Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]#[C:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BrH:29].C(O)(=O)C>C(Cl)Cl>[Br:29][C:16]1[CH:15]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:18]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:17]=1
Reactant: COc1cc(C(=O)C#CCNS(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Reactant: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(-c2cc(Br)cn2S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(p-toluenesulfonylamino)-1-propinyl 3,4,5-trimethoxyphenyl ketone (4.03 g, 10.0 mmol) in CH2Cl2 (40 ml), a 33% HBr/acetic acid solution (2.63 ml, 15.0 mmol) is added dropwise at 4° C. within 10 min. The reaction mixture is stirred for 1 h at 40° C. and extracted with CH2Cl2 and aqueous 1 N HCl solution. The organic layer is dried over MgSO4, the solvents evaporated, and the residue chromatographed on SiO2 with gradients of hexane/ethyl acetate (4:1 to 3:1) to yield the title compound as a greyish solid. 1H-NMR (300 MHz, CDCl3): 7.49 (d, J=2.0 Hz, 1H); 7.3-7.2; 7.2-7.1 (2m, 4H); 6.38 (s, 2H); 6.17 (d, J=2.0 Hz, 1H); 3.92 (s, 3H); 3.77 (s, 6H); 2.38 (s, 3H).
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[N:26]=[CH:25][O:24][N:23]=1)C1C=CC=CC=1>C(Cl)Cl>[OH:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[N:26]=[CH:25][O:24][N:23]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2ncon2)N1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=C1N(O)[C@@H]2CC[C@@H](c3ncon3)N1C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 127.8 %

Procedure:
BCl3 (1M, 3.34 mL, 3.33 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-2-(1,2,4-oxadiazol-3-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (200 mg, 0.67 mmol) in dry DCM (45 mL) at −78° C. The mixture was stirred at 0° C. for 2 hrs., then it was cooled to −78° C. and quenched with MeOH (8 mL). The solvent was removed by vacuum to give (2S,5R)-6-hydroxy-2-(1,2,4-oxadiazol-3-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (180 mg) as a white solid, which was used directly in the next step. ESI-MS (EI+, m/z): 209 [M−H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>ClCCl.CS(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH:14]=[O:15])[C@@H:10]([CH3:11])[CH2:12][CH3:13])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Yield: 90.3 %

Procedure:
To a suspension of N-Boc-L-isoleucinol (5 g, 23 mmol) in dichloromethane (250 mL) and DMSO (50 mL) at 0° C. was added TEA (10 mL, 73 mmol) followed by slow addition of the solution of sulfur trioxide pyridine complex (11 mL, 69 mmol) in DMSO (50 mL) via syringe. The reaction mixture was concentrated and was diluted with ether (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×200 mL), which was then washed with brine (150 mL), water (150 mL) and NaHCO3 (150 mL) sequentially. The organic layers were dried over MgSO4, filtered and concentrated. The residue was dried on pump to afford ((1S,2S)-1-formyl-2-methyl-butyl)-carbamic acid tert-butyl ester (4.47 g, 90% yield) as light-yellow clear liquid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(N(CC)CC)C.[CH3:28][CH:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1>[CH3:28][CH:29]([N:36]1[CH2:41][CH2:40][N:39]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(c1ccccc1)N1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(c1ccccc1)N1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1

Procedure:
5.8 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 3 ml of triethylamine and 4.2 gm of 1-(α-methyl benzyl)-piperazine (R1 = ##STR10## were stirred in 40 ml of dioxane for 2 hours at 80° C. The dark solution was then evaporated in vacuo, and the residue was taken up in chloroform/water and shaken. The organic phase was then clarified with activated charcoal, dried with sodium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and cyclohexane.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[B:10].C(=O)([O-])[O-].[Na+:15].[Na+]>C(OCC)C.O>[Na+:15].[F:9][C:4]1[CH:3]=[C:2]([B-:10]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)[C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: [B]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Fc1cc(F)cc([B-](c2cc(F)cc(F)c2)(c2cc(F)cc(F)c2)c2cc(F)cc(F)c2)c1
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A dried flask made of Pyrex glass (capacity of 500 ml) provided with a reflux condenser was charged with an inert gas to purge the air from theflask. Then, metallic magnesium (4.65 g) and anhydrous diethyl ether (100 ml) were fed to the flask, and the resulting solution was stirred and cooled by ice bath. A solution prepared separately by adding anhydrous diethylether (50 ml) to 1-bromo-3,5-difluorobenzene (43.52 g) was added dropwise thereto over one hour, and the resulting solution was left still for three hours. At the end of the reaction, a liquid containing boron trifluorideethercomplex (4.542 g) in anhydrous diethyl ether was added dropwise over 40 minutes, and left still for 16 hours with stirring at the room temperature. Then, an aqueous solution of sodium carbonate (30 g) in pure water (100 g) was dropped with 30 minutes. After the solution was kept stirring at the room temperature for 24 hours, the water phase and the organic phase were separated from each other. The separated organic phase was dried with sodium sulfate and filtered; the filtrate was put into an evaporator (oil bath temperature: 70° C.); and diethyl ether was evaporated, thereby obtaining a liver-brown colored solid. The liver-brown colored solid was further purified with silica gel, and a white solid of tetrakis(3,5-difluorophenyl)borate sodium salt (10.3 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH3:30][N:31]1[C:35](=[O:36])[C:34](=[CH:37][C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)[S:33][C:32]1=[S:46]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:42][C:41]3[CH:40]=[CH:39][C:38]([CH:37]=[C:34]4[S:33][C:32](=[S:46])[N:31]([CH3:30])[C:35]4=[O:36])=[CH:45][CH:44]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CN1C(=O)C(=Cc2ccc(C=O)cc2)SC1=S
Product: CN1C(=O)C(=Cc2ccc(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)SC1=S

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4-(3-methyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 637.9.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[F:18][C:19]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:20]=1[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[F:18][C:19]1[CH:34]=[C:33]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:32]=[CH:31][C:20]=1[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Yield: 66.7 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.5 g, 4.8 mmol) was reacted with tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate (2.6 g, 7.3 mmol) to afford the desired product (1.5 g, 65%) as a brown solid: ESI MS m/z 469 [C25H25FN2O4S+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:2]1.Cl[C:15]1[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:16]=1.C(N(CC)CC)C>O1CCCC1>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:3]2[O:4][CH2:5][CH2:6][N:1]([C:15]3[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[N:16]=3)[CH2:2]2)=[CH:8][CH:9]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: Nc1ccc([C@H]2CNCCO2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H](c3ccc(N)cc3)C2)nc(-c2ccncc2)cc1=O
Yield: 54.3 %

Procedure:
A solution of 4-((2S)-morpholin-2-yl)phenylamine (0.17 g, 0.95 mmol), 2-chloro-3-methyl-4-oxo-6-(pyridin-4-yl)-3,4-dihydropyrimidine (0.17 g, 0.76 mmol), and triethylamine (0.25 g, 2.85 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for one hour. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to afford 2-[(2S)-2-(4-aminophenyl)morpholin-4-yl]-3-methyl-6-(pyridin-4-yl)-pyrimidin-4(3H)-one (0.15 g, 54%) as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[S:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: ClCc1csc(-c2ccccc2)n1
Product: c1ccc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)cs2)cc1
Yield: 91 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 4-chloromethyl-2-phenylthiazole to give 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-phenylthiazole. The yield was 91%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 93-94° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH:41][CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[N:29][CH:28]=[N:27]4)=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:35][CH:34]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-n2cncn2)cc1)N1CCC(NCCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A catalytic amount of p-toluenesulfonic acid was added to a solution of 0.45 g of 4-oxo-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine and 0.39 g of 2-(4-chlorophenyl)ethylamine in 10 ml of toluene. The mixture was refluxed by heating, for 5 hours while removing the generated water using a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure. To the residue was added 10 ml of ethanol. Thereto was added 70 mg of sodium borohydride at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was made acidic with cocentrated hydrochloric acid and then concentrated under reduced pressure. To the residue was added ice water. The mixture was made basic with an aqueous sodium hydroxide solution and extracted with two 30-ml portions of ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution in this order, dried with sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluant: methylene chloride/methanol=25/1) and then recrystallized from ethyl acetate to obtain 4-(2-(4-chlorophenyl)ethylamino]-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:22][C:21]([CH3:23])=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[NH:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:25]([C:34]([OH:36])=O)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CO.C(O)(C(F)(F)F)=O.[Pd]>[C:40]([O:39][C:37](=[O:38])[NH:24][CH:25]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:34]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:22][C:21]([CH3:23])=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:36])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: Cc1cc2ncnc(N3CCN(Cc4ccccc4)CC3)c2s1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc2ncnc(N3CCN(C(=O)C(Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c2s1
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To a solution of 4-(4-Benzyl-piperazin-1-yl)-6-methylthieno[3,2-d]pyrimidine (65 mg, 0.20 mmol) in MeOH (10 mL) was added Pd/C (10%, 20 mg) and two drop of TFA. The mixture was stirred under H2 balloon for 4 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in DCM (6 mL) and TEA (2 mL), then Boc-D-Phe(4-Cl)—OH (59 mg, 0.20 mmol) was added, followed by HOBT (50 mg, 0.37 mmol) and EDCI (74 mg, 0.39 mmol). The mixture was stirred at room temperature for 12 hours. The solvent was removed and the residue was subject to chromatography on silica gel to give the product {1-(4-chlorobenzyl)-2-[4-(6-methylthieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (60 mg, 59%). 1H NMR (CDCl3, 400 Hz) δ 8.54 (s, 1H), 7.28-7.26 (d, J=7.2 Hz, 2H), 7.17-7.15 (d, J=8.4 Hz, 2H), 7.08 (s, 1H), 5.37-5.35 9d, J=8.8 Hz, 1H), 4.86-4.84 (m, 1H), 3.87-3.57 (m, 7H), 3.24-3.22 (m, 1H), 3.00-2.98 (d, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.43 (s, 9H). MS (ESI+) [M+H]+ 516.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:9]([N:6]1[CH2:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH2:4][CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: CCc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCC1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
A solution of 4-ethylpyridine (3.0 g, 28 mmol) in anhydrous dimethylformamide (10 ml) was treated with benzyl bromide (3.7 ml, 31 mmol) and the mixture was stirred at room temperature for two hours. The reaction mixture was diluted with absolute ethanol (60 ml), treated with sodium borohydride (1.3 g, 35 mmol) and stirred at reflux for one hour. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed with 1:1 hexane/ethyl acetate as eluant to give the title compound (1.92 g, 34% over two steps) as a colourless oil; δH (CDCl3) 1.00 (3H, t, J 7.5 Hz, CH2CH3), 1.94-2.12 (4H, m, CH2CH3 and tetrahydropyridinyl CH2), 2.55 (2H, t, J 6.3 Hz, tetrahydropyridinyl CH2), 2.90-3.00 (2H, m, tetrahydropyridinyl CH2), 3.58 (2H, s, PhCH2N), 5.32-5.40 (1H, m, tetrahydropyridinyl 5-H), and 7.20-7.40 (5H, m, ArH); m/z (CI+, NH3) 202 (M+1)+.
Reaction SMILES: C([N:4]1[C:12]2[CH:7]([N:8](C(=O)C)[CH2:9][N:10](C(=O)C)[C:11]=2Cl)[N:6]([C@@H:20]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]2[OH:22])[CH2:5]1)(=O)C.[CH2:29]([NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH:30]=[CH2:31]>C(O)CCC>[CH2:29]([N:32]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:11]1[C:12]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:20]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH:30]=[CH2:31]
Reactant: CC(=O)N1CN(C(C)=O)C2C(=C1Cl)N(C(C)=O)CN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C=CCNC1CCCCC1
Solvent: CCCCO
Product: C=CCN(c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)C1CCCCC1
Yield: 59 %

Procedure:
10 g. triacetyl-6-chloro-9-(β-D-ribofuranosyl)-purine and 10 g. allyl-cyclohexylamine were heated under reflux for 1 hour in 100 ml. butanol. The butanol was then distilled off in a vacuum, the residue was dissolved in chloroform and the chloroform solution was then shaken out successively with dilute hydrochloric acid, dilute aqueous sodium bicarbonate solution and water. The chloroform solution was then dried over anhydrous sodium sulfate and evaporated to a syrup. This was dissolved in methanol and the solution, after the addition of 5 ml. 1N sodium methylate solution was heated for 10 minutes on a steambath. After cooling, the solution was distilled off to dryness, the residue was dissolved in chloroform and the chloroform solution was washed with water. The organic phase was dried and evaporated and the residue obtained recrystallized from ethanol. 6.1 g. (59% of theory) N(6)-allyl-N(6)-cyclohexyl-adenosine were obtained; m.p. 123° - 125° C.
Reaction SMILES: [CH3:1][C:2](=[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3].[NH2:17][NH2:18].O>C(O)C>[CH2:6]([C:5]1[CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([CH3:3])([CH3:1])[NH:18][N:17]=1)[CH2:7][CH2:8][CH3:9]
Reactant: NN
Reactant: CCCCC(=O)C(=C(C)C)c1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCC1=NNC(C)(C)C1c1ccccc1
Yield: 98.6 %

Procedure:
To a magnetically stirred solution of 2-methyl-3-phenyloct-2-en-4-one (Intermediate III-1) (1.96 gram, 9.07 mmol) in absolute ethanol (15 ml) was added hydrazine.hydrate (0.88 ml, 18.14 mmol) and the resulting solution was heated at reflux temperature for 4 hours under a nitrogen atmosphere. The resulting solution was allowed to attain room temperature, concentrated and taken up in a mixture of MTBE and water. The organic layer was collected, dried over MgSO4, filtered and concentrated to give crude 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole (Intermediate IV-1) (2.06 gram) as an oil. 1H-NMR (400 MHz, CDCl3) δ 0.80-0.89 (m, 6H), 1.23-1.37 (m, 5H), 1.42-1.54 (m, 2H), 2.06-2.35 (m, 2H), 3.52 (s, 1H), 4.90 (br s, 1H), 7.07 (br d, J˜8 Hz, 2H), 7.19-7.38 (m, 3H).
Reaction SMILES: C1(O[C:8](=[S:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=3)[CH2:34][CH2:33]2)=[S:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=S)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=S)N2CCN(c3cccc(Cl)c3)CC2)c(OC)nc1C
Yield: 88 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([NH:11][CH3:12])=[O:10].[Cl:20][C:21]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=S)=[CH:31][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1.C(Cl)CCl>CC#N>[Cl:20][C:21]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[NH:19][C:18]3[CH:17]=[CH:16][C:4]([O:5][C:6]4[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=4)[C:9]([NH:11][CH3:12])=[O:10])=[CH:3][C:2]=3[N:1]=2)=[CH:31][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Reactant: CNC(=O)c1cccc(Oc2ccc(N)c(N)c2)c1
Solvent: CC#N
Solvent: ClCCCl
Product: CNC(=O)c1cccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(3,4-Diamino-phenoxy)-N-methyl-benzamide (Step C, 400 mg, 1.5 mmol, 1.0 eq.) was dissolved in anh. CH3CN (10 mL) and a solution of 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (330 mg, 1.2 mmol, 0.8 eq.) in CH3CN (10 mL) was added dropwise. The reaction was stirred at RT for 2 h. EDC (240 mg, 1.3 mmol, 0.9 eq.) was added, the mixture was heated to 80° C. and stirred for 2 h. The CH3CN was evaporated and the crude compound was dissolved in CH2Cl2, washed with water and sat. NaHCO3 (aq.). The organic layer was dried (MgSO4), filtered and concentrated. Further purification by column chromatography (0-10% EtOH/CH2Cl2, two runs were required) gave pure 3-{2-[4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-1H-benzimidazol-5-yloxy}-N-methyl-benzamide. MS m/z=505.2 (M+H)+; MW Calc'd for C27H29N6O2: 504.20.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[CH:5][NH:4][N:3]=1.[C:9]([O:18]CC)(=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].CC([O-])(C)C.[K+]>C(O)(C)(C)C>[CH2:15]([O:14][C:12]([C:11](=[CH:7][C:6]1[C:2]([CH3:1])=[N:3][NH:4][CH:5]=1)[CH2:10][C:9]([OH:18])=[O:17])=[O:13])[CH3:16]
Reactant: Cc1n[nH]cc1C=O
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(=Cc1c[nH]nc1C)CC(=O)O
Temperature: 80 °C
Yield: 102.4 %

Procedure:
To a solution of 3-methyl-1H-pyrazole-4-carbaldehyde (9 g, 82 mmol) and diethyl succinate (57 g, 327 mmol) in t-butanol (50 mL), a solution of t-BuOK (37.3 g, 245 mmol) in t-butanol (40 mL) was added and the mixture was heated to 80° C. for 4 hours. The mixture was concentrated; the obtained residue was dissolved in water (50 mL), acidified (pH˜2) using 6 N HCl and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with aqueous NaHCO3 (2×50 mL). The combined aqueous layers were acidified (pH˜2) and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layers were washed with saturated aqueous NaCl (25 mL), dried over anhydrous Na2SO4 and concentrated to afford 3-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-4-yl)but-3-enoic acid (20 g, 100%) as gum. 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.65 (s, 1H), 4.3 (t, 2H), 3.65 (s, 2H), 4.4 (s, 3H), 1.3 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8](=O)[CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:20][C:21]1[CH:29]=[C:25]([C:26]([OH:28])=[O:27])[C:24]([OH:30])=[CH:23][CH:22]=1.C(O)(=O)C>O>[C:26]([C:25]1[CH:29]=[C:21]([N:20]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:9]=[C:8]2[C:7]2[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:22]=[CH:23][C:24]=1[OH:30])([OH:28])=[O:27]
Reactant: O=C(CC1CCCCC1=O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccc([N+](=O)[O-])cc3)cc3c2CCCC3)ccc1O

Procedure:
A mixture of 40 g. (0.15 mole) of 2-(p-nitrophenacyl)cyclohexanone, 23 g. (0.15 mole) of 5-aminosalicylic acid and 187 ml. of glacial acetic acid was heated under reflux under nitrogen for 3 3/4 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and concentrated to a red solid which was chromatographed on silica gel. The material eluted with 3% methanol in chloroform was recrystallied from acetonitrile to provide 3.8 g. (7%) of orange crystals, m.p. 241°-242°.