Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N2C3N=CN=C(N)C=3[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[N:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)=C2)CCC1.Br[C:32]1[N:33]=[C:34]([CH:42]2[CH2:45][CH2:44][CH2:43]2)[N:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]=12>>[CH:42]1([C:34]2[N:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]3=[C:32]([C:15]3[CH:7]=[C:19]4[C:18]([C:17]([CH3:16])=[N:22][C:21]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:23][CH:24]=3)[N:33]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: Nc1ncnc2c1c(-c1ccc3cnc(-c4ccccc4)nc3c1)cn2C1CCC1
Reactant: Nc1nccn2c(C3CCC3)nc(Br)c12
Product: Cc1nc(-c2ccccc2)nc2cc(-c3nc(C4CCC4)n4ccnc(N)c34)ccc12

Procedure:
Synthesized as 7-cyclobutyl-5-(2-phenylquinazolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine from of 1-bromo-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine (16 mg, 0.06 mmol). Crude material was purified by preparative TLC (silica gel, 5% MeOH in DCM) followed by a recrystallization (EtOAc) and trituration (hexanes) to afford the title compound as a light yellow solid; MS (ES+): m/z 407.1 (100); HPLC: tR (min) 2.44 (OpenLynx, polar 5 min).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCCC=Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C(=Cc1ccccc1)CCCOCc1ccccc1
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (50%; 0.6 g) (deprived of mineral oil) in tetrahydrofuran (10 ml), there was added dropwise a solution of 5-phenyl-4-pentenol [1.66 g; known compound; cf. e.g. Journal of the Chemical Society, page 1863 (1961)] in tetrahydruforan (10 ml) in argon atmosphere at room temperature. The mixture was stirred at the same temperature for 5 minutes. A solution of benzyl bromide (1.93 g) in tetrahydrofuran (10 ml) was added dropwise and the mixture was stirred at the same temperature for 20 hours. The tetrahydrofuran was distilled off under reduced pressure and water was added to the residue, followed by extraction with ether. After washing with water and drying over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel chromatography, elution being carried out with chlorofrom to give 5-benzyloxy-1-phenyl-1-pentene (2.5 g) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[N:27]=[CH:26][N:25]=1>C1(C)C(C)=CC=CC=1>[Cl:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:2])[CH:29]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cc(Cl)ncn2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 47 %

Procedure:
N-(6-Chloro-4-pyrimidinyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 4-amino-6-chloro-pyrimidine. Yield: 47% of theory; m.p. 263° C (decomp.; from xylene).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H][H]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)C=C1CCC(c2ccc(O)cc2)CC1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 0 °C

Procedure:
[4-(4-hydroxyphenyl)cyclohexylidene]acetic acid methyl ester (29 g, 0.12 mol) and 10% pd/c (2.9 g) were put into ethyl acetate and stirred under 25° C. hydrogen gas for 24 hours. The reaction mixture was filtered with celite and concentrated in the vacuum to obtain a yellow solid. The mixture was dissolved in hot ethyl acetate (29 mL) and cooled to reach ambient temperature. The reaction mixture was cooled with ice water again, a filtrate was filtered and washed with ethyl acetate (15 mL) to obtain trans [4-(4-hydroxyphenyl)cyclohexyl]acetic acid methyl ester as a white solid (12.6 g, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[N:15]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Br)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(Cc2ccccc2)c2ccccc2Br)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(2-Bromo-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.30 mmol) was dissolved in dry N,N-dimethylformamide (5.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 63.6 mg, 1.59 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C. benzyl bromide (0.267 g, 1.56 mmol). The reaction mixture was stirred at 0° C. for one hour, then at room temperature under nitrogen atmosphere for 1 day. The reaction mixture was then added into an excess of water-ice and a gum formed. The gum was filtered by suction, washed with water and dried to yield a crude solid. The crude solid was purified via flash chromatography (30% ethyl acetate/hexanes) to yield the title compound as a solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.[CH2:32](O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([O:12][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of N-Boc-trans-4-fluoro-L-proline (4.5 g, 19.29 mmol) in CH2Cl2 (68 mL) were added DCC (4.78 g, 23.15 mmol), DMAP (0.236 g, 1.93 mmol) and benzyl alcohol (2 mL, 19.29 mmol). The resulting white suspension was stirred at RT for 48 h and filtered. The filtrate was concentrated to give a colorless oil which was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4-1) to give the desired compound. TLC, Rf (c-hexane/EtOAc 3:1)=0.3; MS: 346.0 [M+Na]+; tR (HPLC conditions a): 3.85 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([Cl:18])=[O:17])[CH2:9]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O1CCOCC1>CN(C=O)C>[ClH:18].[CH2:36]([NH:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:16]([C@@H:10]3[CH:11]4[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]4)[CH2:9]3)=[O:17])=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)(=[O:34])=[O:33])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1)[C@H]1CN2CCC1CC2
Reaction time: 18 h

Procedure:
73.5 mg (0.60 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 74.5 mg (0.35 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 60 mg (0.18 mmol) of 4′-amino-N-benzylbiphenyl-4-sulfonamide (Example 10A) in 2.2 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100° C., a further 74.5 mg (0.35 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride are added. After a further 24 h at 100° C., the reaction mixture is concentrated in vacuo. The residue is dissolved in water and acetonitrile and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 64 mg (70.5% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:14][CH3:15])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][CH2:23][O:24][C:25]([CH2:27]Br)=[O:26]>CC(C)=O>[CH3:15][O:14][C:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([O:8][CH2:27][C:25]([O:24][CH2:23][CH3:22])=[O:26])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(OC)cc(C(=O)OC)cc1OC
Yield: 74.6 %

Procedure:
To a mixture of methyl syringate (100 grams, 472 mmol), anhydrous K2CO3 (250 grams, 1.809 mol) in anhydrous acetone (1200 mL) was added Ethyl bromo acetate (113 grams, 677 mmol) and refluxed for 48 hours. Acetone was distilled and water (1200 mL) was added. Crude 11 was filtered, dried, and recrystallized from toluene to give pure 11 (105 grams, 75%) as a white powder. The melting point was found to be 90.5-92.5° C. The structure was confirmed by I.R and NMR. IHNMR (CDCl3) δ 1.32 (t, 3H, CH2CH3), 3.88 (s, 3H, Ester), 3.90 (s, 6H, OCH3), 4.25 (q, 2H, CH2CH3), 4.69 (s, 2H, OCH2), 7.24 (s, 2H, Ar).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=2)=[C:4]([C:8]([Cl:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:23](O)=O>O>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]2[C:3]3[C:4]([C:5]([OH:7])=[O:6])=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=3[N:1]=[CH:23]2)=[CH:15][CH:16]=1)([OH:22])=[O:21]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1NCc1ccc(C(=O)O)cc1
Reactant: O=CO
Solvent: O
Product: O=C(O)c1ccc(Cn2cnc3ccc(Cl)c(C(=O)O)c32)cc1
Yield: 100 %

Procedure:
A solution of 3-amino-2-[(4-carboxyphenyl)methyl]amino-6-chlorobenzoic acid (80 mg, 0.24 mmol, prepared as in Example 2 (i-ii)) in 0.5 ml of 98% formic acid was refluxed under argon for 2.5 hours. The reaction mixture was diluted with water and the resulting solid was collected to give 80 mg (100%) of the title compound; mp 291°-292° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[C:10]([CH3:22])[CH:9]=2)=[O:5])C.CO.[OH-].[K+]>O>[C:17]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[CH3:22])[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:15][C:14]2=[O:16])(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)c1cc2c(=O)cc(C(=O)OCC)[nH]c2cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(=O)c1cc2c(=O)cc(C(=O)O)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2 g of 6-butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid ethyl ester are heated under reflux for 4 hours together with 20 ml of methanol, 1.2 g of potassium hydroxide and 0.5 ml of water. The reaction mixture is concentrated to dryness by evaporation and taken up in water. The solution is acidified to pH 1 with 2N hydrochloric acid and filtered with suction. The product obtained by filtering with suction is thoroughly washed with water, resuspended in water, thoroughly triturated and stirred at room temperature for 5 hours, then filtered with suction, washed with water, and recrystallised twice from methanol. In this manner 6-butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid having a melting point of 255°-258° is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][OH:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: OCC#Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
In a dry flask containing in suspension copper iodide (84 mg, 0.44 mmol) and triethylamine (24.70 mL), was added Pd(PPh3)2Cl2 (310 mg, 0.44 mmol) under N2. A yellow suspension is obtained. The reaction mixture was cooled to 0° C. in an ice-bath before the addition of 1-fluoro-4-iodobenzene (1.95 g, 8.80 mmol). After five minutes at 0° C., a solution of prop-2-yn-1-ol (493 mg, 8.80 mmol) in triethylamine (4 mL) was slowly added under N2 over a period of 15 min. Immediately the color of the reaction turns to black. The mixture was stirred 0° C. for 30 min and then warmed to room temperature for 20h under N2. Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water, brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 1.10 g of 3-(4-fluorophenyl)prop-2-yn-1-ol (Yield: 83%) as a yellow oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28]2)=[O:24].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:28]2)=[O:24]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: COC(=O)c1ccc2c(c1)CNC2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 34.9 %

Procedure:
133 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 74 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([NH:39]O)=[NH:38])[CH:35]=2)[N:30]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:29]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:38]=[C:37]([C:34]3[CH:35]=[C:36]4[C:31](=[CH:32][CH:33]=3)[N:30]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:29]=[C:28]4[Cl:27])[N:39]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(C(=N)NO)ccc21
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OC)c(Br)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The 3-bromo-4-(methyloxy)benzoic acid (commercial: ICN) (243 mg, 1.05 mmol) stirring in DMF (10 ml) was treated with EDC (219 mg, 0.1.14 mmol) followed by HOBt (156 mg, 0.1.14 mmol). The resultant solution was stirred for 10 minutes. Added ethyl 3-{3-chloro-5-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D96) (324 mg, 1.05 mmol) and stirred at RT for 45 minutes. The solution was heated at 80° C. for 4 hours then left standing overnight. The solution was heated at 80° C. for a further 4 hours to give one major product. Evaporated off the DMF, added EtOAc (50 ml) and washed with water (50 ml). The EtOAc was washed with sat. aqueous sodium hydrogen carbonate (50 ml) and water (50 ml) then dried over MgSO4. Evaporated off the solvent and crystallised from ethanol to yield the title compound as 280 mg of cream solid. δH (400 MHz, d6-DMSO) 1.10 (3H, t), 2.90 (2H, t), 3.99-4.05 (5H, m), 4.49 (2H, t), 7.38 (1H, d), 7.74 (1H, s), 7.80 (1H, d), 7.97 (1H, d), 8.21-8.23 (2H, m), 8.36 (1H, d). MS (ES) C22H1981Br35ClN3O4 requires 505; found 506 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH:12]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)/[CH:13]=[CH:14]/[P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].[N-:44]=[N+:45]=[N-:46].[Na+]>CN(C)C=O>[N:44]([C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH:12]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)/[CH:13]=[CH:14]/[P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[N+:45]=[N-:46]
Reactant: CC(C)OP(=O)(/C=C/C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cn1cnc2c(Cl)ncnc21)OC(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(/C=C/C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cn1cnc2c(N=[N+]=[N-])ncnc21)OC(C)C
Temperature: 70 °C
Yield: 75.4 %

Procedure:
A mixture of (E)-6-chloro-9-[2-(t-butyldiphenylsilyloxy)methyl-4-(diisopropoxyphosphoryl)but-3-enyl]purine (244 mg, 381 μmol) and sodium azide (25 mg, 381 μmol) in N,N-dimethylformamide (7 ml) was heated at 70° C. for 2.8 h. The solvent was removed and the residue purified by column chromatography on silica gel eluting with acetone-hexane (1:4, 1:1) to give (E)-6-azido-9-[2-(t-butyldiphenylsilyloxy)methyl-4-(diisopropoxyphosphoryl)but-3-enyl]purine as a gum (186 mg, 75%); λmax (EtOH) 282 (10,363)nm; υmax (film) 2980, 2935, 2155, 1640, 1375, 1250 and 1110 cm-1 ; δH (CDCl3) 1.00-1.40 (21H, m, CH3), 3.05 (1H, m, CH), 3.70 (2H, m, CH2O ), 4.30-4.80 (4H, m, CH2N and CH(CH3)), 5.58 (1H, m, PCH= CH) , 6.70 (1H, m, PCH=CH) , 7.30-7.70 (10H, m, C6H5) , 7.86 (0.35H, s, H-2/H-8), 8.05 (0.65H, s, H-2/H-8), 8.64 (0.35H, s, H-2/H-8), 9.44 (0.65H, s, H-2/H-8)*; FABMS (TDE/Na) 670 (MNa+), 648 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:13]=2)[O:9][N:8]=1.[I:24]N1C(=O)CCC1=O>C(#N)C>[I:24][C:11]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][O:9][C:10]=1[C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:13]=1
Reactant: Cc1ccc(-c2noc(-c3cc(-c4ccccn4)no3)n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1ccc(-c2noc(-c3onc(-c4ccccn4)c3I)n2)cc1
Yield: 378 %

Procedure:
A solution of 5-(3-(pyridin-2-yl)isoxazol-5-yl)-3-p-tolyl-1,2,4-oxadiazole (1.0 g, 3.29 mmol), 1-iodopyrrolidine-2,5-dione (1.11 g, 4.76 mmol), and PdOAc2 (0.148 g, 0.657 mmol) in acetonitrile (14 mL) was heated to 120° C. via microwave for 40 minutes. The reaction was repeated 4 additional times on a similar scale, and the contents of each reaction tube were combined, concentrated, and purified by flash silica gel chromatography (eluting with Hexanes/EtOAc—4/1) to yield 5-(4-iodo-3-(pyridin-2-yl)isoxazol-5-yl)-3-p-tolyl-1,2,4-oxadiazole (5.35 g, 76% yield). The compound had an HPLC retention time=3.81 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=431+. 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (s, 3H), 7.36 (d, J=8.03 Hz, 2H), 7.46-7.52 (m, 1H), 7.90 (td, J=7.72, 1.63 Hz, 1H), 8.01 (d, J=7.78 Hz, 1H), 8.12 (d, J=8.28 Hz, 2H), and 8.86 (d, J=4.27 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[CH:9]1[C:22]2[C:13](=[CH:14][C:15]3[C:20]([C:21]=2B(O)O)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1>>[CH:9]1[C:22]2[C:13](=[CH:14][C:15]3[C:20]([C:21]=2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:14]2[C:15]4[C:20]([CH:21]=[C:22]5[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]5)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccc1Br
Reactant: OB(O)c1c2ccccc2cc2ccccc12
Product: c1ccc(-c2c3ccccc3cc3ccccc23)c(-c2c3ccccc3cc3ccccc23)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Procedure analogous to Example 3a. Instead of 149.0 ml (1.2 mol) of 1,2-dibromobenzene and 98.0 g (308 mmol) of 9,10-anthracenediboronic acid ethylene glycol ester, 12.1 ml (100 mmol) of dibromobenzene and 68.0 g (306 mmol) of 9-anthraceneboronic acid are used. After cooling, the solid is filtered off with suction, washed three times with 100 ml of ethanol each time and then washed twice by stirring with 1000 ml of refluxing acetic acid each time (1 h) and each time filtered off with suction after cooling to 90° C. The mother liquor is discarded in each case. The solid is finally washed once with boiling ethanol. Yield: 33.0 g (76 mmol), 76.6% of theory; purity: 98% according to 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.[CH3:18][O:19][C:20]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21]>C1(C)C=CC=CC=1>[CH3:18][O:19][C:20](=[O:21])/[CH:22]=[CH:6]/[C:5]1[CH:8]=[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCOc1cc(C=O)c([N+](=O)[O-])cc1Cl
Solvent: Cc1ccccc1
Product: COCCOc1cc(/C=C/C(=O)OC)c([N+](=O)[O-])cc1Cl

Procedure:
1-Chloro-2-(2-methoxyethoxy)-4-methyl-5-nitrobenzene (300 mg; 1.22 mmol) in DMF (3 ml) was treated with tert.butoxy-bis(dimethylamino)methan (1.06 ml; 5.1 mmol) in DMF (13 ml) at 160° C. for 20 min. The reaction mixture was evaporated to dryness and taken up in THF (6 ml). NalO4 (1.6 g; 7.3 mmol) in water (25 ml) was added at room temperature within 0.5 h and after stirring for another 1 h, the reaction mixture was extracted with EtOAc twice. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield the intermediate 4-chloro-5-(2-methoxyethoxy)-2-nitrobenzaldehyde as brown solid (360 mg; quant.). 4-chloro-5-(2-methoxyethoxy)-2-nitrobenzaldehyde (360 mg; 1.22 mmol) and (methoxycarbonylmethylen)triphenylphosphoran (449 mg; 1.34 mmol) were refluxed for 1 h in toluene (20 ml). After cooling the reaction mixture, toluene (100 ml) was added and the resulting crystals filtered off and purified via chromatography (SiO2, TBME/hexanes 1/1) to yield the title compound as a cis-trans mixture (290 mg). Recrystallisation from hot TBME rendered the pure trans isomer (180 mg; 47%) as slightly yellow crystals.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1C(O)=O.[OH:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][C:13]=1[C:21]([NH2:23])=[O:22]>>[NH:3]1[CH2:2][CH2:7][CH:6]([O:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:13]=2[C:21]([NH2:23])=[O:22])[CH2:5][CH2:4]1
Reactant: O=C(O)N1CCCCC1Cl
Reactant: NC(=O)c1sc2ccccc2c1O
Product: NC(=O)c1sc2ccccc2c1OC1CCNCC1

Procedure:
Referring to Scheme 4, methoxybenzothiophene ester 1, for example, is converted to the corresponding hydroxybenzothiophene carboxylic acid 2 with boron tribromide. Carboxylic acid 2 is coupled with Hca amine to yield hydroxybenzothiophene amide 3. 1-Substituted 4-hydroxypiperidine 4 is coupled with amide 3 to yield (piperidin-4-yloxy)benzothiopheneamide 5.