Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][NH2:15])[N:13]=1.[F:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30](O)=[O:31])[C:23]2=[O:36])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30]([NH:15][CH2:14][C:12]3[N:13]=[C:9]([CH3:8])[S:10][CH:11]=3)=[O:31])[C:23]2=[O:36])=[CH:37][CH:38]=1
Reactant: Cc1nc(CN)cs1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1cocn1
Product: Cc1nc(CNC(=O)c2ccnc(N3CCN(Cc4ccc(F)cc4)C3=O)c2)cs1
Yield: 26 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (2-methylthiazol-4-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((2-methylthiazol-4-yl)methyl)isonicotinamide was obtained as a colorless solid in 26% yield: mp 76-78° C.; 1H NMR (300 MHz, CDCl3) δ 8.60 (d, J=0.6 Hz, 1H), 8.34 (d, J=5.7 Hz, 1H), 7.36 (dd, J=5.4, 1.5 Hz, 1H), 7.28-7.24 (m, 2H), 7.05-6.99 (m, 4H), 4.66 (d, J=5.7 Hz, 2H), 4.43 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.36 (t, J=8.1 Hz, 2H), 2.68 (s, 3H); MS (ES+) m/z 425.8 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.Br.Br[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.CN(C=O)C.[H-].[Na+]>C(Cl)(Cl)Cl.O>[O:1]=[C:2]1[N:7]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
Benzyl 3-oxopiperazine-1-carboxylate (400 mg) and 3-(bromomethyl)pyridine hydrobromide (647 mg) were mixed with DMF (8 ml), and sodium hydride (55% suspended in oil) (194 mg) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. Water and CHCl3 were added to the reaction mixture at 0° C., and the organic layer was washed with water and saturated brine, dried over anhydrous sodium carbonate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (EtOAc/hexane) to obtain benzyl 3-oxo-4-(pyridin-3-ylmethyl)piperazine-1-carboxylate (345 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH2:14]CN(CC)CC2)=[O:7])=[CH:4][C:3]=1[Cl:19].[CH3:20][NH:21][CH:22](NC)CN>>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:14][N:21]([CH3:22])[CH3:20])=[O:7])=[CH:4][C:3]=1[Cl:19]
Reactant: CNC(CN)NC
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Product: CN(C)CCNC(=O)c1ccc(N)c(Cl)c1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 212, on a 15 mmol scale utilising 2,2-Dimethyaminoethylamine (Aldrich; 1.455 g, 16.5 mmol), as a white solid (1.45 g, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[Cl:24].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 53.9 %

Procedure:
To a solution of 5-bromo-2-fluoro-benzaldehyde (5.13 g, 25.4 mmol) in DMF (25 mL) were added K2CO3 (7.15 g, 51.8 mmol) and 3,4-dichloro-phenol (4.67 g, 28.8 mmol). The mixture was heated at 90° C. for 24 h and then was allowed to cool to room temperature (rt). Water was added and the mixture was extracted with Et2O. The combined organic layers were dried (MgSO4) and concentrated. The residue was diluted with DCM and hexanes and the resulting solid was collected by vacuum filtration to provide the desired product (4.74 g, 54%). 1H NMR (CDCl3): 10.36 (s, 1H), 8.06 (d, J=2.5, 1H), 7.67 (dd, J=8.8, 2.6, 1H), 7.46 (d, J=8.8, 1H), 7.17 (d, J=2.8, 1H), 6.92 (dd, J=8.8, 2.8, 1H), 6.84 (d, J=8.8, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:21][CH2:22][OH:23]>CN(C)C=O.C[O-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][CH2:22][OH:23])[CH:10]=2)=[O:8])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Reactant: OCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(CCO)c3ccccc23)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
5 g of 3-(p-methoxybenzoyl)indole were dissolved in 30 ml of dimethylformamide containing 1.3 g of sodium methoxide. 1.93 g of 2-chloroethanol was added to the solution followed by stirring at 110° C. for 1 hour. The solution was concentrated under reduced pressure and was extracted with 100 ml of chloroform and 50 ml of water. After evaporating the organic layer to dryness, the residue was recrystallized from ethanol to give 3-(p-methoxybenzoyl)-N-(2-hydroxyethyl)indole (compound 21). (Yield: 51%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.[Si]([O:50][C@@H:51]([CH3:54])[CH:52]=O)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.O1CCCC1>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][N:29]([CH2:52][C@@H:51]([OH:50])[CH3:54])[CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:14])[F:15])[C:5]=12
Reactant: C[C@@H](C=O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(C[C@H](C)O)C1
Reaction time: 8 h
Yield: 6.7 %

Procedure:
To a mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (25 mg, 0.051 mmol), (2S)-2-{[tert-butyl(diphenyl)silyl]oxy}propanal (18 mg, 0.057 mmol) and triethylamine (22 μL, 0.15 mmol) in methylene chloride (0.3 mL) was added sodium triacetoxyborohydride resin (45 mg, 0.10 mmol). The mixture was stirred overnight then filtered and concentrated. To the residue was added tetrahydrofuran (1.0 mL) and 1.0 M tetra-n-butylammonium fluoride in THF (0.51 mL, 0.51 mmol). The resulting mixture was stirred overnight at room temp. The solvent was evaporated and the crude material was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 1.6 mg (6.6%) of the desired product. The product was isolated as a single diastereomer. LCMS calculated for C23H28F2N7O2 (M+H)+: m/z=472.2; Found: 472.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.O>CN(C)C=O>[CH2:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:13]
Reactant: CCc1ccc2ncnc(N)c2c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CNc1ncnc2ccc(CC)cc12)C(=O)OCC
Temperature: 110 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A mixture of 4-amino-6-ethylquinazoline (6.35 g) and diethyl ethoxymethylenepropanedioate (9.52 g) in N,N-dimethylformamide (25 ml) was stirred for 3 hours at 110° C. and then cooled to ambient temperature. A small volume of water was added to the resultant mixture to precipitate crystals, which were separated by filtration and washed with water. The crystals were dissolved in chloroform, washed with an aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and hexane to give crystalline diethyl [(6-ethyl-4-quinazolinylamino)methylene]propanedioate (8.40 g). Further, crystals (2.75 g) of the same compound were recovered from the mother liquor in the same manner as mentioned above.
Reaction SMILES: [N+:1]([C:4]1[CH:49]=[CH:48][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:20]4[C:40]5[C:35](=[C:36]([CH2:42][NH:43][CH:44]([CH3:46])[CH3:45])[C:37]([Cl:41])=[CH:38][CH:39]=5)[C:22]5([CH2:27][CH2:26][N:25](CC6C=CC=CC=6)[CH2:24][CH2:23]5)[CH2:21]4)[C:14]=3[C@H:13]([CH3:47])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)OC(Cl)C>ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:20]4[C:40]5[C:35](=[C:36]([CH2:42][NH:43][CH:44]([CH3:46])[CH3:45])[C:37]([Cl:41])=[CH:38][CH:39]=5)[C:22]5([CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)[CH2:21]4)[C:14]=3[C@H:13]([CH3:47])[CH2:12]2)=[O:9])=[CH:48][CH:49]=1)([O-:3])=[O:2]
Reactant: CC(C)NCc1c(Cl)ccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)C[C@H]2OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: CC(C)NCc1c(Cl)ccc2c1C1(CCNCC1)CN2c1ncnc2c1[C@H](C)C[C@H]2OC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 40.6 %

Procedure:
To a stirred solution of (5R,7R)-4-(1′-benzyl-5-chloro-4-((isopropylamino)methyl)spiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (17 mg, 0.025 mmol) in dichloroethane (0.5 mL) was added 1-chloroethyl carbonochloridate (8.1 μL, 0.075 mmol) at 0° C. The reaction mixture was heated at reflux overnight. After cooling, the solvents were evaporated in vacuo. The residue was dissolved in MeOH (1 mL) and heated at reflux for 1 hour. After cooling, the solvent was evaporated in vacuo. The residue was taken up in DCM, washed with saturated aqueous NaHCO3 solution and brine, dried, and concentrated. The residue was purified by column chromatography (4% 7N ammonia in MeOH/DCM) to give (5R,7R)-4-(5-chloro-4-((isopropylamino)methyl)spiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (6 mg, 41%). LCMS (APCI+) m/z 591, 593 [M+H]+; Rt=2.78 min.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH3:28])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)=[C:21]([CH3:28])[CH:20]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: Cc1cc(Cl)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cc1cc(Cl)ccc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
A mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (200 mg, 0.68 mmol), 4-chloro-2-methylphenylboronic acid (138.72 mg, 0.816 mmol), cesium carbonate (268 mg, 0.816 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25 mg, 0.05 eq) in acetonitrile/water (10 mL, 10:1) was stirred at 130° C. under microwave irradiation for 30 min under nitrogen. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered. The solid was washed with ethyl acetate (20 mL×4). The organic layer was combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to give the desired product (94.6 mg, 41.3%). LCMS (ESI): RT (Min)=1.328, M+H+=336.8, method=A. 1H NMR (400 MHz, DMSO-d6) δ0.95 (s, 1H), 9.16 (s, 1H), 8.49 (s, 1H), 7.99 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.68 (dd, J=1.6, 8.4 Hz, 1H), 7.48-7.34 (m, 3H), 2.28 (s, 3H), 2.07-2.05 (m, 1H), 0.86-0.82 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CNc1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To the suspension of ethyl N-(4-chlorophenyl)-glycinate (10.4 g) in ethanol (4 ml) the solution of NaOH (4 g) in water (40 ml) was added. Upon heating a clear solution is formed, which is refuxed for 0.5 h. The solution is decolorized with activated carbon and filtered while hot. The filtrate is cooled in an ice bath and conc. HCl (5 ml) is added dropwise with stirring (pH 1-2). The precipitate formed is collected by suction filtration and washed with water. After drying in vacuo N-(4-chlorophenyl)-glycine (6.51 g) is obtained as colourless crystals.
Reaction SMILES: [OH:1][C:2]1([CH2:15][N+:16]([O-])=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:16][CH2:15][C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C[N+](=O)[O-])CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Reaction time: 72 h

Procedure:
A mixture of tert-butyl 4-hydroxy-4-(nitromethyl)piperidine-1-carboxylate (20.42 g, 78.4 mmol) and 20% palladium hydroxide on carbon (1.21 g) in ethanol (250 mL) was hydrogenated at 40 psi (2.8×105 Pa) for 3 d on a Parr apparatus. More 20% palladium hydroxide on carbon (1.0 g) was added and the hydrogenation was continued for 2 more days. The mixture was filtered through CELITE filter agent and the filtrate was concentrated to provide tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate, which was concentrated from toluene (200 mL) to remove residual ethanol before use in the next reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C@H:15]([CH3:18])[CH2:16]O.C(OCC)(=O)C.C(N(CC)C(C)C)(C)C>C(#N)C.N1C=CC=CC=1.O>[CH3:16][CH:15]1[CH2:18][N@:14]1[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: C[C@@H](N)CO
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CC1C[N@@]1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: CC1C[N@]1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C

Procedure:
4-Nitrobenzene-1-sulfonyl chloride (6.9 g, 31 mmol) was dissolved in acetonitrile (8 ml) and stirred in an ice bath. A solution of (R)-2-aminopropan-1-ol (1 g, 13.3 mmol) in pyridine (5 ml) was added slowly and the reaction was stirred for 2 h. Ethyl acetate (25 ml) and water (10 ml) were added and the reaction was stirred for 10 min. The layers were separated and the organic layer was washed with 1M citric acid solution twice and with water once. The organic layer was cooled to 10° C. and 7 ml of water was added followed by dropwise addition of N,N-diisopropylethylamine (3.7 ml, 21.3 mmol). After stirring for 1 h the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed twice with 1M citric acid solution and twice with water. Isopropanol (70 ml) was then added and the solvents were evaporated slowly leaving mostly isopropanol. (R)-2-Methyl-1-(4-nitro-benzenesulfonyl)-aziridine 2.2 g (69%) was obtained after crystallization from isopropanol. 1H NMR (300 MHz, CDCl3) δ: 8.40 (d, J=9.1 Hz, 2H), 8.16 (d, J=9.1 Hz, 2H), 2.92-3.04 (m, 1H), 2.74 (d, J=7.2 Hz, 1H), 2.13 (d, J=4.5 Hz, 1H), 1.30 (d, J=5.7 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[C:37]5[C:32](=[CH:33][CH:34]=4)[C:31](=[O:48])[N:30]([CH:27]4[CH2:29][CH2:28]4)[CH2:38]5)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC1Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 120 °C

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.0209 g, 0.0500 mmol), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (0.0194 g, 0.0650 mmol), in 1,4-dioxane (0.30 mL) was stirred at r.t. for 10 min. Potassium carbonate (27.6 mg, 0.200 mmol) in water (0.15 mL) was added. The mixture was degassed and refilled with nitrogen three times. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.5 mg, 0.0030 mmol) was added The mixture was degassed and refilled with nitrogen three times, and heated at 120° C.) (oil bath temperature) for 1 h. After cooling, the mixture was diluted with methanol, and filtered. The filtrate was purified on RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=510.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[CH3:29])[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:25])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]=[N+]=[N-])=[C:13]([O:23][CH3:24])[CH:12]=1>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[CH3:29])[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:25])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH2:20])=[C:13]([O:23][CH3:24])[CH:12]=1
Reactant: COc1cc(CC(=O)NCCOc2ccc(C)c(C)c2)ccc1OCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CC(=O)NCCOc2ccc(C)c(C)c2)ccc1OCCN
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.4 %

Procedure:
1.00 g (2.5 mmol) of N-{2-(3,4-dimethylphenoxy)ethyl}-4-(2-azidoethoxy)-3-methoxyphenylacetamide obtained in step 3 was dissolved in 100 ml of methanol and thereto was added 0.40 g of 10% Pd/C. The mixture was stirred under a hydrogen atmosphere at an ambient temperature for 5 hours. The reaction mixture was passed through a Celite™ layer to remove Pd/C, and the filtrate was concentrated under a reduced pressure to produce a residue, which was recrystallized form dichloromethane/hexane to obtain 0.60 g (yield 64%) of the title compound as a white solid.
Reaction SMILES: [K+].[N:2]1([CH2:8][C:9]([O-:11])=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[C:19]1([C:25]2[CH:30]=[C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:28]=[CH:27][C:26]=2[NH:37][C:38]([C:40]2[NH:41][CH:42]=[C:43]([C:45]#[N:46])[N:44]=2)=[O:39])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:19]1([C:25]2[CH:30]=[C:29]([CH:31]3[CH2:32][CH2:33][N:34]([C:9](=[O:11])[CH2:8][N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)[CH2:35][CH2:36]3)[CH:28]=[CH:27][C:26]=2[NH:37][C:38]([C:40]2[NH:41][CH:42]=[C:43]([C:45]#[N:46])[N:44]=2)=[O:39])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: O=C([O-])CN1CCOCC1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CN4CCOCC4)CC3)cc2C2=CCCCC2)n1
Reaction time: 8 h
Yield: 12.4 %

Procedure:
To a solution of morpholin-4-yl-acetic acid ethyl ester (117 mg, 0.67 mmol) in ethanol (4 mL) was added 6N KOH (110 μL, 0.67 mmol) via syringe and stirring was continued for 3 h. Concentration in vacuo afforded 122 mg (100%) of morpholin-4-yl-acetic acid potassium salt. To a mixture of morpholin-4-yl-acetic acid potassium salt (29 mg, 0.15 mmol), 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (65.1 mg, 0.13 mmol, as prepared in Example 14, step (b)) and PyBroP (93 mg, 0.19 mmol) in CH2Cl2 (4 mL) was added DIEA (51 μL, 0.29 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with CH2Cl2 (50 mL), washed with H2O (2×25 mL), dried (Na2SO4) and concentrated in vacuo. Purification of the crude product by silica gel preparative TLC afforded 8.1 mg (12%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.68-2.04 (m, 5H), 2.20-2.29 (m, 4H), 2.53-2.78 (m, 5H), 3.09-3.23 (m, 6H), 3.35-3.40 (m, 1H), 3.72 (br s, 4H), 4.16-4.22 (m, 1H), 4.73-4.77 (m, 1H), 5.82 (s, 1H), 7.00 (s, 1H), 7.12 (dd, 1H, J=0.6, 8.0 Hz), 7.73 (s, 1H), 8.27 (d, 1H, J=8.1Hz), 9.48 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C28H34N6O3, 503.27 (M+H), found 503.1.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.P([O-])(O)(O)=O.[K+].[O:15]=[CH:16][C@@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])O>>[CH:5]1[N:1]([C@@H:23]2[O:24][C@H:17]([CH2:16][OH:15])[C@@H:19]([OH:20])[C@H:21]2[OH:22])[N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: NC(=O)c1nc[nH]n1
Agent: O=P([O-])(O)O
Agent: [K+]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 20 h

Procedure:
To each suspension was added each 1 ml of an aqueous solution (pH 7.0) containing 20 mM 1,2,4-triazole-3-carboxamide, 20 ml of various ribose donors as shown in Table 10 and 25 mM monopotassium dihydrogen phosphate, and the reaction was carried out at 60° C. for 20 hours. After the reaction, the microbial cells were removed by centrifugation and the supernatant was analyzed to give the results of ribavirin yields as shown in Table 10.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C2C=NN(C)C=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1B(O)O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:18]=2[CH3:17])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Reactant: Cc1ccncc1B(O)O
Product: Cc1ccc(-c2cnccc2C)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using (4-methylpyridin-3-yl)boronic acid. ESI-MS (m/z): 228 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[N:10]1(C(OC(C)(C)C)=O)[CH2:15][CH2:14][CH:13]([C:16]([O-])=O)[CH2:12][CH2:11]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:16]([CH:13]3[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]3)[O:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Product: Clc1ccc2nc(C3CCNCC3)oc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
500 mg 2-amino-5-chlorophenol and 800 mg mono-tert-butyl piperidine-1,4-dicarboxylate are heated to 200° C. in 4 ml polyphosphoric acid for 4 h. After cooling the reaction mixture is combined with ice water and stirred for 30 min. The precipitate is suction filtered, washed with water and dried. 850 mg product are obtained as the phosphate.