Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:37][C:38]1[CH:42]=[C:41]([CH2:43][C:44](O)=[O:45])[O:40][N:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]4[O:7][C:3]([CH2:2][NH:1][C:44](=[O:45])[CH2:43][C:41]5[O:40][N:39]=[C:38]([CH3:37])[CH:42]=5)=[N:4][N:5]=4)=[CH:13][CH:12]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Reactant: Cc1cc(CC(=O)O)on1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CC(=O)NCc2nnc(-c3ccc(-c4cc(C(=O)NC5CC5)ccc4C)cc3)o2)on1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4′-[5-(Aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg), EDC (19.8 mg), HOBt (11.7 mg), 3-methyl-5-isoxazoleacetic acid (12.2 mg) and DIPEA (0.02 ml) were mixed in DMF (5 ml). The reaction was stirred at room temperature for 48 hours, the DMF evaporated under vacuum and the residue dissolved in DCM. The solution was washed with water (2×10 ml) and the DCM was evaporated under vacuum. The residue was dissolved in methanol and filtered through a bond-elut (SCX, 2 g). The solvent was evaporated from the filtrate and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate/cyclohexane gradient to give, after evaporation of the solvent, N-cyclopropyl-6-methyl-4′-[5-({[(3-methylisoxazol-5-yl)acetyl]amino}methyl)-1,3,4-oxadiazol-2-yl]-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH3:1][CH:2]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:22]=[CH:21]2)=[CH:16][CH:15]=1)[CH2:3][C:4]([NH:6][C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])=O.[BH4-].[Na+].[Cl-].[Mg+2].[Cl-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl>C(O)C.O.C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][C@@H:4]([NH:6][C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:22]=[CH:21]3)[CH:18]=2)[NH:13]1
Reactant: CCOC(=O)c1cn(-c2ccc(NC(C)CC(=O)NC(=O)OC(C)C)cc2)cn1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3)cn1
Temperature: -15 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of ethyl 1-(4-{[1-methyl-3-({[(1-methylethyl)oxy]carbonyl}amino)-3-oxopropyl]amino}phenyl)-1H-imidazole-4-carboxylate (for a preparation see intermediate 84) (5 g, 12.4 mmol) in ethanol (80 mL) was cooled to −15° C. The solution was treated with sodium borohydride (423 mg, 11.2 mmol) followed by a solution of magnesium chloride (2.78 g, 13.7 mmol) in water (15 mL) maintaining the temperature below −10° C. The mixture was stirred below 0° C. for 1 h then at room temperature for 1 h. The suspension formed was poured onto a stirred mixture of citric acid (4.89 g, 25.5 mmol), HCl (1M in water, 130 mL) and DCM (65 mL). The resulting mixture was stirred vigorously for 30 min and the layers were separated. The aqueous phase was basified by the addition of solid K2CO3 (CARE: gas evolved) and extracted with AcOEt (4×70 mL). The combined organic phases were washed with water then brine, dried over MgSO4 and concentrated in vacuo to give ethyl 1-[(cis)-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazole-4-carboxylate (3.6 g, 9.32 mmol, 75%) as a colourless foam which was used in the next step without further purification.
Reaction SMILES: C[Li].[CH3:3][C:4]1([CH3:13])[O:8][C@@H:7]2[CH:9]=[CH:10][C:11](=[O:12])[C@@H:6]2[O:5]1.[CH2:14]1COCC1.CCOCC>CCOCC.[Cu]I>[CH3:3][C:4]1([CH3:13])[O:8][C@@H:7]2[C@@H:9]([CH3:14])[CH2:10][C:11](=[O:12])[C@@H:6]2[O:5]1
Reactant: C1CCOC1
Reactant: CC1(C)O[C@@H]2C=CC(=O)[C@@H]2O1
Agent: [Cu]I
Agent: [Li]C
Solvent: CCOCC
Product: C[C@H]1CC(=O)[C@@H]2OC(C)(C)O[C@H]12
Temperature: -40 °C

Procedure:
Copper(I) iodide (3.7 g, 19.5 mmol, 5 equiv) was suspended in Et2O (35 mL) and cooled to −40° C. Methyllithium (20.2 mL, 32.3 mmol, 8.3 equiv, 1.6M in THF) was added dropwise over 45 minutes. The mixture was warmed to 0° C. and (3aR,6aR)-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (5-1) (600 mg, 3.9 mmol, 1 equiv) in 1:1 THF/Et2O (20 mL) was added dropwise over 10 minutes. The resulting mixture was stirred warming to ambient temperature over 1 hour. The mixture was then cooled to 0° C., quenched carefully with 25 mL of 15% acetic acid and extracted with EtOAc (3×40 mL). The combined organics were washed with NH4Cl (50 mL), dilute NH4OH (2×50 mL) and water (50 mL), dried over MgSO4, filtered and concentrated to afford (3aR,6S,6aR)-2,2,6-trimethyldihydro-3aH-cyclopenta[d][1,3]dioxol-4(5H)-one (6-1) as a light yellow oil. 1H NMR (500 MHz, CDCl3): δ 4.50 (d, J=5.5 Hz, 1H); 4.23 (d, J=5.0 Hz, 1H); 2.80 (dd, J=18.5, 8.0 Hz, 1H); 2.53 (quin, J=8.0 Hz, 1H); 1.96 (d, J=18.5 Hz, 1H); 1.43 (s, 3H); 1.35 (s, 3H); 1.05 (d, J=7.5 Hz, 3H).
Reaction SMILES: C([OH:5])(C)(C)C.O.CC[C@H]1[C@H]2C[C@H]([C@H](OC3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]([O:41][C@H:42]([C:53]4C=CN=[C:59]5[C:54]=4[CH:55]=[C:56]([O:63]C)[CH:57]=[CH:58]5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH2:34]([O:41][C:42]1[CH:53]=[C:54]([C@H:55]([OH:5])[CH2:56][OH:63])[CH:59]=[CH:58][CH:57]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)O
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: OC[C@@H](O)c1cccc(OCc2ccccc2)c1
Reaction time: 3.5 h

Procedure:
At 0° C. were combined t-butyl alcohol (150 mL), water (150 mL), and AD-mix-α (42 g). Example 1 (6.4 g, 30 mmol) was added and stirred for 3.5 hours. The reaction was refrigerated overnight (15.5 hours), stirred for 8 hours, refrigerated for another 16 hours, and stirred for a further 1 hour. Sodium sulphite (45 g, 36 mmol) was added and the reaction stirred for 2 hours at room temperature. The mixture was poured into ethyl acetate (300 mL) and the aqueous extracted with ethyl acetate (3×150 mL). The organics were dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (ethyl acetate:heptane 9:1) gave the product as a yellow oil, 30 mmol, 100%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=[O:13])[CH:11]=[CH2:12])=[N:7][CH:8]=1.C(O)C.O1CCCC1.[OH:29][CH:30]([C:34]1[S:38][C:37]([CH:39]=[O:40])=[N:36][CH:35]=1)[CH2:31][O:32][CH3:33]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[OH:29][CH:30]([C:34]1[S:38][C:37]([C:39](=[O:40])[CH2:12][CH2:11][C:10](=[O:13])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[N:36][CH:35]=1)[CH2:31][O:32][CH3:33]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Reactant: COCC(O)c1cnc(C=O)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(SC)cn2)s1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a solution of 4-[5-(methylsulfanyl)pyridin-2-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (168 mg) in a mixed solvent of ethanol (1.5 mL) and tetrahydrofuran (1.5 mL) were added 5-(1-hydroxy-2-methoxyethyl)-1,3-thiazole-2-carbaldehyde (119 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (15.5 mg) and triethylamine (32.1 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (103 mg, yield 37%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18](O)=[O:19])=[N:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:54][O:55][C:56]1[N:61]=[CH:60][C:59]([C:62]([NH2:65])([CH3:64])[CH3:63])=[CH:58][CH:57]=1>CN(C=O)C>[O:55]([C:56]1[N:61]=[CH:60][C:59]([C:62]([NH:65][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:19])([CH3:63])[CH3:64])=[CH:58][CH:57]=1)[CH3:54]
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: COc1ccc(C(C)(C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)(C)NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a stirred solution of Intermediate 1 (see Example 1.1, 100 mg, 0.362 mmol), HATU (165 mg, 0.434 mmol) and DIEA (0.126 mL, 0.724 mmol) in DMF was added 2-(6-methoxypyridin-3-yl)propan-2-amine (72.2 mg, 0.434 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound (138 mg) as white solid. LCMS m/z=425.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.6 and 3.5 Hz, 1H), 1.12-1.15 (m, 1H), 1.76 (s, 3H), 1.77 (s, 3H), 2.08-2.12 (m, 1H), 2.22-2.27 (m, 1H), 2.91 (d, J=16.6 Hz, 1H), 3.00 (dd, J=6.2 and 16.5 Hz, 1H), 3.91 (s, 3H), 6.69 (d, J=8.7 Hz, 1H), 7.00-7.07 (m, 2H), 7.14 (s, 1H), 7.62-7.68 (m, 2H), 8.25 (d, J=2.6 Hz, 1H).
Reaction SMILES: [OH:1]C1C=CC=CN=1.CC(C)([O-])C.[K+].ClC1N=N[C:18]([O:21][C:22]2[C:27]([CH3:28])=[C:26]([CH3:29])[CH:25]=[C:24]([CH3:30])[C:23]=2[CH:31](SCC)[CH3:32])=C(OC)C=1>CS(C)=O>[CH3:18][O:21][C:22]1[C:27]([CH3:28])=[C:26]([CH3:29])[CH:25]=[C:24]([CH3:30])[C:23]=1[C:31](=[O:1])[CH3:32]
Reactant: Oc1ccccn1
Reactant: CCSC(C)c1c(C)cc(C)c(C)c1Oc1nnc(Cl)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1c(C)c(C)cc(C)c1C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In dimethylsulfoxide (1 mL) was dissolved 34.0 mg (0.358 mmol) of 2-hydroxypyridine, 41.0 mg (0.366 mmol) of potassium tert-butoxide was added to the solution at room temperature, and the resulting mixture was stirred at room temperature for 20 minutes. To the mixture was added a dimethylsulfoxide (1 mL) solution containing 26.7 mg (0.0728 mmol) of 6-chloro-3-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-methoxypyridazine obtained in (1), and the resulting mixture was stirred at 60° C. After completion of the reaction, the reaction mixture was allowed to stand for cooling, and poured into water. After making the mixture acidic by adding hydrochloric acid to the mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, and washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed. The obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by ethyl acetate) to obtain 6.6 mg (0.019 mmol, Yield: 26%) of 6-chloro-3-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-pyridazinol (Compound No. 2606).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24](=O)[C:25]#[CH:26])[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1.Cl.[OH:31][C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[NH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][N:35]=[C:33]([C:32]([OH:31])([CH3:37])[CH3:36])[N:34]=3)[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Cl)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)n1
Temperature: 75 °C
Yield: 12.1 %

Procedure:
To a solution of 5-chloro-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-6-(6-methyl-pyridin-2-ylmethoxy)-3H-pyrimidin-4-one of Step C (67 mg, 0.16 mmol) in acetonitrile (2 mL) was added 2-hydroxy-2-methylpropionamidine HCl (34 mg, 0.25 mmol) and potassium carbonate (68 mg, 0.49 mmol) and the slurry was heated at 75° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (9.5 mg, 12% yield). MS (M+H): 492; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.14 (s, 3H), 2.21 (s, 3H), 2.60 (s, 3H), 4.79 (s, 1H), 5.61-5.74 (m, 2H), 7.13 (d, J=7.43 Hz, 1H), 7.40 (d, J=7.04 Hz, 1H), 7.54-7.58 (m, 2H), 7.68 (s, 1H), 7.93 (s, 1H), 8.14 (d, J=7.83 Hz, 1H), 8.77 (d, J=5.09 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8].O=CCCCNC(=O)C1C=CC=CC=1>>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)=[O:8]
Reactant: O=C(NCCCCO)N1CC=C(c2ccccc2)CC1
Agent: O=CCCCNC(=O)c1ccccc1
Product: O=CCCCNC(=O)N1CC=C(c2ccccc2)CC1

Procedure:
4-Phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid (4-oxobutyl)amide (62C) is prepared from 62B as described for 1E. The product is obtained in almost quantitative yield.
Reaction SMILES: [OH:1][C:2]1([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[CH:22]=[C:23]([C:25]([NH2:27])=[O:26])[N:24]=[C:17]4[C:16]=3[CH:28]=2)[CH2:8][C@H:7]2[NH:9][C@H:4]([CH2:5][CH2:6]2)[CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)O[C:31](C)=O.[Na+]>CO>[OH:1][C:2]1([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[C:17](=[N:24][C:23]([C:25]([NH2:27])=[O:26])=[CH:22]4)[C:16]=3[CH:28]=2)[CH2:3][CH:4]2[N:9]([CH3:31])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)C[C@H]4CC[C@@H](C3)N4)ccc1OCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN1C2CCC1CC(O)(C#Cc1ccc3c(c1)-c1nc(C(N)=O)cn1CCO3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
In a solution of 10-(((1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)ethynyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (0.15 g, 0.4 mmol) in methanol (20 ml) was added (HCHO)n (144 mg, 4.8 mmol) and NaBH(OAc)3 (260 mg, 1.2 mmol). The solution was stirred for 1 h at room temperature. The reaction mixture was quenched with water and purified by Prep HPLC to afford 9-(3-Hydroxy-8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylethynyl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (13.5 mg, 8.5%). 1H NMR (Methanol-d4, 400 MHz): δ 8.30 (m, 1H), 8.10 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 4.67 (s, 4H), 3.94 (s, 2H), 2.81 (s, 3H), 2.65-2.20 (m, 8H). LCMS [M+H]+=393.0.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].C([O-])([O-])=O.[Cs+].[Cs+].C(#N)C>C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1cccc(CCl)n1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1cccc(COc2ccccc2Br)n1
Temperature: 80 °C

Procedure:
To a sealable 4 mL vial, containing 6-(chloromethyl)picolinonitrile (100 mg, 0.66 mmol) and 2-bromophenol (113 mg, 0.66 mmol), were added Cs2CO3 (320 mg, 0.98 mmol) and acetonitrile (1.7 mL). The vial was then heated at 80° Celsius for 15 hours. The reaction was then diluted with ethyl acetate, filtered through a celite plug and concentrated to dryness. The material was used without further purification. 1H NMR (500 MHz, CDCl3) δ 8.02-7.93 (m, 1H), 7.93-7.85 (m, 1H), 7.65-7.59 (dd, J=7.7, 1.1, 1H), 7.58-7.53 (dd, J=7.9, 1.6, 1H), 7.29-7.22 (m, 1H), 6.93-6.90 (dd, J=8.3, 1.3, 1H), 6.90-6.86 (m, 1H), 5.23 (s, 2H).
Reaction SMILES: [CH3:1][C@@:2]1([OH:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].[C:19]([OH:22])(=O)[CH3:20]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:3]([O:18][C@:2]1([CH3:1])[C@H:6]([O:7][C:6](=[O:7])[CH3:5])[C@@H:5]([CH2:8][O:9][C:19](=[O:22])[CH3:20])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])(=[O:4])[CH3:2]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(OC(C)=O)[C@@H]1OC(C)=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
The preparation of Compound 55 is illustrated in Scheme 5, above. To a solution of 2′-C-methyluridine (1 g) in pyridine (40 ml) were added acetic acid (3 ml) and DMAP. The mixture was stirred at 50° C. during 3 hours, followed by two days at room temperature. Then, the mixture was concentrated and co-evaporated with toluene and the residue purified by silica gel chromatography eluting with 0→10% methanol in dichloromethane to yield 2′,3′,5′-Tri-O-acetyl-2′-C-methyluridine (93%). MS (ESI, EI+) m/z=385.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[CH:12][N:13]([C@@H:15]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:21]([O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[N:14]=[C:9]3[C:10]2=[C:4]([C:5](=O)[NH:6][N:7]=[CH:8]3)[CH:3]=1.N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42]>O1CCOCC1>[NH2:1][C:2]1[C:11]2=[CH:12][N:13]([C@@H:15]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:21]([O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[N:14]=[C:9]3[C:10]2=[C:4]([C:5](=[S:42])[NH:6][N:7]=[CH:8]3)[CH:3]=1
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3c(N)cc4c(=O)[nH]ncc(n2)c34)O[C@@H]1COC(C)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3c(N)cc4c(=S)[nH]ncc(n2)c34)O[C@@H]1COC(C)=O

Procedure:
To a solution of the compound from Step 1 (75 mg, 0.16 mmol) in dioxane (2 mL) is added pyridine (2.5 mL) followed by phosphorus pentasulfide (2 equiv). The reaction mixture is heated at reflux for 24 h. The solvent is evaporated then and the residue washed with pyridine. The combined washings are evaporated and the residue is dissolved in CHCl3 and washed with 10% aq. NaHCO3 and water and dried (Na2SO4). The evaporated residue is used as such for the next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:23]=[CH:22][NH:21][CH:20]=2)=[O:18])=[C:10]([CH3:24])[N:9]=1)(C)(C)C.CC([O-])(C)C.[K+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.C(O)(C(F)(F)F)=O>CN(C1C=CN=CC=1)C.C1COCC1.CO.O.C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:24])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:23]=[CH:22][N:21]([S:40]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=3)(=[O:42])=[O:41])[CH:20]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cc[nH]c1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2ccc(C(=O)NCc3c(C)cc(N)nc3C)c2)cc1
Reaction time: 0.33 h

Procedure:
To a mixture of (4,6-dimethyl-5-{[(1H-pyrrole-3-carbonyl)-amino]-methyl}-pyridin-2-yl)-carbamic acid tert-butyl ester (45 mg, 0.131 mmol) and 4-DMAP (6.38 mg, 0.052 mmol) in dry THF (0.8 ml) was added under argon atmosphere a 1.0 M solution of KOtBu in THF (0.196 ml, 0.196 mmol). The reaction mixture was stirred at it for 20 min. 4-Methoxy-benzenesulfonyl chloride (32.4 mg, 0.157 mmol) was added in one portion and the mixture was stirred for an additional 17 h at rt. The reaction mixture was diluted with MeOH (1 ml) and H2O (1 ml) and the resulting solution was filtered over a PTFE membrane (0.45 um). The filtrate was purified by a preparative LC-MS system using a Waters Sunfire™ C-18 OBD column [150×30 mm, 5 um particle size] and elution at 50 ml/min using the following gradient: 0-1.5 min (90% water containing 0.1% TFA/10% acetonitrile), 1.5-11.5 min (linear gradient from 90% water containing 0.1% TFA/10 acetonitrile to 35% water containing 0.1% TFA/65% acetonitrile), 11.5-12.5 min (linear gradient from 35% water containing 0.1% TFA/65% acetonitrile to 0% water containing 0.1% TFA/100% acetonitrile), 12.5-13.5 min (0% water containing 0.1% TFA/100% acetonitrile). Product collection was triggered by the MS signal and the resulting fractions were pooled and freeze-dried to yield a colorless powder. A 50% solution of TFA in DCM (1.0 ml) was added and the reaction mixture was stirred at rt for 2 h. After evaporation to dryness, the residue was dissolved in a mixture of acetonitrile/water and freeze-dried to yield the title compound. 1H-NMR (DMSO, 400 MHz): 13.52 (br s, 1H), 8.26 (t, 1H), 7.96-7.92 (m, 2H), 7.87-7.86 (m, 1H), 7.68 (br s, 2H), 7.37 (t, 1H), 7.19-7.16 (m, 2H), 6.67-6.66 (m, 1H), 6.63 (s, 1H), 4.26 (d, 2H), 3.85 (s, 3H), 2.50 (s, 3H), 2.37 (s, 3H); LCMS (Method T) RtT=0.88 min; [M+H]+=414.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]O.S(Cl)([Cl:27])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][Cl:27]
Reactant: O=S(Cl)Cl
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Product: Cc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 6, 2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is warmed with thionylchloride to give 2',5-dichloro-2-[3-(chloromethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone of melting point 127°-130° C.