Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:15][C:13]([CH2:12][O:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cccnc1C(N)=O
Temperature: 80 °C
Yield: 53.3 %

Procedure:
A mixture of 3-hydroxy picolinic amide (10 g, 72 mmol), ethyl bromoacetate (12.02 g, 72 mmol) and anhydrous potassium carbonate (10.9 g, 79.2 mmol) in 250 ml of dry 2-butanone is heated at 80° C. for 20 hours. After cooling, the inorganic salts are filtered off and the filtrate is reduced to approximately 120 ml. After addition of cold t-butyl methyl ether the resulting precipitate is filtered off, rinsed with cold t-butyl methyl ether and dried to give 8.6 g of 3-(ethoxycarbonylmethoxy)picolinamide (53%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[O:35]>Cl>[CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N:14]([CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[O:35])[S:15]([C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1NS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C=Cc1ccc(Cl)cc1N(CC(=O)c1ccc(Cl)cc1)S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of 3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylic acid ethyl ester (3.00 g, 7.90 mmol) in NN-dimethylacetamide (15.0 ml) was added potassium carbonate (2.18 g, 15.8 mmol) and 2-bromo-4′-chloroacetophenone (2.03 g, 8.69 mmol). The reaction was stirred for 30 minutes, poured into 1N hydrochloric acid (30 ml) and extracted with methyl f-butyl ether (2×30 ml). The organic extracts were dried over magnesium sulfate, filtered, concentrated to a low volume. Hexanes was added and a solid precipitated. The precipitate was filtered to provide 3-{4-chloro-2-[[2-(4-chloro-phenyl)-2-oxo-ethyl]-(toluene-4-sulfonyl)-amino]-phenyl}-acrylic acid ethyl ester (3.19 g, 76%). mp=162-165° C. 1H NMR (300 MHz, CDCl3) d 1.38 (t, 3, J=7.2), 2.47 (s, 3), 4.28 (q, 2, J=7.2), 5.00 (bs, 2), 6.23 (d, 1, J=16.0), 7.29-7.36 (m, 4), 7.47 (d, 2, J=8.7), 7.54 (d, 1, J=8.4), 7.59 (d, 2, J=8.3), 7.74 (d, 1, J=16.0), 7.88 (d, 2, J=8.7). 13C NMR (75 MHz, CDCl3) d 14.33, 21.62, 57.72, 60.66, 112.49, 120.69, 128.07, 129.21, 129.58, 129.70, 131.22, 132.80, 133.83, 134.80, 135.84, 138.55, 139.28, 140.38, 144.46, 166.02, 191.70. IR 1720, 1698, 1590, 1338, 1313, 1179, 1161, 1089 cm−1. Analysis calculated for C26H23Cl2NO5S: C, 58.65; H, 4.35; N, 2.63. Found: C, 58.74; H, 4.56; N, 2.72.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:13]Br>C(O)(=O)C>[Br:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([CH3:1])[C:3]=1[OH:12]
Reactant: BrBr
Reactant: Cc1cc2ccccc2cc1O
Solvent: CC(=O)O
Product: Cc1cc2ccccc2c(Br)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.3 %

Procedure:
3-Methylnaphthalen-2-ol (4A) (2.09 g, 13.2 mmol) was taken in acetic acid (50 mL) and bromine (2.11 g) was added to it. The mixture was stirred at room temperature for 20 minutes, concentrated and purified by flash chromatography (silica gel, ethyl acetate/hexanes) to give the desired product (2.7 g, 80%). 1H-NMR: 300 MHz, (CDCl3) δ 7.98 (d, 1 H), 7.60 (d, 1 H), 7.58 (s, 1 H), 7.53 (dd, 1 H), 7.38 (dd, 1 H), 6.05 (s, 1 H), 2.48 (s, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([F:48])=[C:36]([C@:38]2([CH:45]([F:47])[F:46])[CH2:43][CH2:42][O:41][C:40]([NH2:44])=[N:39]2)[CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[NH2:44][C:40]1[O:41][CH2:42][CH2:43][C@:38]([C:36]2[CH:37]=[C:32]([NH:31][C:9](=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:33]=[CH:34][C:35]=2[F:48])([CH:45]([F:46])[F:47])[N:39]=1
Reactant: NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)CCO1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@]3(C(F)F)CCOC(N)=N3)c2)nc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
To a solution of commercially available 5-cyanopicolinic acid (55.5 mg, 375 μmol) in methanol (5 ml) was added at 0° C. 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (129 mg, 437 μmol) and the colourless solution was stirred at 0° C. for 30 min. Then a solution of (S)-4-(5-amino-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (intermediate E9.1) (81 mg, 312 μmol) in methanol (5 ml) was added dropwise at 0° C. via syringe. The reaction mixture was stirred at 23° C. for 16 h. Poured into 1 M Na2CO3-sol., extracted with dichloromethane, washed the organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left a light brown oil which was chromatographed on 20 g silica gel with dichloromethane/methanol 0-10% to give (S)—N-(3-(2-amino-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide (89 mg, 229 μmol, 73.2% yield) as a white solid. MS (ISP): m/z=390.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CC2)CC1
Reaction time: 2 h
Yield: 26.7 %

Procedure:
1-(5-chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.063 g, 0.22 mmol) was combined with cyclopropanecarbonyl chloride (0.029 mL, 0.32 mmol) and triethylamine (0.090 mL, 0.64 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromthane) to give the desired product (21 mg, 27%). LCMS calculated for C19H21ClN3O2 (M+H)+: m/z=358.1; Found: 358.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>>[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:27]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1cccc(C(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c1

Procedure:
Compound 60 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-methylbenzoyl chloride and conditions outlined in procedure N. M.p.=188-190° C.; 300 MHz 1H NMR (CDCl3) δ 8.08 (d, J=7.8 Hz, 1H), 7.77 (d, J=6.9 Hz, 1H), 7.68 (m, 1H), 7.51 (m, 1H), 7.25 (m, 4H), 4.60 (m, 1H), 3.80 (m, 1H), 3.42 (m 2H), 2.98 (s, 2H), 2.38 (s, 3H), 2.24 (brm, 2H), 1.90 (brm, 2H); LCMS: 420 [M+H].
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[F:12][C:13](I)([F:15])[F:14].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:12][C:13]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([F:15])[F:14]
Reactant: FC(F)(F)I
Reactant: c1ccccc1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: FC(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20 %

Procedure:
100 μl of benzene, 2.0 ml of dimethyl sulfoxide, 2.0 ml of a 1 N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron(II) sulfate were charged in a two-neck flask in which the atmosphere was replaced with argon, and the mixture was stirred for 20 minutes. During the stirring, the temperature of the reaction system rose up in the range of from 40° C. to 50° C. Thereafter the resulting solution was cooled to room temperature. Formation of trifluoromethylbenzene (19F-NMR yield: 20%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. The subsequent procedure was conducted in the same manner as in Example 1 and trifluoromethylbenzene was obtained as a colorless oil (0.02 g, yield: 13%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:20]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[CH:6]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(Br)cc12
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a stirred solution of (R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (see Example 27, WO 92/06973) (21.44 g, 73.2 mmol) in tetrahydrofuran (110 ml) at 0° C. under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil, 3.51 g, 87.7 mmol) portionwise, maintaining the temperature below 5° C. Upon completion of the addition, the dark brown solution was stirred at 0-5° C. for 1 hr before benzyl bromide (10.4 ml, 87.4 mmol) was added dropwise maintaining the temperature below 5° C. The brown solution was then warmed to ambient temperature over a 1 hr period before being quenched into water (100 ml). The mixture was then extracted with ethyl acetate (3×25 ml) and the organic extracts were combined and evaporated in vacuo to yield a brown oil. This was purified by flash column chromatography (ethyl acetatehexane:diethylamine 1:1:0.1 as eluant) to give the subtitle compound (17.6 g, 63%) as a brown viscous oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCc1ccccn1
Product: BrCCCCCCOCCCCc1ccccn1

Procedure:
From 2-pyridinebutanol (3.96 g) and 1,6-dibromohexane (15 ml), with a reaction time of 4 h. FCC eluting with hexane→ether gave the title compound as a pale yellow oil (3.7 g), t.l.c. (hexane-diethyl ether 1:1) Rf 0.22.
Reaction SMILES: C[N:2]1[CH2:12][C@H:11](C2C=CC=CC=2)[C:10]2[CH:9]=[C:8]([OH:19])[C:7](Cl)=[CH:6][C:5]=2CC1.CC([C@]1([OH:47])C[C@H]2N(C[C@H]3C4C2=CC=CC=4CCC2C=CC=CC3=2)CC1)(C)C>>[NH2:2][CH2:12][CH2:11][C:10]1[CH:5]=[CH:6][C:7]([OH:47])=[C:8]([OH:19])[CH:9]=1
Reactant: CC(C)(C)[C@@]1(O)CCN2C[C@@H]3c4ccccc4CCc4cccc(c43)[C@H]2C1
Reactant: CN1CCc2cc(Cl)c(O)cc2[C@@H](c2ccccc2)C1
Product: NCCc1ccc(O)c(O)c1

Procedure:
HEK cells were transfected with DNA encoding D1-NLS-GFP (2 micrograms), and D1-WT (6 micrograms) for 48 hours. These cells were treated 6 hrs after transfection with SCH-23390 (10 micromolar), or (+)butaclamol (10 micromolar). The medium containing antagonist was changed at 6, 22, 30 and 42 hours after transfection. Control cells received no antagonist treatment.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:53]([NH:57][CH2:58][CH:59]([CH3:61])[CH3:60])[CH:54]([CH3:56])[CH3:55]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:22])[N:57]([CH2:58][CH:59]([CH3:61])[CH3:60])[CH2:53][CH:54]([CH3:56])[CH3:55])[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCNC(=O)OC(C)(C)C)c1
Reactant: CC(C)CNCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid (200 mg in 12 mL methylene chloride) was added 104 mg 1-hydroxybenzotriazole followed by 118 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture stirred at room temperature. After 30 minutes, 0.35 mL of diisobutylamine was added and the mixture stirred at room temperature for 14 hours. The reaction was then concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 2:1) to give the title compound (230 mg).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[SiH:5]1[N:9]([CH:10]([CH3:12])[CH3:11])[CH:8]=[CH:7][N:6]1[CH:13]([CH3:15])[CH3:14]>CCCCCC>[CH2:1]([NH:3][SiH:5]1[N:9]([CH:10]([CH3:11])[CH3:12])[CH:8]=[CH:7][N:6]1[CH:13]([CH3:15])[CH3:14])[CH3:2]
Reactant: CCN
Reactant: CC(C)N1C=CN(C(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CCN[SiH]1N(C(C)C)C=CN1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
In an argon atmosphere, 6.80 g (151 mmol) of ethylamine was dissolved in 20 mL of hexane, and a solution obtained by dissolving 5.73 g (28.0 mmol) of Si(iPrNCHCHNiPr)(H)Cl in 5 mL of hexane was added thereto at −20° C. After stirring at room temperature for 4 hours, insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 74° C./4.3×102 Pa) to obtain 2-ethylamino-1,3-di-isopropyl-1,3-diaza-2-silacyclopent-4-ene (Si(iPrNCHCHNiPr)(H)NHEt) as a colorless liquid (yielded amount: 5.34 g, yield: 89%).
Reaction SMILES: CC1(C)[C:30]2[NH:31][C:27](=[C:28](F)[C:29]=2F)[C:26](C)(C)[C:24]2[NH:25][C:21](=[C:22](F)[C:23]=2F)[C:20](C)(C)[C:18]2[NH:19][C:15](=[C:16](F)[C:17]=2F)[C:14](C)(C)[C:12]2[NH:13][C:9](=[C:10](F)[C:11]=2F)[C:8](C)(C)C2NC1=C(F)C=2F.CO.FC1C=CNC=1F.CS(O)(=O)=O>CC(C)=O>[CH2:26]1[C:27]2[NH:31][C:30](=[CH:29][CH:28]=2)[CH2:8][C:9]2[NH:13][C:12](=[CH:11][CH:10]=2)[CH2:14][C:15]2[NH:19][C:18](=[CH:17][CH:16]=2)[CH2:20][C:21]2[NH:25][C:24]1=[CH:23][CH:22]=2
Reactant: CC1(C)c2[nH]c(c(F)c2F)C(C)(C)c2[nH]c(c(F)c2F)C(C)(C)c2[nH]c(c(F)c2F)C(C)(C)c2[nH]c(c(F)c2F)C(C)(C)c2[nH]c1c(F)c2F
Agent: CS(=O)(=O)O
Agent: Fc1cc[nH]c1F
Solvent: CO
Solvent: CC(C)=O
Product: c1cc2[nH]c1Cc1ccc([nH]1)Cc1ccc([nH]1)Cc1ccc([nH]1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 52 %

Procedure:
β-Decafluoro-meso-decamethylcalix[5]pyrrole, 46 and β-hexadecafluoro-meso-hexadecamethylcalix[8]pyrrole, 48. To a round bottom flask containing methanol (37.5 mL), difluoropyrrole (773 mg, 7.50 mmol), and acetone (548 μL, 7.50 mmol were added. After dissolution of the reactants, methanesulfonic acid (490 μL, 7.50 mmol) was added and the reaction mixture was allowed to stir at ambient temperature for 2 days. The reaction mixture was then washed with aqueous NaCO3 (200 mL saturated) and taken into dichloromethane (100 mL). The resulting organic layer was then washed with water (2×100 mL), dried (Na2SO4), and the solvent was removed on the rotary evaporator. Purification of the crude reaction mixture, which was found to contain 44, 46 and 48 in appriciable yields as judged by TLC analysis, was effected via flash chromatography, using hexanes-acetone 4/1 v/v as the eluent. This resulted in the isolation of 44 (rf=0.4, 560 mg, 0.98 mmol, 52%), 46 (rf=0.2, 249 mg, 0.35 mmol, 23%), and 48 (rf=0.1, 150 mg, 0.13 mmol, 14%).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])=[CH:14][CH:13]=1>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[OH:28])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2CCc3ccccc3C2=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2CCc3ccccc3C2O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Step A Add DIBAL-H (83.8 mL, 83.8 mmol, 1M in THF) dropwise to a -78° C. solution of 2-(4'-methoxy-phenyl)-1,2,3,4-tetrahydronaphthalen-1-one (7.15 g, 27.94 mmol) in anhydrous THF (150 mL). Allow the reaction to come to room temperature overnight. Cool the mixture to 0° C. and quench with sodium sulfate decahydrate. Stir the mixture overnight, then vacuum filter and thoroughly wash the filtercake with THF. Concentrate the filtrate in vacuo, then chromatograph the resulting oil on silica gel using 20% EtOAc/hexanes to give a solid. Recrystallize from EtOAc/hexane to obtain 4.84 g (67%) of 2-(4'-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol, mp 89°-90.5° C.
Reaction SMILES: [NH:1]([C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C@@H:18]1[C@@H:22]([CH2:23][OH:24])[O:21][C@@H:20](N2C=CC(=O)NC2=O)[CH2:19]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH:1]([C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C@@H:20]1[O:21][C@H:22]([CH2:23][OH:24])[C@@H:18]([F:17])[CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2ncnc3[nH]cnc23)cc1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(Nc4ccccc4)ncnc32)C[C@@H]1F
Temperature: 45 °C
Reaction time: 96 h
Yield: 44.6 %

Procedure:
6-Anilino-9H-purine (0.55 g 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 4 days, 180 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOh. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (93:7). Solvent was removed and lyophilization yielded 0.323 g of 6-anilino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (45%): mp 83° C.; TLC Rf 0.72 (silica gel, MeCN:15N NH4OHiH2O/85:5:10); [α]D20 -18.8 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7,288 (22.2); at pH 13, 288 (21.0); 1H NMR (300 MHz, DMSO-d6) δ9.98 (s, 1H, NH), 8.54 and 8.41 (2s, 2H, H2 and H8), 7.95 (d, 2H, J=7.6 Hz), 7.31-7.37 (m, 2H), 7.06 (t, 1H, J=7.4 Hz), 6.48 (dd, 1H, H1', J=9.2 Hz, J=5.7 Hz), 5.38-5.58 (m, 2H, OH5' and H3'), 4.28 (dt, 1H, H4', J=26.8 Hz, J=4.6 Hz) 3.65 (m, 2H, H5' and H5"), and 2.97-3.18 and 2.64-2.78 (m, 2H, H2' and H2"); MS (ci) 330 (M+1), 310 (M-F), 212 (MH2 --C5H8FO2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:15][NH:16]C(OC(C)(C)C)=O)([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([OH:13])[CH:7]=1.Br[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=[O:29])[O:27]1>CC(C)=O>[CH3:1][O:2][C:3](=[O:24])[C:4]([NH:15][NH2:16])([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:28](=[O:29])[O:27]2)[CH:7]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: COC(=O)C(C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Solvent: CC(C)=O
Product: COC(=O)C(C)(Cc1ccc(O)c(OC2OC(=O)c3ccccc32)c1)NN
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.2 %

Procedure:
A mixture of compound 108 (380 mg, 1.1 mmol), bromophthalide (213 mg, 1 mmol) and CsHCO3 (325 mg, 1 mmol) in acetone was stirred at room temperature for 16 h. After removing the solvent under reduced pressure, the residue was partitioned between 10% citric acid and ethyl acetate. The organic phase was separated and dried over MgSO4. After removing the solvent under reduced pressure, the resulting residue was treated with 50% trifluoroacetic acid in dichloromethane at room temperature for 30 min. After removing the solvent, the resulting residue was purified by reverse phase preparative HPLC to afford two separated stereoisomers 113 (123 mg) and 114 (120 mg), respectively. Compound 113: 1H NMR (CD3OD, 400 MHz): 1.43 (s, 3H), 2.98 (dd, 2H), 3.80 (s, 3H), 6.62–7.20 (m, 4H), 7.66–7.95 (m, 4H). MS (ESI) m/z 373.25 (M+H+) and Compound 114:1H NMR (CD3OD, 400 MHz): 1.44 (s, 3H), 2.99 (dd, 2H), 3.84 (s, 3H), 6.80–7.18 (m, 4H), 7.69–7.93 (m, 4H). MS (ESI) m/z 373.25 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1.[H-].[Na+].Br[CH2:16][CH2:17]Br>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)[CH2:17][CH2:16]1)=[O:12]
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cccc(Br)c2)CC1
Reaction time: 0.5 h

Procedure:
A solution of (3-Bromo-phenyl)-acetic acid methyl ester (4.54 g, 20 mmol) dissolved in dry THF (10 mL) was added dropwise to suspension of NaH (95% dry, 1.05 g, 44 mmol) in DMF (40 mL) and THF (10 mL), under a nitrogen atmosphere, at 0° C. After 30 min, gas evolution ceased, and 1,2-dibromoethane (3.79 mL, 44 mmol) was added dropwise over 20 min. The resulting mixture was stirred for 1 h, then quenched with 1N HCl, extracted with ether, washed with brine, dried over MgSO4, and stripped of solvent. The resulting oil was distilled under high vacuum. The product was collected between 95° C. and 105° C. Yield 2 g, 39%.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:18])[NH2:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21].[Cl:22][CH2:23][C:24](=O)[CH2:25]Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:18][CH:25]=[C:24]([CH2:23][Cl:22])[N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21]
Reactant: CN1Cc2c(C(N)=S)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: O=C(CCl)CCl
Solvent: C1COCCO1
Product: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)c(Cl)c2C1=O
Yield: 35.1 %

Procedure:
A yellow suspension of 2.45 g (0.00754 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide in 130 ml of dioxan was treated with 1.05 g (0.00829 mol) of 1,3-dichloro-2-propanone. The suspension was boiled at reflux for 20 hrs. and cooled. A further 1.05 g (0.00829 mol) of 1,3-dichloro-2-propanone and 60 ml of dioxan were added and the solution was boiled at reflux for a further 16 hrs. The solution was cooled and completely freed from the solvents. The residue was chromatographed over silica gel with cyclohexane/ethyl acetate 1:2 as the eluent and recrystallized from hot acetonitrile. There were obtained 1.05 g (35%) of 7-chloro-3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 234-235°.