Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][C:16]1[N:20]([CH2:21][CH2:22][O:23][CH3:24])[N:19]=[N:18][N:17]=1.O.Cl>N1C=CC=CC=1.CC(=O)OCC>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[N:20]([CH2:21][CH2:22][O:23][CH3:24])[N:19]=[N:18][N:17]=1)=[O:5]
Reactant: COCCn1nnnc1N
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COCCn1nnnc1NC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
176 mg (0.75 mmol) of 2-chloro-4-(methylsulfonyl)benzoyl chloride, 145 mg (1.0 mmol) of 5-amino-1-(2-methoxyethyl)tetrazole in 2 ml of pyridine are stirred at 60° C. for 12 h. 0.1 ml of water is then added, the mixture is stirred at 60° C. for 30 min and EA and 2N HCl are added. The organic phase is separated off and washed with 2N HCl and brine, dried over Na2SO4, concentrated and purified by RP—HPLC (acetonitrile/water). Yield 66 mg (23%).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:2][CH2:3][CH2:4][OH:5])=[C:9]([C:14]([F:15])([F:16])[F:17])[CH:8]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: OCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: OCCCOc1ccc(Br)cc1C(F)(F)F

Procedure:
3-Iodopropanol (11.23 g) was added to a mixture of 4-bromo-2-(trifluoromethyl)-phenol (15 g) and potassium carbonate (172 g) in acetonitrile (150 ml). The above mixture was refluxed for 4 hours then diluted with ethyl acetate (500 ml) and water (300 ml). Organic layer was seperated, dried over magnesium sulphate, solvent removed under reduced pressure to give expected product clean enough for use at the next step (18.6 g). 1H NMR (CDCl3) δ: 7.67 (d, 1H), 7.58 (dd, 1H), 6.90 (dd, 1H), 4.18 (t, 2H), 3.87 (q, 2H), 2.07 (tt, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:7]=1
Reactant: OCc1ccccn1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 303 (M+, 52), 302 ([M—H]+, 74), 286 (30), 108 (100), 92 (63), 65 (52).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=O)[CH2:24][C:25]([CH:27]1[CH2:29][CH2:28]1)=O)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.[F:53][C:54]([F:64])([F:63])[C:55]1[CH:60]=[CH:59][C:58]([NH:61][NH2:62])=[CH:57][CH:56]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:61]([C:58]2[CH:57]=[CH:56][C:55]([C:54]([F:63])([F:64])[F:53])=[CH:60][CH:59]=2)[N:62]=[C:25]([CH:27]2[CH2:28][CH2:29]2)[CH:24]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(=O)C1CC1
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-cyclopropyl-3-oxo-propionyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and 4-(trifluoromethyl)phenylhydrazine (CAS Reg. No. 368-90-1) to give the title compound as yellow oil.
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](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=N)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[CH2:47]1[C:55]2[C:50](=[CH:51][C:52]([C:56]3([OH:63])[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]3)=[CH:53][CH:54]=2)[CH2:49][NH:48]1.C(N(CC)CC)C>CN(C=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:48]1[CH2:49][C:50]2[C:55](=[CH:54][CH:53]=[C:52]([C:56]3([OH:63])[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]3)[CH:51]=2)[CH2:47]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(O)(c2ccc3c(c2)CNC3)CC1
Reactant: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(C4(O)CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.58 h
Yield: 68.8 %

Procedure:
2,4-Bis-benzyloxy-5-isopropenyl-benzoic acid (1.65 g, 4.4 mmol), 1-[3-(dimethylamino)propyl)]-3-ethylcarbodiimide hydrochloride (843 mg, 4.4 mmol) and 1-hydroxybenzotriazole (595 mg, 4.4 mmol) were dissolved in DMF (20 mL). After 35 minutes, the solution was added to a suspension of 4-(2,3-dihydro-1H-isoindol-5-yl)-1-methyl-piperidin-4-ol dihydrochloride (1.22 g, 4.0 mmol) in DMF (5 mL) and triethylamine (1.4 mL, 10 mmol). The mixture was stirred for 3 hours then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with a mixture of water (adjusted to pH 14 with 2N sodium hydroxide solution) and brine. The aqueous phase was extracted twice further with ethyl acetate then the combined organic extracts were washed with sodium bicarbonate solution and brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography (gradient elution with 2M methanolic ammonia/dichloromethane, 2% to 10%) to afford the title compound as a brown foam (1.62 g, 69%). 1H NMR (methanol-d4) 7.51-7.14 (14H, m), 6.85 (0.5H, s), 6.84 (0.5H, s), 5.16 (2H, s), 5.15 (2H, s), 5.10-5.08 (1H, m), 5.07-5.05 (1H, m), 4.87 (1H, s), 4.86 (1H, s), 4.61 (2H, br.s), 2.78-2.70 (2H, m), 2.57 (1H, td), 2.54 (1H, td), 2.36 (1.5H, s), 2.34 (1.5H, s), 2.16-2.05 (5H, m including 2.09 (3H, s)), 1.78-1.70 (2H, m). MS: [M+H]+ 589.
Reaction SMILES: C(O)[C:2](N)([CH2:5]O)[CH2:3][OH:4].Cl.[Cl-].[Cl-].[Ca+2].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)[OH:14].C[O:45][C:46]1[CH:47]=[C:48]([CH:55]=[CH:56][C:57](=O)[CH2:58][CH2:59][CH2:60][CH2:61][C:62]2C=C[CH:65]=[CH:64][CH:63]=2)[CH:49]=[C:50](OC)[C:51]=1O>>[CH3:65][CH2:64][CH2:63][CH2:62][CH2:61][CH:60]=[CH:59][CH2:58][CH:57]=[CH:56][CH2:55][CH:48]=[CH:49][CH:50]=[CH:51][CH:46]([OH:45])[CH2:47][CH2:5][CH2:2][C:3]([OH:4])=[O:14]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: NC(CO)(CO)CO
Reactant: COc1cc(C=CC(=O)CCCCc2ccccc2)cc(OC)c1O
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Product: CCCCCC=CCC=CCC=CC=CC(O)CCCC(=O)O
Reaction time: 0.25 h

Procedure:
76 μl of 50 mM Tris-HCl buffer (pH 7.4) containing 2.56 mM of CaCl2 and 2.56 mM of ATP and 20 μl of 5-lipoxygenase sample prepared above were added to 2μl of a solution containing a prescribed amount of the diarylheptanoide derivative (1) prepared in Example 1 in DSMO. The mixture was incubated at 37° C. After 15 minutes, the reaction was terminated with the addition of 200 μl of a 145:55:0.1 mixture of acetonitrile, methanol, and acetic acid. The reaction mixture was centrifuged (1300 rpm, 30 min., 40° C.). The amount of 5-HETE in the supernatant was measured by HPLC (column: Nova-pak 5C18; eluant: a 60:40 acetonitrile:0.05 M KH2PO4 solution with 5 mM trihexyl bromide added; flow rate: 0.8 ml/min.; wavelength: 235 nm). The amount of 5-HETE produced was calculated from the peak area of the 5-HETE. This procedure was repeated twice to determine the 5-lipoxygenase inhibiting activity of the diarylheptanoide derivative (1) from the average production amount of 5-HETE. The results are shown in FIG. 1, which indicates the 5-lipoxygenase inhibiting activity of the diarylheptanoide derivative (1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:9][C:10]1[C:15]2[O:16][C:17]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]([OH:30])=[O:29])=[CH:23][C:18]=3[S:19](=[O:22])(=[O:21])[CH2:20][C:14]=2[CH:13]=[C:12]([S:31](Cl)(=[O:33])=[O:32])[CH:11]=1.O>C(OCC)(=O)C>[Cl:9][C:10]1[C:15]2[O:16][C:17]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]([OH:30])=[O:29])=[CH:23][C:18]=3[S:19](=[O:22])(=[O:21])[CH2:20][C:14]=2[CH:13]=[C:12]([S:31](=[O:32])(=[O:33])[NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Reactant: NCc1cccnc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)NCc3cccnc3)cc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(Aminomethyl)pyridine (0.22 mL, 2.1 mmol) was added to a suspension of Example 49j (0.8 g, 1.8 mmol) in ethyl acetate (40 mL). The reaction mixture was stirred at room temperature for 15 h, treated with water and extracted with butanol. The organic layer was washed with water, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 0.2 g, (20%); 1H NMR (DMSO-d6): δ 2.69 (s, 3H, CH3), 4.18 (d, 2H, CH2), 5.45 (s, 2H, CH2), 7.26 (d, 1H, Ar), 7.6 (d, 1H, Ar), 7.9 (s, 1H, Ar), 8.09 (s, 1H, Ar), 8.18 (s, 1H, Ar), 8.24 (s, 1H, Ar), 8.41 (d, 1H, Ar), 8.47 (s, 1H, Ar), 8.6 (s, 1H, OH).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14].Cl>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Clc1nc2c(Br)cccn2n1
Agent: Cl
Product: CS(=O)(=O)c1cccc(Nc2cccn3nc(Cl)nc23)c1

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) and 3-methanesulfonyl-phenylamine; hydrochloride (245.0 mg, 1.180 mmol) in a manner analogous to Example 2d. Product was isolated as a pale yellow solid (0.268 g, 77%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=6.7 Hz, 1H), 7.87 (s, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.30-7.25 (m, 1H), 7.03 (s, 1H), 6.99 (t, J=6.9 Hz, 1H), 3.09 (s, 3H). MS=323, 325 (MH)+. 109b) N(8)-(3-Methanesulfonyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-phenyl)-amine (75.0 mg, 0.232 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (50.0 mg, 0.261 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.009 g, 8%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=6.2 Hz, 1H), 7.81 (s, 1H), 7.59-7.43 (m, 5H), 7.20 (d, J=8.0 Hz, 1H), 6.97 (d, J=7.5 Hz, 2H), 6.85 (s, 1H), 6.79 (t, J=7.4 Hz, 1H), 6.59 (s, 1H), 3.19-3.14 (m, 4H), 3.07 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=478 (MH)+.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[C:8]([NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21](F)=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[CH2:13][CH2:12]1)=[O:9])#[N:2].C(OC(=O)C1C=C(OCC)C([Cl:49])=C(OCC)C=1)C.ClC1C(OCC)=CC(CN2CCC(NC(=O)C3C=C(OC)C=C(CO)C=3)CC2)=CC=1OCC.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[Cl:49][C:21]1[C:22]([O:24][CH2:25][CH3:26])=[CH:23][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:8](=[O:9])[C:7]3[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:5]([O:4][CH2:3][C:1]#[N:2])[CH:6]=3)[CH2:12][CH2:13]2)=[CH:19][C:20]=1[O:28][CH2:29][CH3:30]
Reactant: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC#N)c3)CC2)cc(OCC)c1F
Agent: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC#N)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 50k), 3-cyanomethoxy-5-methoxy-N-piperidin-4-yl-benzamide (example 245) was reacted with 4-chloro-3,5-diethoxy-benzaldehyde (example 219), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 502.2 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CS([C:26]1[N:31]=[C:30]([N:32]2[C:40]3[C:35](=[C:36]([CH2:41][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])[CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)[CH:29]=[CH:28][N:27]=1)=O>CN1C(=O)CCC1>[CH3:47][O:46][CH2:45][CH2:44][N:42]([CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:35]=1[CH:34]=[CH:33][N:32]2[C:30]1[CH:29]=[CH:28][N:27]=[C:26]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][CH2:3]2)[N:31]=1)[CH3:43]
Reactant: COCCN(C)Cc1cccc2c1ccn2-c1ccnc(S(C)=O)n1
Reactant: CN(C1CCC(N)CC1)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COCCN(C)Cc1cccc2c1ccn2-c1ccnc(NC2CCC(N(C)S(C)(=O)=O)CC2)n1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
N-(4-amino-cyclohexyl)-N-methyl-methanesulfonamide (567 mg, 2.12 mmol) and DIEA (0.44 mL) were stirred in NMP (0.7 mL) at RT for 1 h. [1-(2-Methanesulfinyl-pyrimidin-4-yl)-1H-indol-4-ylmethyl]-(2-methoxyethyl)-methyl-amine (305 mg, 0.85 mmol) in NMP (0.8 mL) was added, and the tube sealed and heated to 130° C. for 1 h. The mixture was then cooled to RT, decanted into water, stirred at RT overnight, and the filtrate filtered off and dried in vacuo, dissolved in DCM/ether, the precipitate filtered off, and the residue concentrated and crystallized from DCM/ether to yield N-{4-[4-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-N-methyl-methanesulfonamide (Compound 203).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][N+:15]([O-])=[CH:14][CH:13]=1.CN(C=[O:23])C>CC(OC(C)=O)=O.CO.O>[CH:1]1([CH2:7][O:8][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:23])[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OCC1CCCCC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: O=c1cc(OCC2CCCCC2)cc[nH]1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of cyclohexylmethanol (1.1 mL, 9.3 mmol) in DMF (8 mL) was added NaH (60% weight dispersion in mineral oil, 0.37 g, 9.3 mmol) in one portion. After the bubbles disappeared, 4-chloropyridine N-oxide (1.0 g, 7.7 mmol) was added. The reaction was stirred at room temperature under Ar until complete. The reaction was quenched with water and the aqueous mixture was extracted with CH2Cl2. The combined organic extracts were washed with H2O and 5% aqueous LiCl and dried over Na2SO4. After filtration and concentration, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give a yellow solid. The yellow solid was suspended in Ac2O (5 mL) and heated at 140° C. for 4 h. The reaction mixture was cooled, diluted with CH3OH/H2O (10 mL, 1:1) and stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give the title compound (0.92 g, 58%) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.21 (d, J=7.2 Hz, 1H), 5.83 (dd, J=7.2, 2.4 Hz, 1H), 5.64 (d, J=2.4 Hz, 1H), 3.72 (d, J=6.0 Hz, 2H), 1.84-1.68 (m, 6H), 1.30-1.01 (m, 5H).
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]1[O:23][CH:21]1[CH3:22]>CO>[OH:23][CH:21]([CH3:22])[CH2:20][C:7]1[CH:19]=[CH:18][C:10]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:18][CH:19]=3)[CH2:6][CH2:5]2)=[CH:9][CH:8]=1
Reactant: CC1CO1
Reactant: CCCCOC(=O)c1ccc(N2CCNCC2)cc1
Solvent: CO
Product: CCCCOC(=O)c1ccc(N2CCN(c3ccc(CC(C)O)cc3)CC2)cc1
Yield: 78 %

Procedure:
A mixture of 13.1 g. (50 mmole) n-butyl 4-(piperazin-1-yl)-benzoate, 2.9 g. (50 mmole) propylene oxide and 6 ml. methanol is stirred for 24 hours at 20° C. The solvent is then evaporated off and the residue is triturated with ligroin to give a yield of 78% of theory of the desired product; m.p. 85°-86° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Sn](C)(C)C)=[CH:17][CH:16]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:36][C@H:35]([CH2:37][N:38]3[CH:42]=[CH:41][N:40]=[N:39]3)[O:34][C:33]2=[O:43])=[CH:28][CH:27]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1>[Si:1]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:36][C@H:35]([CH2:37][N:38]5[CH:42]=[CH:41][N:40]=[N:39]5)[O:34][C:33]4=[O:43])=[CH:30][CH:31]=3)=[CH:17][CH:16]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc([Sn](C)(C)C)cc2)=NO1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)cc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3)cc2)=NO1
Temperature: 90 °C
Yield: 40.9 %

Procedure:
5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-[4-(trimethylstannyl)phenyl]-4,5-dihydroisoxazole (0.5 g, 1.1 mmol), (5R)-3-(4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (0.49 g, 1.32 mmol), and tri-2-furylphosphine (0.051 g, 0.22 mmol) were dissolved in 1,4-dioxane (6 ml) and degassed three times. Tris (dibenzylideneacetone)palladium (0) (0.1 g, 0.11 mmol) was added and the solution was degassed three times. The solution was stirred and heated to 90° C. for 18 hours. The mixture was concentrated in vacuo and then purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent giving 0.24 g desired product.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH:15]=2)[N:9]=1)[NH2:3].O.NN.[ClH:31]>CO>[ClH:31].[ClH:31].[ClH:31].[NH2:17][CH2:16][C:14]1[CH:15]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[CH:11]=[N:12][CH:13]=1
Reactant: NC(N)=Nc1nc(-c2cncc(CN3C(=O)c4ccccc4C3=O)c2)cs1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: NCc1cncc(-c2csc(N=C(N)N)n2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-(5-phthalimidomethylpyridin-3-yl)thiazole (2.47 g) and hydrazine hydrate (0.4 g) in methanol was stirred at room temperature for 5 hours. 3N hydrochloride solution (40 ml) was added slowly and then the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was suspended in water (30 ml) and then the resulting precipitate was removed by filtration. The solvent was removed under reduced pressure to afford 4-(5-aminomethylpyridin-3-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride. NMR (DMSO-d6, δ): 4.31 (2H, q, J=5.2 Hz ), 8.27 (1H, s), 8.44 (4H, s), 8.99 (1H, br), 9.08 (2H, br), 9.52 (1H, br), 9.50 (1H, br)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.I[CH2:15][CH2:16][C@@H:17]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:22][C:19]1([CH3:23])[O:18][C@H:17]([CH2:16][CH2:15][N:8]2[C:9](=[O:12])[CH:10]=[N:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:13][C:7]2=3)[CH2:21][O:20]1
Reactant: CC1(C)OC[C@@H](CCI)O1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ncc(=O)n(CC[C@@H]3COC(C)(C)O3)c2n1
Temperature: 50 °C
Reaction time: 13 h
Yield: 100.1 %

Procedure:
In N,N-dimethylformamide (40 ml) were dissolved 6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.48 g, 8.34 mmol) and (4R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (3.20 g, 12.51 mmol). Cesium carbonate (3.81 g, 11.68 mmol) was added to the solution and the mixture was stirred at 50° C. for 13 hours. After cooling in the air, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 2.55 g (100%) of the title compound in the form of a light yellow oily product.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[C:12]#[N:13].C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C>O1CCCC1>[C:12]([C:11]1[CH:14]=[C:7]([B:20]([OH:21])[OH:19])[CH:8]=[CH:9][C:10]=1[F:15])#[N:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cc(B(O)O)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (5.6 ml, 2.5M in hexanes) was added over a 20 minute period to a solution of 5-bromo-2-fluorobenzonitrile and triisopropylborate (3.46 ml) in tetrahydrofuran (10 ml) at −78° C. The resulting solution was stirred at −78° C. for 30 minutes and then quenched by the addition of a 2M hydrochloric acid (20 ml) and extracted into ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by trituration using diethyl ether: hexane 1:2 to afford the sub-title compound as a solid (1.24 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([OH:20])=[C:14]([O:21][CH3:22])[C:13]=2[Br:23])=[C:4]([Cl:24])[N:3]=1.[C:25]([O-])(=O)C>>[Br:23][C:13]1[C:14]([O:21][CH3:22])=[C:15]([O:20][CH3:25])[C:16]([O:18][CH3:19])=[CH:17][C:12]=1[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:24].[Cl:24][C:4]1[N:3]=[C:2]([NH2:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:25])=[C:14]([O:21][CH3:22])[CH:13]=1
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(Br)c(OC)c1O
Reactant: CC(=O)[O-]
Product: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(Br)c(OC)c1OC
Product: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)cc(OC)c1OC

Procedure:
The title compound was obtained by O-methylation of 4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol (see previous example) according to the general procedure 2.6. The title compound could also be obtained by bromination of 6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine (see example 48) in acetate buffer according to the general procedure 3.1. HPLC Rt: 5.742 min. 1H-NMR (CDCl3): δ 7.85 (s, 1H), 6.66 (s, 1H), 5.32 (s, 2H), 5.11 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.76 (s, 3H).