Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:16])[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(c2cccc(Br)c2)COCC(=O)N1

Procedure:
The crude N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (70 g, 230 mmol) was dissolved in tert-butanol (1 l). The solution was treated with portions of potassium tert-butoxide (52 g, 460 mmol). The mixture was refluxed for 30 min, after cooling quenched with water and evaporated. The residue was dissolved in EtOAc (500 ml) and washed with water and brine. The organic phase was dried with Na2SO4 and concentrated in vacuo to yield the crude title compound. The crude product was purified by chromatography on silica gel (PE/EtOAc=20:1 to 1:1) to give the title compound in the form of a grey solid. 1H-NMR (400 MHz, DMSO-d6): 8.66 (s, 1H), 7.60 (s, 1H), 7.48 (d, 1H), 7.44 (d, 1H), 7.34 (t, 1H), 4.02 (s, 2H), 3.92 (d, 1H), 3.68 (d, 1H), 1.38 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[C:9]([O:17][CH3:18])[CH:10]=[C:11]3[CH2:16][CH2:15][CH2:14][C:12]3=2)[CH:7]=[C:6]1[CH3:19].B(Br)(Br)Br.C(=O)([O-])[O-].[Cs+].[Cs+].BrC[C:36]([O:38][CH3:39])=[O:37]>C(Cl)Cl.CO.C(=O)(O)[O-].[Na+]>[CH3:39][O:38][C:36](=[O:37])[CH2:18][O:17][C:9]1[CH:10]=[C:11]2[CH2:16][CH2:15][CH2:14][C:12]2=[C:13]2[C:8]=1[CH:7]=[C:6]([CH3:19])[N:5]2[CH2:4][C:3]1[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=1[Br:1]
Reactant: COc1cc2c(c3c1cc(C)n3Cc1ccccc1Br)CCC2
Reactant: COC(=O)CBr
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)COc1cc2c(c3c1cc(C)n3Cc1ccccc1Br)CCC2
Temperature: -10 °C
Yield: 82.8 %

Procedure:
A solution of 1-(2-bromobenzyl)-2-methyl-4-methoxy-1,6,7,8-tetrahydrocyclopent[g]indole (1.28 g, 3.40 mmol) in methylene chloride (20 mL) was cooled in an ice/methanol bath and treated with boron tribromide (0.65 mL, 6.9 mmol). The mixture was warmed to −10° C. over 1.5 h then diluted with methanol (2 mL) and excess saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and extracted with a fresh portion of methylene chloride. The combined methylene chloride layers were washed once with water, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through a pad of silica gel. The filtrate was concentrated in vacuo and the residue dissolved in N,N-dimethylformamide (5 mL) and treated with cesium carbonate (1.00 g, 3.06 mmol) and methyl bromoacetate (0.29 mL, 3.1 mmol) at room temperature for 20 h. The mixture was concentrated in vacuo via vacuum transfer and the residue dissolved in methylene chloride and filtered through a pad of silica gel. The filtrate was concentrated in vacuo. Chromatography (silica gel, methylene chloride/hexanes) of the residue provided 1.10 g (84%) of the title compound. 1H NMR (CDCl3) δ 7.59 (m, 1H), 7.07 (m, 2H), 6.47 (s, 1H), 6.33 (s, 1H), 6.18 (m, 1H), 5.35 (bs, 2H), 4.74 (s, 3H), 3.80 (s, 3H), 2.86 (m, 4H), 2.26 (s, 3H), 1.99 (quintet, J=7.3 Hz, 2H); MS ES+ m/e 428, 430 (p+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][CH2:17][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=[CH:8]3)[CH2:5][CH2:6]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: c1ccc2c(c1)ncn2C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(OCCCN2CCC(n3cnc4ccccc43)CC2)cc1
Temperature: 90 °C
Yield: 66.6 %

Procedure:
To a stirred solution of 1-piperidin-4-yl-1H-benzimidazole (4.02 g) and 1-(3-chloropropoxy)-4-fluorobenzene (4.16 g) in DMF (50 ml) was added K2CO3 (4.1 g) and KI (0.2 g). The mixture was heated at 90° C. for 2 h, and then allowed to cool to rt. Water (100 ml) was added and the mixture extracted with ethyl acetate (2×80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The free base converted to the hydrochloride salt by action of HCl in ethanol. The solid was recrystallised from ethanol-diethylether to yield 4.7 g of the title compound as colourless crystals. MP. 233-235° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=[C:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][NH:18][C:19](=[O:24])[CH2:20][CH2:21][C:22]#[CH:23].[OH-].[Na+]>O=P(Cl)(Cl)Cl>[CH2:20]([C:19]1[O:24][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][N:18]=1)[CH2:21][C:22]#[CH:23]
Reactant: C#CCCC(=O)NCC(=O)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: C#CCCc1ncc(-c2ccccc2)o1
Temperature: 105 °C
Reaction time: 2 h
Yield: 21.6 %

Procedure:
907 mg (6.39 mmol) of P2O5 were added to a solution of pent-4-ynoic acid (2-oxo-2-phenyl-ethyl)-amide (160 mg, 0.74 mmol) in POCl3 (10.4 mL). The reaction mixture was stirred for 2 hours at 105° C. and then poured carefully onto ice. The solution was basified with NaOH 1N followed by NaOH pellets till pH=8. The aqueous phase was extracted thrice with DCM. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 31 mg (0.16 mmol, 21%) of 2-(but-3-ynyl)-5-phenyloxazole as an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[NH2:41][C:42]1[C:43]([C:56]([NH2:58])=[O:57])=[N:44][N:45]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)[C:46]=1[CH2:47][CH3:48]>C(OCC)(=O)C>[C:56]([C:43]1[C:42]([NH:41][C:6](=[O:7])[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)(=[O:14])=[O:15])[CH:11]=[N:12][C:4]=2[O:3][CH2:1][CH3:2])=[C:46]([CH2:47][CH3:48])[N:45]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)[N:44]=1)(=[O:57])[NH2:58]
Reactant: CCc1c(N)c(C(N)=O)nn1Cc1ccccn1
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CCOC(C)=O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(Cc2ccccn2)c1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
2-Ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (0.875 Kg, 2.55 mol) was charged followed by ethyl acetate (7L, 8 ml/g) to the reaction vessel and 2 ml/g was distilled off at atmospheric pressure to ensure the reaction system was dry. The slurry was cooled to room temperature under a nitrogen atmosphere and carbonyldiimidazole (0.43 Kg, 2.65 mol) added in one portion. The slurry was heated to 35° C. and held for half an hour. The reaction was further heated to 45-50° C. and held for a further half hour. The reaction was then heated to reflux, stirring at reflux for one hour. On confirmation of complete imidazolide formation the reaction was cooled to 45-50° C. under nitrogen and 4-amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide (0.59 Kg, 2.42 mol) charged in one portion before returning to reflux and a further 1 ml/g was distilled off at atmospheric pressure. The reaction was stirred at reflux for 16 hours with crystallisation of product occurring after 4 hours. The reaction was cooled to 10-15° C. and granulated for one hour. The reaction slurry was filtered and washed (ethyl acetate) which was dried under vacuum at 50° C. to afford the title compound (1.252 Kg, 90.7%) as a white solid. Mpt 178-179° C. ? (CDCl3): 1.04 (3H, t), 1.06 (3H, t), 1.59 (3H, t), 240 (2H, q), 2.50 (4H, q), 2.90 (4H, q), 3.08 (4H, m), 2.78 (2H, q), 5.35 (1H, s) 5.48 (2H, s), 6.68 (1H, s), 6.92 (1H, d), 7.22 (IH, m), 7.65 (1H, m), 8.58 (1H, d), 8.64 (1H, d), 8.83 (1H, d). m/z (Found:571 [M+H]+, 100%. C26H34N8O5S requires 571.67).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](SC)=[N:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.Cl.[C:30]1([N:36]2C=CN=C2N2CCN([C@@H]3CN[C@H](C(N4CCSC4)=O)C3)CC2)C=CC=[CH:32][CH:31]=1.C(N)C#C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:31]([CH3:32])=[CH:30][N:36]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=Nc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C([C@@H]1C[C@H](N2CCN(c3nccn3-c3ccccc3)CC2)CN1)N1CCSC1
Agent: C#CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: Cc1cnc(N2CCN(C(=O)OCc3ccccc3)CC2)n1-c1ccccc1

Procedure:
1-Benzyloxycarbonyl-4-[(methylthio)phenyliminomethyl]piperazine [product of Example 224 (2), 2.70 g] and propargylamine (2.3 mL) were dissolved in 1-butanol (25 mL), and p-toluenesulfonic acid monohydrate (156 mg) was added thereto. The mixture was refluxed for 20 hr. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with chloroform, and the extract was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-benzyloxycarbonyl-4-(5-methyl-1-phenyl-2-imidazolyl)piperazine (1.82 g) as a brown oil.
Reaction SMILES: FC(F)(F)C(NC1C=CC(C#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=CC=1)=O.I[C:22]1[CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[N+:28]([C:24]1[CH:23]=[C:22]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:27]=[CH:26][CH:25]=1)([O-:30])=[O:29]
Reactant: O=C(Nc1ccc(C#CCCCCO)cc1)C(F)(F)F
Reactant: O=[N+]([O-])c1cccc(I)c1
Product: O=[N+]([O-])c1cccc(C#CCCCO)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 39, using 3-iodonitrobenzene as a substrate. ES/MS calcd. for C11H12NO3+ 206.1. Found m/z=206.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH:24]3[CH2:26][CH2:25]3)=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:27][N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:30]2[CH2:31][CH2:32][N:28]([CH3:27])[C:29]2=[O:33])[CH:7]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2Br)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2N2CCN(C)C2=O)CC1
Yield: 28.2 %

Procedure:
Using (2-bromo-4-chlorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (848 mg) described in Preparation Example 235 and 1-methylimidazolidin-2-one (293 mg) and by the reaction and treatment in the same manner as in Preparation Example 241, the title compound (250 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14](=O)[C:15](OCC)=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH2:14][CH2:15][OH:16])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)Nc1nc(-c2ccc(Cl)cc2)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCCNc1nc(-c2ccc(Cl)cc2)cs1
Reaction time: 1 h
Yield: 54.7 %

Procedure:
A solution of ethyl {[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino}(oxo)acetate (2.50 g, 8.04 mmol), prepared in the previous step, in dry tetrahydrofuran (25 mL) was added, under nitrogen, to a stirred suspension of lithium aluminum hydride (0.92 g, 24 mmol) in dry tetrahydrofuran (25 mL). After the addition was complete, the mixture was stirred for an additional 1 h. Ethyl acetate (4.8 mL) was added dropwise, followed by water (0.92 mL), 4N NaOH (0.92 mL) and water (2.8 mL). The mixture was then filtered and evaporated to afford 2-{[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino}ethanol (1.12 g, 55%) which was used without further purification. HRMS: calcd for C11H11ClN2OS [M+H+], 255.03534; found (ESI+, [M+H]+), 255.03505.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:15][C:16]([OH:18])=[O:17])[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A mixture of 3-trifluoromethoxy-benzaldehyde (3 g, 15.78 mmol), malonic acid (2.13 g, 20.51 mmol), piperidine (0.134 g, 1.58 mmol) and pyridine (10 ml) was kept at reflux temperature until carbon dioxide formation ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 60 g ice and 30 ml 6N HCl. The precipitate was isolated, washed with water and dried yielding 2.21 g (60%) 3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[N:31]=[N:32][N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:34]=2)[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+].O>CO>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3-c3nnn[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
0.70 g (0.98 mmol) of 2-butyl-4-chloro-1-{[2-[2-[2-(triphenylmethyl)-2H-tetrazol-5-yl]phenyl]quinolin-6-yl]methyl}-1H-imidazole-5-carbaldehyde obtained in Example 8 was suspended in 12 ml of methanol. 12 ml of concentrated hydrochloric acid was added thereto while in an iced water bath followed by stirring at room temperature for 24 hours. The reaction mixture was iced and alkalized with a 10N sodium hydroxide solution. After adding 10 ml of water thereto, the mixture was filtered and the filtered cake was washed with 10 ml of a 1N sodium hydroxide solution. The filtrate was acidified by adding concentrated hydrochloric acid dropwise thereto and extracted with 100 ml of ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain 0.102 g of 2-butyl-4-chloro-1-{[2-[2-(1 H-tetrazol-5-yl)phenyl]-quinolin-6-yl]methyl}-1H-imidazole-5-carbaldehyde.
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:33][CH2:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[CH3:42])[CH:30]=[CH:31][CH3:32].C(N(CC)CC)C>C(O)(C)C>[CH2:29]([N:33]([CH2:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[CH3:42])[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]=[CH:31][CH3:32]
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: CC=CCNCc1cc(C)ccc1C
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC=CCN(Cc1cc(C)ccc1C)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 0.17 h

Procedure:
10 g. Triacetyl-6-chloro-9-(β-D-ribofuranosyl)-purine, 5.7 g. N-but-2-enyl-(2,5-dimethylbenzyl)-amine and 2.5 g. triethylamine were heated under reflux for 1 hour in 150 ml. isopropanol. Subsequently, the solvent was removed in a vacuum and the residue taken up in chloroform. The chloroform phase was washed several times with water, dried and evaporated. The syrupy residue was dissolved in 150 ml. methanol and the solution mixed with 5 ml. 1N sodium methylate solution and then boiled for 10 minutes. Thereafter, the methanol was replaced by ethyl acetate and the ethyl acetate solution washed two or three times with water. After drying and evaporating the solution, the residue was recrystallized twice from 100 ml. methanol/water (1:1), with the addition of active charcoal. There were finally obtained 5.9 g. (56% of theory) N(6)-but-2-enyl-N(6)-(2,5-dimethylbenzyl)-adenosine, which had a melting point of 125°-127°C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[NH:23]1[CH:30]=[CH:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:23]4[CH:30]=[CH:29][C:27](=[O:28])[NH:26][C:24]4=[O:25])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccc(=O)[nH]c3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 39 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (66 mg, 0.15 mmol), uracil (46 mg, 0.41 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the titled compound (25 mg). MS 428.0 and 430.0 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([CH2:23][C:24]#[N:25])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(O)C>[NH2:25][C:24]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#CCC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(-c2ccccc2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (0.2459 g) in ethanol (2 ml) was added to a stirred solution of benzoylacetonitrile (0.145 g) in ethanol (8 ml ) and the resulting solution heated under reflux for 6 hours. Glacial acetic acid (1 ml) was added and the resulting mixture heated under reflux for a further 6 hours and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (10 g), using dichloromethane as eluant, followed by reverse phase HPLC on C18 silica, using acetonitrile:methanol:water (50:10:40) as eluant, to afford the title compound as a white solid, m.p. 141.5-142.5° C. δ(CDCl3): 3.60 (br.s,2H), 6.08 (s,1H), 7.30-7.45 (m,3H), 7.80 (s,2H), 7.80-7.85 (m,2H). MS (thermospray): M/Z [M+H] 372.1; C16H10Cl2F3N2+H requires 372.03.
Reaction SMILES: [CH:1]#[N:2].[Cl:3][C:4]([Cl:15])([Cl:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.[C-]#N.[K+]>C(Cl)Cl.O.CN(C)CC1C=CC=CC=1>[Cl:3][C:4]([Cl:15])([Cl:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([C:1]#[N:2])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1
Reactant: C#N
Agent: CN(C)Cc1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N#CC(=O)c1ccc(C(Cl)(Cl)Cl)cc1
Reaction time: 2 h
Yield: 48 %

Procedure:
50 ml of hydrogen cyanide, dissolved in 150 ml of methylene chloride, are added dropwise at -10° C. to -20° C. to a solution of 275 g of p-trichloromethylbenzoyl chloride and 2 g of dimethylbenzylamine in 1.5 l of methylene chloride. Subsequently, a solution of 60 g of potassium cyanide in 120 ml of water is slowly added dropwise at the same temperature and, finally, the mixture is stirred for a further two hours. The solids which have precipitated are filtered off with suction, the phases are separated and the organic phase is washed several times with water, dried over Na2SO4 and concentrated. A little ether is added to the remaining oily residue, whereupon 52 g (20%) of dimeric p-trichloromethylbenzoyl cyanide crystallize out, and the crystals are filtered off with suction. 127 g (48% of theoretical) of p-trichloromethylbenzoyl cyanide can be obtained from the filtrate by vacuum distillation.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13](Cl)(=[O:15])=[O:14].[NH4+].[Cl-]>ClCCl>[I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]([S:13]([CH3:12])(=[O:15])=[O:14])[S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1I)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-iodo-4-nitroaniline (1.02 g, 3.86 mmol) in dichloromethane (10 ml), has been added under stirring triethylamine (1.77 ml, 12.7 mmol). To this mixture, a solution of methanesulphonyl chloride (0.98 ml, 12.7 mmol) in dichloromethane (2 ml) has been added dropwise, very slowly and in an ice-bath. The mixture so obtained was left under stirring at room temperature overnight. The day after, the reaction mixture was neutralized with a saturated aqueous solution of NH4Cl. The organic phase was separated, and, after evaporation of the solvent, the residue has been washed with ethanol and filtered to give N-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)-methanesulfonamide as yellow solid.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]#[CH:21])[CH:17]=[CH:18][CH:19]=1>CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:12][C:3]1[C:4]([F:11])=[C:5]([F:10])[C:6]([F:9])=[C:7]([F:8])[C:2]=1[C:21]#[C:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[NH2:13]
Reactant: C#Cc1cccc(N)c1
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Nc1cccc(C#Cc2c(F)c(F)c(F)c(F)c2F)c1
Temperature: 70 °C
Yield: 50 %

Procedure:
A multinecked flash as described in Example 1 was charged with 5.0 g (0.020 mol) of bromopentafluoro-benzene, 2.37 g (0.020 mol) of 3-aminophenylacetylene, 0.096 g (0.137 mmol) of bis(triphenylphosphine) palladium II chloride, 0.148 g (0.564 mmol) of triphenylphosphine, and 0.06 g (0.315 mmol) of cuprous iodide. The reaction mixture was heated at 70° C. for 40 hours after which gas chromatography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 75 ml of ether. Filtration of the insoluble triethylamine hydrobromide salt by-product followed by concentration of the filtrate gave 5.7 g, (0.02 mol) of crude product as a yellow solid. Short path distillation of the crude under reduced pressure gave 2.84 g (0.010 mol, 50% yield) of the product as a colorless liquid that crystallized on standing.