Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:16])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]1[CH:26]=[C:27]([B:31]([OH:33])[OH:32])[CH:28]=[CH:29][CH:30]=1>CC(C)=O>[CH:1]1([N:6]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH2:24][C:25]4[CH:26]=[C:27]([B:31]([OH:33])[OH:32])[CH:28]=[CH:29][CH:30]=4)[CH:12]=3)[C:7]2=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccc(O)cc2CN1C1CCCC1
Reactant: OB(O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccc(OCc3cccc(B(O)O)c3)cc2CN1C1CCCC1
Yield: 72.1 %

Procedure:
To a solution of 2-cyclopentyl-5-hydroxyisoindolin-1-one (500 mg, 2.3 mmol) in acetone (20 mL), K2CO3 (1.2 g, 8.7 mmol) and 3-(bromomethyl)phenylboronic acid (650 mg, 3.0 mmol) were added and refluxed for 3 h. The reaction mixture was filtered and solvent was evaporated in vacuo to obtain 3-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)phenylboronic acid as a white solid (582.7 mg, 72%). The crude product was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.86 (s, 1H), 7.75-7.69 (m, 2H), 7.55-7.32 (m, 4H), 7.19 (s, 1H), 7.09-7.07 (m, 1H), 5.15 (s, 2H), 4.55-4.49 (m, 1H), 4.37 (s, 2H), 1.84-1.56 (m, 8H). LRMS calcd. for C20H22BNO4 [M+H]+ 352 found: 352.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:20][CH3:21])=[CH:6][C:7]([CH2:11][C:12]2[C:13]([NH2:19])=[N:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[OH-].[K+].[CH3:24]I>CO>[CH2:1]([C:4]1[C:9]([O:10][CH3:24])=[CH:8][C:7]([CH2:11][C:12]2[C:13]([NH2:19])=[N:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:6][C:5]=1[O:20][CH3:21])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)cc(Cc2cnc(N)nc2N)cc1OC
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Yield: 75 %

Procedure:
A mixture of 1.43 g. of 6-allyl-α-(2,4-diamino-5-pyrimidyl)-5-methoxy-m-cresol, 5 ml. of 1-N potassium hydroxide and 300 ml. of 40% aqueous methanol was treated with 0.32 ml. of methyl iodide and stirred at room temperature for 48 hours. The methanol was removed by distillation and the residue was extracted with ethyl acetate. Working-up of the ethyl acetate extract yielded 5-(4-allyl-3,5-dimethoxybenzyl)-2,4-diaminopyrimidine of melting point 185°-187° C. (from methanol) in a yield of 75%.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[N:23]1[CH:22]=[CH:21][C:20]([C:17]2[S:16][C:15]([N:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)=[N:19][CH:18]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccncc3)s2)CC1
Agent: Cl
Solvent: CO
Product: c1cc(-c2cnc(N3CCNCC3)s2)ccn1
Reaction time: 1 h

Procedure:
A saturated solution of hydrochloride in methanol (12 ml) was added to 1-(tert-butoxycarbonyl)-4-[5-(pyridin-4-yl)thiazol-2-yl]piperazine (400 mg) at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, whereby the residue, that is, 1-[5-(pyridin-4-yl)thiazol-2-yl]piperazine hydrochloride was obtained as a white solid. In a solution of the resulting residue in methylene chloride (15 ml) was dissolved [1-phenylsulfonyl-5-(trimethylsilylethynyl)indol-2-yl]sulfonyl chloride (630 mg), followed by the addition of diisopropylethylamine (746 μl) at 0° C. After stirring for 4 hours, methylene chloride (10 ml) and a saturated aqueous solution (30 ml) of sodium bicarbonate were added to the reaction mixture to separate it into layers. The water layer was extracted with methylene chloride (2×10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride acetone=6:1), whereby 1-[5-(2-methylpyridin-4-yl)thiazol-2-yl)-4-[[1-phenylsulfonyl-5-(trimethylsilylethynyl)indol-2-yl]sulfonyl]piperazine (214 mg) was obtained as a foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:32]([O:36][NH2:37])([CH3:35])([CH3:34])[CH3:33].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:20][CH:19]=1)[C:13]([NH:37][O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)ON
Reactant: O=C(N[C@@H](CSc1ccc(Oc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)ONC(=O)[C@H](CSc1ccc(Oc2ccccc2)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The above-prepared (R)-2-(benzyloxycarbonylamino)-3-(4-phenoxyphenylthio)-propionic acid was dissolved in methylene chloride (175 ml), cooled to 0° C., and treated with O-(tert-butyl)hydroxylamine hydrochloride (7.7 g), 4-methylmorpholine (9.4 ml), 1-hydroxybenzotriazole (2.8 g), and N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (7.9 g). The mixture was allowed to warm to room temperature, stirred for 1.5 hours, then partitioned between methylene chloride and water. Solvent was removed from the organic phase under reduced pressure, and the residue purified by flash chromatography on silica gel, eluting with 0 to 50% ethyl acetate/hexane, to provide (R)-2 -(benzyloxycarbonylamino)-N-tert-butoxy-3-(4-phenoxyphenylthio)-propionamide (7.4 g) as a white foam.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH:26]([S:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH2:30]([S:29][CH:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:7]=[CH:6][C:5]([C:4]([OH:33])=[O:3])=[CH:10][CH:9]=4)[CH2:16][CH2:15]3)=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)[CH2:31][CH3:32]
Reactant: CCCSC1CCN(c2ccc(N3CCN(c4ccc(C(=O)OCC)cc4)CC3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCSC1CCN(c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2)CC1
Yield: 86.3 %

Procedure:
To a solution of 4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl]piperazin-4-yl]benzoic acid ethyl ester (1.22 g) in a mixture of ethanol (10 ml) and tetrahydrofuran (40 ml) was added 10% aqueous NaOH (2.1 ml) and 1N-NaOR (10 ml), and the mixture was refluxed for 6 hours. The reaction mixture was cooled and adjusted to pH 2.5-3.0 with 1N-HCl. The resulting precipitates were collected by filtration, washed in turn with water (30 ml) and IPE (50 ml) and dried in vacuo to give 4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl]piperazin-4-yl]benzoic acid (0.99 g).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]#[C:8][C:9]1[C:10](=[O:23])[NH:11][C:12](=[O:22])[N:13]([CH:21]=1)[C@@H:14]1[O:20][C@H:17]([CH2:18][OH:19])[CH2:16][CH2:15]1)=O.[O-:26][P:27]([O:30][P:31]([O:34][P:35]([O-])([O-:37])=[O:36])([O-:33])=[O:32])(=[O:29])[O-:28]>>[P:35]([O:19][CH2:18][C@H:17]1[O:20][C@@H:14]([N:13]2[CH:21]=[C:9]([C:8]#[C:7][CH2:6][NH2:5])[C:10](=[O:23])[NH:11][C:12]2=[O:22])[CH2:15][CH2:16]1)([O:34][P:31]([O:30][P:27]([OH:28])([OH:29])=[O:26])([OH:33])=[O:32])(=[O:36])[OH:37]
Reactant: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Reactant: O=C(NCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Product: NCC#Cc1cn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Reaction time: 3.5 h

Procedure:
Alkynylamino nucleoside 22 (0.30 mmol) was converted to the corresponding triphosphate and its trifluoroacetyl group was removed following the general procedure given in Example 5E. After addition of the second aliquot of phosphorus oxychloride, phosphorylation was allowed to proceed for 210 minutes. Assuming an absorption coefficient for the product equal to that of the starting material (13,000), the yield of triphosphate 23, based on its UV absorption at 291.5 nm, was 18%.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].O.[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH3:19])[CH:18]=[CH:17][C:16]([C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])=[CH:15][CH:14]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(=O)C2CCC2)cc1
Reaction time: 0.33 h

Procedure:
Cyclobutylcarbonyl chloride (23.8 g.) in dry toluene (25 ml) was added dropwise during 1 hour to a stirred suspension of anhydrous aluminium chloride (29.4 g) in dry toluene (150 ml). After stirring a further 20 minutes, the mixture was poured into iced water (1 l) and the organic layer was separated, washed with water, dried over magnesium sulphate, filtered and evaporated. The residue was distilled under reduced pressure and the fraction b.p. 79-80°/0.03 mm was collected. On standing the product solidified and the solid had m.p. 32°-34°.
Reaction SMILES: [CH2:1]([CH2:8][NH:9][C:10]([CH3:14])([CH3:13])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CCOCC>[CH2:1]([CH2:8][NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)NCCc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(C)(CN)NCCc1ccccc1
Yield: 55.5 %

Procedure:
A solution of 2-benzylmethylamino-2-methylpropionitrile (6.7 g.) in ether (100 ml.) was added dropwise to a stirred solution of sodium dihydro bis[2-methoxyethoxy] aluminate (28.5 g.) in ether (150 ml.), kept at 0° C. The mixture was then gently refluxed for 20 hrs, and then excess reducing agent was decomposed by the dropwise addition of water to the cooled suspension. The mixture was dried (anhyd.Na2SO4), filtered (hyflo) and the excess ether evaporated under reduced pressure. The residual liquid was distilled under water pump vacuum to give 2-benzylmethylamino-2-methyl-propylamine (3.8 g.) b.p. 138°-140° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].C([O-])([O-])=O.[Na+].[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O.O>[CH2:13]([O:20][C:21]([NH:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a cold (0° C.) solution of (S)-2-amino-1-butanol (2.0 g, 22.5 mmol) in acetone/H2O 1:1 (50 mL), Na2CO3 (8.7 g, 81.9 mmol) and BnOCOCl (5.8 g, 33.8 mmol) were added. After stirring at 0° C. for 1 h, the solid was filtered off and washed with acetone (2×30 mL). The filtrates were concentrated in vacuo and the residue was purified by column chromatography on silica (100% CH2Cl2 to CH2Cl2/MeOH 20:1) to obtain alcohol 7 as a white solid (2.14 g, 43% yield).
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[N:18]=[C:19]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[N:20]=[CH:21][C:22]=3[N:23]=2)=[CH:11][C:10]=1[F:36])C1C=CC=CC=1.[N+](C1C=CC(S([O:49][CH2:50][C@H:51]2[CH2:53][C:52]2([F:55])[F:54])(=O)=O)=CC=1)([O-])=O>>[F:55][C:52]1([F:54])[CH2:53][C@@H:51]1[CH2:50][O:49][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[N:18]=[C:19]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH3:27])[N:20]=[CH:21][C:22]=3[N:23]=2)=[CH:11][C:10]=1[F:36]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Reactant: C[C@@H](COc1ncc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2n1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1ncc2nc(-c3ccc(OC[C@H]4CC4(F)F)c(F)c3)oc2n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((2-(4-(benzyloxy)-3-fluorophenyl)[1,3]oxazolo[5,4-d]pyrimidin-5-yl)oxy)propan-2-yl)carbamate and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Step A of Example 4 and Example 5, the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[CH3:38][O-:39].[Na+]>CN(C=O)C>[OH:1][C:2]1([C:29]2[S:33][C:32]([O:39][CH3:38])=[N:31][CH:30]=2)[CH2:3][CH2:4][CH:5]([N:8]2[CH2:9][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:11]2)[CH2:6][CH2:7]1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
A solution of N-({1-[4-Hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a, 100 mg, 0.18 mmol) was treated with NaOMe (Aldrich, 0.5 M in MeOH, 1 mL) in DMF (1 mL) at 80° C. for 4 hours. The crude solution was directly purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
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: CCO
Solvent: O
Product: COc1ccc(-c2ccc(C=O)cc2)cc1
Reaction time: 12 h
Yield: 71.4 %

Procedure:
To a solution of (4-methoxyphenyl)boronic acid (1 g, 6.6 mmol) and 4-bromobenzaldehyde (1.2 g, 3.5 mmol) in ethanol water mixture was added potassium carbonate (1.7 g, 12.0 mmol) and degasified well and added tetrakis (0.7 g, 0.6 mmol) and stirred under argon for 12 h, reaction mass diluted with water and extracted with ethyl acetate, organic layer was washed with water and brine solutions, dried over anhydrous Na2SO4 and concentrated to brown solid as product (1 g, yield: 71.4%). 1H NMR (300 MHz, CDCl3): δ 9.96 (s, 1H), 7.84 (d, 2H), 7.63-7.66 (d, 2H), 7.51-7.54 (s, 2H), 6.93-6.95 (d, 2H), 3.80 (s, 3H)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH3:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:15]=2[NH:14][C:13]1=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N+:18]([O-:34])=[C:17]([CH3:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:15]=2[NH:14][C:13]1=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Solvent: ClCCl
Product: CC1=[N+]([O-])C(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Yield: 76.8 %

Procedure:
To a suspension of (3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (3.22 g) in methylene chloride (50 ml) was added m-chloroperbenzoic acid (2.50 g, 1.5 eq. mol) portionwise under stirring at ice-bath cooling. The mixture was stirred for 3 days at ambient temperatures. From the reaction mixture methylene chloride was removed in vacuo and to the residue was added an aqueous solution of sodium bicarbonate and stirred for several minutes. The mixture was extracted with ethyl acetate twice and the combined extract was washed with aqueous sodium bicarbonate, water twice and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo to afford an amorphous mass, which was triturated in methanol and collected by filtration to give (3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide (2.59 g) as a crystalline powder. From the mother liquid, the second crop (0.25 g) of the desired powder was prepared by crystallization in a mixture of methanol and diisopropyl ether (3:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OC)=O)[C:9]([O:11]C)=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.C(OCC)(=O)C.CCCCCC>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)Cc1ccc(F)cc1[N+](=O)[O-]
Yield: 89.9 %

Procedure:
Dimethyl 4-fluoro-2-nitrophenylmalonate (5.0 g) was refluxed in 20 mL of 6N hydrochloric acid for 24 hours. The reaction was cooled and the white solid collected by vacuum filtration, washed with water and dried to give 3.3 g (87% yield) of 4-fluoro-2-nitrophenylacetic acid, Rf 0.6 on thin layer chromatography (ethyl acetate:hexane 1:2, silica gel).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](OCC)(=[O:18])[CH2:12][C:13](OCC)=[O:14].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:3]1([C:2]2[N:10]=[C:13]([OH:14])[CH:12]=[C:11]([OH:18])[N:9]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)c1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Oc1cc(O)nc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of benzamidine hydrochloride (44.41 g; 0.284 mol), diethyl malonate (45.51 g; 0.284 mol) and DBU (86.40 g; 0.568 mol) in DMF (250 mL) was heated at 85° C. for 20 h. After cooling to room temperature, the flask was placed in a refrigerator overnight. The crystalline product was collected by filtration and washed with DMF (300 mL), then dissolved in water (ca. 110 mL) and acidified with 2 M HCl (110 mL) with water added, as necessary, to maintain a suspension. The product was collected by filtration, washed with water (100 mL) and dried to a constant weight under high vacuum giving 39.09 g (73%) of an off-white solid. LC (method B) tR=6.2 min; 1H NMR (200 MHz, DMSO-d6) δ 8.08 (m, 2H), 7.54 (m, 3H), 5.34 (s, 1H); ESIMS 189.0 ([M+H]+).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][C:35]1[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:36]=1[C:37]#[N:38].[S:44]1[C:48]([CH2:49]O)=[CH:47][N:46]=[CH:45]1>O1CCCC1>[F:34][C:35]1[CH:42]=[C:41]([O:43][CH2:49][C:48]2[S:44][CH:45]=[N:46][CH:47]=2)[CH:40]=[CH:39][C:36]=1[C:37]#[N:38]
Reactant: OCc1cncs1
Reactant: N#Cc1ccc(O)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2cncs2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diisopropylazodicarboxylate (4.0 g) was dissolved in a little anhydrous tetrahydrofuran (about 10 ml) and added dropwise to a stirred solution of triphenylphosphine (5.2 g) in anhydrous tetrahydrofuran (150 ml) at 0° C. under nitrogen. After stirring at 0° C. for 15 minutes, during which time a white precipitate formed, a mixture of 2-fluoro-4-hydroxybenzonitrile (S. M. Kelly, Helv.Chim.Acta. 1984, Volume 67, P.1572-1579) (2.0 g) and thiazole-5-methanol (2.3 g) in anhydrous tetrahydrofuran (20 ml) was added dropwise whilst maintaining the temperature at or below 5° C. The reaction mixture was stirred in the cooling bath for a further 2 hours then allowed to warm slowly to room temperature. After standing at room temperature overnight the reaction mixture was partitioned between ethyl acetate (200 ml) and saturated aqueous ammonium chloride solution (200 ml). The layers were separated and the organic phase washed with water (100 ml), dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (1:1, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound as a pale yellow solid (2.0 g).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[Br:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:29]1([NH:34][C:35]2[N:43]=[CH:42][N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][N:39]3[C@H:44]2[CH:51]3[C@H:47]([O:48][C:49]([CH3:53])([CH3:52])[O:50]3)[C@@H:46]([CH2:54][CH:55]=O)[O:45]2)[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1>[Br:8]/[CH:9]=[CH:55]/[CH2:54][C@@H:46]1[C@@H:47]2[CH:51]([O:50][C:49]([CH3:53])([CH3:52])[O:48]2)[C@H:44]([N:39]2[CH:38]=[N:37][C:36]3[C:40]2=[N:41][CH:42]=[N:43][C:35]=3[NH:34][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)[O:45]1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OC2[C@H](n3cnc4c(NC5CCCC5)ncnc43)O[C@H](CC=O)[C@H]2O1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OC2[C@H](n3cnc4c(NC5CCCC5)ncnc43)O[C@H](C/C=C/Br)[C@H]2O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of potassium-tert-butoxide (0.78 g, 6.93 mmol) in tetrahydrofuran (45 mL) was added (bromomethyl)triphenylphosphonium bromide (1.51 g, 3.27 mmol) in small portions at −78° C. The resulting mixture was stirred at −78° C. for 2 hours. 2-{(1R,2R,4R)-4-[6-(cyclopentylamino)purin-9-yl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}ethan-1-one, a compound of Formula (11) (0.89 g, 2.31 mmol) dissolved in THF (15 mL) was added slowly and the mixture stirred under an atmosphere of N2 at −78° C. for 3 hours, brought to room temperature slowly and stirred for 4 days. The reaction mixture was quenched with saturated NH4Cl aqueous solution (15 mL) and diluted with H2O (60 mL), and then extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (2×50 mL), dried over Na2SO4, and evaporated under reduced pressure, to provide {9-[4-((2E)-3-bromoprop-2-enyl)(2R,4R,5R)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]purin-6-yl}cyclopentylamine, a compound of formula (12), which was isolated by column chromatography.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([NH2:15])=[CH:13][NH:12][N:11]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:14]([NH:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][NH:12][N:11]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: Fc1ccccn1
Product: c1ccc(Nc2c[nH]nc2-c2nc3ccccc3[nH]2)nc1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 5.8 %

Procedure:
A mixture of 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (150 mg, 0.75 mmol) and 2-fluoropyridine (0.26 ml, 3.0 mmol) was heated in the microwave at 150° C. and 100 W for 15 min. Petroleum ether was added and the solid formed collected by filtration. Recrystallisation from methanol gave [3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-pyridin-2-yl-amine (12 mg). (LC/MS: Rt 0.91, [M+H]+ 277.00).