Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][CH:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.O>C1(SC)C=CC=CC=1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][CH:33]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:34][CH2:35]3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Solvent: O
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H](Cc1ccc(O)cc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
To a room temperature, stirred mixture of (S)-3-(4-benzyloxy-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid (0.033 g, 0.000058 mol) in thioanisole (0.34 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and rotary-evaporated under reduced pressure to remove volatiles. The resulting yellow solution was chromatographed on silica gel (5.5 g) eluting with dichloromethane (10×5 mL) followed by dichloromethane-methanol (14:1). Fractions containing product were rotary-evaporated. The residue was suspended in water and stirred to give the title compound as an off-white solid; yield 0.0079 g (28%), mp 108-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C>[Si:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Nc1cc(Cl)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1N

Procedure:
A solution of 2-amino-4-chlorophenol (14.3 g, 100 mmol), tert-butyldimethylsilyl chloride (18 g, 120 mmol) and imidazole (14 g, 200 mmol) in DMF (250 mL) was stirred at room temperature for 24 hours, concentrated, and partitioned between brine (300 mL) and ethyl acetate (300 mL). The aqueous phase was extracted with ethyl acetate. The combined phases were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide 18.5 g (71.7% )of the desired product. MS (DCI/NH3) m/z 258 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 6.70 (d, J=2.71 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 6.57 (dd, J=2.7 and 8.5 Hz, 1H), 3.75 (br s, 2H), 1.01 (s, 9H), 0.23 (s, 6H).
Reaction SMILES: ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CCC)=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[N:38]([C:39]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)=[O:40])[C:37]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=3[O:56][CH2:57][CH3:58])=[N:36][CH:35]2[CH2:59][CH:60]2CCC[CH2:61]2)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[N:38]([C:39]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)=[O:40])[C:37]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=3[O:56][CH2:57][CH3:58])=[N:36][CH:35]2[CH2:59][CH2:60][CH3:61])=[CH:30][CH:29]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Agent: CCCC1N=C(c2ccc(OC)cc2OCC)NC1c1ccc(Cl)cc1
Product: CCCC1N=C(c2ccc(OC)cc2OCC)N(C(=O)N2CCN(C)CC2)C1c1ccc(Cl)cc1

Procedure:
[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-propyl-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-propyl-4,5-dihydro-1H-imidazole (Example 18) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 499.2477, calculated for C27H36N4O3Cl [(M+H)+]499.2471.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[CH2:25][C:26]([NH:28][CH:29]1[C:34]([CH3:36])([CH3:35])[CH:33]2[CH2:37][C:30]1([CH3:38])[CH2:31][CH2:32]2)=O.[OH2:39]>O1CCCC1>[CH:8]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:25](=[O:39])[CH2:26][NH:28][CH:29]2[C:34]([CH3:36])([CH3:35])[CH:33]3[CH2:37][C:30]2([CH3:38])[CH2:31][CH2:32]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O
Reactant: c1ccc(NC2CCCCC2)cc1
Reactant: CC12CCC(C1)C(C)(C)C2NC(=O)CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC12CCC(C1)C(C)(C)C2NCC(=O)N(c1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-cyclohexylaniline (100 mg, 0.56 mmol) in tetrahydrofuran (4 ml) at −78° C. was added LiHMDS (1 ml of a 1M solution in tetrahydrofuran) dropwise. The solution was allowed to warm to 0° C., then recooled to −78° C., and a solution of 2-chloro-N-(1,3,3-trimethylbicyclo[2,2,1]hept-2-yl)acetamide (124 mg, 0.56 mmol) in tetrahydrofuran (1 ml) added dropwise. The mixture was allowed to warm to room temperature, and was stirred for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. The ethyl acetate solution was absorbed onto silica gel, which was eluted with 3% methanol/methylene chloride, to yield N-cyclohexyl-N-phenyl-2-(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-ylamino)-acetamide.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br>O1CCCC1.CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc(Br)c1)C(=O)OCC
Reaction time: 0.25 h

Procedure:
Sodium hydride (60%, 1.6 g) was suspended into 20 ml of dry tetrahydrofuran/15 ml of dry N,N-dimethyl formamide, and 7.6 ml of diethyl malonate was added dropwise under ice-cooling. The mixture was stirred for 15 minutes. A solution of 5 g of 3-bromobenzyl bromide/10 ml of dry tetrahydrofuran was then added, and stirred for 1 hour under ice-cooling. To the reaction solution was added ice-cold water, and extracted with ether, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=10:1) to provide 5.41 g of the objective compound as colorless oil.
Reaction SMILES: [BH4-].[Na+].C1COCC1.[Cl:8][C:9]1[C:13]([Cl:14])=[C:12]([C:15](Cl)=[O:16])[S:11][N:10]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[Cl:8][C:9]1[C:13]([Cl:14])=[C:12]([CH2:15][OH:16])[S:11][N:10]=1
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1snc(Cl)c1Cl
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
1.9 g (50.5 mmol) of sodium borohydride was suspended in 40 ml of water. To the suspension was dropwise added, at 10 to 15° C., a THF (4 ml) solution of the above-produced 3,4-dichloroisothiazole-5-carbonyl chloride. The mixture was stirred at 15° C. for 30 minutes. Then, an aqueous citric acid solution was added to the mixture to make it weakly acidic, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The resulting crystals were washed with hexane to obtain 3.0 g (yield: 81%) of (3,4-dichloroisothiazol-5-yl)methanol as colorless crystals (melting point: 94 to 95° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](SC#N)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].CC[N:29]([CH:33]([CH3:35])[CH3:34])C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:29][C@H:33]1[CH2:34][CH2:21][C@H:18]([CH2:19][NH:20][C:6]2[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=[C:2]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[O:16][C:15]([F:25])([F:26])[F:14])[N:7]=2)[CH2:17][CH2:35]1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Reactant: NCc1ccccc1OC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of 2-chloro-5-nitro-4-thiocyanatopyrimidine (1 g, 4.6 mmol) in DMF (5 mL) was added 2-(trifluoromethoxy)benzylamine (883 mg, 4.6 mmol) followed by DIPEA (804 μL, 4.6 mmol). The reaction mixture was stirred at room temperature for 30 min and diluted with EtOAc. The solution was washed with water (×4). The organic phase was dried over anhydrous Na2SO4 and then concentrated in vacuo. The resulting residue was purified by silica gel prep TLC using CH2Cl2 as an eluent to afford 727 mg (42%) of the desired product as a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H][H]>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: COc1ccc(C=C2NC(=O)NC2=O)cc1OCc1ccccc1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(CC2NC(=O)NC2=O)cc1OCc1ccccc1
Yield: 47 %

Procedure:
A solution of 16.20 g (0.05 mole) of the benzylidene hydantoin from Example 4 in 100 mL of methanol and 25.0 g (0. 055 mole) of 20% tetramethylammonium hydroxide-in-methanol is reduced with hydrogen and Raney nickel catalyst. After the theoretical uptake of hydrogen the mixture is filtered and acetic acid (ca 5 mL) and then water is added until just turbid. The first crop of solid is filtered. This is starting material. An additional 2 L of water is added to precipitate the product as crop 2; wt 7.60 g (47% yield). Recrystallization from methanol gives pure product; mp 155°-157° C. Anal. Calc. for C18H18N2O4 : C, 66.24; H, 5.56; N, 8.59. Found: C, 66.19; H, 5.60; N, 8.68.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2>ClCCCl>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]2[CH:14]=[O:15]
Reactant: CN(C=O)c1ccccc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
In a 1 L round bottom flask 10.5 mL of phosphorus oxychloride was added to 15.5 g of N-methylformanilide at room temperature that resulted in a yellow solid after 15 min. At this time, 170 mL of 1,2-dichloroethane and 20.1 g of ethyl 5-bromoindole-2-carboxylate were added. The resulting suspension was heated under reflux for 4 hours and then concentrated to remove the organic solvent. 75 g of sodium acetate in 750 mL of water were added and the solid suspension was stirred for 30 min at room temperature, filtered and washed 3 times with water. The crude material was dried under vacuum for 1 hour and swished with 500 mL of EtOH to yield 21.2 g of the title compound as off-white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2].[CH2:13](O)[CH2:14][OH:15].O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]1[O:15][CH2:14][CH2:13][O:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C=O
Reactant: OCCO
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)Oc1ccccc1C1OCCO1

Procedure:
2-Hydroxygenzaldehyde (10 g) was dissolved in acetic anhydride (30 ml) and pyridine (30 ml) followed by stirring at room temperature for 3 hours. The reaction mixture was poured into ice-water and the resulting precipitate was recovered by filtration. The precipitate was dissolved in chloroform (100 ml), washed with water, dried and evaporated to give 2-acetoxybenzaldehyde. To a solution of 2-acetoxy-benzaldehyde (13 g) and ethyleneglycol (10 ml) in benzene (80 ml) was added Amberlist 15 (Rohm and Haas Co.) (3 g) and followed by refluxing for 5 hours. Water generated during refluxing was removed as an azeotropic mixture. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, and then with water, and dried and evaporated. The residue was distilled under reduced pressure to collect a fraction distilled out at 115°-125° C./4 mmHg to give 10 g of 2-(2-acetoxyphenyl)-1,3-dioxolan. To a solution of 2-(2-acetoxy-phenyl)-1,3-dioxolan (19.6 g) in dichloromethane (50 ml), bis(trimethylsilyl)-5-fluorouracil prepared as in Example 1 from 5-fluorouracil (10 g) was added and treated as in Example 10 to give 4.2 g of crystalline 1-[α-(2-hydroxyethoxy)-2-acetoxybenzyl]-5-fluorouracil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccccc1Cl
Yield: 97.6 %

Procedure:
Step AR (1): 2-(2-Chlorophenyl)acetic acid (5.0 g, 29.3 mmol) was deprotonated with NaHMDS (2.0 M in THF, 29.3 mL, 58.6 mmol) and reacted with 1-chloro-4-iodobutane (5.38 mL, 44.0 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(2-chlorophenyl)hexanoic acid (7.47 g, 88% yield). LC-MS (M−H)− 259.1. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]2[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][CH:17]=2)=[C:13]([OH:15])[CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[O:20]1[C:19]2([CH2:24][CH2:25][CH:16]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=3[OH:15])[CH2:17][CH2:18]2)[O:23][CH2:22][CH2:21]1
Reactant: Oc1cc(OCc2ccccc2)ccc1C1=CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(C2CCC3(CC2)OCCO3)c(O)c1
Reaction time: 64 h
Yield: 99.9 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 5-(benzyloxy)-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol (6.90 g, 20.4 mmol), ethanol (300 ml) and palladium (2.00 g, 10% on activated carbon). The reaction vessel was then evacuated and placed under a hydrogen atmosphere. This process was repeated 15 times before stirring vigorously for 64 hr under a hydrogen atmosphere. The reaction mixture was filtered through a celite plug, washing with ethyl acetate. The filtrate was concentrated in vacuo, furnishing the title compound (5.10 g, 100%) as a solid. m/z (ES+) 251(M+H+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[O:18]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(COc1ccccc1)c1ccc(Cl)cc1

Procedure:
A mixture of 23.3 g. (0.1 mol.) of α-bromo-p-chloroacetophenone, 10.0 g. (0.1 mol.) of phenol and 14.5 g. (0.1 mol.) of potassium carbonate in 65 ml. of dry acetone is refluxed for 12 hours. The reaction mixture is cooled, poured into 500 ml. of water and the precipitate formed is collected by filtration and recrystallized from ethanol to give α-phenoxy-p-chloroacetophenone.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([OH:17])([C:13](F)(F)F)=[O:12]>>[S:9]1[C:10]2[C:2]([CH2:13][C:11]([OH:17])=[O:12])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=[CH:8]1
Reactant: Brc1cccc2ncsc12
Reactant: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cccc2ncsc12

Procedure:
The title compound (20 mg) was prepared from 7-bromobenzo[d]thiazole according to protocol P. LCMS (0.05% TFA): [M+1]+ 194.1. 1H-NMR (CDCl3, 400MHz): δ9.05 (s, 1H), 8.10(d, 1H, J=6.8Hz), 7.53 (m, 1H), 7.39 (d, 1H, J=6.8Hz), 3.96(s, 2H).
Reaction SMILES: [P:1]([O:13]C[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].P(O[CH2:42][C@H:43]1[O:47][C@@H:46]([N:48]2[C:58]3[N:57]=[C:55]([NH2:56])[NH:54][C:52](=O)[C:51]=3[N:50]=[CH:49]2)[CH2:45][C@@H:44]1[OH:59])(OP(OP(O)(O)=O)(O)=O)(=O)O>[Au]>[CH:55]1[N:57]=[C:58]2[N:48]([C@@H:46]3[O:47][C@H:43]([CH2:42][O:12][P:9]([O:8][P:5]([O:4][P:1]([OH:13])([OH:3])=[O:2])([OH:7])=[O:6])([OH:11])=[O:10])[C@@H:44]([OH:59])[CH2:45]3)[CH:49]=[N:50][C:51]2=[C:52]([NH2:54])[N:56]=1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Agent: [Au]
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1

Procedure:
The reaction conditions for the PCR followed a protocol recommended by the enzyme manufacturer (PE Applied Biosystems, Foster City, Calif.). The Banyuls promoter was isolated from Arabidopsis genomic DNA using 30 nanomoles each of primers Ban+1500 and Ban GSP1, 10 micromoles each of dATP, dCTP, dGTP, and TTP, 2.5 units of AmpliTaq Gold in 1× Opti-Prime™ Buffer 3 (Stratagene, La Jolla, Calif.). After an initial incubation at 95° C. for 10 minutes, 30 cycles of PCR were performed with 92° C. for 30 seconds, 56° C. for 30 seconds, and 72° C. for 2 minutes followed by 1 cycle of 72° C. for 7 minutes.
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH2:22]O)[CH:16]=[C:17]([F:19])[CH:18]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>N1C=CC=CC=1.O>[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH2:22][N:24]=[N+:25]=[N-:26])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: OCCCc1cc(F)cc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: [N-]=[N+]=NCCCc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
Tosyl chloride (0.0814 mol) was added to a cooled (0°) solution of 3-(3,5-difluorophenyl)propanol (0.0407 mol) in pyridine (75 ml). The reaction was stirred 2 hours at 25°, then it was poured into ice/water and extracted into ethyl ether. The ethereal extracts were washed with 3N aqueous hydrogen chloride and water, then were dried over sodium sulfate and concentrated. The residue was dissolved in dimethylformamide (75 ml) and sodium azide (0.0814 mol) was added. The reaction was stirred 8 hours, then was diluted with water and extracted into ethyl acetate. The organic extract was washed with 3N aqueous hydrogen chloride and water, then dried over sodium sulfate and concentrated to yield 6.7 g (64%) of an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].CCN(CC)CC.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)Cl>[CH2:22]([O:21][C:19]([NH:7][CH2:6][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: NCCc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCc1cccc(Br)c1

Procedure:
A solution of m-bromophenethylamine (6.71 g, 33.55 mmol) and Et3N (7 mL, 50.32 mmoL) in CH2Cl2 (100 mL) is cooled to 0° and ethyl chloroformate (4 mL, 50.32 mmoL) is added. After addition is complete the resulting mixture is allowed to come to room temperature and the solvent is removed in vacuo. The residue is then dissolved in EtOAc (200 mL) and the organic phase washed with 2N HCl (1×250 mL), H2O (1×200 mL), saturated NaHCO3 solution (1×200 mL), saturated NaCl solution (1×200 mL), dried over MgSO4 and concentrated in vacuo to give N-ethoxycarbonyl-m-bromophenethylamine.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]([CH3:12])([CH2:10][CH3:11])[C:7](O)=[O:8].[NH2:13][C:14]1[S:15][C:16]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[N:17][N:18]=1.O>CN(C)C(=O)C>[C:21]1([C:19]([C:16]2[S:15][C:14]([NH:13][C:7](=[O:8])[C:6]([OH:5])([CH3:12])[CH2:10][CH3:11])=[N:18][N:17]=2)=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCC(C)(O)C(=O)O
Reactant: Nc1nnc(C(=O)c2ccccc2)s1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCC(C)(O)C(=O)Nc1nnc(C(=O)c2ccccc2)s1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (60 μl, 0.82 mmol) is added to 2-hydroxy-methylbutyric acid (96.0 mg, 0.813 mmol) in 5.0 ml of N,N-dimethylacetamide at -20°/-15° C. and the mixture is stirred at -15°/-10° C. for one hour. After adding 2-amino-5-(phenylcarbonyl)-1,3,4-thiadiazole (102.3 mg, 0.499 mmol) and equilibrating the reaction mixture to room temperature, it is stirred overnight. The reaction mixture is poured into 100 ml of water and subjected to extraction with 3×25 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and filtered and the solvent is distilled off. The oil which remains is purified by flash chromatography (eluent: 33% v/v ethyl acetate in petroleum ether (40/60)).
Reaction SMILES: [NH:1]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22](O)=[O:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH2:38][C@H:39]([C:49]([NH:51][C@H:52]([C:60]([N:62]1[CH2:73][CH2:72][CH2:71][C@H:63]1[C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])=[O:61])[C@@H:53]([CH3:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:50])[CH2:40][CH2:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:6]([NH:5][C:3]([CH2:2][NH:1][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[O:4])[C:14]([OH:15])=[O:43])=[CH:13][CH:12]=1.[NH2:16][CH2:17][C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([NH:38][C@H:39]([C:49]([NH:51][C@H:52]([C:60]([N:62]1[CH2:73][CH2:72][CH2:71][C@H:63]1[C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])=[O:61])[C@@H:53]([CH3:59])[O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:50])[CH2:40][CH2:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:23])=[O:19]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H]1CCCN1C(=O)CN)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Product: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
667 mg of Z-Gly-Phe-Gly-Pro-OH are dissolved in 20 ml of acetonitrile together with 608 mg of H-Glu(OtBu)-Thr(tBu)-Pro-OtBu obtained under 4 and after the addition of 222 mg of N-hydroxysuccinimide and 269 mg of dicyclohexylcarbodiimide, stirred for 16 hours at room temperature. The precipitated dicyclohexyl urea is filtered off, the filtrate . evaporated, the residue dissolved in much ethyl acetate and the solution washed as described under 1, above. After drying and evaporation of the solution in vacuo, the crude product is purified by chromatography on a column of silica gel. It can be eluted with ethyl acetate an ethyl acetate×ethanol (4:1). It is then reprecipitated from ether. Melting point: 96° - 99°C. Thin-layer chromatogram on silica gel: RfCHCl3-MeOH(δ:1) = 0.40; Rf102A = 0.75; Rf52 = 0.80