Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:16].[K+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([NH2:15])=[O:16])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2cccc(Br)c2)CCOCC1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)O
Product: NC(=O)C1(c2cccc(Br)c2)CCOCC1
Temperature: 82 °C

Procedure:
Propan-2-ol (100 ml), tetrahydro-4-(3-bromophenyl)-2H-pyran-4-nitrile (20.0 g, 0.075 mole, 1 eq.), potassium hydroxide (13.74 g, 0.245 mole, 3.26 eq.) were added to a reaction flask set for boiling at reflux under a nitrogen atmosphere, and the reaction mixture was heated with stirring at reflux, about 82° C. for 5-6 hours under nitrogen. After reaction completion, the mixture was cooled (<30° C.) and quenched with water (100 ml). The resultant slurry was filtered and the product residue, washed with water (30 ml), and dried under vacuum at 45-50° C. to yield a white solid. Yield 19.05 g, 89.2%. mp 245-247° C.; m/z 285 (m+1); 1H NMR (300 MHz, DMSO) δ7.43 (m, 5H), 7.14 (s, 1H), 3.76 (d, 2H), 3.47 (t, 2H), 2.44 (d, 2H), 1.79 (m, 2H).; IR (drifts) vmax 3363, 3174, 3062, 2973, 2935, 2879, 2828, 1685, 1631, 1588.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([S:20][CH2:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1.CSC.B(F)(F)F.CCOCC>ClCCl>[CH3:1][O:2][C:3](=[O:23])[CH:4]([S:20][CH2:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: CCSC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CSC
Solvent: ClCCl
Product: CCSC(Cc1ccc(O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
3-(4-Benzyloxyphenyl)-2-ethylsulfanyl propanoic acid methyl ester (0,37 g; 1.12 mmole) was dissolved in dichloromethane (3.5 ml). Dimethylsulfide (3 ml), was added followed by addition of boron trifluoride etherate (1.6 g; 11 mmole), The reaction mixture was stirred for 3 hours at room temperature and then quenched with water (3 ml). More dichloromethane was added and the phases were separated. The organic phase was washed twice with brine and dried with sodium sulfate. Evaporation of the solvent gave 0.2 g (74.3% yield) of ethylsulfanyl-3-(4-hydroxyphenyl)propanoic acid methyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.CC(O)=O.Cl.CCO>O.[Pt](=O)=O.O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2]1
Reactant: OCCCc1cccnc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: OCCCC1CCCNC1
Reaction time: 72 h

Procedure:
A 500 mL Parr hydrogenation bottle was charged with 3-Pyridinepropanol (10.0 g, 72.9 mmol), platinum(IV)oxide hydrate (Adam's Catalyst) (500 mg), AcOH (30 mL), and HCl, 37% (1 mL). Contents of the bottle were hydrogenated at 47 psi for three days. EtOH and water were added, and the reaction mixture was filtered through CELITE. NaOH (10 N) was added and the mixture was extracted with methylene chloride, dried with anhydrous MgSO4, filtered and concentrated. The product was concentrated from PhMe and used without further purification. 1H NMR (CD3OD): δ 3.55 (t, J=5 Hz, 2H), 3.0{tilde over (5)} 2.95 (m, 2H), 2.5{tilde over (5)} 2.45 (m, 1H), 2.23 (t, J=10 Hz, 1H), 1.8 9 1.86 (m, 1H), 1.7{tilde over (0)} 1.66 (m, 1H), 1.6 0 1.44 (m, 4H), 1.2{tilde over (8)} 1.22 (m, 2H), 1.0 6 1.00 (m, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:7][CH2:6]1)=[O:4].Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>CC#N>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][C:23]2=[O:25])[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@H]1CC[C@H](CNCCc2ccccc2N)CC1
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](CN2CCc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-{[2-(2-Amino-phenyl)-ethylamino]-methyl}-cyclohexanecarboxylic acid methyl ester (2.99 g, 7.97 mmol) in CH3CN (100 mL) at 0° C. under argon was added portion wise triphosgene (1.53 g, 5.15 mmol) over 30 min. The reaction mixture was stirred at 0° C. for 30 min, warmed to room temperature and stirred additionally for 7 h. Then an excess of TEA was added and a precipitate was formed. Solvent was removed under reduced pressure and the crude product purified by flash chromatography on silica to afford the titled compound (4.3 g, yield 59%).
Reaction SMILES: C(=O)([O-])O.[Na+].Br[C:7]1[N:11](CC2C=CC(OC)=CC=2)[N:10]=[C:9]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:8]=1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.Br[C:34]1C(C2C=CN=CC=2)=C(C2SC(Cl)=CC=2)N(CC2C=CC(OC)=CC=2)N=1.CB1OB(C)OB(C)O1>C(COC)OC.O.C(OCC)(=O)C>[Cl:26][C:23]1[S:22][C:21]([C:9]2[NH:10][N:11]=[C:7]([CH3:34])[C:8]=2[C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2nc(Br)c(-c3ccncc3)c2-c2ccc(Cl)s2)cc1
Reactant: COc1ccc(Cn2nc(-c3ccc(Cl)s3)c(-c3ccncc3)c2Br)cc1
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1n[nH]c(-c2ccc(Cl)s2)c1-c1ccncc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a mixture of sodium hydrogen carbonate (2.0 mmol) and PdCl2dppf:CH2Cl2 1:1 (0.03 mmol) under argon, was added a degassed solution of 4-[5-bromo-3-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine and 4-[3-bromo-5-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine (mixture of isomers 2:1, 0.65 mmol) in 10.5 mL dimethoxyethane and 3 mL of water. Trimethylboroxin (50% solution in THF, 1.3 mmol) was then added and the mixture was stirred at 90° C. for 3 h. After cooling to room temperature, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 3 mL of trifluoroacetic acid and stirred at 65° C. for 2 h. Water and ethyl acetate were added. And the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with a saturated solution of sodium hydrogen carbonate, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol 20:1 to 10:1) to afford 57 mg of 4-[5-(5-chloro-2-thienyl)-3-methyl-1H-pyrazol-4-yl]pyridine (30% yield).
Reaction SMILES: C([Li])(CC)C.[CH3:6][O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11].CN(C)CCN(C)C.[CH:29](=[O:32])[CH2:30]C>O1CCCC1.C(OCC)C>[OH:32][CH:29]([C:17]1[C:9]([C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11])=[C:8]([O:7][CH3:6])[CH:20]=[CH:19][CH:18]=1)[CH3:30]
Reactant: CCN(CC)C(=O)c1ccccc1OC
Reactant: CCC=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(CC)C(=O)c1c(OC)cccc1C(C)O
Temperature: -78 °C

Procedure:
13.7 ml of sec-butyllithium (1.4M in cyclohexane/isopentane) are added dropwise to a solution of 5.2 g of 2-methoxy-N,N-diethyl-benzamide and 2.91 g of tetramethylethylenediamine in 50 ml of absolute tetrahydrofuran in such a manner that the temperature does not exceed -68° C. When the addition is complete, the reaction mixture is stirred at -78° C. for a further hour and then 2.5 ml of propionaldehyde are added. The reaction mixture is allowed to warm slowly to room temperature, is subsequently stirred for one hour and is diluted with 300 ml of diethyl ether. The organic phase is washed with 2N hydrochloric acid and then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated by evaporation to yield 6-(1-hydroxyethyl)-2-methoxy-N,N-diethyl-benzamide in the form of a crude product.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]([C:8]([O-:10])=[O:9])[CH:2]2[C:11]([O-:13])=[O:12].[Na+:14].[Na+]>O.[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O-:10])=[O:9])[CH:2]2[C:11]([O-:13])=[O:12].[Na+:14].[Na+:14]
Reactant: O=C([O-])C1C2C=CC(C2)C1C(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: O=C([O-])C1C2CCC(C2)C1C(=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of disodium bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (10.0 g) in water (100 g) was added 0.5 g palladium on activated carbon (5 wt%). The mixture was transferred into a Parr reactor and was subjected to hydrogenation (50 psi, room temperature) for 8 hours. The activated carbon was filtered out, and the water was removed in vacuo at 75° C. The resulting product (m.p >300° C.) was dried and milled. NMR and IR analyses were consistent with that of the expected structure.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:19]([NH2:21])=[O:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C(O)C>[OH:20][C:19]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:21]=1
Reactant: NC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2ccccc2)nc2c1[nH]c1ccccc12

Procedure:
A mixture of 3-Benzamidoindole-2-carboxamide (276 mg), sodium hydride (5 mg) and ethanol (5 mL) was refluxed for 2h. The reaction mixture was quenched with saturated ammonium carbonate and the product was extracted with methylene chloride. After drying over magnesium sulfate, the solvent was removed in vacuo and the residue was triturated with ether to afford 4-Hydroxy-2-Phenyl-5h-indolo[3,2-d]pyrimidine (Compound 2) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(O[N:51]1N=N[C:53]2[CH:54]=CC=C[C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:51][CH2:52][CH2:53][CH3:54])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCCN
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCC(C)CC4)CC3)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and propylamine (6.78 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18.6 mg, 55%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][SH:4].[H-].[Na+].[CH2:7]([CH:10]1[C:14](O)([CH3:15])[CH:13]=[CH:12][C:11]1=[O:17])[CH:8]=[CH2:9]>O1CCCC1>[CH2:7]([C:10]1[C:11](=[O:17])[CH2:12][CH:13]([S:4][CH2:3][CH2:2][OH:1])[C:14]=1[CH3:15])[CH:8]=[CH2:9]
Reactant: OCCS
Reactant: C=CCC1C(=O)C=CC1(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1=C(C)C(SCCO)CC1=O
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Into the same flask as used in Example 1, 2-hydroxyethylmercaptan (35 g) and tetrahydrofuran (10 g) were charged, and sodium hydride (0.6 g) was added thereto at a temperature of 10° to 20° C. At the same temperature, the reaction mixture was stirred for 1 hour. Thereafter, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g) was dropwise added thereto at a temperature of 15° to 30° C. for 1 hour, followed by stirring at the same temperature for 2 hours and at a temperature of 40° to 70° C. for 3 hours. After completion of the reaction, the mixture was treated in the same manner as in Example 1 to obtain 2-allyl-3-methyl-4-(2'-hydroxyethylthio)-2-cyclopentenone (20.4 g). Yield, 96 %. nD20 1.5243.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].C([NH:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[CH2:37][S:36][C:35]1=[O:40])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.NCCN1C(=O)/C(=C/C2C=CC=CC=2)/SC1=O>>[NH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])/[C:37](=[CH:6]/[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3][CH2:1][CH3:2])/[S:36][C:35]1=[O:40]
Reactant: CCOc1ccccc1C=O
Reactant: O=C1CSC(=O)N1CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NCCN1C(=O)S/C(=C\c2ccccc2)C1=O
Solvent: C1CCNCC1
Product: CCOc1ccccc1/C=C1\SC(=O)N(CCN)C1=O

Procedure:
The title compound 30c was prepared from 2-ethoxybenzaldehyde (87 μL, 0.62 mmol) and compound 29 (250 mg, 0.62 mmol) and piperidine (7.0 μL, 0.062 mmol) in a manner similar to that described for 30a in 35.4% (64 mg) yield as a white solid.
Reaction SMILES: [Li]CCCC.[CH2:6]([C:8]1[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:10]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[CH3:7].[OH2:35].[CH2:36]1[CH2:40][O:39][CH2:38][CH2:37]1>>[CH2:6]([C:8]1[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:10]([O:20][C:21]2[CH:28]=[CH:27][C:24](/[CH:25]=[CH:37]/[C:38]([O:39][CH2:40][CH3:36])=[O:35])=[CH:23][CH:22]=2)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[CH3:7]
Reactant: O
Reactant: C1CCOC1
Reactant: CCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Agent: [Li]CCCC
Product: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(CC)cc3cc(OC)ccc23)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Triethylphosphonoacetate (0.44 g, 1.89 mmol) was dissolved in THF (12 mL). Cooled to −78° C., nBuLi (1.6 M in hexanes, 1.20 mL, 1.89 mmoL) was added dropwise. The mixture was stirred at −78° C. for 30 min. To this solution was added 4-{[3-ethyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzaldehyde (58) (0.60 g, 1.58 mmol) in THF (12 mL) slowly. The resulting mixture was allowed to warm up to room temperature and stirred at room temperature (3 h in total). The mixture was poured into water (50 mL) and extracted with EtOAc (2×50 mL). The extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light yellow oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (25:1) to give 0.67 g (94%) of the title compound (59) as a white foam. 1H NMR (400 MHz, CDCl3): δ 1.12 (t, J=7.5 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H), 2.56 (q, J=7.5 Hz, 2H), 3.93 (s, 3H), 4.22 (q, J=7.2 Hz, 2H), 6.21 (d, J=16.0 Hz, 1H), 6.56 (d, J=8.6 Hz, 2H), 7.04 (dd, J1=8.6 Hz, J2=2.4 Hz, 1H), 7.10-7.20 (m, 3H), 7.20-7.27 (m, 5H), 7.54 (d, J=16.0 Hz, 1H), 7.59 (s, 1H), 7.72 (d, J=9.2 Hz, 1H). LCMS (APCI): m/z 453 (M+H)+.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH2:24]([O:32][C:33](=[O:39])[CH2:34][C:35]([CH2:37][Cl:38])=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O>[CH2:24]([O:32][C:33](=[O:39])[CH2:34][C@@H:35]([OH:36])[CH2:37][Cl:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCOC(=O)CC(=O)CCl
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: CCCCCCCCOC(=O)C[C@@H](O)CCl
Reaction time: 24 h
Yield: 69.4 %

Procedure:
One hundred grams of commercial fresh Baker's yeast Saccharomyces cerevisiae (Red Star) was suspended in 250 ml of tap water to which was added 10 g of sucrose and 3.6 g of γ-chloroacetoacetic octyl ester. After the contents were incubated at 25° C. on a rotary shaker (250 cycles/minute--2" radius) for 24 hours, an additional 10 g of sucrose was added to the flask and the reaction was allowed to proceed for another 24 hours. The cells were then removed by filtration through a pad of celite. The cells were washed with water and ethyl acetate. The washings were combined with the filtrate and exhaustively extracted with ethyl acetate. The ethyl acetate layer was dried over MgSO4 and evaporated to give an oily residue, which was chromatographed over a silica gel column to yield 2.52 g of 4-chloro-3(R)-hydroxybutyric acid octyl ester, as a low melting solid; [α]D23 +13.2° (c, 4.0, CHCl3).
Reaction SMILES: [Mg].II.Br[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[F:10][CH:11]([F:32])[C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]([CH:26]=[O:27])=[C:14]([C:28]([F:31])([F:30])[F:29])[N:13]=1.Cl>CCOCC.O>[F:32][CH:11]([F:10])[C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]([CH:26]([OH:27])[C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)=[C:14]([C:28]([F:31])([F:29])[F:30])[N:13]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C=O)c1CC(C)C
Reactant: Brc1cccs1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2cccs2)c1CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
This example illustrates the preparation of Compound Number 53. To a suspension of magnesium (1.4 g, 58 mmol) in anhydrous ether (40 mL) containing several iodine crystals was added dropwise a solution of 2-bromothiophene (10 g, 62 mmol) in anhydrous ether (20 mL). The reaction was exothermic; the mixture was stirred at ambient temperature for 1.5 h. The resulting Grignard reagent was cooled to 0°-5° C. and a solution of methyl 2-(difluoromethyl)-5-formyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (6.8 g, 20 mmol) in anhydrous ether (20 mL) was added. The mixture was stirred for 2 h, poured into iced water, and acidified with conc. HCl. The organic layer was separated, washed with water and brine, dried (MgSO4), and conc. The residue was eluted on a silica gel column with 15% ethyl acetate/cyclohexane to yield 6.6 g of methyl 2-(difluoromethyl)-5-(hydroxy-2-thienylmethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate, a 77.6 % yield. m.p. 78°-88° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2 (1H)-pyrimidinone (0.1 mole), acetic anhydride (0.11 mole), toluenesulfonic acid (0.05 gram) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is heated on a steam bath with stirring for a period of about 2 hours. After this time the reaction mixture is cooled to room temperature and is stripped of solvent under reduced pressure leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acetyloxy-2(1H) -pyrimidinone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]([C@@H:8]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C3C=CC=CC=3)[C@@H:19]([O:20]C(=O)C3C=CC=CC=3)[C@H:9]2[O:10]C(=O)C2C=CC=CC=2)[CH:4]2[NH:41][C:42](=[O:44])[S:43][C:3]=12.[NH2:45][C:46]1[C:47]2[S:54][C:53](=[O:55])[N:52]([C@@H:56]3[O:78][C@H:77]([CH2:79][O:80]C(=O)C4C=CC=CC=4)[C@@H:67]([O:68]C(=O)C4C=CC=CC=4)[C@H:57]3[O:58]C(=O)C3C=CC=CC=3)[C:48]=2[N:49]=[CH:50][N:51]=1.C[O-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]([C@@H:8]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:19]([OH:20])[C@H:9]2[OH:10])[CH:4]2[NH:41][C:42](=[O:44])[S:43][C:3]=12.[NH2:45][C:46]1[C:47]2[S:54][C:53](=[O:55])[N:52]([C@@H:56]3[O:78][C@H:77]([CH2:79][OH:80])[C@@H:67]([OH:68])[C@H:57]3[OH:58])[C:48]=2[N:49]=[CH:50][N:51]=1
Reactant: NC1=C2SC(=O)NC2N([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)C=N1
Reactant: Nc1ncnc2c1sc(=O)n2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC1=C2SC(=O)NC2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C=N1
Product: Nc1ncnc2c1sc(=O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Treatment of 28 with NaSH in DMF at 0° C. yielded the 2-mercapto derivative, 7-aminothiazolo[4,5-d]pyrimidine-2(3H)-thione (29). The conversion of the 2-thioxo function in 29 to a 2-oxo function was accomplished using cold alkaline hydrogen peroxide to yield 7-aminothiazolo[4,5-d]pyrimidin-2(3H)-one (30). Reaction of 30 with the benzoyl-protected sugar, 5, under the same glycosylation conditions (at room temperature) as used to produce the blocked guanosine analog, 6, resulted in the formation of the unexpected blocked 4-ribofuranosyl isomer, 7-amino-4-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidin-2(3H)-one (31), as the only isomer detected and isolated. If, however, the same reaction was carried out at elevated temperature (80° C.), the predominant product obtained was the desired 3-ribofuranosyl isomer, 7-amino-3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidin-2(3H)-one (32). Both isomers, 31 and 32, were deprotected using sodium methoxide in dry methanol to obtain 7-amino-4-β-D-ribofuranosylthiazolo[4,5-d]pyrimidin-2(3H)-one (33) and 7-amino-3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidin-2(3H)-one (34), respectively.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[C:5]([C:24](O)=[O:25])[N:4]=[C:3]1[C:27]([F:30])([F:29])[F:28].[NH:31]1[CH2:34][CH2:33][CH2:32]1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>>[CH3:22][N:12]1[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=[C:11]1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:27]([F:28])([F:30])[F:29])=[N:4][C:5]=1[C:24]([N:31]1[CH2:34][CH2:33][CH2:32]1)=[O:25])=[O:23]
Reactant: Cn1cc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)nc(C(F)(F)F)n1C
Reactant: C1CNC1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)N2CCC2)nc(C(F)(F)F)n1C

Procedure:
The product was obtained starting from 1-methyl-5-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethylcarbamoyl)-2-(trifluoromethyl)-1H-imidazole-4-carboxylic acid (30 mg, 71.2 μmol) and azetidine (4.98 mg, 5.88 μL, 85.4 μmol) via COMU coupling according to the method described in example 61, step 3 as white solid (20.5 mg, 44.5 μmol, 62.5%).