Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[N:10][OH:11])[NH2:9])=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=O>C1(C)C=CC=CC=1.CC(O)=O>[C:13]([C:18]1[O:11][N:10]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=2)[N:9]=1)([CH3:17])([CH3:14])[CH3:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC(=NO)c1ccc(Cl)nc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(-c2ccc(Cl)nc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
A mixture of 1.5 g (8.74 mmol) of 6-chloro-N′-hydroxypyridine-3-carboximidamide and 1.13 mL (9.18 mmol) of trimethylacetyl chloride in 15 mL of toluene is stirred for 1 hour at room temperature and then refluxed for 4 hours. The medium is filtered. The insoluble material formed is dissolved in 15 mL of AcOH and then heated at 60° C. for 5 hours. After cooling to room temperature, the medium is concentrated under reduced pressure and then purified by chromatography on silica gel, eluting with a cyclohexane/EtOAc mixture (9/1). 0.39 g of 5-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-2-chloropyridine is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][NH:21][CH2:22][CH3:23])=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2].FC(F)(F)C([O-])=O.[CH2:33]([N:40]=[C:41]=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][N:21]([CH2:22][CH3:23])[C:41]([NH:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C)cnc1-c1cc(CC(=O)OCC)ccc1OC
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
[3-(3-Ethylaminomethyl-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, trifluoroacetate (0.36 mmol) was reacted with benzyl isocyanate (0.05 mL, 0.44 mmol) and triethylamine (0.152 mL, 1.09 mmol) in CH2Cl2 to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:20][C:10]=2[N:9]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[C:13]([N:12]1[C:11]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:20][C:10]=2[N:9]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:32]1[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)n1c(-c2ccccc2Br)nc2cc(-c3cnc(N)nc3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)cn1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a solution of 5-[2-(2-bromo-phenyl)-1-tert-butyl-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (70 mg, 0.17 mmol) in DMF (5 mL) and H2O (1 mL) are added 1-methylpyrazole-4-boronic acid pinacol ester (52 mg, 0.25 mmol), Pd(PPh3)4 (19 mg, 0.017 mmol) and K2CO3 (23 mg, 0.17 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and then filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel flash chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (24 mg, 34%) as a white solid. LCMS (ESMS): m/z 424.20 (M++1)
Reaction SMILES: CS(O[C:6]1[C:17]2=[C:18]3[N:13]([CH2:14][CH2:15][CH2:16]2)[CH:12]=[C:11]([C:19]([OH:21])=[O:20])[C:10](=[O:22])[C:9]3=[CH:8][CH:7]=1)(=O)=O.[F:23][C:24]([F:32])([F:31])[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[ClH:33]>CS(C)=O>[ClH:33].[F:23][C:24]([F:32])([F:31])[N:25]1[CH2:30][CH2:29][N:28]([C:6]2[C:17]3=[C:18]4[N:13]([CH2:14][CH2:15][CH2:16]3)[CH:12]=[C:11]([C:19]([OH:21])=[O:20])[C:10](=[O:22])[C:9]4=[CH:8][CH:7]=2)[CH2:27][CH2:26]1
Reactant: FC(F)(F)N1CCNCC1
Reactant: CS(=O)(=O)Oc1ccc2c(=O)c(C(=O)O)cn3c2c1CCC3
Agent: Cl
Solvent: CS(C)=O
Product: O=C(O)c1cn2c3c(c(N4CCN(C(F)(F)F)CC4)ccc3c1=O)CCC2
Reaction time: 20 h

Procedure:
A mixture of 3.37 g of 8-methanesulfonyloxy-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoromethylpiperazine and 200 ml of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 170° to 180° C. for 20 hours under nitrogen gas flow at a pressure of 8 atms. The reaction mixture was treated in the same manner as in Example 73 and further treated with concentrated hydrochloric acid to obtain 1.7 g of 8-(4-trifluoromethyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white rhombic crystals having a melting point of 300° C. or more.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[C:7](C)([CH3:9])[CH3:8])(C)([CH3:3])[CH3:2].C(N)(C)C.C(N(CC)CC)C.C(Cl)(=O)C(C)C>>[CH:1]([NH:5][C:6](=[O:11])[CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Agent: CC(C)C(=O)Cl
Solvent: CC(C)N
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)C(C)C
Yield: 94 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of isopropylamine (9.0 mL, 105 mmol) and triethylamine (14.9 mL, 105 mmol) with isobutyryl chloride (10.8 mL, 100 mmol) afforded LiPr,iPrH as white crystalline solid (12.14 g, 94%) upon sublimation at 55° C./0.05 Torr: mp 104-106° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=3[F:29])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][S:37]([CH2:40][CH2:41][OH:42])(=[O:39])=[O:38]>[Cu](I)I>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:24][C:23]=3[F:29])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)CCO
Reactant: Cc1c(Nc2ccc(I)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(Nc2ccc(OCCS(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C
Yield: 3 %

Procedure:
General procedure of coupling alcohol to aryl halides: A mixture of 4-[6-(2-fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (103 mg, 0.2 mmole), cesium carbonate (130 mg, 0.4 mmole), copper iodide (8 mg, 0.04 mmole), and 1, 10-phenanthroline (14 mg, 0.08 mmole) in 2-methanesulfonyl-ethanol (3 mL) was heated under microwave irradiation at 150° C. for 1 hour. The crude mixture was purified by HPLC to provide Compound A95 as a yellow solid (3 mg, 3%). Exact mass calculated for C23H31FN4O6S 510.2, found 511.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[CH3:18])([CH3:4])([CH3:3])[CH3:2].[C:20]([Li])(C)(C)C.CN(C=O)C>C1COCC1>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:9](=[CH:10][CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=2)[CH:18]=[CH:20]1)=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C(C)(C)C
Reactant: Cc1ccc(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2ccc(C(C)(C)C)cc21
Temperature: 25 °C

Procedure:
(5-tert-Butyl-2-methyl-phenyl)-carbamic acid tert-butyl ester (prepared in Example CC; 19.7 g, 75 mmol) in 100 mL of THF was cooled to −40° C. To it was added tert-butyllithium (1.5 M, 100 mL, 150 mmol), dropwise with stirring, at −45° C. to −35° C. After the addition was complete, the reaction was stirred at −35° C. for another 15 minutes. DMF (10.97 g, 150 mmol) was added dropwise, and the reaction mixture was stirred at −35° C. for 30 minutes, followed by slow warming to room temperature. The reaction was quenched with saturated NH4Cl solution and diluted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated. The residue was dissolved in 100 mL of THF and 2 mL of concentrated HCl and stirred at room temperature for 1 hour. EtOAc was added, and the solution was washed with saturated NaHCO3 solution and brine and dried (MgSO4). Concentration gave a residue that was purified by flash silica gel chromatography (5%-50% EtOAc in hexanes). MS(APCI): 274 (M+H).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]([CH3:13])([N+:10]([O-])=O)[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1(C)C=CC=CC=1.[Ni]>[NH2:10][C:7]([CH3:13])([CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:8][OH:9]
Reactant: [H][H]
Reactant: CC(C)(C)OCC(C)(CO)[N+](=O)[O-]
Agent: [Ni]
Solvent: Cc1ccccc1
Product: CC(N)(CO)COC(C)(C)C
Temperature: 40 °C

Procedure:
To a solution of 150 g (0.78 mol) of 3-tert-butoxy-2-methyl-2-nitro-propan-1-ol [prepared according to Example 1c or 1c′] in 700 ml of toluene in a pressure vessel is added 15 g of Raney-Ni and 40 ml of a pH 7.00 buffer [NORMEX (RTM), Carlo Erba]. Through the closed autoclave is added at room temperature hydrogen under 50-60 bar pressure. The reaction mixture is heated to 40° C. and maintained at this temperature for 8 hours. The reaction mixture is then cooled to room temperature, diluted with toluene, filtered and the filtrate concentrated using a vacuum rotary evaporator. The residue yields 2-amino-3-tert-butoxy-2-methyl-propan-1-ol (compound 301, Table 1), pale green solid, m.p. 30-35° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH:24]1[C:28]([CH2:29][N:30]2[C:34](=[O:35])[CH2:33][S:32][C:31]2=[O:36])=[N:27][N:26]=[N:25]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14](/[CH:16]=[C:33]4/[C:34](=[O:35])[N:30]([CH2:29][C:28]5[NH:24][N:25]=[N:26][N:27]=5)[C:31](=[O:36])[S:32]/4)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:21])[F:22])[CH:3]=1
Reactant: O=C1CSC(=O)N1Cc1nnn[nH]1
Reactant: O=Cc1ccc2c(c1)nnn2Cc1ccc(Cl)cc1C(F)(F)F
Product: O=C1S/C(=C\c2ccc3c(c2)nnn3Cc2ccc(Cl)cc2C(F)(F)F)C(=O)N1Cc1nnn[nH]1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-benzotriazol-5-yl}methylidene)-3-(1H-tetrazol-5-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from 1-(4-chloro-2-trifluoromethylbenzyl)-1H-benzotriazole-5-carbaldehyde (from Example 258) and 3-(1H-tetrazol-5-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 72) following General Procedure F.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH:25]([O:27][CH2:28][CH3:29])[CH3:26].[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:26][CH2:25][O:27][CH2:28][CH3:29])=[C:18]([F:23])[N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Reactant: CCOC(C)Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc(OCCOCC)c(F)n2)cc1

Procedure:
A mixture of 0.1 mol of 2C, 0.1 mol of 1-bromoethoxyethane, 0.1 mol of sodium hydroxide, 20 ml of ethanol and 50 ml of water is heated at the boil for 2 hours. The mixture is cooled, dilute hydrochloric acid is added, and the aqueous phase is extracted with dichloromethane. The solvent is removed under reduced pressure, and the residue is purified by column chromatography, giving the product 2-(4-octyloxyphenyl)-5-(2-ethoxyethoxy)-6-fluoropyridine.
Reaction SMILES: [CH2:1]([F:3])[F:2].[CH:4](/[C:7]([F:10])([F:9])[F:8])=[CH:5]\F>>[CH2:5]=[C:4]([F:2])[C:7]([F:10])([F:9])[F:8].[CH2:1]([F:3])[F:2]
Reactant: F/C=C/C(F)(F)F
Agent: FCF
Product: C=C(F)C(F)(F)F

Procedure:
HFC-32/HFO-1243zf/HFO-1234ze mixture;
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[C:15]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:15]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2c(N3CCN(CCCCn4cnc5ccccc54)CC3)cccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-naphthyl) piperazine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.8 g compound (I-16) with a yield of 59.1%. ESI-MS [M+H]+: m/z 385.2.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[Br:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[C:16]([Br:15])[C:17]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:18][CH:19]=1
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: COC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)c(Br)c1
Yield: 37 %

Procedure:
As described for example 5, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (3.60 mg, 19.0 mmol) was converted using methyl 5-bromo-6-chloronicotinate instead of 6-chloronicotinonitrile to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 2.83 g, 37%) which was obtained as a white solid. MS: m/e=403.3/405.2 [M+H]′.
Reaction SMILES: Br[C:2]1[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]=1[O:8]C.Cl.[CH3:12][CH:13]([CH3:17])[C:14](=[NH:16])[NH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH3:12][CH:13]([C:14]1[NH:16][C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]=2[N:15]=1)[CH3:17]
Reactant: COC1=C(Br)C(=O)CCC1
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1nc2c([nH]1)CCCC2=O
Temperature: 100 °C
Yield: 53.1 %

Procedure:
To a stirred solution of 2-bromo-3-(methyloxy)-2-cyclohexen-1-one (1.88 g) in anhydrous N,N-dimethylformamide (35 mL) at ambient temperature was added solid 2-methylpropanimidamide hydrochloride (1.349 g) and potassium carbonate (3.17 g). The reaction was then heated to 100° C. under an atmosphere of nitrogen for 3 hr. The reaction was diluted with dichloromethane (100 mL) the resultant solid was removed by filtration. The filtrate was concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-25% methanol-dichloromethane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (867 mg). LC/MS MH+ 179, Rt 0.34 min (2 min run).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:9](=[O:10])[CH:8]=[C:7]([OH:11])[N:6]=[C:5]1[S:12][CH3:13]>[OH-].[Na+]>[CH3:3][N:4]1[C:9](=[O:10])[C:8]([Br:1])=[C:7]([OH:11])[N:6]=[C:5]1[S:12][CH3:13]
Reactant: CSc1nc(O)cc(=O)n1C
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc(O)c(Br)c(=O)n1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
16 g (0.1 mol) of bromine were added to a solution of 17.2 g (0.1 mol) of 1-methyl-2-methylthio-4-hydroxy-6-oxo-1,6-dihydro-pyrimidine in 110 ml of 1 N sodium hydroxide solution at room temperature. After the end of the addition, the batch was stirred for a further 0.5 hour and was then cooled to 5° C. The product which had precipitated was filtered off and rinsed with water. 18 g (76% of theory) of 1-methyl-2-methylthio-4-hydroxy-5-bromo-6-oxo-1,6-dihydro-pyrimidine were thus obtained in the form of pale yellow crystals of melting point 184° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH:9]([C:14](Cl)=[O:15])[CH:8]2[C:17](Cl)=[O:18]>O1CCCC1>[C:2]([O:4][C:17]([CH:8]1[CH:9]([C:14]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:15])[CH:10]2[CH2:13][CH:7]1[CH:12]=[CH:11]2)=[O:18])([CH3:5])([CH3:3])[CH3:1]
Reactant: O=C(Cl)C1C2C=CC(C2)C1C(=O)Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1C2C=CC(C2)C1C(=O)OC(C)(C)C

Procedure:
Potassium tert-butoxide (34 g; 0.3 mol) was dissolved in 250 ml of anhydrous tetrahydrofuran (THF) in a round-bottom flask. 5-norbornene-2,3-dicarbonyl chloride (22 g; 0.1 mol) then was slowly added thereto at room temperature, and the reactant was reacted at a temperature of 45° C. for about 12 hours.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH-:19].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=1
Reactant: COc1ccccc1C[NH-]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1CNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
5.7 g of 4-(trifluoromethyl)benzoic acid and 4.0 g of 2-methoxybenzylamide were dissolved in 100 ml N,N-dimethylformamide, and 4.8 ml diethyl cyanophosphonate and 4.2 ml triethylamine were added under ice-cooling. The reaction mixture was stirred at room temperature for 16 hours, then poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 8.7 g of N1-(2-methoxybenzyl)-4-(trifluoromethyl)benzamide was obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([F:29])=[N:23][C:24]=2Cl)(=O)C.[O:30]([CH2:37][C@H:38]([NH2:40])[CH3:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>O1CCOCC1>[F:29][C:22]1[N:23]=[C:24]([NH:40][C@H:38]([CH3:39])[CH2:37][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[N:26]=[CH:27][N:19]([C:20]=2[N:21]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: C[C@@H](N)COc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(F)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](COc1ccccc1)Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 28.1 %

Procedure:
9-(2,3,5-Tri- O-acetyl-β-D-ribofuranosyl)-6-chloro-2-fluoro-9H-purine (1.03 g, 2.38 mmol) PCT Publication No. WO 938206, (R)-1-phenoxy-2-propylamine (0.36 g, 2.38 mmol) and triethylamine (0.29 g, 0.28 mmol) in dioxan (20 ml) were stirred at room temperature for 18 h. The reaction mixture was filtered and evaporated to a residue which was purified by flash chromatography. The resultant 2',3',5'-tri- O-acetyl-2-fluoro- N-[(R)-1-phenoxy-2-propyl]adenosine was deprotected using methanolic ammonia to provide the title 2-fluoro- N-[(R)-1-phenoxy-2-propyl]adenosine (0.28 g, 23%)(after column chromatography), mp 148°-150° C.; 1H NMR (DMSO-d6)δ 1.33 (3H, d, -3.59 (1H, m, H-5'a), 3.63-3.71 (1H, m, H-5'b), 3.92-3.99 (2H, m, H-4' and --C--H), 4.10-4.18 (2H, m, H-3' and --C--H), 4.51 (1H, q, H-2'), 4.61 (1H, m, --CH3C H--), 5.06 (1H, t, 5'-OH), 5.22, 5.48 (2H, 2d, 2' and 3'-OH), 5.82 (1H, d, H-1'), 6.89-6.97 (3H, m, Ar--H), 7.25-7.30 (2H, t, Ar--H), 8.39 (1H, s, H-8), 8.49 (1H, d, N--H).
Reaction SMILES: COC1C=C(C(C=O)=O)C=CC=1OC.CO.[NH2:17][C:18]1[N:27]=[C:26]([O:28][CH2:29]C)[C:25]2[C:20](=[N:21][C:22]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)=[CH:23][N:24]=2)[N:19]=1>C(O)(C)C>[NH2:17][C:18]1[N:27]=[C:26]([O:28][CH3:29])[C:25]2[C:20](=[N:21][C:22]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)=[CH:23][N:24]=2)[N:19]=1
Reactant: CCOc1nc(N)nc2nc(-c3ccc(OC)c(OC)c3)cnc12
Agent: COc1ccc(C(=O)C=O)cc1OC
Solvent: CC(C)O
Solvent: CO
Product: COc1ccc(-c2cnc3c(OC)nc(N)nc3n2)cc1OC

Procedure:
The sequence of reactions described in examples 106 to 110 was followed, however starting from 3,4-dimethoxyphenylglyoxal instead of 4-methoxyphenylglyoxal in the first step, and from methanol instead if isopropanol in the last step. This provided 2-amino-4-ethoxy-7-(3,4-dimethoxyphenyl) pteridine, a compound which was further characterized by its mass spectrum: 314 ([M+H]+, 100), 300 ([M+H-methane]+, 20).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[S:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)(O)[O-].[K+].C(=O)=O>C(O)C.O>[CH2:19]([O:18][C:16]([C:15]1[S:10][C:9]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13][CH:12]=2)=[N:11][C:21]=1[CH3:23])=[O:17])[CH3:20]
Reactant: CC(C)(C)c1ccc(C(N)=S)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(C(C)(C)C)cc2)nc1C
Temperature: 25 °C
Yield: 87.3 %

Procedure:
The solution of 3.87 g (20 mmol) of 4-tert-butyl-thiobenzamide and 3.45 g (21 mmol) of ethyl 2-chloro-acetoacetate in 15 ml of ethanol was heated at reflux for 3 hours. Afterwards, the reaction mixture was cooled to ambient temperature and a solution of 3 g of potassium bicarbonate in 15 ml of water was added and the mixture was stirred until the gas evolution (CO2) had ceased. The compound was then extracted with 3 portions of 50 ml of tert-butyl methyl ether, the combined organic phases were washed with water, then with brine, dried over anhydrous sodium sulfate and finally evaporated. 5.3 g of 2-(4-tert-butyl-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (87.4% of theory) were obtained as pale yellow viscous oil.