Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:30]([O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1)=[O:34])[CH3:31]>C(Cl)Cl>[CH2:30]([O:32][C:33](=[O:34])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([N:16]([C:12]2[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[CH:15]=[CH:14][N:13]=2)[CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:43])=[CH:37][CH:36]=1)[CH3:31]
Reactant: CC(C)c1ccc(-c2ccnc(NCc3cccs3)n2)cc1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)N(Cc2cccs2)c2nccc(-c3ccc(C(C)C)cc3)n2)cc1
Temperature: 100 °C
Yield: 13.7 %

Procedure:
To a solution of [4-(4-isopropyl-phenyl)-pyrimidin-2-yl]-thiophen-2-ylmethyl-amine (50 mg, 0.16 mmol) in DCM (2 mL) was added triethylamine (33 μL, 0.24 mmol) and 4-(ethoxycarbonyl)phenyl isocyanate (34 mg, 0.18 mmol). The resulting reaction mixture was heated in a CEM Exployer PLS™ microwave at 100° C. for 30 min. After cooling to room temperature the solvent was evaporated. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 9:1 to give 11 mg of 4-{3-[4-(4-Isopropyl-phenyl)-pyrimidin-2-yl}-3-thiophen-2-ylmethyl-ureido}-benzoic acid ethyl ester. LCMS m/z: 502 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17](O)=[O:18])=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[CH3:32].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[CH3:16][C:11]1[NH:12][C:13](=[O:15])[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:8][CH:7]=2)[C:10]=1[C:17]([NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[CH3:32])=[O:18]
Reactant: Cc1n[nH]c2ccc(N)cc12
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(C)c3c2)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.6 %

Procedure:
The product of Example 5, Step 2 (225 mg, 0.75 mmol, 1.00 equiv), 5-amino-3-methylindazole (110 mg, 0.75 mmol, 1.0 equiv), and EDC (172 mg, 0.90 mmol, 1.20 equiv) were suspended in 2.0 mL DMF. Et3N (0.125 mL, 0.90 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) and further purified by reverse-phase HPLC (10-70% CH3CN/H2O—NH4OH to pH 10 over 20 minutes, retention time 11.74 min) to provide 18 mg (6%) of the title compound as a white solid. MS (ES+) m/e 429 [M+H]+
Reaction SMILES: [C:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH3:18][O:19][C:20]1([C:26]2[CH:27]=[C:28]([CH2:32]Br)[CH:29]=[CH:30][CH:31]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CC(N(C)C)=O>[CH3:18][O:19][C:20]1([C:26]2[CH:27]=[C:28]([CH2:32][CH:2]([C:3]([O:5][CH3:6])=[O:4])[C:1]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])[CH:29]=[CH:30][CH:31]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: COC(=O)CC(=O)OCc1ccccc1
Reactant: COC1(c2cccc(CBr)c2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)C(Cc1cccc(C2(OC)CCOCC2)c1)C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 53 %

Procedure:
A solution of benzyl methyl malonate (0.88 g, 4.22 mmol) in 3 mL of anhydrous DMA was added to a suspension of sodium hydride (0.11 g, 4.45 mmol) in 2 mL of anhydrous DMA at 5° C., and the reaction mixture was stirred for 40 min at 5° C. Then 3-[(4-methoxy)tetrahydropyran-4-yl]-α-bromotoluene [prepared as described in U.S. Pat. No. 5,424,320] (1.21 g, 4.24 mmol) was dissolved in 6 mL of anhydrous DMA and added to this solution. The reaction mixture was stirred for 2 h at 5° C., and for 18 h at room temperature. The reaction mixture was quenched with water (100 mL). The aqueous solution was extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, to give 0.93 g (53%) of benzyl methyl 2-[3-[(4-methoxy) tetrahydropyran-4-yl]phenylmethyl]malonate as a clear oil: HRMS: calcd for C24H28O6 413.1964, found 413.1952.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:16][CH:15]=1.[N:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1>C1COCC1>[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]2[S:21][C:22]([C:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)([OH:33])[CH3:32])=[CH:23][N:24]=2)=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccncc1
Reactant: Fc1ccc(-c2nccs2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)nc2)s1
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To a solution of diisopropylamine (0.12 mL, 0.833 mmol) in dry THF (5 mL) was added n-BuLi in hexanes (1.6M, 0.7 mL, 1.111 mmol) slowly at −78° C. The mixture was stirred for 30 min, 2-(6-fluoropyridin-3-yl)thiazole (0.1 g, 0.555 mmol) in THF (5.0 mL) at −78° C. added, and the mixture stirred for 30 min A solution of 1-(pyridin-4-yl)ethanone (0.09 mL, 0.833 mmol) in THF (5.0 mL) was added to reaction mixture, stirred for 2 hours at −78° C. The reaction mixture was quenched with saturated NH4Cl (50 mL) solution and extracted with EtOAc (3×50 mL). The organic layer was washed with water (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by preparative TLC (3% methanol in dichloromethane) to obtain 1-(2-(6-fluoropyridin-3-yl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-white solid (0.035 g, 22% yield) in 99.7% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 8.21 (d, 2H), 7.79 (d, 1H), 7.71 (d, 1H), 7.67 (s, 1H), 7.11 (s, 1H), 6.91 (d 2H), 1.83 (s, 3H); LC-MS m/z calculated for [M+H]+ 302.07. found 302.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2Cl.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][C:18]=1[F:25])[CH3:15]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2[N:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:14][CH3:15])=[C:18]([F:25])[CH:19]=1)[CH3:24]
Reactant: Cc1nc(Cl)c2cc(Br)ccc2n1
Reactant: CCOc1ccc(NC)cc1F
Solvent: CC(C)O
Product: CCOc1ccc(N(C)c2nc(C)nc3ccc(Br)cc23)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
A mixture of 0.21 g (0.82 mmol) of 6-bromo-4-chloro-2-methyl-quinazoline and 0.16 g (0.89 mmol) of (4-ethoxy-3-fluoro-phenyl)-methyl-amine in i-PrOH (20 mL) was stirred at ambient temperature for 18 hours. The precipitate was collected and washed with Et2O to give 0.1 g of the title compound as the HCl salt. 1H NMR (DMSO-d6) δ 8.32-6.8 (6H), 4.23 (q, 2H), 3.72 (s, 3H), 2.73 (s, 3H), 1.39 (t, 3H); LC-MS (ESI+; 391 ([M+H]+)).
Reaction SMILES: CS[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)([CH3:6])[C:4]#[N:5].C[S-].[Na+].[Cl-].[NH4+]>CO>[O:13]([C:9]1[CH:8]=[C:7]([CH:3]([CH3:6])[C:4]#[N:5])[CH:12]=[CH:11][CH:10]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CSC(C)(C#N)c1cccc(Oc2ccccc2)c1
Agent: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
451 mg of alpha-(methylthio)-alpha-(m-phenoxyphenyl)propionitrile was dissolved in 1 ml of anhydrous methanol, and 1.1 ml of a 2.3 M methanol solution of sodium methanethiolate was added. The mixture was stirred at room temperature for 2 hours. An aqueous solution of ammonium chloride (2 g/10 ml) was added, and the mixture was extracted with 10 ml of ether three times. The extract was washed with 15 ml of water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; hexane and methylene chloride) to afford 316 mg (yield 83%) of alpha-(m-phenoxyphenyl)-propionitrile as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[N:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=1.C1COCC1.ClCCl.[NH3:24]>[Cl-].[Na+].O.C(OCC)(=O)C>[Br:7][C:8]1[N:9]=[C:10]([C:13](=[O:15])[NH2:24])[S:11][CH:12]=1
Reactant: N
Reactant: O=C(O)c1nc(Br)cs1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1nc(Br)cs1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Oxalyl dichloride (1.61 ml) was added to 100 ml of a mixed solution composed of 4-bromo-2-carboxythiazole and THF-dichloromethane (2:1), and the mixture was stirred at 60° C. for 2 hr. Under ice cooling, 15 ml of 30% aqueous ammonia was added to the reaction solution, and the mixture was stirred at the same temperature for 30 min. Ethyl acetate (50 ml) and 50 ml of semi-saturated brine were added thereto, followed by separation. The organic layer was then dried over anhydrous magnesium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=40:1) to give 1.36 g of 4-bromo-2-carbamoylthiazole.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].CS(C)=O.[Cl-].[NH2:25][C:26]([NH2:28])=[NH2+:27].[OH-].[Na+]>O>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([N:25]=[C:26]([NH2:28])[NH2:27])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=C(N)N)nn12
Yield: 32.2 %

Procedure:
3.36 g 3-(5-nitro-1-methyl-2-imidazolyl)-6-chloro-s-triazolo[ 4,3-b] pyridazine were dissolved in 30 ml. dimethyl sulfoxide and mixed at 70°C., while stirring, with 3.4 g guanidinium chloride. 5 ml. water were then added thereto, followed by the dropwise addition of 2.4 ml. 1ON aqueous sodium hydroxide solution, whereafter the reaction mixture was further stirred for an hour at 70°C. After cooling and diluting with water, the precipitated crystals were filtered off with suction, washed with water and dried in a vacuum. 2.5 g of crude product were thus obtained which, after recrystallization from 25 ml. dimethyl formamide, with the addition of active charcoal, gave 1.17 g 3-(5-nitro-1-methyl-2-imidazolyl)-6-(diaminomethylene-amino)-s-triazolo [4,3-b] pyridazine in the form of a yellow material which melted, with decomposition, at 278° - 280°C.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]=[C:13]([CH2:15][NH2:16])[O:12][N:11]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:16][CH2:15][C:13]2[O:12][N:11]=[C:10]([C:2]3[O:1][C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[CH:3]=3)[N:14]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: NCc1nc(-c2cc3cnccc3o2)no1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(NCc2nc(-c3cc4cnccc4o3)no2)CC1

Procedure:
Reductive alkylation of C-(3-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-5-yl)-methylamine (Preparation 13) with 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, utilising a procedure similar to that described in Example 30, afforded the title compound: RT=2.15 min; m/z (ES+)=400.1 [M+H]+.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[CH2:6]([CH:9]([C:13]([CH3:15])=[CH2:14])[C:10](=[O:12])[CH3:11])[CH:7]=[CH2:8].C(OO)(=O)C>ClCCl>[CH2:6]([CH:9]([C:13]1([CH3:15])[O:3][CH2:14]1)[C:10](=[O:12])[CH3:11])[CH:7]=[CH2:8]
Reactant: CC(=O)[O-]
Reactant: C=CCC(C(=C)C)C(C)=O
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClCCl
Product: C=CCC(C(C)=O)C1(C)CO1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
2.5 Grams of sodium acetate was added at 30° C. to a mixture of 3-allyl-4-methyl-pent-4-en-2-one (5.0 g) and dichloromethane (100 ml), and then a 9% peracetic acid solution (153 g) was added dropwise thereto over 1 hour. After stirring at 30° C. for 4 hours, the reaction solution was treated in the same manner as in Example 3 to obtain 1.20 g of pure 3-allyl-4-methyl-4,5-epoxy-pentan-2-one.
Reaction SMILES: N[C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[I-:16].[Cs+].II.N(OCCC(C)C)=O>C(Cl)Cl.[Cu]I>[I:16][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: Nc1cc(C(F)(F)F)cc2[nH]c(=O)[nH]c12
Reactant: [I-]
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: ClCCl
Product: O=c1[nH]c2cc(C(F)(F)F)cc(I)c2[nH]1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
(Analogous to the procedure described in Heterocycles, 2001, 55, 461-464). To a solution of 4-amino-6-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one from step (a) above (0.76 g, 3.5 mmol) in 20 mL of DCM was added CsI (0.91 g, 3.5 mmol), I2 (0.44 g, 1.75 mmol), and CuI (0.2 g, 1.06 mmol). To the mixture was added isoamyl nitrite (2.8 mL, Aldrich) and the reaction mixture was heated at 60° C. with stirring for 3 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was diluted with EcOAc (60 mL). The solution was washed with 25% NH4OH (2×30 mL), 5% Na2S2O3 (20 mL) and brine, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography, eluting with 30% EtOAc/hexane to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 329 (M+1)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[C:26]([F:34])[CH:25]=1.CCN(CC)CC>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[C:26]([F:34])[CH:25]=2)[CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3-chloro-phenyl)-pyrrolidin-3-yl]-methyl-amine (2.20 g, 7.31 mmol) in THF (70 ml) was added 4-bromomethyl-2-fluoro-1-trifluoromethyl-benzene (2.25 g, 8.75 mmol) and Et3N (1.21 ml, 8.75 mmol). The reaction mixture was stirred overnight at 40° C., concentrated under vacuo, diluted with EtOAc, washed with H2O. The organic phase was dried over Na2SO4 and the product purified by flash chromatography (SiO2, EtOAc/Heptane 1:3) to afford 2.0 g (57%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:28])[NH:5][C:6](=[O:27])[N:7]([CH:26]=1)[C@@H:8]1[O:25][C@H:12]([CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33]>CN(C=O)C.O.CO>[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][CH2:13][C@H:12]1[O:25][C@@H:8]([N:7]2[CH:26]=[C:3]([CH2:1][CH3:2])[C:4](=[O:28])[NH:5][C:6]2=[O:27])[CH2:9][C@@H:10]1[OH:11]
Reactant: NCc1ccccc1Br
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNCc3ccccc3Br)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
2.5 g of 2'-deoxy-5-ethyl-5'-O-(p-toluenesulphonyl)-uridine were dissolved in 15 ml of DMF and added to 2-bromobenzylamine. The mixture was heated at 80° C. under nitrogen for 5 hours. The solvent was removed by evaporation and the residue was re-evaporated with toluene to give an oil. This was taken up in 20 ml of water/methanol (1:3) and stored in a refrigerator for 1.5 hours. A solid crystallized out and this was filtered off and washed with water/methanol (1:3) to give 0.99 g of 5'-(2-bromobenzylamino)-2',5'-dideoxy-5-ethyluridine, mp 144°-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH2:7]2.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C1COCC1.O.C(N(CC)CC)C>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:28])=[CH:25][CH:24]=1)[CH2:5]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(C(=O)O)cc1)C2
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(C(=O)N3CCOCC3)cc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-[4-(4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzoic acid (3.50 g), morpholine (1.42 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.12 g), 1-hydroxybenzotriazole monohydrate (2.45 g), and triethylamine (2.30 ml) in THF (70 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride and dried. Removal of the solvent in vacuo gave the entitled compound (4.00 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:28][C:29]([NH:31][CH2:32][C:33](=[O:39])[CH2:34][CH2:35][C:36](O)=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:21]([O:28][C:29]([NH:31][CH2:32][C:33](=[O:39])[CH2:34][CH2:35][C:36]([O:18][CH2:17][CH2:16][N:11]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]1[CH2:19][CH3:20])=[O:37])=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)CCC(=O)CNC(=O)OCc1ccccc1
Reactant: CCc1c(OCc2ccccc2)c(=O)ccn1CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCc1c(OCc2ccccc2)c(=O)ccn1CCOC(=O)CCC(=O)CNC(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 86.7 %

Procedure:
4-(Dimethylamino)pyridine (3.3 mg, 0.0274 mmol) was added to a stirred solution of 3-(benzyloxy)-2-ethyl-1-(2-hydroxyethyl)pyridin-4(1H)-one (6) (149 mg, 0.547 mmol), 5-(benzyloxycarbonylamino)-4-oxopentanoic acid (5) (145 mg, 0.547 mmol) and N,N′-dicyclohexylcarbodiimide (118 mg, 0.574 mmol) in dichloromethane (8 mL). After 24 h, the resulting suspension was filtered through cotton wool, eluting with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate then methanol, to give the title compound 7 (247 mg, 87%) as a colourless oil, RF 0.7 (MeOH); δH (300 MHz; CDCl3) 7.46-7.20 (11H, m, Ar and Pyr 6-H), 6.40 (1H, d, J 9.0 Hz, Pyr 5-H), 5.97 (1H, br s, NH), 5.22 (2H, s, PhCH2), 5.09 (2H, s, PhCH2), 4.22 (2H, t, J 6.0 Hz, OCH2CH2), 4.10-3.95 (4H, m, HNCH2 and OCH2CH2), 2.71-2.50 (6H, m, CH3CH2 and C(O)CH2CH2) and 0.99 (3H, t, J 7.0 Hz, CH3) δC (75 MHz; CDCl3) 204.7, 174.3, 172.3, 156.9, 146.2, 139.4, 138.0, 136.8, 129.1, 128.9, 128.8, 128.7, 128.5, 128.4, 128.3, 117.8, 73.3, 67.3, 63.3, 51.5, 50.9, 34.4, 27.9, 19.8 and 13.5.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[BH4-].[Na+].O>S(Cl)(Cl)=O.O1CCOCC1>[OH:14][CH2:13][C:12]1[CH:11]=[C:10]([S:9][C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1cccnc1Sc1cccc(C(=O)O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccnc1Sc1cccc(CO)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
Dissolve 3-(3-cyano-pyridin-2-ylsulfanyl)-benzoic acid (1.50 g, 5.85 mmol) in thionyl chloride (50 mL) and stir. Heat to reflux. After 2 hours, concentrate under reduced pressure to give a residue. Dissolve residue in dioxane (100 μL) and add sodium borohydride (2.21 g, 58.5 mmol). Heat to 50° C. After 2 hours, cool to ambient temperature and add water. Extract with ethyl acetate, combine organic layers, dry with sodium sulfate, filter and concentrate to give the title compound as a yellow oil (1.20 g, 85%): 1H NMR (DMSO-d6) δ 4.54 (d, 2H), 5.30 (t, 1H), 7.37 (dd, 1H), 7.43 (m, 3H), 7.50 (m, 1H), 8.29 (dd, 1H), 8.56 (dd, 1H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:21]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:20]=2)=[CH:27][CH:28]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 7.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonamide (0.15 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether) yielded the title compound as a light brown solid (0.01 g, 2%). MS (ISP) 432.3 [(M+H)+]; mp 281° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1.Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][O:14][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:10][CH:11]=1
Reactant: OCCc1ccc(Oc2ccc(F)c(F)c2)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1ccc(Oc3ccc(F)c(F)c3)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(4-(3,4-difluorophenoxy)phenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.