Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH:2]=C.[Cl:14]Cl.[CH:16]([Cl:19])(Cl)Cl>>[Cl:14][CH:2]([CH2:16][Cl:19])[CH2:1][S:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:5]
Reactant: C=CCS(=O)(=O)Oc1ccccc1
Reactant: ClC(Cl)Cl
Reactant: ClCl
Product: O=S(=O)(CC(Cl)CCl)Oc1ccccc1
Yield: 83.3 %

Procedure:
To a solution of 11.9 g of phenyl 2-propenesulfonate in 80 ml of chloroform was added 7.1 g of chlorine absorbed in 20 ml of chloroform dropwise with stirring below 0°C. After the addition, the mixture was stirred for two hours at room temperature. By distillation of the solvent and fractionation, 22.4 g of phenyl 2,3-dichloropropanesulfonate, B.P. 120°-125°C/0.005 mmHg, was obtained in a yield of 83.3%.
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@H:3]2[O:4][C@@H:2]12.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>N1C=CC=CC=1>[Si:19]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[CH:10]2)[C@@H:2]2[O:4][C@H:3]12)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]2O[C@H]21
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2O[C@@H]21
Reaction time: 3.5 h
Yield: 96 %

Procedure:
To a stirred solution of 9.5 g (38.1 mmol) of 2',3'-anhydroadenosine (Robins, M. J.; Hansske, F; Low, N. H.; Park, J. I. Tetrahedron Lett. 1984, 367-370) in 114 mL of pyridine was added 11.5 g (76.2 mmol) of t-butyldimethylsilyl chloride. After 3.5 h at room temperature, an additional 5.75 g (38.1 mmol) of t-butyldimethylsilyl chloride was added. After a total of 4.25 h, the reaction mixture was diluted into 2 L of water and extracted with 3×500 mL of dichloromethane. The combined dichloromethane extracts were washed with one liter of saturated aqueous sodium bicarbonate, with 3×500 mL of water, and then dried over magnesium sulfate. Concentration under reduced pressure afforded 13.3 g of 5'-O-(t-butyldimethylsilyl)-2',3'-anhydroadenosine. To a stirred solution of 2.0 g (5.50 mmol) of 5'-O-(t-butyldimethylsilyl)-2',3'-anhydroadenosine in 55 mL of THF at 0° C. was added 22 mL (22 mmol) of a 1M solution of lithium triethyl borohydride in THF. The reaction mixture was then allowed to warm to room temperature. After 3 hours, the reaction mixture was recooled to 0° C. and then carefully treated with 4.0 mL of 5% aqueous acetic acid. The resulting mixture was diluted with 150 mL of EtOAc, washed with 3×100 mL of saturated aqueous NaCl, dried over magnesium sulfate, concentrated under reduced pressure, and then coevaporated with three portions of chloroform. Chromatography of the residue on silica gel with a 100:0 to 97:3 chloroform/methanol gradient afforded 1.8 g (90%) of the title compound: colorless glass; Rf =0.10 (silica gel 60 F-254, 0.25 mm, E. Merck (SG), 95:5 CHCl3 :MeOH); [α]D23 -47.8° (c 2.47, CHCl3); IR (CDCl3) 3480, 3415, 3320, 3165, 3125, 2960, 2935, 2860, 1635, 1595, 1575, 1470, 1415, 1330, 1290, 1255, 1210, 1135, 1090, 995 cm-1 ; 1H NMR (300 MHz, CDCl3, TMS=0.00 ppm) δ0.08, 0.09 (2s, 6H, (CH3)2Si), 0.88 (s, 9H, (CH3)3CSi), 2.10 (ddd, 1H, J=13.5 Hz, J'= 6.5 Hz, J"=4.0 Hz, 3'-H), 2.34 (ddd, 1H, J=13.5 Hz, J'=7.5 Hz, J"=6.0 Hz, 3'-H), 3.74 (dd, 1H, J=12.0 Hz, J'=3.0 Hz, 5'-H), 4.05 (dd, 1H, J=12.0 Hz, J'=3.0 Hz), 4.62 (dddd, 1H, J=7.5 Hz, J'=6.5 Hz, J"=J'"=3.0 Hz, 4'-H), 4.70 (ddd, 1H, J=6.0 Hz, J'=4.0 Hz, J"=2.5 Hz, 2'-H), 5.88 (bs, 1H, OH), 6.01 (d, 1H, J=2.5 Hz, 1'-H), 6.15 (bs, 2H, NH2), 8.30, 8.33 (2s, 2H, H-2, H-8); FAB MS, m/z 366 (M+H)+ , 136.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH2:15][O:16][C:17]1([C:29]2[N:30]=[CH:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:33]=2)[CH2:26][CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=[CH:19][C:18]1=2>ClCCl>[CH3:8][S:9]([O:13][CH2:14][CH2:15][O:16][C:17]1([C:29]2[N:30]=[CH:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:33]=2)[C:18]2[C:23](=[CH:22][C:21]([C:27]#[N:28])=[CH:20][CH:19]=2)[CH2:24][CH2:25][CH2:26]1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc2c(c1)CCCC2(OCCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 mmol of triethylamine and 2.0 mmol of methanesulphonyl chloride are added to a solution of 1.0 mmol of 5-(2-hydroxyethoxy)-5-(1-trityl-1H-imidazol-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile in 10 ml of dichloromethane at 0° C. The reaction mixture is stirred at 0° C. for 1 hour, diluted with dichloromethane, washed with 1N HCl, dried with sodium sulphate and evaporated. The crude title compound is identified on the basis of the Rf and used without further purification in the next stage.
Reaction SMILES: CO.[C:3]([O-])(=[S:5])[CH3:4].[K+].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([CH:18](Br)[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].CCCCCCC>O>[C:3]([CH:18]([C:15]1[CH:16]=[CH:17][C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:13][CH:14]=1)[C:19]([O:21][CH3:22])=[O:20])(=[S:5])[CH3:4]
Reactant: CC([O-])=S
Reactant: COC(=O)C(Br)c1ccc(C(C)(C)C)cc1
Agent: [K+]
Solvent: CCCCCCC
Solvent: CO
Solvent: O
Product: COC(=O)C(C(C)=S)c1ccc(C(C)(C)C)cc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a methanol (203 g) solution of potassium thioacetate (70.4 g, 0.616 mol, 1.3 equivalent amounts based on the starting material), a mixed solution of a 33 mass % methanol solution (408.5 g, 0.473 mol) of methyl 2-(4-t-butylphenyl)-2-bromoacetate and methanol (270 g) was dropwise added over a period of 1 hour and 20 minutes, followed by stirring at from 30 to 40° C. for 1 hour. Then, the reaction solution was mixed with heptane (674 g) and water (675 g) and stirred for 20 minutes, followed by liquid separation. The solvent was distilled off from the obtained organic layer under reduced pressure at 40° C. until the total amount became 382 g. The obtained solution was cooled to 30° C. over a period of 1 hour, and 0.13 g of seed crystals were added. Then, the solution was stirred for 1 hour and further cooled to −10° C. over a period of 3 hours. Then, the solution was stirred for 1 hour and subjected to filtration, and the obtained crystals were dried to give the desired product (110.7 g, yield: 83.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[C:4]([F:16])[CH:3]=1.[C:17]1(=O)[CH2:20][CH2:19]C1.C[Si]([C:26]#[N:27])(C)C>C(OCC)(=O)C>[C:26]([C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[C:4]([F:16])[CH:3]=1)([CH3:19])[CH3:17])#[N:27]
Reactant: CN(C)C(=O)CCCc1ccc(N)cc1F
Reactant: O=C1CCC1
Reactant: C[Si](C)(C)C#N
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CCCc1ccc(NC(C)(C)C#N)cc1F
Temperature: 80 °C
Reaction time: 15 h
Yield: 82.4 %

Procedure:
A mixture of 4-(4-Amino-2-fluorophenyl)-N,N-dimethylbutanamide (76) (10 mg, 0.05 mmol), cyclobutanone (6 mg, 0.09 mmol) and trimethylsilyl cyanide (TMSCN, 9 mg, 0.09 mmol) was heated to 80° C. and stirred for 15 h. To the medium was added ethyl acetate (2×20 mL) and then washed with water (2×20 mL). The organic layer was dried over MgSO4 and concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 9:1) to give 4-(4-(2-Cyanopropan-2-ylamino)-2-fluorophenyl)-N,N-dimethylbutanamide (75) (12 mg, 89%): 1H NMR δ 7.04 (dd, 1H, J=8.0, 7.8 Hz), 6.36 (dd, 1H, J=8.0, 2.3 Hz), 6.32 (dd, 1H, J=11.6, 2.3 Hz), 4.08 (br s, 1H), 2.96 (s, 3H), 2.93 (s, 3H), 2.77-2.81 (m, 2H), 2.61 (t, 2H, J=7.4 Hz) 2.35-2.38 (m, 2H), 2.31 (t, 2H, J=7.6 Hz), 2.10-2.37 (m, 2H), 1.87-1.95 (m, 2H).
Reaction SMILES: CN(C)P(=O)(N(C)C)N(C)C.[CH3:12][O-:13].[Na+].C1(C)C=CC=CC=1.[CH3:22][O:23][C:24]1[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=[C:36]([CH3:44])[C:25]=1[C:26]([C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[CH:30][C:29]=1Cl)=[O:27]>O>[CH3:22][O:23][C:24]1[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=[C:36]([CH3:44])[C:25]=1[C:26]([C:28]1[C:29]([O:13][CH3:12])=[CH:30][N:31]=[CH:32][C:33]=1[Cl:34])=[O:27]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cncc2Cl)c(OC)c1OC
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(Cl)cncc2OC)c(OC)c1OC
Yield: 690.4 %

Procedure:
5.0 g (2.8 mmol) of hexamethylphosphoric triamide and 1.1 g (2.1 mmol) of sodium methoxide were added to a toluene (60 ml) solution of 5.0 g (1.4 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3,5-dichloropyridine (compound No. 191), followed by stirring under reflux by heating for 5 hours. After the mixture was cooled, 50 ml of water was added to the mixture to terminate the reaction, and ethyl acetate was added thereto for extraction. The organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 3.4 g (yield 69%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-methoxypyridine (compound No. 244; pale yellow oily substance).
Reaction SMILES: [CH2:1]([NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].C(N([CH2:16][CH3:17])CC)C.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>CN(C1C=CN=CC=1)C>[CH2:1]([NH:10][C:23]([C:19]1[O:18][CH:22]=[CH:16][CH:17]=1)=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:23]([C:19]1[O:18][CH:22]=[CH:21][CH:20]=1)=[O:24]
Reactant: O=C(Cl)c1ccco1
Reactant: NCCCCCCCCN
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Product: O=C(NCCCCCCCCNC(=O)c1ccco1)c1ccco1

Procedure:
The general procedure was carried out using 1,8-octanediamine (10.0 g, 69.3 mmol), triethylamine (14.2 g, 141 mmol), DMAP (0.17 g, 1.35 mmol) and furoyl chloride (19.0 g, 146 mmol). The resulting compound was purified by column chromatography (98:2 DCM:EtOAc), and the product obtained as a white solid (21.5 g/92%).
Reaction SMILES: [CH2:1]([N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]([O:19]C)=O)[C:14]([OH:21])=[C:13]([OH:22])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>CO>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=2)=[O:19])[C:14]([OH:21])=[C:13]([OH:22])[N:12]=1)[C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(CCN(Cc2ccccc2)C(=O)OC(C)(C)C)nc(O)c1O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1)Cc1ccccc1
Temperature: 25 °C

Procedure:
Crude methyl 2-{2-[benzyl(tert-butoxycarbonyl)amino]ethyl}-5,6-dihydroxypyrimidine-4-carboxylate (prepared as described in Step 2) was dissolved in methanol and treated with p-fluorobenzylamine (2.5 equivalents) at 80° C. for 12 hours. The mixture was then cooled to room temperature, volatiles were evaporated and the residue was poured in EtOAc and washed 0.5 N HCl and brine. The organic phase was dried (Na2SO4), filtered and concentrated to a brown solid residue. MS (ES) C26H29FN4O5 requires 496. Found: 497 (M+H+).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][C:12]3[O:13][C:14]4[CH:20]=[CH:19][CH:18]=[C:17](Br)[C:15]=4[CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:22]([Cu])#[N:23].Cl.[N:26]1C2C(=CC=CC=2)C=C[CH:27]=1>>[C:27]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([C:22]#[N:23])=[CH:17][C:15]=4[CH:16]=3)=[CH:8][C:7]=2[CH:2]=1)#[N:26]
Reactant: N#C[Cu]
Reactant: c1ccc2ncccc2c1
Reactant: Brc1cccc2oc(Cc3cc4c(Br)cccc4o3)cc12
Agent: Cl
Product: N#Cc1ccc2oc(Cc3cc4cc(C#N)ccc4o3)cc2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A mixture of bis(6-bromobenzofuran-2-yl)methanone (84) (3.50 g, 8.62 mmol) and CuCN (6.12 g, 69.0 mmol) was heated under reflux in dry quinoline (10 mL) for 2 hours. The hot reaction mixture was poured into 2 M HCl solution and resulting mixture was stirred at 50-70° C. for 1 hour. Olive precipitate was filtered off, dried under high vacuum and suspended into 300 mL chlorobenzene. The mixture was stirred for 1 hour at room temperature, insoluble material was separated, and filtrate was concentrated. A dark solid residue (2 g, 78%) was purified by column chromatography (SiO2, CHCl3) to afford desired product as light yellow crystals (1.62 g, 63%): mp 173-174° C. (CHCl3). 1H NMR (DMSO-d6) δ7.96 (d, J=8.2 Hz, 2H), 7.77 (d, J=7.7 Hz, 2H), 7.46 (tt, J=8.2, 7.7 Hz, 2H), 7.09 (s, 2H), 4.64 (s, 2H). HPLC (method B) tR 7.92 min (100.00 area %). Anal. (C19H10N2O2) C, H, N.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[CH:4][C:5]2[N:9]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[NH:7][C:6]=2[CH:26]=1.C(N(CC)C(C)C)(C)C.[CH3:40][Si:41]([CH3:48])([CH3:47])[CH2:42][CH2:43][O:44][CH2:45]Cl>ClCCl>[Br:1][C:2]1[C:3]([C:27]([F:30])([F:28])[F:29])=[CH:4][C:5]2[N:9]([CH2:45][O:44][CH2:43][CH2:42][Si:41]([CH3:48])([CH3:47])[CH3:40])[C:8]([N:10]3[CH2:11][CH2:12][N:13]([C:16]4[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:26]=1
Reactant: FC(F)(F)c1cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2cc1Br
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2cc(Br)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-5-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (203 mg, 0.41 mmol, Example 89g) in dichloromethane (6 mL) was added N,N-diisopropylethylamine (148 mg, 1.15 mmol) followed by 2-(trimethylsilyl)ethoxymethyl chloride (94 mg,; 0.57 mmol, Aldrich). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with EtOAc/hexane (1:3) to afford the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 624 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:27])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Cl)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:7][CH2:6]1.[Cl-].[Na+].C(Cl)Cl>CC(CC(C)C)=O>[CH3:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:27])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:2]([CH3:3])[CH3:1])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:7][CH2:6]1
Reactant: CNC
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1OCCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1OCCN(C)C
Temperature: 110 °C

Procedure:
40 ml of a 50% aqueous dimethylamine solution was added to a solution of 2 g of N-(cis-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 106) in 40 ml of methylisobutylketone. The solution was reacted for 18 hours by heating heated to 110° C., in a closed system. After reaction, the reaction solution was added with 200 ml of an aqueous sodium chloride solution and 100 ml of methylene chloride, and subjected to extraction. The aqueous layer was extracted twice with 100 ml of methylene chloride. The organic layer obtained was washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 1.6 g of N-(cis-4-methylcyclohexyl)-4-(2-dimethylaminoethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([S:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:8]=[N:9][C:4]=2[CH:3]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([S:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=3)[N:8]=[N:9][C:4]=2[CH:3]=1
Reactant: Oc1ccc(Sc2nnc3cc(Cl)ccc3n2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Sc2nnc3cc(Cl)ccc3n2)cc1
Yield: 79.2 %

Procedure:
A mixture of 4-[(7-chloro-1,2,4-benzotriazin-3-yl)thio]phenol (1.83 g), ethyl 2-bromopropionate (1.37 g), anhydrous potassium carbonate (0.96 g) and methyl ethyl ketone (50 ml) was heated under reflux for a period of 3 hours. The solvent was removed by distillation under reduced pressure and the residue was partitioned between water and dichloromethane. The organic phase was separated, dried (over anhydrous magnesium sulfate) and the solvent was removed by distillation under reduced pressure to give a solid. The crude product was purified by chromatography over silica gel (eluent dichloromethane) to give the title compound (1.95 g) as a crystalline solid, mp 86°-88° C.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.[H-].[Na+].[CH3:14][S:15]([N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20](=O)[CH2:19]1)(=[O:17])=[O:16]>O1CCCC1.O.Cl>[CH3:14][S:15]([N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([CH2:9][C:10]#[N:11])=[CH:19]1)(=[O:16])=[O:17]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CS(=O)(=O)N1CC(=O)c2cccnc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)n1cc(CC#N)c2cccnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
Diethyl(cyanomethyl)phosphonate (0.47 ml, 3.1 mmol) was dissolved in tetrahydrofuran (5 ml) and cooled to 0° C. Sodium hydride (0.12 g, 3.1 mmol) was added portionwise and the reaction was stirred for 10 min. 1-Methanesulfonyl-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-one (0.332 g, 1.57 mmoles) suspended in tetrahydrofuran (3 ml) was added dropwise, whereupon it immediately dissolved. The reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with water and neutralized with 1M hydrochloric acid The aqueous solution was extracted with ethyl acetate. The organic extract was washed with brine, dried (sodium sulfate) and concentrated under reduced pressure. The crude product was chromatographed over silica gel eluting with 50% ethyl acetate in hexane to provide pure (1-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetonitrile (0.30 g, 45%). 1H NMR (CDCl3) δ: 3.61 (3H, s), 3.81 (2H, s), 7.34 (1H, dd, J=4.8 Hz, 7.9 Hz), 8.02 (1H, dd, J=1.6 Hz, 7.9 Hz), 8.54 (1H, dd, J=1.6 Hz, 4.8 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[O:4].[CH:17]([C:20]1[N:25]=[C:24]([O:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH:23]=[C:22]([CH3:34])[N:21]=1)([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][C:24]3[CH:23]=[C:22]([CH3:34])[N:21]=[C:20]([CH:17]([CH3:19])[CH3:18])[N:25]=3)=[CH:33][CH:32]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Reactant: Cc1cc(Oc2ccc(N)cc2)nc(C(C)C)n1
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2ccc(NC(=O)C3C(=O)N(C)C(=O)N(C)C3=O)cc2)nc(C(C)C)n1

Procedure:
3.0 g (0.013 mole) of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid and 3.2 g (0.013 mole) of 4-(2-isopropyl-6-methylpyrimidin-4-yloxy)aniline are suspended in 30 ml of toluene and heated for 18 hours at reflux temperature in an inert gas atmosphere (nitrogen). After cooling, the precipitate is isolated by filtration, washed with alcohol and dried.
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](C)(C)C)=[CH:5][CH:4]=[N:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19](I)[S:20][C:13]=12>CC1C=CC=CC=1C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[S:20][C:13]=12
Reactant: Clc1ccnc2cc(I)sc12
Reactant: Cn1nccc1[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: Cn1nccc1-c1cc2nccc(Cl)c2s1

Procedure:
A mixture of 1-methyl-5-trimethylstannanyl-1H-pyrazole 10a (2.1 g, 8.5 mmole), 7-chloro-2-iodo-thieno[3,2-b]pyridine (2.5 g, 8.5 mmole), tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.4 mmole, 5 mol %) in o-xylene (85 ml was degassed, purged with nitrogen and heated to 120°, which gave an orange solution. After 14 hours the black reaction mixture was diluted with toluene (100 ml) and extracted with 1.2 M HCl (3×60 ml). The combined aqueous layers were washed with toluene (100 ml). The organic layers were discarded and the aqueous layer was treated with NaOH to pH 14. The resultant white solid was collected (1.1 g, 52%): TLC (6% methanol-dichloromethane) Rf 0.8; 1H-NMR (DMSO-d6, 400 MHz) δ 8.70 (1H, d, J=5.3 Hz), 8.00 (1H, s), 7.63 (1H,d, J=5.3 Hz), 7.56 (1H, d, J=2.0 Hz), 6.79 (1H, d, J=2.0 Hz), 4.09 (3H, s). ESIMS m/z 250 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2c(Br)cccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1cccc2c(Br)cccc12
Yield: 63.3 %

Procedure:
A suspension of 1-bromo-5-hydroxy-naphthalene (1.56 g, 7.0 mmol, prepared according to patent WO0146181), K2CO3 (1.45 g, 10.5 mmol), tetrabutylammonium chloride (15 mg, 0.05 mmol) and dimethyl sulfate (1.32 ml, 10.5 mmol) in MeCN was refluxed for 1 hour. After the addition of water, the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were washed with water, dried over MgSO4, filtered and the solvent was removed under reduced to provide 1-bromo-5-methoxy-naphthalene (1.05 g, 64%) as a white solid, MS: m/e=236 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:24]/[CH:25]=[O:26])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(Oc2ncccn2)cc1
Product: O=C/C=C/c1ccc(Oc2ncccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyrimidinyloxy)benzaldehyde (prepared as described in Reference Example 9) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 227 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1>CO.C(Cl)Cl>[CH3:15][C:16]1[N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH:18]=[CH:19][N:20]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound is prepared by hearing 1-bromo-4-nitro-2-trifluoromethyl-benzene and 2-methyl-imidazole between 100-150° C. during 15 h: M+H=272.0; Rf (MeOH/CH2Cl2=1:5): 0.60.