Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:2]([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CNCc1ccncc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C)Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.3 %

Procedure:
To a solution of N-methyl-N-(4-picolyl)amine (0.40 g, 3.3 mmol) and triethylamine (1.5 mL, 10.8 mmol) in CH2Cl2 (15 mL) was added 4-methoxybenzoyl chloride (1.2 g, 7.3 mmol). The resulting mixture was stirred at rt for 15 min, and then partitioned between 2.5N NaOH and Et2O. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 2-4% MeOH/CHCl3. The material that was isolated was triturated with Et2O to provide the title compound as a light yellow solid (0.18 g, 21%): 1H NMR (CDCl3): d 8.60 (d, 2H); 7.43 (br d, 2H); 7.20 (br s, 2H); 6.90 (br d, 2H); 4.66 (br s, 2H); 3.80 (s, 3H); 3.00 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@@H:15]([OH:16])[CH:14]=[CH:13][CH2:12][O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:25])C=1.CSC>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]1[C@@H:15]([OH:16])[C@H:14]2[C@H:13]([O:25]2)[CH2:12][O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OCC=C[C@@H]1O
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1OC[C@H]2O[C@H]2[C@@H]1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C., stirred solution of cis-2-(tert-butyldimethylsilanyloxymethyl)-3,6-dihydro-2H-pyran-3-ol (0.200 g, 0.91 mmol) in CH2Cl2 (15 ml) was added m-CPBA (75%, 0.46 g, 2.68 mmol) and the mixture was stirred for 1 H at 0° C. Dimethyl sulfide (0.01 ml) was added and stirring was continued for 10 min. The solvent was removed in vacuo and the crude product was diluted with EtOAc (30 ml). The resulting solution was washed successively with saturated aqueous Na2CO3 (10 ml), water (10 ml×2) and brine (10 ml). The organic phase was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography (25-40% EtOAc in hexane).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([NH:17][C@@H:18]([C:21]3[C:22]([O:28][CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=3)[CH2:19][OH:20])=[N:13][C:12]=12)=[O:7].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C(#N)C>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[C@@H:18]([C:21]4[C:22]([O:28][CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=4)[CH2:19][O:20][C:35]3=[O:36])=[N:13][C:12]=12)=[O:7]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ncc(F)cc1[C@@H](CO)Nc1ccn2ncc(C(=O)NCCCCl)c2n1
Solvent: CC#N
Product: COc1ncc(F)cc1[C@H]1COC(=O)N1c1ccn2ncc(C(=O)NCCCCl)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a solution of (S)-N-(3-chloropropyl)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (60 mg, 0.14 mmol) in ACN (2 mL) was added CDI (35 mg, 0.21 mmol). The solution was stirred at ambient temperature for 16 hours then partitioned between saturated NH4Cl solution (20 mL) and EtOAc (10 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with 1% MeOH/DCM to afford (S)-N-(3-chloropropyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (37 mg, 58% yield) as a white solid. MS (apci) m/z=449.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=1)[CH3:2].C(N(C(C)C)CC)(C)C.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[CH:6]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1ccc(Br)c(CNCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Temperature: 25 °C

Procedure:
3-(Benzylamino-methyl)-4-bromo-benzoic acid ethyl ester (5.0 g, 12.9 mmol) and diisopropylethylamine (6.7 mL, 38.7 mmol) were combined in CH2Cl2 (100 mL) at room temperature. Cyclopropanecarbonyl chloride (1.77 mL, 19.4 mmol) was added dropwise, and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was worked-up and purified by silica gel chromatography to give 3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-benzoic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:29]=[C:30]([CH3:32])[CH:31]=2)[O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(=O)OCC)=S)=[N:18][CH:19]=2)=[O:8])=[CH:5][C:4]([CH3:33])=[N:3]1.[Cl-].O[NH3+].C([N:40](CC)C(C)C)(C)C.C(O)C>CO>[NH2:40][C:21]1[N:20]=[C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=4)=[O:8])[CH:31]=[C:30]([CH3:32])[CH:29]=3)=[CH:19][N:18]2[N:23]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cc(C)cc(NC(=O)c3cc(C)nn3C)c2)cn1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CO
Solvent: CCO
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)nn3c2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 71.8 %

Procedure:
A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-5-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (2.65 g, 4.76 mmol), hydroxylammonium chloride (2.96 g, 42.5 mmol), N,N-diisopropylethylamine (5.00 mL, 28.7 mmol), ethanol (100 mL) and methanol (100 mL) was stirred at 80° C. for 14 hr. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure and washed with ethanol-ethyl acetate to give the title compound (1.29 g, 72%) as a white solid.
Reaction SMILES: [I-:1].[Na+].[Li+].[Br-].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH2:21][NH:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1>>[I:1][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH2:21][NH:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: [I-]
Reactant: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Cl)c3c2)o1
Agent: [Br-]
Agent: [Li+]
Agent: [Na+]
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(I)c3c2)o1

Procedure:
The process was repeated as in Example 9 where 1.50 g of sodium iodide (NaI, 10 mmoles) were used instead of LiBr. 3.2 g of N-{[5-(4-iodoquinazoline-6-yl)furan-2-yl]methyl}-2-(methylsulfonyl)ethanamine of formula (VII, X═I) were obtained with a molar yield equivalent to 70%.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(#N)C.P(Br)(Br)[Br:28]>N1C=CC=CC=1>[Br:28][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCCCOc1ccccc1CO
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccccc1CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound is prepared by the procedure of Example 20 using 2.5 g of product from Example 21, 10 ml acetonitrile, 2.11 g of phosphorus tribromide and 0.339 g of pyridine. The reaction is cooled for 10 minutes at 0° C., followed by stirring at room temperature for 1 hour. The product, 2.58 g, is obtained as cream crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[O:4][NH:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10].[CH2:17]=[O:18].O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[O:4][N:5]([CH2:17][OH:18])[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCNC(=O)NOc1cc(Cl)ccc1Cl
Reactant: C=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)N(CO)Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 2.0 g (7.6 mmoles) of 3-(2,5-dichlorophenoxy)-1-n-propyl-urea, and then 1.87 g (22.8 mmoles) of 37% aqueous formalin solution was added The mixture was stirred at 25° C. for 3 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The ethyl acetate was evaporated under reduced pressure The residue was recrystallized from ethyl acetate and toluene to give 1.4 g (yield 63%) of the desired compound as colorless crystals.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH3:16])[CH2:15][CH2:14][CH2:13]2)=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18])=O.CO.C(=O)([O-])[O-].[K+].[K+].O>>[CH3:16][C:12]1([C:9]2[CH:10]=[CH:11][C:6]([NH2:5])=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=2)[CH2:13][CH2:14][CH2:15]1
Reactant: CC1(c2ccc(NC(=O)C(F)(F)F)c([N+](=O)[O-])c2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(c2ccc(N)c([N+](=O)[O-])c2)CCC1
Temperature: 45 °C
Yield: 102.1 %

Procedure:
A solution of 2,2,2-trifluoro-N-[4-(1-methylcyclobutyl)-2-nitrophenyl]acetamide (580 mg. 1.9 mmol) in Methanol (18 ml, 440 mmol) was treated with a solution of Potassium carbonate (788 mg, 5.70 mmol) in Water (4.5 ml, 250 mmol) and the mixture was heated at 45° C. for 50 minutes The reaction mixture was cooled to RT and the methanol was removed in vacuo. The remaining aqueous phase was diluted with 10 ml H2O and extracted with three 20 ml portions of EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated to yield an oil. The material was placed on high vacuum where upon it solidified giving the desired compound (400 mg). The material was used directly in the next step 1H NMR (400 MHz. CDCl3) d ppm 7.90 (d, J=2.07 Hz, 1H), 7.23 (dd, J=8.50, 2.28 Hz, 1H), 6.77 (d, J=8.71 Hz, 1H), 5.96 (br. s., 2H), 2.33 (m, 2H), 2.13 (m, 1H), 2.04 (m, 2H), 1.84 (m, 1H), 1.43 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([OH:28])[CH:25]=3)[CH2:20]2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O[CH2:49][CH2:50][Cl:51])(=O)=O)=CC=1>>[Cl:51][CH2:50][CH2:49][O:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([S:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[C:12]#[N:13])[CH2:27]2
Reactant: COc1cc2c(cc1O)CN(CCCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Product: COc1ccc(C(C#N)(CCCCCN2Cc3cc(OC)c(OCCCl)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 73 %

Procedure:
The procedure of Example of 32 is used with 0.45 g of α-(3,4-dimethoxyphenyl)-1,3-dihydro-5-hydroxy-6-methoxy-α-[(4-methylphenyl)thio]-2H-isoindole-2-heptanenitrile and 0.65 g of 2-chloroethyl p-toluenesulfonate. This affords 0.367 g of the desired product as a light brown oil. MS(Hi res): m/z Calcd for C33H39N2SClO4 595.2397 Found 595.2391(M+H)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:30][CH2:31][CH2:32][CH2:33][S:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([C:7]([NH:30][CH2:31][CH2:32][CH2:33][S:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCCCSc1ccncc1
Reactant: Cc1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCCSc2ccncc2)s1
Yield: 64.5 %

Procedure:
To a solution of 1.27 g (8.91 mmol) of 5-methyl-2-thiophenecarboxylic acid and 1.33 g (11.6 mmol) of N-hydroxysuccinimide in 90 ml of methylene chloride, 2.05 g (10.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.50 g (8.91 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 1.68 g of the desired compound (yield: 64.5%, colorless powder).
Reaction SMILES: [I-].[I-].[CH3:3][N+:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][C:13]2[CH:30]=[CH:29][C:28]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32](C4C=[N+](C)C=CC=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:14]=2)=[O:11])[CH:5]=1.C1([CH2:47][N:48]2[CH:53]=[CH:52][C:51](C(N)=O)=[CH:50][CH2:49]2)C=CC=CC=1>C(#N)C.C(Cl)Cl>[CH3:3][N:4]1[CH:9]=[CH:8][CH2:7][C:6]([C:10]([O:12][C:13]2[C:14]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32]([C:52]4[CH2:51][CH:50]=[CH:49][N:48]([CH3:47])[CH:53]=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:28]=[CH:29][CH:30]=2)=[O:11])=[CH:5]1
Reactant: NC(=O)C1=CCN(Cc2ccccc2)C=C1
Reactant: C[n+]1cccc(C(=O)Oc2ccc3c(c2)CC[C@@H]2[C@@H]3CC[C@]3(C)[C@@H](OC(=O)c4ccc[n+](C)c4)CC[C@@H]23)c1
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Product: CN1C=CCC(C(=O)Oc2cccc3c2[C@H]2CC[C@]4(C)[C@@H](OC(=O)C5=CN(C)C=CC5)CC[C@H]4[C@@H]2CC3)=C1
Temperature: 0 °C

Procedure:
One gram (1.31 mmol) of the product of Example 71 was dissolved in 100 mL of dry acetonitrile. To that solution, which was flushed with nitrogen, 0.28 g (1.31 mmol) of 1-(phenylmethyl)-4-(aminocarbonyl)-1,2-dihydropyridine was added, and the reaction mixture was stirred at 0° C. for l hour. Removal of the solvent under reduced pressure afforded a solid, which was suspended in methylene chloride and removed by filtration. The filtrate was chromatographed several times on a neutral alumina column prepared with methylene chloride. Purification and evaporation of the solvent in vacuo gave a solid foam. The product had the formula ##STR106## as confirmed by UV, NMR and elemental analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CO[CH:10]=[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].CC(N(C)C)=O.Cl>C(OCC)C>[C:21]1([C:11]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:10][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccccn1
Reactant: COC=C(c1ccccc1)S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: O=S(=O)(C(=CNc1ccccn1)c1ccccc1)c1ccccc1
Yield: 12.2 %

Procedure:
A solution of 2-aminopyridine (1.05 g) and 2-methoxy-1-phenyl-1-phenylsulphonylethene (2.0 g) in a mixture of anhydrous dimethylacetamide (50 ml) and a solution of hydrogen chloride in diethyl ether (6N; 0.5 ml) was heated at reflux for 25 hours, and then it was cooled and poured onto ice (150 g). The yellow precipitate was filtered off, subjected twice to medium pressure chromatography on silica gel, eluting with chloroform, triturated with light petroleum ether (b.p. 60°-80° C.) and recrystallised from a mixture of diethyl ether and light petroleum ether (b.p. 60°-80° C.), to give 1-phenyl-1-phenylsulphonyl-2-(pyrid-2-ylamino)ethene (0.3 g), m.p. 159°-160° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1>O>[C:24]1([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1cccc(C(=CCBr)c2ccccc2)c1
Reactant: OCCO
Agent: [Li]CCCC
Solvent: O
Product: OCCOCC=C(c1ccccc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of n-butyllithium in hexanes (16 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to dry ethylene glycol (40 ml) at 10° C. When addition was complete the mixture was stirred for 0.5 h at room temperature. 3-Bromo-1-phenyl-1-(3-(trifluoromethyl)phenyl)-1-propene (12.0 g, 35 mmol, prepared similarly to the method described in Example 23) was added and the reaction mixture was stirred at room temperature for 72 h. The mixture was poured into water (300 ml) and extracted with ethyl acetate (2×100 ml). The combined organic extracts was dried over sodium sulphate and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (150 g) using a mixture of cyclohexane and ethyl acetate (7:3) as eluent provided 5.9 g (52%) of 2-(3-phenyl-3-(3-(trifluoromethyl)phenyl)-2-propen-1-yloxy)ethanol. 2-(3-phenyl-3-(3-(trifluoromethyl)phenyl)-2-propen-1-yloxy) ethanol (5.0 g, 15.5 mmol) was dissolved into dry dioxan (80 ml) and stirred under an atmosphere of hydrogen for 18 h at room temperature in the presence of 10% palladium on carbon catalyst (50% aqueous paste) and then filtered. The filtrate was evaporated in vacuo to give 4.0 g (95%) of 2-(3-phenyl-3-(3-trifluoromethyl)phenyl)-1-propyloxy)ethanol. 1H NMR (CDCl3)δ 4.20 (t, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:27].C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>C(Cl)Cl>[NH2:27][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([S:14][C:15]1[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][C:38]([CH:35]1[CH2:37][CH2:36]1)=[O:39]
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN)OCO2
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCNC(=O)C1CC1)OCO2

Procedure:
9-(3-Aminopropyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (60 mg, 0.155 mmol), triethylamine (17 mg, 24 μL, 0.170 mmol), cyclopropane carbonyl chloride (16 mg, 14 μL, 0.155 mmol) in CH2Cl2 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH2Cl2:MeOH—NH3(7N), 20:1) to give MRP-I-28 (66 mg, 93%). 1H NMR (600 MHz, CDCl3): δ 8.33 (s, 1H), 7.40 (t, J=6.1 Hz, 1H), 6.77 (s, 1H), 6.52 (s, 1H), 6.40 (br s, 2H), 5.90 (s, 2H), 4.29 (t, J=6.2 Hz, 2H), 3.11 (q, J=6.0 Hz, 2H), 2.68 (s, 6H), 1.87-1.91 (m, 2H), 1.45-1.49 (m, 1H), 0.98-0.96 (m, 2H), 0.77-0.74 (m, 2H); 13C NMR (150 MHz, CDCl3): δ 173.7, 154.9, 153.0, 151.8, 148.3, 147.5, 146.6, 144.7, 119.9, 119.5, 109.6, 102.5, 101.7, 45.3, 40.6, 35.3, 29.1, 14.9, 7.1 HRMS (ESI) m/z [M+H]+ calcd. for C21H26N7O3S, 456.1818. found 456.1812.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](Cl)=[CH:4][C:5]([F:8])([F:7])[F:6].[H][H].[OH-].[K+]>C(O)C.[Ni]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: [H][H]
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)CCC(F)(F)F
Yield: 47.8 %

Procedure:
In a stainless steel autoclave, 40 g of 1,1,1,4,4,4-hexafluoro-2-chloro-2-butene in 300 ml of ethanol were hydrogenated with hydrogen in the presence of 12 g of potassium hydroxide and 25 g of Raney nickel for 3 hours at 20° C. and another 1 hour at 100° C. at a pressure of from 30 to 40 bar. The solid components were then removed from the reaction mixture by filtration and the remaining liquid was distilled to give 16 g of 1,1,1,4,4,4-hexafluorobutane having a boiling point of 25°-30° C. at 1013 mbar. The mass spectrum showed a molecular ion at m/e 166.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32]C1C=CC=CC=1CCl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1Cl
Reactant: COc1ccccc1CC(O)(c1cccc(F)c1)C1CN(Cc2ccccc2)CCO1
Product: OC(Cc1ccccc1Cl)(c1cccc(F)c1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of 4a, 1-(4-Benzyl-morpholin-2-yl)-1-(3-fluoro-phenyl)-2-(2-methoxy-phenyl)-ethanol was followed using 2-chorobenzyl chloride (available from Aldrich Chemical Company) as starting material, and making non-critical variations, to yield the title compound which was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=426 @ Rt 2.85 min. major peak.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13]Cl)[O:6][CH2:5][CH2:4][O:3]1.[C-:15]#[N:16].[Na+].[Na+].[I-].[C-]#N.[K+]>CCO.O>[CH3:1][C:2]1([CH2:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][C:15]#[N:16])[O:6][CH2:5][CH2:4][O:3]1
Reactant: [C-]#N
Reactant: CC1(CCC#CCCCCl)OCCO1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(CCC#CCCCC#N)OCCO1
Yield: 96.5 %

Procedure:
2-Methyl-2-(7-chloro-3-heptynyl)-1,3-dioxolane (21.6 g, 0.1 mol) was dissolved in 120 ml EtOH (convenience; dimethylformamide, dimethylsulfoxide, or other polar solvents may be used) and added to a solution of NaCN (9.8 g, 0.2 mol) and NaI (2.0 g, 0.013 mol) in 80 ml H2O. KCN, NH4CN or other cyanide salts may be used. The reaction was concentrated to remove the solvent and was extracted with three 100 ml portions of ether. The combined organic extracts were washed with 2-50 ml portions of water and brine. After drying over anhydrous MgSO4, the solvent was removed to give 20 g of 2-methyl-2-(7-cyano-3-heptynyl)-1,3-dioxolane, pure enough to use directly in the next step. Yield: 20 g, 99%. IR (CHCl3): 3000, 2950, 2890, 2250, 1675 cm-1.