Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][C:29]4[CH:34]=CC=CC=4)[CH:24]=3)[C:19]2=[O:35])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:36]1(N=C=N)[CH2:41]CCC[CH2:37]1.CN(C=O)C>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH2:29][CH:34]=[C:36]([CH3:41])[CH3:37])[CH:24]=3)[C:19]2=[O:35])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(N2C(=O)c3ccc(Oc4ccccc4)cc3C2=O)ccc1OCCN1CCCC1
Reactant: N=C=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(N2C(=O)c3ccc(OCC=C(C)C)cc3C2=O)ccc1OCCN1CCCC1

Procedure:
A mixture of this acid (67 mg, 0.27 mmol), 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [Example A4] (67 mg, 0.28 mmol) and N-cyclohexylcarbodiimide resin (1.69 mol. eq./g, 0.46 g, 0.78 mmol) was stirred in a 50:50 mixture of DMF and dichloromethane (1.5 ml) at room temperature under argon for 16 h. The mixture was filtered through filter-aid and the resin washed several times with dichloromethane. The filtrate was evaporated and the crude residue purified by flash chromatography on silica gel eluting with methanol in dichloromethane to yield the title compound as a brown oil;
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([CH2:27][NH:28][CH:29]2[CH2:32][CH:31]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:30]2)[O:18]1.I[CH:46]([CH3:48])[CH3:47]>CC#N.CCOC(C)=O>[NH2:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:25])([CH3:26])[O:24][C@@H:20]2[C@@H:19]([CH2:27][N:28]([CH:46]([CH3:48])[CH3:47])[CH:29]2[CH2:32][CH:31]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[CH2:30]2)[O:18]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
K2CO3 (528.92 mg, 3.83 mmol) was added to a solution of benzyl 3-[3-({[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}amino)cyclobutyl]propanoate (1.00 g, 1.91 mmol) and 2-iodopropane (0.57 ml, 5.74 mmol) in MeCN and stirred at 95° C. in a sealed tube for 18 hours. The reaction mixture was diluted with EtOAc (20 ml), filtered and evaporated to dryness. Purification by silica gel chromatography, eluting with 7N NH3 in MeOH:DCM (1:99-5:95) gave the desired product as a colourless oil, 700 mg (65%); MS (ESI+) for C30H40N6O5 m/z 565.70 [M+H]+; HPLC purity 96% (ret. time, 1.48 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 8.35 (d, J=3.5 Hz, 1H), 7.88 (d, J=3.2 Hz, 1H), 7.44-7.29 (m, 5H), 6.03 (t, J=2.2 Hz, 1H), 5.62-5.42 (m, 3H), 5.10 (d, J=3.3 Hz, 2H), 5.06-4.92 (m, 1H), 4.26 (dt, J=9.9, 3.4 Hz, 1H), 3.46-2.84 (m, 2H), 2.88-2.61 (m, 1H), 2.51 (ddd, J=14.0, 9.1, 7.5 Hz, 1H), 2.33-2.15 (m, 2H), 2.50-2.13 (m, 2H), 2.16-1.74 (m, 4H), 1.60 (s, 3H), 1.43-1.35 (m, 4H), 0.96 (d, J=6.7 Hz, 3H), 0.79 (d, J=6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:6][C:5]([CH:18]=[O:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:34](O)[CH2:35][OH:36]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[O:36][CH2:35][CH2:34][O:19]2)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: COc1cc(OC)cc(-c2cc(C=O)c([N+](=O)[O-])cc2F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(-c2cc(C3OCCO3)c([N+](=O)[O-])cc2F)c1
Temperature: 130 °C
Yield: 89 %

Procedure:
A mixture of 6-fluoro-3′,5′-dimethoxy-4-nitrobiphenyl-3-carbaldehyde (1.7 g, 5.6 mmol) and 4-toluenesulfonic acid (95.8 mg, 0.6 mmol) in 1,2-ethanediol (4.3 mL) and toluene (60 mL) was heated at 130° C. for 3 hours. After that, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed by water (100 mL*3) and brine (100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=8/1 to 5/1) to afford the title compound (1.8 g, 89%) as a yellow solid. MS (ES+) C17H16FNO6 requires: 349, found: 350 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][OH:8].[H-].[Na+].I[CH3:12]>O1CCCC1>[CH3:12][O:8][CH2:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1]
Reactant: CI
Reactant: Cc1ccsc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1sccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.3 g (3-methyl-thiophen-2-yl)-methanol in 65 ml tetrahydrofuran was added 2.73 g sodium hydride 55% in oil and the mixture was stirred at room temperature for 1 h. To ethe resulting mixture was added 4.3 ml iodomethane and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between aqueous potassium hydrogensulfate and ethyl acetate. The phases were separated and the organic phase was washed with water and brine dried over magnesium sulfate dehydrate and purified by distillation (13 mBar 160° C.) to yield 6.5 g of the title compound as light brown oil.
Reaction SMILES: [CH2:1]1[C@H:5]2[C:6](=[O:16])[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[CH3:19][N:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10](=[O:11])[N:4]2[CH2:3][CH2:2][CH2:1][CH:5]2[C:6]1=[O:16]
Reactant: O=C1Nc2ccccc2C(=O)N2CCC[C@@H]12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (S)-(+)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazapine-5,11(10H,11aH)-dione (9.9 g, 45.8 mmol) in DMF (150 ml) at 0° C. was added NaH (2.0 g, 50.4 mmol). The mixture was warmed to room temperature and stirred for 1 h before methyl iodide (8.56 ml, 137 mmol) was added dropwise. After stirring for an additional 1 h, the mixture was dumped into water (1 l) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to a solid which was recrystallized from ethyl acetate-hexane (5.7 g, 54%), m.p. 118-120° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C@:24]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])=[O:30])[CH2:25]2)[CH2:17][CH2:16]1)[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>ClCCl>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C@:24]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[C:35]([O:37][S:56]([CH3:55])(=[O:58])=[O:57])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])=[O:30])[CH2:25]2)[CH2:17][CH2:16]1)[CH3:2]
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(O)ccc4OC)C3)CC2)nc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(OS(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 125.2 %

Procedure:
Treat a stirred solution of 1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-(5-hydroxy-2-methoxy-phenyl)-methanone (0.25 g, 0.22 mmol) and dichloromethane (5 mL) at 0° C. with diisopropylethylamine (0.14 mL, 0.84 mmol) and methane sulfonyl chloride (0.04 mL, 0.5 mmol). Stir the reaction mixture at 0° C. for two hours, dilute with dichloromethane and wash with water. Dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the product by column chromatography (silica gel, elute sequentially with 3% methanol in dichloromethane then with 5% methanol in dichloromethane) and concentrate the appropriate fractions to afford 0.19 g of the title compound, Rf=0.28 (silica gel, 5% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods swell known in the art.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:24][C:2]1[S:1][C:5]2[C:6]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: N#Cc1ccc2c(c1)OCCc1ccsc1-2
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)OCCc1cc(Br)sc1-2
Yield: 62.2 %

Procedure:
A solution of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile (240 mg, 1.05 mmol) in 3 ml of DMF was treated with NBS (206 mg, 1.16 mmol) at room temperature for 15 hours. The reaction mixture was diluted with a large volume of EtOAc and the organic was washed with water and saline and concentrated in vacuo to a solid. This residue was filtered onto celite and purified by MPLC on a 14 gram silica column, eluting with 20-80% EtOAc/heptanes to give 200 mg (62%) of 2-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile as a white powder in high purity as determined by LC/MS.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:8][CH2:9][CH:10]=O>ClCCCl.CC(O)=O.[OH-].[Na+]>[Cl:8][CH2:9][CH2:10][N:5]1[CH2:6][CH2:7][C@H:3]([F:2])[CH2:4]1
Reactant: FC1CCNC1
Reactant: O=CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: F[C@H]1CCN(CCCl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 3-fluoropyrrolidine hydrochloride (0.59 g, 4.7 mmol) in 1,2-dichloroethane (8.2 mL) and AcOH (0.54 mL) was added chloroacetaldehyde (0.74 mL, 4.7 mmol, 50% in H2O solution) and Na(AcO)3BH (3.7 g, 17 mmol). The reaction mixture was stirred at ambient temperature for 1 h, and then the reaction mixture was diluted with 1 N NaOH and extracted with CH2Cl2 (3×50 mL). The organics were washed with brine (2×25 mL), dried (Na2SO4) and concentrated to yield the title compound (0.242 g, 33%) as a red-orange oil: 1H NMR (500 MHz, DMSO-d6) δ 5.24-5.11 (m, 1H), 4.25-4.23 (m, 1H), 3.60 (t, J=7.0 Hz, 2H), 2.95-2.82 (m, 4H), 2.60-2.56 (m, 1H), 2.20-2.04 (m, 2H); ESI MS m/z 152 [M+H]+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:35](=[O:36])[CH:34]=[CH:33][C:32]2[C:37]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:38]([C:40]([NH2:42])=O)[S:39][C:31]1=2.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:35](=[O:36])[CH:34]=[CH:33][C:32]2[C:37]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:38]([C:40](=[S:10])[NH2:42])[S:39][C:31]1=2
Reactant: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2Cl)c1-c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NC(=S)c1sc2c(ccc(=O)n2-c2ccccc2Cl)c1-c1ccccc1
Yield: 38.8 %

Procedure:
To a mixture of Lawesson's reagent (26.3 mg, 0.065 mmol) and the compound of Example 127 (50 mg, 0.13 mmol) was added toluene (10 mL) and the reaction heated at 110° for 1 h. A further portion of Lawesson's reagent (52.6 mg, 0.13 mmol) was added and reaction heated for 6.5 h. The reaction was diluted with DCM, washed with water, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 5–10% EtOAc in DCM) to give the title compound as a yellow solid (10 mg, 20%). δH (MeOH-d4) 7.67 (1H, m), 7.58–7.46 (7H, m), 7.40 (3H, m), 6.48 (1H, d, J 9.6 Hz). LCMS (ES+) RT 3.41 minutes, 397 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.N1C=CC=CC=1>ClCCl>[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
p-Toluenesulfonyl chloride (29.8 g, 157 mmol) was added portionwise to a mixture of tetrahydro-2H-pyran-4-yl-methanol (20.0 g, 172 mmol) and pyridine (25.2 ml, 313 mmol) in dichloromethane (200 ml). The mixture was stirred at room temperature for 17 h, then quenched with aqueous hydrochloric acid (2 M; 100 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2×100 ml). The organic layers were combined and concentrated in vacuo. Recrystallisation from dichloromethane: n-heptane (5:1) afforded toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester. The mother liquors were further purified by silica gel column chromatography eluting with 50% dichloromethane in n-heptane to yield a further quantity of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester (total yield 41.6 g, 154 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]1([CH3:20])[C:12]([C:17](Cl)=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:20])=[O:18]
Reactant: COc1cccc(Cl)c1Cl
Reactant: Cc1ccccc1C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccccc2C)c(Cl)c1Cl

Procedure:
The Friedel-Crafts procedure of Example 24a is repeated with 35.4 g of 2,3-dichloroanisole, 32.4 g of o-toluoyl chloride and 28 g of AlCl3 being combined in 125 ml of 1,2-dichloroethane to yield a product of 2,3-dichloro-4-methoxy-2'-methylbenzophenone.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([I:11])=[C:9]([NH:12][C:13]([CH3:15])=[O:14])[C:8]([I:16])=[C:7]([C:17]([O-:19])=[O:18])[C:6]=1[I:20])=[O:3].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O>[C:13]([NH:12][C:9]1[C:8]([I:16])=[C:7]([C:6]([I:20])=[C:5]([NH:4][C:2](=[O:3])[CH3:1])[C:10]=1[I:11])[C:17]([O:19][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:18])(=[O:14])[CH3:15]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Reactant: CCOC(=O)CCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.6 %

Procedure:
Sodium diatrizoate (16.1 g, 25.3 mmol) was dissolved in 180 ml of dry dimethylformamide and to this solution was added, in one portion, ethyl 6-bromohexanoate (4.5 ml, 25.3 mmol). The reaction mixture was stirred for 12 hr at ambient temperature and then poured into 1.6 1 of ice-water with stirring. The resulting white precipitate was collected by filtration, dissolved in 1:1 ethanol-ethyl acetate and the solution was treated sequentially with magnesium sulfate, decolorizing charcoal and then filtered through a short pad of silica gel. The filtrate was concentrated to dryness and dried to give 16 g (84%) of the desired product. Recrystallization from methanol-water gave analytically pure material, mp 235°-238° C. (decomp. at 275° C.); MS:M+ 756. The 1H-NMR (300 MHz) spectral data was consistent with the desired product. Calculated for C19H23I3N2O6 : C 30.18, H 3.07, I 50.35, N 3.70; Found: C 30.26, H 2.88, I 50.40, N 3.65.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:18])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NCC(C)C)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)CC(C)C)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 5-chloro-3-(isobutyl amino)-2-methylbenzoate (1.0 g, 3.9 mmol) in dry acetonitrile (10 mL), cesium carbonate (2.55 g, 7.8 mmol) and methyl iodide (5.55 g, 39 mmol) were added. The mixture was heated at 80° C. for 12 h. On completion, the mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to the title compound (1.0 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: COc1ccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1

Procedure:
The title compound, MS: m/e=324.8 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-methoxy-benzene boronic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K]>CN(C)C=O>[C:37]1(=[O:47])[N:41]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=2[C:11]([NH:13][C:14]2[CH:32]=[CH:31][C:17]([C:18]([N:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1OCCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1OCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.6 %

Procedure:
A mixture of 1-{4-[2-(6-bromohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (4.00 g), potassium phthalimide (2.02 g) and dimethylformamide (100 ml) is stirred at 100° C. for 5 hours. The reaction mixture is filtered and the filtrate is distilled off. The resulting residue is extracted with ethyl acetate and the organic layer is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane), and recrystallized from methanol/diethyl ether to give 1-{4-[2-(6-phthalimidohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (4.06 g) as white powder, m.p. 145-146.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)O.[ClH:28]>[Pd].C(OCC)(=O)C.CO>[ClH:28].[ClH:28].[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CN(C)CCCC(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)CCCCc1ccc(N2CCNCC2)cc1

Procedure:
Prepared analogously to example A20b) from 4-[4-[4-(dimethyl-amino)-1-hydroxybutyl]phenyl]-1-(phenylmethyl)piperazine by catalytic hydrogenation in the presence of palladium/charcoal and hydrochloric acid in a quantitative yield. Colourless, amorphous substance of Rf 0.37 (eluant: ethyl acetate/methanol 50/50/0.5 v/v/v).
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([C:8]([NH2:10])=[O:9])[C:4]=1[N+:11]([O-:13])=[O:12])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].CS(O[CH:27]1[CH2:30][N:29]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28]1)(=O)=O>O1CCCC1.O>[CH:31]([N:29]1[CH2:30][CH:27]([N:7]2[C:3]([CH2:1][CH3:2])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([C:8]([NH2:10])=[O:9])=[N:6]2)[CH2:28]1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCc1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 30.8 %

Procedure:
5-Ethyl-4-nitro-1H-pyrazole-3-carboxamide (WO 98/49166) (25.0 g, 136 mmol), sodium carbonate (57.6 g, 543 mmol), sodium iodide (40.7 g, 272 mmol) and 1-benzhydryl-3-azetidinyl methanesulfonate (86.2 g, 272 mmol) were suspended in tetrahydrofuran (338 mL) and water (38 mL) and heated under reflux for 5 days. The reaction mixture was then concentrated in vacuo and taken up in ethyl acetate (500 mL) and water (300 mL). The resulting precipitate was filtered, washed with ethyl acetate and water to yield the title compound as a white solid (17 g, 41.9 mmol, 31%): mp 257-260° C.; 1H NMR (400 MHz, DMSO-d6): δ=1.09 (t, 3H, J=7.6 Hz), 2.95 (q, 2H, J=7.3 Hz), 3.43 (t, 2H, J=7.6 Hz), 3.61 (t 2H, J=7.6 Hz), 4.59 (s, 1H), 5.23 (quintet, 1H, J=7.3 Hz), 7.15-7.20 (m, 2H), 7.24-7.31 (m, 4H), 7.43-7.48 (m, 4H), 7.70 (br s, 1H), 7.95 (br s, 1H); LRMS (m/z) (TSP+) 406.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C1CCN2C(=NCCC2)CC1.F[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([N+:31]([O-:33])=[O:32])=[CH:23][CH:22]=1>C(#N)C>[N+:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:22][CH:23]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: Nc1cc(O)ccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a stirred suspension of 2-aminopyridin-4-ol (53.9 g, 489 mmol) in acetonitrile (500 mL) was added DBU (102 mL, 678 mmol) dropwise over 30 min. The resulting solution was stirred at RT for 30 min and was then treated dropwise with a solution of 1-fluoro-4-nitronaphthalene (72.0 g, 377 mmol) in acetonitrile (400 mL) over 50 min. After stirring overnight at RT the reaction was heated at 50° C. for 2 hr. The reaction was removed from the heat, but not cooled and with stirring, treated with water (6×100 mL). The mixture was allowed to cool to RT over 2 hr and was then cooled further to 0° C. The yellow precipitate was collected by filtration and washed sequentially with a mixture of water and acetonitrile (1:1, 2×100 mL) and then with water (500 mL) to give the title compound as a yellow solid (76.0 g, 70%): m/z 283 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:24][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:21])[CH2:19][CH3:20]
Reactant: CI
Reactant: CCC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Temperature: 25 °C

Procedure:
A mixture of 2.52 g of N-[3-(3-methyl-1,2,4-triazolo [4,3-b]pyridazin-6-yl)phenyl]propanamide, 100 ml of dimethylformamide and 0.43 g of sodium hydride (60% in oil) was stirred at room temperature. A 1.53 g portion of methyl iodide in 10 ml of dimethylformamide was added and the procedure of Example 1 was followed, giving 1.15 g of the desired product, mp 150°-152° C.