. The ethanol was removed and the mixture then diluted with EtOAc (50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford crude 4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.2 g) as a light green semi solid which was taken on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[C:4]([CH2:15][N:16]([CH3:58])[C:17](=[O:57])[CH:18]([NH:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C:37]([N:41]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:36][CH:35]=[C:34]3[F:56])[C:19]2[CH:24]=[CH:23][C:22]([C@@H:25]([CH3:28])[CH2:26][OH:27])=[C:21]([CH3:29])[CH:20]=2)[CH:3]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:52]([O:51][C:49]([N:41]([C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])[C:37]1[C:38]2[C:33](=[CH:32][C:31]([NH:30][C@H:18]3[C:17](=[O:57])[N:16]([CH3:58])[CH2:15][C:4]4[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=4[C@@H:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])[NH:1][C:59](=[O:60])[O:27][CH2:26][C@H:25]([CH3:28])[C:22]4[CH:23]=[CH:24][C:19]3=[CH:20][C:21]=4[CH3:29])=[CH:40][CH:39]=2)[C:34]([F:56])=[CH:35][N:36]=1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: O=C(Cl)Cl
Reactant: CC[C@@H](C(=O)OC)c1ccc(N)cc1CN(C)C(=O)C(Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1)c1ccc([C@@H](C)CO)c(C)c1
Solvent: CC#N
Solvent: ClCCl
Product: CC[C@@H](C(=O)OC)c1ccc2cc1CN(C)C(=O)[C@H](Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c1)c1ccc(c(C)c1)[C@@H](C)COC(=O)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33 %

Procedure:
A solution of 13F (235 mg, 0.293 mmol) in acetonitrile (4 mL) and dichloromethane (2 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.159 mL, 0.322 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.408 mL, 2.93 mmol) in CH2Cl2 (100 mL) at rt. The solution was stirred at rt for 16 h. The reaction mixture was concentrated and purified by flash chromatography to give a mixture of diastereoisomers (198 mg, 82% yield). The diastereoisomers (169 mg, 0.204 mmol) were separated by a prep chiral HPLC to give 13G (80 mg, 47.3% yield). MS (ESI) m/z: 827.9 (M+H)+.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([OH:5])=[O:4].C([OH:24])C.O.[OH-].[K+]>O>[O:24]=[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:2][C:3]([OH:5])=[O:4]
Reactant: CCO
Reactant: CCCCCCCCCCCCCCCCC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCC(=O)CCCCCCCCCCC(=O)O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
12-Hydroxystearic acid (2 g) dissolved in a 10% methanolic hydrochloric acid solution was stirred at room temperature for 2 hours. The mixture was then concentrated and distributed into chloroform and water, and the chloroform layer was washed with a 1% aqueous sodium hydrogen carbonate solution and water, dried with anhydrous sodium sulfate and concentrated to give the methyl ester of 12-hydroxystearic acid (2.0 g). To the methyl ester of 2-hydroxystearic acid (2.0 g) dissolved in methylene chloride (50 ml) were added Celite (4 g) and pyridinium chlorochromate (6 g), and the mixture was stirred at room temperature for 24 hours. Precipitates produced were removed by filtration. The filtrate mixed with silica gel (10 g) was concentrated and eluted with n-hexane-ethyl acetate (5:1) to give the methyl ester of 12-oxo-stearic acid (1.8 g). Then, the methyl ester of -oxo-stearic acid (1.8 g) was suspended into the mixed solvent of ethanol-water (1:1), and the potassium hydroxide (1.7 g) was dissolved in the suspension. The reaction mixture was heated to a temperature of 70° C. and stirred for 30 minutes. The reaction mixture was then cooled, adjusted to acidic range of pH by adding water and an excessive amount of citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 12-oxostearic acid (1.6 g). After the 12-oxostearic acid (500 mg) was dissolved in N,N-dimethylformamide (DMF), para-nitrophenol (231 mg) and N,N'-dicyclohexylcarbodiimide (343 mg) were added, and the mixture was stirred for 12 hours. The-reaction mixture was filtered, and the solvent was removed by distillation to give the active ester of 12-oxostearic acid. The active ester (438 mg) was dissolved in DMF, 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (400 mg) and triethylamine (2.0 ml) were added to the solution. The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK102 in the yield of 143 mg.
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:12](=[O:13])[NH:11][C:9](=[O:10])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][OH:15])[C@H:2]1[N:16]=[N+:17]=[N-:18].[O-:19][P:20]([O:23][P:24]([O:27]P([O-])([O-])=O)([O-:26])=[O:25])(=[O:22])[O-:21].[CH2:32]([OH:47])[C@H:33]1[O:38][C@H:37](OP(O)(O)=O)[C@H:36]([OH:44])[C@@H:35]([OH:45])[C@@H:34]1[OH:46].[Mg+2].[Cl-].[Cl-].C(O)C(N)(CO)CO.Cl.C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1.Cl(O)(=O)(=O)=O>>[N:16]([C@@H:2]1[C@@H:3]([CH2:14][OH:15])[O:4][C@@H:5]([N:6]2[CH:7]=[CH:8][C:9](=[O:10])[NH:11][C:12]2=[O:13])[CH2:1]1)=[N+:17]=[N-:18].[P:24]([O:27][C@H:33]([CH2:32][OH:47])[C@@H:34]([OH:46])[C@H:35]([OH:45])[C@@H:36]([OH:44])[CH:37]=[O:38])([O:23][P:20]([OH:21])([OH:19])=[O:22])([OH:26])=[O:25]
Reactant: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Reactant: O=P(O)(O)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)OP(=O)(O)OP(=O)(O)O
Reaction time: 4 h

Procedure:
To 150 milligrams of AzddU-triphosphate was added 400 milligrams of glucose-1-phosphate, 6 millimole of MgCl2, 0.70 millimole of Tris-HCl pH 7.6, bacterial UDPG-pyrophosphorylase and inorganic pyrophosphatase. After 4 hours at room temperature, the reaction was stopped with perchloric acid (7N). After 30 minutes in ice, samples were centrifuged and the supernatant was neutralized with base. After another 30 minutes in ice, samples were recentrifuged and AzddU-5'-diphosphoglucose was purified by column chromatography.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[CH3:3]>N.[Ni]>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])[CH3:1]
Reactant: CN(C)Cc1cccc(C#N)c1
Agent: [Ni]
Agent: N
Product: CN(C)Cc1cccc(CN)c1

Procedure:
7.00 g (34.95 mmol) 3-dimethylaminomethyl-benzonitrile are placed in 100 ml of methanolic ammonia solution and hydrogenated with 1.40 g Raney nickel at ambient temperature under a pressure of 3 bar. The catalyst is suction filtered, the filtrate is evaporated down. The residue is purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:15][S:14][C:4]=2[N:5]=[C:6]([CH2:8][C:9](OCC)=[O:10])[N:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:3]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:15][S:14][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][OH:10])[N:7]=1
Reactant: CCOC(=O)Cc1nc(Cl)c2c(-c3ccc(F)cc3)csc2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCCc1nc(Cl)c2c(-c3ccc(F)cc3)csc2n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 4.5 %

Procedure:
Ethyl 2-[4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]acetate (9.98 g, 0.285 mol) was dissolved in dry THF (100 mL) under nitrogen. To this was added diisobutyl aluminium hydride (1 M in THF, 95 mL). The reaction was stirred at room temperature for 5.5 hrs before being quenched by careful addition to a saturated solution of Rochelle's salt. The mixture was stirred for 1 hr then allowed to stand overnight. The mixture was extracted with DCM (3×700 mL), the extracts were then combined, dried and concentrated in vacuo. The residue was purified by silica column chromatography eluting with DCM, then 3:1 v/v DCM/ethyl Acetate. Fractions were analysed by TLC, combined and concentrated to give 2-[4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]ethanol as a brown solid (4 g). LCMS RT=4.25 min, M+1=309.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.C(N(CC)CC)C.[F:35][C:36]([F:41])([F:40])[C:37](O)=O>ClCCl>[CH3:25][S:24][C:21]1[N:22]=[CH:23][C:12]2[C:11](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]4[N:27]=[C:37]([C:36]([F:41])([F:40])[F:35])[O:1][N:2]=4)[CH:5]=3)[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]=2[N:20]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(C(F)(F)F)n3)c1)C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
(S)—N′-Hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (190 mg, 0.49 mmol) obtained in Step 1 of Example 75 was dissolved in dichloromethane (1.5 mL), and the mixture was cooled to 0° C. after adding triethylamine (0.14 mL, 0.99 mmol). Thereafter, anhydrous trifluoroacetic acid (0.14 mL, 0.99 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (186 mg, 81%).
Reaction SMILES: [CH3:1][CH:2]1[S:6](=[O:8])(=[O:7])[O:5][CH2:4][CH2:3]1.[CH3:9][NH:10][CH3:11]>>[CH3:9][N:10]([CH3:11])[CH2:4][CH2:3][CH:2]([S:6]([OH:5])(=[O:8])=[O:7])[CH3:1]
Reactant: CC1CCOS1(=O)=O
Reactant: CNC
Product: CC(CCN(C)C)S(=O)(=O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2,4-butanesultone (1.27 g, 8.9 mmol) was added to an ice-chilled solution of dimethylamine (40% w/w in water). The solution was stirred at 0° C. for 4 hours. The solvent was evaporated in vacuo until complete dryness. The solid was washed with acetone (50 mL), collected by filtration and dried in vacuo. 1H NMR (D2O, 500 MHz) δ ppm 3.18 (t, 2H, J=8.1 Hz), 2.85 (m, 1H), 2.76 (s, 6H), 2.09 (m, 1H), 1.81 (m, 1H), 1.17 (d, 3H, J=7.3 Hz). 13C (D2O, 125 MHz) δ ppm 55.65, 53.05, 42.88, 26.72, 14.81. ES-MS182a (M+1).