Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 44 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 44% of theory, C26H26N6O4 (486.5); Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=487; (M+2H)++=244; (M+H+Na)++=255.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:35])C.[OH-].[Na+].Cl>C(O)C>[CH:30]1([O:29][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH3:35])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OC3CCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OC3CCCC3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester (160 mg; 0.31 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 105 mg (70%). HPLC-MS: m/z: 482.2 (M+H)+; Rt: 1.77 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]=[CH:6][C:7]1[C:8]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)[CH3:2].[H][H]>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[C:8]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)CCc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 78.4 %

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-acrylic acid ethyl ester (0.102 g, 0.21 mmol) in ethanol (20 mL) was added platinum oxide (0.010 g). The reaction mixture was shaken under positive pressure of hydrogen gas (20 psi) for 20 minutes. The resulting mixture was filtered through a pad of celite, the filter cake was washed with ethanol, and the combined filtrate was concentrated in vacuo to give the title compound (0.081 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C(OCC)C>[C:16]([O:15][C:13]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:12])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To the suspension of 10 g (76.2 mmol ) of L-leucine in 140 mL of diethyl ether was added 80 mL of 10% NaOH. After all solid dissolves, 20 mL (87.1 mmol) of BOC2O was added to the reaction mixture. The resulting reaction mixture was stirred at 23° C. for 12 h. After this period, the layers were separated and the aqueous layer was acidified to pH 1 by careful addition of 1N aqueous HCl at 0° C. The resulting mixture was extracted with ethyl acetate (3×100 mL). The organic layers were combined and washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to provide title product which was used directly for next reaction without further purification (yield, 97%). 1H NMR (400MHz, CDCl3) δ 4.89 (broad d, 1H, J =8.3 Hz), 4.31 (m, 1H), 1.74-1.49 (m, 3H), 1.44 (s, 9H), 0.95 (d, 6H, J=6.5 Hz).
Reaction SMILES: C([N:4]1[CH:10]([CH3:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6](=[O:16])[CH:5]1[CH:17]=[CH:18][C:19]1C=CC=CC=1)C=C.Cl>CCOCC.C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[CH3:11][CH:10]1[N:4]2[CH2:19][CH:18]=[CH:17][CH:5]2[C:6](=[O:16])[NH:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]1=2
Reactant: C=CCN1C(C=Cc2ccccc2)C(=O)Nc2ccccc2C1C
Agent: Cl[Ru]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C=Cc1ccccc1
Product: CC1c2ccccc2NC(=O)C2C=CCN21
Reaction time: 72 h
Yield: 46.7 %

Procedure:
The product of Example 15 (103 mg, 0.32 mmol) was first converted to the HCl salt with excess 1M HCl in ether, and all of the volatiles were removed. The resulting solid was then dissolved in dry dichloromethane (15 mL) and bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (132 mg, 0.16 mmol) was added, and the flask was flushed with Ar(g). The reaction was allowed to proceed at room temperature for three days, after which time, the reaction was diluted with an additional 10 mL of dichloromethane, and transferred to a separatory funnel. The organic layer was washed with a saturated solution of sodium bicarbonate (3×15 mL), the aqueous layers were then combined and extracted with dichloromethane (2×10 mL). The organic layers were then combined, washed once with brine (15 mL), dried over magnesium sulfate, filtered and evaporated to yield a crude residue which was purified by flash column chromatography using ethyl acetate-hexane (3:1) to yield 32 mg (61% yield) of a dark oil. 1H NMR (360 MHz, CDCl3) δ 7.60 (bs, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.32-7.19 (m, 2H), 7.00-6.95 (m, 1H), 6.16-6.10 (m, 1H), 5.88-5.82 (m, 1H), 4.34 (bs, 1H), 3.96-3.81 (m, 2H), 3.55-3.46 (m, 1H), 1.58 (d, J=6.5 Hz, 3H).
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[CH:8]1[CH:12]([O:13][C:14](=[O:27])[CH:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:11]([OH:29])([CH3:28])[CH:10]([N:30]2[CH:35]=[CH:34][C:33]([N:36]=CN(C)C)=[N:32][C:31]2=[O:41])[O:9]1)(C)(C)C.[NH4+].[F-]>CO>[NH2:36][C:33]1[CH:34]=[CH:35][N:30]([CH:10]2[O:9][CH:8]([CH2:7][OH:6])[CH:12]([O:13][C:14](=[O:27])[CH:15]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:11]2([OH:29])[CH3:28])[C:31](=[O:41])[N:32]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(N=CN(C)C)nc2=O)C1(C)O
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(CO)OC(n2ccc(N)nc2=O)C1(C)O

Procedure:
In another method to synthesize the compounds of the invention, shown in FIG. 6, benzoylcytosine, BSA and SnCl4/acetonitrile are reacted with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (FIG. 6, compound 1a) to form 4-benzoylamino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (FIG. 6, compound 2a); reacting (FIG. 6, compound 2a) with NH3 in methanol and chromatographically separating the product, 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (FIG. 6, compound 3a), also known as β-D-2′-C-methyl-cytidine; reacting (FIG. 6, compound 3a) with Me2NCH(OMe)2 in DMF at room temperature for 1.5 hours to form N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (FIG. 6, compound 4a); reacting (FIG. 6, compound 4a) with TBDPSCl and pyridine at room temperature for 6 hours to provide N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (FIG. 6, compound 5a); reacting (FIG. 6, compound 5a) with N-Boc-L-valine, DEC and DMAP in THF/DMF at room temperature for 2 days and subjecting the product formed from this reaction to HPLC in order to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylaminomethyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (FIG. 6, compound 6a); refluxing (FIG. 6, compound 6a) with NH4F in MeOH for about 3 hours to remove the silyl and amino-protecting groups, and subjecting the product to chromatographic purification to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (FIG. 6, compound 7a); and finally reacting (FIG. 6, compound 7a) with HCl in EtOAc at room temperature to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (FIG. 6, compound 8a) as a final product.
Reaction SMILES: [CH2:1]1[O:18][C:17]2[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br)=[CH:4][C:3]=2[O:2]1.[I-:19].[Na+]>CC(C)=O>[CH2:1]1[O:18][C:17]2[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][I:19])=[CH:4][C:3]=2[O:2]1
Reactant: BrCCCCCCCOc1ccc2c(c1)OCO2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCCCOc1ccc2c(c1)OCO2

Procedure:
A mixture of 43.5 g. of 7-(3,4-methylenedioxyphenoxy)heptyl bromide, 20.7 g. of sodium iodide and 300 ml. of acetone was heated at reflux for 2 hours. The reaction mixture was filtered, the filtrate evaporated in vacuo, and the residue partitioned between water and methylene dichloride. The methylene dichloride layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue comprising 7-(3,4-methylenedioxyphenoxy)heptyl iodide was used without further purification in the following reaction.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Cl)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>CN(C)C=O>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH2:19][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:14][CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(=O)CCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a 0° C. slurry of 8.24 g of imidazole in 15 ml. dry dimethylformamide was added 5.79 g of p-t-butyl-gamma-chlorobutyrophenone and the mixture was stirred overnight at room temperature, then for one day at 60° C. The above solution was poured into 400 ml. of water and extracted three times with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent evaporated to afford 5.25 g of 1-[4-(4-t-butylphenyl)butan-4-onyl]imidazole as a golden oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[CH2:10][CH2:9]1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOC(=O)C=CCC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1

Procedure:
A solution of 1.57 g (4.82 mmol) 4-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-but-2-enoic acid ethyl ester and 200 mg of Pd/C (10%) in 20 ml of MeOH was stirred at RT under H2-atmosphere for 3 h. After filtration, the solution was concentrated under reduced pressure to dryness, to give 1.58 g of clean trans-4-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-butyric acid ethyl ester. 1.58 g (4.82 mmol) trans-4-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-butyric acid ethyl ester in 20 ml of THF, was treated at RT with 390 mg of LiAlH4. After stirring the solution for 30 min at RT, the excess of LiAlH4 was destroyed by adding dropwise 10 ml of saturated brine under ice-cooling. The reaction mixture was partitioned between Et2O/1M HCl and H2O. The ether-solution was concentrated in vacuo, to give 1.37 g (99%) of pure trans-[4-(4-Hydroxy-butyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:3]=1[C:4]([NH:6][C:7]1C=NC(C2C=CC=CC=2)=NC=1)=[O:5].C(N([CH:35]([CH3:37])[CH3:36])CC)(C)C.[Cl:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](Cl)=[O:44]>C1COCC1.C(Cl)Cl>[Cl:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([NH:1][C:2]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[N:6]=[CH:4][C:3]([C:36]2[CH:35]=[CH:37][CH:21]=[CH:20][CH:19]=2)=[CH:2][N:1]=1)=[O:5])=[O:44]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ncc(-c2ccccc2)cn1)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 100 mg of 2-amino-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide 2d, and 138 mg of diisopropylethylamine in 2 mL of 1:1 THF/DCM was added dropwise 46 mg of 3-(chloromethyl)benzoyl chloride. The mixture was stirred overnight at room temperature and the solvent was evaporated. All of this material was used in the next step without further characterization.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[S:17](Cl)Cl.C(N(CC)CC)C.[NH:27]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[CH2:40]([O:39][C:37]([CH2:36][CH2:35][N:27]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[S:17][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:38])[CH3:41]
Reactant: ClSCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CCOC(=O)CCNCCC(=O)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(CCC(=O)OCC)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 11 g quantity (0.05 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate was dissolved in 70 ml of methylene chloride, 5.2 g (0.05 mole) of sulfur dichloride was added to the solution with cooling, and 5 g (0.05 mole) of triethylamine was further added dropwise to the solution at -10° to -5° C. The mixture was stirred at 0° C. for one hour and further at room temperature for 2 hours. After cooling to -10° to -5° C., 10.9 g (0.05 mole) of diethyl iminodipropionate was added dropwise to the mixture, and 5 g (0.05 mole) of triethylamine was further added dropwise to the mixture. The resulting mixture was stirred at 0° C. for 2 hours and thereafter allowed to stand overnight at room temperature. With addition of 100 ml of methylene chloride, the reaction mixture was washed with 100 ml of water three times. The methylene chloride layer was dried and then concentrated in a vacuum to give an oily product, which was almost entirely composed of the desired product although containing small amounts of impurities. Yield: 16.9 g (72.2%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=O.[O:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][C:15]=2[NH2:24])[CH2:8][CH2:7]1>ClCCl>[Cl:1][CH2:2][C:3]1[N:13]([CH2:12][CH:9]2[CH2:8][CH2:7][O:6][CH2:11][CH2:10]2)[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1
Reactant: Nc1cnc2ccccc2c1NCC1CCOCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: ClCc1nc2cnc3ccccc3c2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
Chloroacetyl chloride (12 mL, 151 mmol) was dissolved in dichloromethane (30 mL) and added via addition funnel, over 20 minutes, to a stirring solution of N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (35.3 g, 137 mmol) in dichloromethane (300 mL). The resulting solution was stirred at ambient temperature under nitrogen for 24 hours at which point the solution was heated to 40° C. for an additional 24 hours. The mixture was cooled to ambient temperature, diluted with dichloromethane (150 mL) and transferred to a separatory funnel. The organic layer was washed with water (2×200 mL) and brine (2×200 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide 38.3 g of 2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]3[O:10][C:9]([CH3:22])([CH3:21])[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[C:13]=2[CH3:20])=[O:29])=[CH:26][CH:25]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(F)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(F)cc1)C(C)(C)O2
Yield: 75 %

Procedure:
By using 3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 75%. Melting point: 140-142° C. (Ethyl acetate-hexane).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23]([C:24](O)=[O:25])=[C:22]([F:27])[C:21]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:20][CH:19]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:24](=[O:25])[C:23]3[C:18]([Cl:17])=[CH:19][CH:20]=[C:21]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:33])[CH3:34])[C:22]=3[F:27])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 13.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 146 mg, 0.51 mmol), oxalyl chloride (126 mg, 0.99 mmol), DMF (1 drop) and DIPEA (132 mg, 1.03 mmol) in CH2Cl2 (3 mL) to afford 30 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 8.69-8.67 (d, J=7.4 Hz, 1H), 8.51 (s, 1H), 8.18-8.16 (m, 2H), 7.54-7.50 (t, J=8.0 Hz, 1H), 7.44-7.40 (m, 2H), 7.37-7.33 (t, J=8.0 Hz, 1H), 4.32-4.30 (d, J=6.0 Hz, 2H), 1.56 (s, 9H), 1.14 (s, 9H); MS (m/z): 486.25 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([NH:20]C(=O)C)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+]>C(OCC)(=O)C.O>[C:1]1([C:7]2[C:11]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:10]([NH2:20])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1[nH]nc(-c2ccccc2)c1C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1[nH]nc(-c2ccccc2)c1C#Cc1ccccc1
Temperature: 90 °C
Yield: 49.6 %

Procedure:
A mixture of N-[3-phenyl-4-(2-phenylethynyl)-1H-pyrazol-5-yl]acetamide (12.5 g, 42 mmol), ethanol (100 mL) and 25% aq. NaOH solution (100 mL) was stirred and heated to 90° C. for 1 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (phase separator cartridge) and concentrated in vacuo. Diethyl ether was added to the residue and the solid was collected by filtration, washed with diethyl ether and dried in vacuo to provide the title compound as a solid (5.4 g).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14](OC)([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[N:23]([CH3:24])[C@H:12]1[CH2:11]3.[C:27]([O-])(=O)C.[Na+].Cl.[OH:33][CH2:34][CH2:35][CH2:36][NH2:37]>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:37][CH2:36][CH2:35][CH2:34][OH:33])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[N:23]([CH3:24])[CH:13]3[C:14]12[CH3:27]
Reactant: CC(=O)[O-]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@@H]3[C@H](CN21)N3C
Reactant: NCCCO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1=C(NCCCO)C(=O)C2=C(C1=O)N1CC3C(N3C)C1(C)C2CO
Product: NC(=O)O
Reaction time: 24 h
Yield: 61 %

Procedure:
To a solution of 50 mg (0.13 mmol) of N-methylmitomycin A in 10 ml of anhydrous methanol, a solution of 82 mg (1 mmol) sodium acetate in 2.5 ml of methanol and a solution of 130 mg (1 mmol) of 3-hydroxypropylamine hydrochloride in 2.5 ml of methanol were added alternatively with vigorous stirring, over a period of 10 minutes. The progress of the stirred reaction was checked frequently by TLC and appeared to be complete in 24 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with ethyl acetate was evaporated. Recrystallization from a mixture of methylene chloride and hexane gave 31 mg. (61% yield) of the desired product as purple-colored crystals having a melting point of 139°-140° (decomposing) and providing the following analysis:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[NH2:25][C:26]([NH2:28])=[S:27]>CC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[S:27][C:26](=[NH:25])[NH2:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](SC(=N)N)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C

Procedure:
2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (37.5 g) dissolved in acetone (180 ml) with thiourea (10.9 g) at 25° C. Batch heated to reflux for a minimum of 2 hrs. Reaction followed by TLC (1:1 petrol/EtOAc. Starting material 0.69, plus multiple peaks below. Product is a salt and therefore seen on baseline (uv-active)). Batch cooled to R.T. and crystallised as a white crystalline solid (35 g, 79%) with the aid of petrol as anti-solvent. M.p=169-171° C. (Lit3 169° C.). [α]D22+17 (EtOH, C=2.0) (Lit3+16). (1H NMR (DMSO, 400 MHz). δ=1.96, 2.02, 2.09, 2.14 (sx4, 4×3H, —C(O)CH3), 4.08-4.11 (m, 2H, H-6, H-61), 4.4 (t, J6.2 Hz, 1H, H-5), 5.1 (t, J2,39.9 Hz, 1H, H-2), 5.2 (dd, J2,39.9 Hz, J3,43.4 Hz, 1H, H-3), 5.4 (d, J3.3 Hz, 1H, H-4), 5.6 (d, J1,210 Hz, 1H, H-1), 9.2 (Br, 4H, 2×NH2).