Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][SH:39]>C(Cl)Cl>[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][S:39][CH:8]1[C:9]2[C:10]([O:22][CH3:23])=[C:11]3[C:16](=[C:17]([OH:21])[C:18]=2[C:19](=[O:20])[N:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=1)[N:15]=[CH:14][CH:13]=[CH:12]3
Reactant: COC(=O)CCS
Reactant: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCSC1c2c(c(O)c3ncccc3c2OC)C(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 20 (215 mg, 0.422 mmol) in CH2Cl2 (4.2 mL) and TFA (98 μL, 1.26 mmol) was added methyl-3-mercaptopropionate (56 μL, 0.506 mmol). The solution was stirred at ambient temperature for 5 hours when LCMS analysis indicated complete conversion of the starting materials to the products. The solution was dried under reduced pressure and azeotroped with CH2Cl2 three times to provide the product 23 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.30-2.38 (m, 4H), 3.63 (s, 3H), 4.04 (s, 3H),4.42 (d, 1H, J=15 Hz), 5.33 (d, 1H, J=15 Hz), 5.49 (s, 1H), 7.05 (t, 2H, J=9 Hz), 7.38 (dd, 2H, J=5, 8 Hz), 7.59 (dd, 1H, J=4,9 Hz), 8.53 (d, 1H, J=8 Hz), 8.91-9.01 (m, 1H); 19F NMR (282.6 MHz, CDCl3) δ 62.6; EI MS (m/z) 457.3 [MH+], 479.2 [M+Na].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[N:28]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Product: Cc1cc(N2C(=O)OC[C@H]2C)ccc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Yield: 57.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (172 mg) described in Preparation Example 132 and (R)-4-methyloxazolidin-2-one (65 mg) described in Preparation Example 25, the title compound (104 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([S:22][CH3:23])[C:17]([NH:18][CH2:19][CH2:20][CH3:21])=[C:13]2[CH:12]=[CH:11][CH:10]=1.[CH:24](=O)[CH2:25][CH3:26].S(=O)(=O)(O)O.[BH4-].[Na+]>O1CCCC1.C(OCC)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([S:22][CH3:23])[C:17]([N:18]([CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCCNc1c(SC)nn2c(-c3ccc(Cl)cc3Cl)cccc12
Reactant: CCC=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)c1c(SC)nn2c(-c3ccc(Cl)cc3Cl)cccc12
Reaction time: 0.5 h

Procedure:
N-[7-(2,4-dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]-N-propylamine (59 mg) was dissolved in tetrahydrofuran (1 mL), and after adding propionaldehyde (0.035 mL) and 3 M aqueous sulfuric acid (0.16 mL), sodium borohydride (12 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (49 mg) was obtained from the n-hexane:ethyl acetate (100:1) fraction as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4]3[C:5]([C:24](=[O:34])[N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[N:26]=3)=[CH:6][N:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.C(N(CC)C(C)C)(C)C.[C:44](Cl)(=[O:46])[CH3:45].C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[C:44]([O:1][C:2]1[C:3]2[C:4]3[C:5]([C:24](=[O:34])[N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[N:26]=3)=[CH:6][N:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1)(=[O:46])[CH3:45]
Reactant: Cc1ccccc1-n1nc2c3c(O)cccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1cccc2c1c1nn(-c3ccccc3C)c(=O)c-1cn2Cc1ccc(-n2cccn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
9-Hydroxy-2-(2-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 724, 56 mg, 0.12 mmol) was dissolved in dichloromethane (2.5 mL), treated with N,N-dimethyl-4-aminopyridine (1.5 mg, 0.013 mmol, 0.1 equiv) and N,N-diisopropylethylamine (0.033 mL, 0.19 mmol, 1.5 equiv) and cooled to 0° C. To the mixture was added acetyl chloride (0.012 mL, 0.17 mmol, 1.4 equiv), and after 15 minutes the mixture was warmed to ambient temperature. After 15 minutes at ambient temperature, the mixture was poured into sodium bicarbonate (5 mL, aqueous saturated) and extracted with dichloromethane (2×15 mL). The combined organic extracts were washed with hydrochloric acid (2×15 mL, 1 N aqueous) and brine (1×10 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.47 (1H, s), 7.91 (1H, d, J=2.6 Hz), 7.73 (1H, d, J=1.7 Hz), 7.72 (2H, d, J=8.6 Hz), 7.47 (1H, t, J=8.2 Hz), 7.44-7.42 (1H, m), 7.34-7.26 (6H, m), 7.17 (1H, d, J=7.9 Hz), 6.47 (1H, dd, J=2.3, 1.9 Hz), 5.45 (2H, s), 2.33 (3H, s), 2.32 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 490.1900 [(M+H)+; calculated for C29H24N5O3: 490.1874].
Reaction SMILES: [CH2:1]([N:28]1[C:32]([CH3:34])([CH3:33])[C:31](=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[C:38]([C:45]([F:48])([F:47])[F:46])[CH:37]=2)[C:29]1=[O:49])[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=2)[C:7]1=[O:27].Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.CCCCCCC.CCOC(C)=O>[CH2:5]([N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=2)[C:7]1=[O:27])[CH2:4][CH2:3][CH2:2][CH2:1][N:28]1[C:32]([CH3:34])([CH3:33])[C:31](=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([C:45]([F:46])([F:47])[F:48])[CH:37]=2)[C:29]1=[O:49]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC1(C)C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)N1CCCCCN1C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)C1(C)C
Temperature: 80 °C
Yield: 78 %

Procedure:
A mixture of the compound of Example 2 (410 mg, 0.58 mmole) and SnCl2, 2H2O (1.32 g, 5.8 mmoles) in AcOEt (10 ml) is heated at 80° C. for 90 minutes. The reaction medium is then cooled down to 0° C. before being poured into a saturated aqueous solution of Na2CO3 (40 ml). The heterogeneous mixture thus obtained is filtered on celite and rinsed with AcOEt (2×50 ml). After decantation, the organic phases are combined, dried over Na2SO4, filtered and the solvent is evaporated off under reduced pressure. The residue obtained is taken up in a mixture of heptane/AcOEt in order to produce a white solid, after filtration, with a yield of 78% (290 mg). Melting point: 108-109° C.
Reaction SMILES: [C:1]1([N:7]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:8]([C:10]2[C:11]3[C:16]([N:17]=[C:18]4[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]4)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]([F:43])([F:42])[S:37]([O:40]C)(=[O:39])=[O:38].[CH3:44]CCCCC>C(Cl)Cl>[F:35][C:36]([F:43])([F:42])[S:37]([O-:40])(=[O:39])=[O:38].[CH3:44][N+:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:8]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[O:9])=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[CH:22]2
Reactant: Cc1ccc(S(=O)(=O)NN(C(=O)c2c3ccccc3nc3ccccc23)c2ccccc2)cc1
Reactant: CCCCCC
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NN(C(=O)c2c3ccccc3[n+](C)c3ccccc23)c2ccccc2)cc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Phenyl-N-(p-toluenesulfonamido)acridine-9-carboxamide (30 mg, 0.0068 mmol) was dissolved in methylene chloride (5 mL) under argon and methyl trifluoromethanesulfonate (77 μL, 0.068 mmol) was added. The solution was stirred overnight at room temperature to yield a yellow precipitate. Hexane was added and the precipitate filtered. Solid was further washed with ether and dried to obtain the product as yellow crystals. 1H NMR (acetone-d6) δ2.58 (s, 3H), 5.02 (s, 3H), 7.02-8.79 (m, 12H) .
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.I.CS[C:21]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)=[NH:22]>C(O)C>[NH3:2].[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[NH:22])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CN1CCC[C@H]1Cn1ccc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN1CCC[C@H]1Cn1ccc2cc(NC(=N)c3cccs3)ccc21
Product: N
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.6 %

Procedure:
compound 103 (65 mg, 0.283 mmol) is charged to a small, argon purged flask fitted with a magnetic stir bar. Anhydrous ethanol (7 mL) and thiophene-2-carboximidothioic acid methyl ester hydroiodide (121.2 mg, 0.425 mmol) are added to the flask and the reaction was stirred under argon at ambient temperature for 17 hours, at which time the solvent was evaporated and the residue was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (MeOH:CH2Cl2, 1:9 then 2M NH3 in MeOH:CH2Cl2, 5:95 to 1:9) to yield compound 104 (30 mg, 31.3%) as a yellow solid. 1H NMR (DMSO-d6) δ 1.47-1.76 (m, 4H), 2.16 (q, 1H, J=8.5 Hz), 2.25 (s, 3H), 2.50-2.59 (m, 1H), 2.92-3.02 (m, 1H), 3.97 (dd, 1H, J=14.1, 7.1 Hz), 4.23 (dd, 1H, J=14.0, 4.8 Hz), 6.23 (brs, 2H), 6.31 (d, 1H, J=3.0 Hz), 6.69 (d, 1H, J=8.3 Hz), 6.98 (s, 1H), 7.08-7.11 (m, 1H), 7.31 (d, 1H, J=3.0 Hz), 7.39 (d, 1H, J=8.6 Hz), 7.58 (d, 1H, J=5.2 Hz), 7.71 (d, 1H, J=3.7 Hz); ESI-MS (m/z, %): 339 (MH+, 100%); ESI-HRMS calculated for C19H23N4S (MH+): 339.1637, observed: 339.1653.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]([CH3:21])[C:10]=2[C:22](=[O:32])[NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:6]=[CH:7][CH:8]=1)#N.C(O)=[O:34]>[Ni]>[CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]([CH3:21])[C:10]=2[C:22](=[O:32])[NH:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:6]=[CH:7][CH:8]=1)=[O:34]
Reactant: O=CO
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1C(=O)NCCN1CCOCC1
Agent: [Ni]
Product: Cc1nc(-c2ccccc2)cc(-c2cccc(C=O)c2)c1C(=O)NCCN1CCOCC1

Procedure:
A mixture of 4-{3-cyanophenyl)-2-methyl-3-(2- morpholinoethylcarbamoyl)-6-phenylpyridine (1.5 g) and Raney's Nickel (1.5 g) in 75% formic acid (40 ml) was refluxed for one hour under stirring. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water and the resultant solution was adjusted to pH 8.0 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to a column chromatography on silica gel and eluted with a mixture of ethyl acetate and diisopropyl ether (8:2 V/V). The eluted solution was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 4-(3-formylphenyl)-2-methyl-3-(2-morpholinoethylcarbamoyl)-6-phenylpyridine (0.8 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:33])[C:30](Cl)=[O:31].C([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])C>CN(C=O)C.C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([N:37]1[CH2:38][C:39]2[C:41](=[CH:3][CH:4]=[CH:5][C:6]=2[O:31][CH2:30][CH2:29][O:33][CH2:2][CH2:1][O:8][CH3:9])[CH2:40]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)N2Cc3cccc(OCCOCCOC)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A solution of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (96 mg, 0.26 mmol) and DMF (1 drop, cat.) in DCM (3 mL) was cooled in ice then treated with oxalyl chloride (112 L, 1.28 mmol). After 2 hours the mixture was concentrated in vacuo then azeotroped with toluene. The resulting acid chloride was dissolved in DCM (4 mL) and added to a solution of 4-[2-(2-methoxy-ethoxy)-ethoxy]-2,3-dihydro-1H-isoindole (0.26 mmol, assuming a quantitative yield from the preceding step (debenzylation procedure C16)) and triethylamine (0.20 mL, 1.4 mmol) in DCM (1 mL). After 2 hours the mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, brine, sodium bicarbonate solution and brine. The organic phase was dried (MgSO4) and concentrated to give a black residue. This was partially purified by flash chromatography on silica (ethyl acetate/petrol gradient, 20-33%) to afford an impure sample of the intermediate (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-{4-[2-(2-methoxy-ethoxy)-ethoxy]-1,3-dihydro-isoindol-2-yl}-methanone.
Reaction SMILES: OCC1CCCCN1.[NH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O:32][C@@H:33]1[C@H:37]([O:38]C(=O)C2C=CC=CC=2)[C@@H:36]([CH2:47][O:48]C(=O)C2C=CC=CC=2)[O:35][C@H:34]1[N:57]1[CH:65]=[N:64][C:63]2[C:58]1=[N:59][C:60]([Cl:67])=[N:61][C:62]=2Cl)(=O)C1C=CC=CC=1.N>>[C:18]1([S:17][CH2:16][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][NH:10]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1.[Cl:67][C:60]1[N:61]=[C:62]([NH:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:63]2[N:64]=[CH:65][N:57]([C:58]=2[N:59]=1)[C@@H:34]1[O:35][C@H:36]([CH2:47][OH:48])[C@@H:37]([OH:38])[C@H:33]1[OH:32]
Reactant: NN1CCCCC1CSc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Agent: OCC1CCCCN1
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4CSc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: c1ccc(SCC2CCCCN2)cc1
Yield: 10.3 %

Procedure:
2-(Phenylthiomethyl)piperidine was prepared from 2-(hydroxymethyl)piperidine by the method described by Kotsuki et al., Tetrahedron Letters, 1991, 32, 4155-4158; otherwise the synthesis proceeded as described in Example 16. 1-Amino-2-(phenylthiomethyl)piperidine (1.4 g, 6.5 mmol) was reacted with 9-(2',3',5'tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 3.25 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-[2-(phenylthiomethyl)-1-piperidinyl]adenosine (0.17 g, 10%) as a foam (a mixture of diastereoisomers); 1H NMR (DMSO-d6) δ 3.51-3.59 (1H, m, H-5'a), 3.62-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.13 (1H, q, H-3'), 4.47-4.56 (1H, m, H-2'), 5.06 (1H, t, 5'-0H), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.82-5.87 (1H, 2d, H-1'), 7.16-7.54 (5H, 2m, Ar--H), 8.41, 8.46 (1H, 2s, H-8), 9.40 (1H, s, N--H).
Reaction SMILES: [C:1]([C:5]1[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>C(#N)C>[C:1]([C:5]1[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]([CH3:12])=[C:9]([O:11][S:24](=[O:26])(=[O:25])[N:23]([CH3:28])[CH3:22])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1O
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(SC#N)c(C(C)(C)C)cc1OS(=O)(=O)N(C)C

Procedure:
To a round bottom flask equipped with a condenser and magnetic stirrer were added 5-tert-butyl-2-methyl-4-thiocyanato-phenol prepared in Example GGG (1.5 g, 6.8 mmol), cesium carbonate (2.44 g, 7.49 mmol), and acetonitrile (30 mL). This slurry was brought to reflux for 15 minutes. Dimethyl sulfamoyl chloride (0.80 mL, 7.49 mmol) was added to the slurry via syringe. The reaction was quenched with brine and extracted with EtOAc; the organic layer was dried (MgSO4) and concentrated. The residue was submitted to column chromatography (7:3 hexane:EtOAc) to give the title compound. 1H NMR (CDCl3) δ 1.46 (s, 9 H), 2.22 (s, 3 H), 3.03 (s, 6 H), 7.30 (s, 1 H), 7.47 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2.Br[CH2:38][C:39]#[N:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:39]([CH2:38][O:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2)#[N:40]
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(OC)cc3)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(OC)cc3)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid [6-hydroxy-5-(4-methoxy-phenyl)-naphthalen-2-ylmethyl]-amide (301 mg, 0.63 mmol), prepared in the previous step, bromoacetonitrile (52 μL, 0.75 mmol) and potassium carbonate (434 mg, 3.14 mmol) in 20 mL of DMF was stirred under nitrogen at room temperature for 21 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-benzofuran-3-carboxylic acid [6-cyanomethoxy-5-(4-methoxy-phenyl)-naphthalen-2-ylmethyl]-amide (325 mg, 99%) as a brown solid, mp 139-142° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14]C3C=C(OC)C(OC)=C(OC)C=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.N.[NH2:28][C:29]1[CH:30]=[C:31]([CH:48]=[CH:49][CH:50]=1)[C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:37][CH:36]=1)=[O:33]>CS(C)=O>[NH2:14][C:10]1[N:11]=[CH:12][N:13]=[C:8]([C:7]2[C:2]([NH:28][C:29]3[CH:30]=[C:31]([CH:48]=[CH:49][CH:50]=3)[C:32]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:39][CH:40]=3)=[O:33])=[N:3][CH:4]=[CH:5][CH:6]=2)[N:9]=1
Reactant: Nc1cccc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1
Reactant: COc1cc(Nc2ncnc(-c3cccnc3Cl)n2)cc(OC)c1OC
Agent: N
Solvent: CS(C)=O
Product: Nc1ncnc(-c2cccnc2Nc2cccc(C(=O)Nc3ccc(Oc4ccccc4)cc3)c2)n1
Reaction time: 8 h

Procedure:
[4-(2-Chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine (Example 2, Step 4) (247 mg, 1.08 mmol) was suspended in a 2 M solution of NH3 in IpOH (3 ml)(Aldrich), and the reaction mixture was stirred overnight in a sealed tube. Concentration, trituration in a small amount of MeOH, and filtration provided a white solid. A portion of this material (97 mg, 0.47 mmol) was mixed with 3-amino-N-(4-phenoxyphenyl)benzamide (320 mg, 0.96 mmol) and DMSO (250 ml), and stirred overnight at 90° C. The dark residue was diluted with IpOH, sonicated, triturated, and then concentrated. Upon dilution with IpOH, a light green solid was isolated by filtration. MS m/z=476.5. [M+H]+. Calc'd for C27H21N7O2: 475.18.
Reaction SMILES: C1COCC1.[C:6]1([CH3:16])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[Mg]Br.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C>CCCCCC.CCOC(C)=O>[CH3:16][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Brc1ccccn1
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2ccccn2)c(C)c1
Reaction time: 24 h
Yield: 76 %

Procedure:
Using a THF solution of mesitylmagnesium bromide (0.974 mL, 0.77 M, 0.75 mmol), 2-bromopyridine (158.0 mg, 1.0 mmol), FeF3.3H2O (5.01 mg, 0.03 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (38.4 mg, 0.09 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 90° C. for 24 hours in the same manner as in Example 2. After performing silica gel column chromatography (EtOAc=10 and 20% in hexane), the above compound was obtained as a yellow liquid (0.150 g, yield=76%, purity=>99% (GC analysis)).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[NH3:12].O>C(O)COCCO>[CH3:1][C@:2]12[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@H:3]1[NH:12][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=12
Reactant: N
Reactant: CC1Cc2ccccc2C1=O
Solvent: OCCOCCO
Solvent: O
Product: C[C@]12Cc3ccccc3[C@H]1Nc1ccccc12
Reaction time: 8 h

Procedure:
The phenylhydrazone of 2-methyl-1-indanone (1.44 g, 6.1 mmol) was heated in diethylene glycol (20 cm3) to near its reflux temperature, until ammonia started to evolve from the air condenser. Heating was continued overnight, or until the ammonia ceased to evolve. The solution was cooled, poured into an equal volume of water, and extracted into diethylether. The ethereal solution was back-extracted with 2M hydrochloric acid, which was made basic with sodium hydroxide, and re-extracted with diethylether. The extracts were evaporated and the residue was purified by column chromatography using silica eluating with 5% EtOAc petrol to yield the title compound as a colourless solid (Rf 30% EtOAc/petrol 0.8). Yield: (28%). M.p. 72° C. 1H NMR (CDCl3) δ: 1.46 (3H, s,), 3.10 (1H, d), 3.30 (1H, dd,), 4.05 (1H, s,), 4.69 (1H, s,), 6.52 (1H, dd,), 6.71 (1H, ddd,), 6.95 (1H, ddd,), 7.0-7.2 (5H, m,).