Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:16])[CH:14]=[CH2:15])[CH2:9][CH:8]=1.Br[C:18]1[CH:19]=[C:20]2[C:37](=[N:38][CH:39]=1)[NH:36][C:35](=[O:40])[C:22]1([CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)[CH2:21]2.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:40]=[C:35]1[C:22]2([CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH2:21][C:20]2[C:37](=[N:38][CH:39]=[C:18](/[CH:15]=[CH:14]/[C:13](=[O:16])[N:10]3[CH2:11][CH2:12][C:7]([CH2:6][C:2]4[S:1][CH:5]=[CH:4][N:3]=4)=[CH:8][CH2:9]3)[CH:19]=2)[NH:36]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Reactant: C=CC(=O)N1CC=C(Cc2nccs2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc1NC2=O
Temperature: 110 °C
Yield: 22.7 %

Procedure:
To a stirred solution of 1-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one (Intermediate-4) (350 mg, 1.50 mmol) and tert-butyl 6-bromo-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate (Intermediate-6) (500 mg, 1.20 mmol) in DMF/propionitrile (4 mL/16 mL) was added DIPEA (0.55 mL, 3.16 mmol) at 20-35° C. and the mixture was degassed with N2 for 10 minutes. Then Pd(OAc)2 (28 mg, 0.12 mmol) and P(o-tolyl)3 (77 mg, 0.25 mmol) were added, again degassed with N2 for another 10 minutes and heated at 110° C. for 16 h. The reaction mixture was cooled to 20-35° C. and filtered through Celite®. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 3% MeOH/DCM as an eluent to get the desired compound as a light yellow solid (150 mg, 22%); 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.37 (d, J=1.5 Hz, 1H), 8.09 (s, 1H), 7.71 (d, J=3.4 Hz, 1H), 7.61 (d, J=3.5 Hz, 1H), 7.45 (d, J=15.1 Hz, 1H), 7.28-7.16 (m, 1H), 5.68-5.64 (m, 1H), 4.24-4.21 (m, 1H), 4.08-4.03 (m, 1H), 3.75 (s, 2H), 3.64-3.61 (m, 1H), 3.57-3.52 (m, 3H), 3.27-3.21 (m, 2H), 2.94 (s, 2H), 2.18-2.13 (m, 2H), 1.80-1.68 (m, 2H), 1.39 (s, 9H), 1.40-1.31 (m, 2H); ES-MS: 548.2 (M−1)+.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:14]=[C:13]([F:15])[C:11]([NH2:12])=[C:10]([F:16])[CH:9]=1.C(N(CC)CC)C>C1COCC1>[Br:7][C:8]1[CH:14]=[C:13]([F:15])[C:11]([NH:12][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[C:10]([F:16])[CH:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1c(F)cc(Br)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1c(F)cc(Br)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (1.05 ml) was added to a solution of 4-bromo-2,6-difluoroaniline (1.00 g) and triethylamine (1.61 ml) in THF (10 ml) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, passed through NH silica gel pad and concentrated in vacuo. The solid was washed with IPE/hexane to give the title compound (1.08 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:17])=[C:4]([CH2:10][CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=[O:13])[C:5]([I:9])=[CH:6][C:7]=1[I:8].[Cl:18][CH2:19][C:20](Cl)=[O:21].[OH-].[Na+].Cl>CC(N(C)C)=O.O>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[C:3]([I:17])=[C:4]([CH2:10][CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=[O:13])[C:5]([I:9])=[CH:6][C:7]=1[I:8])=[O:21]
Reactant: CCC(Cc1c(I)cc(I)c(N)c1I)C(=O)O
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CCl)c1I)C(=O)O
Reaction time: 1 h
Yield: 9.5 %

Procedure:
To a solution of 50 g of 3-amino-α-ethyl-2,4,6-triiodobenzenepropanoic acid (CAS RN, 96-83-3) (0.0875 mol) in 200 ml of DMA at 0° C., 11.87 g of chloroacetyl chloride (0.10 mol) are added. After 60 minutes at room temperature, the solution is dropwise added to 100 ml of H2O to give a precipitate which is filtered. The residue is dissolved in 100 ml of H2O and 43.7 ml of 2N NaOH (0.0875 mol) are added. 42 ml of 2N HCl (0.0084 mol) are added to precipitate a solid which is filtered. 5.4 g of 3-[(2-chloroacetyl)amino]-α-ethyl-2,4,6-triiodobenzenepropanoic acid are obtained (0.083 mol).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:17]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:18]=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:28]([I:31])(I)I>C1COCC1.[Cl-].[Cr+3].[Cl-].[Cl-]>[Si:1]([O:8][C@H:9]([C@H:17]([O:20][Si:21]([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:22])[CH3:23])/[CH:18]=[CH:28]/[I:31])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)CCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Reactant: IC(I)I
Agent: [Cr+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)CCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](/C=C/I)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.7 %

Procedure:
A solution of (5S,6S)-methyl 5,6-bis(tert-butyldimethylsilyloxy)-7-oxoheptanoate (389 mg, 0.929 mmol) and iodoform (2.19 g, 5.57 mmol) in THF (20 mL) was allowed it to stir for about 10 min. In a separate round bottom flask added chromium chloride (II)(1.36 mg, 11.1 mmol) and dissolved it in THF (10 mL) and cooled the reaction mixture to 0° C. The aldehyde and iodoform mixture were transferred to a stirring solution of chromium chloride at 0° C., warmed to room temperature and allowed to stir for 3 h. The reaction was quenched with water, extracted with ether, dried, and concentrated. Purification by flash chromatography (silica gel, hexanes) afforded 200 mg (40% yield) of (5S,6R,E)-methyl 5,6-bis(tert-butyldimethylsilyloxy)-8-iodooct-7-enoate. 1H NMR (250 MHz, CDCl3): δ 6.46 (dd, J=14.9 Hz, J=7.2 Hz 1H), 6.18 (d, J=15.4 Hz, 1H), 3.85 (m, 1H), 3.63 (s, 3H), 3.52 (m, 1H), 2.27 (t, J=7.1 Hz, 3H), 1.62 (m, 2H), 1.47 (m, 2H), 0.850 (s, 9H), 0.849 (s, 9H), 0.023 (s, 6H), 0.013 (s, 3H), −0.005 (s, 3H).
Reaction SMILES: [CH:1]([C:4]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:29](=[O:31])[NH2:30])N1C(=O)C(CC(O)=O)(C)C(=O)N(C2C=CC=CC=2)C2C=CC=CC1=2)([CH3:3])[CH3:2].C(O[C:46]([CH2:48][C:49]1([CH2:83]C(O)=O)[C:55](=[O:56])[N:54](C(C(C)C)(C2C=CC(OC)=CC=2)C(=O)N)[C:53]2[CH:72]=[CH:73][CH:74]=[CH:75][C:52]=2[N:51]([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C:50]1=[O:82])=[O:47])C1C=CC=CC=1.C(Cl)CCl.C1C=CC2N(O)N=[N:97]C=2C=1.[OH-].[NH4+]>CN(C=O)C.CCOC(C)=O>[CH:1]([C:4]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:29](=[O:31])[NH2:30])[N:51]1[C:50](=[O:82])[C:49]([CH2:48][C:46]([NH2:97])=[O:47])([CH3:83])[C:55](=[O:56])[N:54]([C:53]2[CH:52]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C:81]2[CH:80]=[CH:79][CH:78]=[CH:77][C:76]1=2)([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(CC(=O)O)(CC(=O)OCc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)cc1
Reactant: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(C)(CC(=O)O)C(=O)N(c2ccccc2)c2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(C)(CC(N)=O)C(=O)N(c2ccccc2)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a stirring solution of 233 mg (0.47 mmol) of [1-(Isopropyl-phenyl-carbamoylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-acetic acid, prepared as in Intermediate 7, in 2 mL DMF is added 98 mg (0.51 mmol, 1.1 equiv) of EDC and 76 mg (0.56 mmol, 1.2 equiv) of HOBT. The resulting solution is stirred 5 min, then 75 mL (0.61 mmol, 1.3 equiv) of a 30% solution of ammonium hydroxide is added. The solution is stirred 2 h at RT, then poured into 30 mL of EtOAc and extracted H2O (1×30 mL) and NaHCO3 (1×30 mL). The organic layer is separated, dried (MgSO4), and the solvent removed in vacuo. Purification of the resulting grey solid via reverse phase MPLC using a C-18 column and 60% acetonitrile/40% H2O with 0.1% TFA as eluent followed by lyophilization afforded 35 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz, mixture of conformers) δ7.47-6.80 (m, 14H), 6.70 (s, br, 0.5H), 5.84 (s, br, 0.5H), 5.03 (m, 1H), 4.63 (d, 0.5H, J=16.6), 4.35 (d, 0.5H, J=16.3), 4.08 (d, 0.5H, J=16.6), 3.74 (d, 0.5H, J=16.3), 3.10 (m, 1H), 2.46 (d, 0.5H, J=14.7), 2.23 (d, 0.5H, J=14.7), 1.65 (s, 1.5H), 1.16 (m, 7.5H); low resolution MS (FAB)m/e 499 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C@H:9]1[CH2:11][O:10]1)C=C.[C:19]1(C)[CH:24]=C(C)C=C(C)[CH:20]=1>>[CH2:24]([C:15]1[C:5]2[O:4][CH:9]([CH2:11][OH:10])[CH2:8][O:7][C:6]=2[CH:12]=[CH:13][C:14]=1[N+:16]([O-:18])=[O:17])[CH:19]=[CH2:20]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1OC[C@H]1CO1
Product: C=CCc1c([N+](=O)[O-])ccc2c1OC(CO)CO2

Procedure:
(R)-2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane (20 g, 80 mmoles) prepared as above was heated at 155° C. in mesitylene for 24 hours under nitrogen. Filtration of the black solid which formed gave 1.5 g of very polar material. Evaporation of the solvent in vacuum followed by column chromatography on silica gel with methylene chloride as eluant gave 10 g of recovered starting material and 7.5 g of the desired rearranged (S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol, which slowly crystallized on standing in vacuum (m.p. 67° C.). The yield based on recovered starting material is 75%.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([CH:19]=[CH2:20])=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].Cl[C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>ClCCl>[Cl:8][C:9]1[C:18]([CH:19]2[O:33][N:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20]2)=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C=Cc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Reactant: CCOC(=O)C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)OC)c2Cl)C1
Reaction time: 12 h

Procedure:
6.4 ml (46 mmol) of triethylamine were added slowly dropwise at room temperature to a solution of 8.5 g (31 mmol) of methyl 2-chloro-3-ethenyl-4-methylsulfonylbenzoate and 7.2 g (46 mmol) of ethyl 2-chloro-2-hydroxyiminoacetate in 200 ml of dichloromethane. After the mixture had been stirred for in each case 2 hours, 3 further portions of in each case 4.8 g (31 mmol) of ethyl 2-chloro-2-hydroxyiminoacetate and then 4.3 ml (31 mmol) of triethylamine were added. Stirring was continued for 12 hours at room temperature, and the reaction mixture was then stirred into 600 ml of water. After extraction with dichloromethane, drying and removal of the solvent, the residue was chromatographed.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.COC(=O)C(O)C(C)C.[CH2:35]([O:37][C:38](=[O:42])[C@@H:39](O)[CH3:40])[CH3:36].CO>C(OCC)(=O)C>[CH2:35]([O:37][C:38](=[O:42])[C@H:39]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:40])[CH3:36]
Reactant: CCOC(=O)[C@H](C)O
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Agent: COC(=O)C(O)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)[C@@H](C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2

Procedure:
Following the procedure of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol, 2-hydroxy-3-methyl-butyric acid methyl ester and (S)-2-hydroxypropionic acid ethyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (R)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid ethyl ester as a yellow oil contaminated with triphenylphosphine oxide, no further purification was undertaken. LCMS: RT=3.51 min, [M+H]+=452
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[N-:15]([C:18]#[N:19])[C:16]#[N:17].[Na+].Cl>C(O)CCC>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]([NH:15][C:16]#[N:17])=[NH:19])[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CN(C)Cc1nc(CSCCNC(=N)NC#N)cs1

Procedure:
A reaction mixture was prepared from 1.16 g of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine, 0.45 g of sodium dicyanamide, 4.8 ml 1N aqueous hydrochloric acid and 8 ml of n-butanol. The reaction mixture was heated to reflux temperature for about 16 hours and then was filtered. Evaporation of the filtrate to dryness yielded a residue which was purified by chromatography over silica using a 98:2 ethyl acetate:methanol solvent mixture as the eluant. Fractions shown by tlc to contain the desired product were combined and the solvent evaporated therefrom. N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyanoguanidine thus obtained was a glass.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>C1COCC1>[C:20]([Si:17]([CH3:19])([CH3:18])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:9])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 10.8 %

Procedure:
To a stirring solution consisting of benzyl 4-hydroxyphenyl ketone (650 g) in THF (5.5 L) at room temperature under a nitrogen atmosphere is added tert-butyldimethylsilyl chloride (692 g, 4.59 moles) and imidazole (354 g,). The reaction mixture is stirred overnight and is then concentrated under reduced pressure. The evaporate is dissolved in ether is washed with water and brine, is dried over anhydrous Na2SO4, and is concentrated under reduced pressure to afford a solid. The solid is triturated with pentane. The triturated solids are collected by filtration to afford a solid (850 g.) The filtrate is concentrated under reduced pressure to give a solid. This solid is triturated with pentane and the resulting solids are collected by filtration to provide a second crop of solid (108 g), which afforded a total of 958 g of Compound A.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1.C([C:12]1[C:25]2[C:16](=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:14][CH:13]=1)=C.C1(C=O)C2C(=CC3C(C=2)=CC=CC=3)C=CC=1>>[CH:15]1[C:16]2[C:25](=[CH:24][C:23]3[C:18]([CH:17]=2)=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[CH:13][CH:14]=1
Reactant: C=Cc1cccc2cc3ccccc3cc12
Agent: O=Cc1cccc2cc3ccccc3cc12
Solvent: Cc1cc(C)cc(C)c1
Product: c1ccc2cc3ccccc3cc2c1
Temperature: 150 °C

Procedure:
Approximately 10 mmol mesitylene solution of vinylanthracene (VA) or anthraldehyde (AnA) was put in a round bottom flask and bubbled with nitrogen or argon gas for at least 30 min. A piece of the H-terminated silicon substrate was then immersed in the solution and allowed to react with VA or AnA for about 12 h under reflux at about 150° C. in an oil bath. During the reaction, the solution was also purged with nitrogen (or argon) to eliminate dissolved oxygen and to prevent the substrate from being oxidized. After the reaction, the substrate derivatized with VA or AnA was rinsed with dichloromethane, acetonitrile and methanol; and dried under a stream of nitrogen gas. The derivatization of the H-terminated surface with anthracene moieties as described in Example 3 is illustrated in FIG. 6.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)([CH3:3])C.Cl[C:31]1N=CN=C2C=1N=CN2CCCN1CCN(C2C=CC(F)=CC=2)CC1.C(N)(C)C>>[CH2:1]([NH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH2:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:3][CH3:31]
Reactant: Fc1ccc(N2CCN(CCCn3cnc4c(Cl)ncnc43)CC2)cc1
Reactant: CC(C)Nc1ncnc2c1ncn2CCCN1CCN(c2ccc(F)cc2)CC1
Solvent: CC(C)N
Product: CCCNc1ncnc2c1ncn2CCCN1CCN(c2ccccc2)CC1
Yield: 58 %

Procedure:
N6 -isopropyl-9-{3-[4-(4-fluorophenyl)-piperazino]-propyl}-adenine from 6-chloro-9-{3-[4-(4-fluorophenyl)-piperazino]-propyl}-purine and isopropylamine; yield 58% of theory; m.p. of the dihydrochloride 232°-233° C after recrystallization from methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=2[Cl:24])=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])([O-:3])=[O:2].[OH-].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:17]([Cl:24])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=2[Cl:22])=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc(Oc2c(Cl)cc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(Oc2c(Cl)cc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Yield: 66.9 %

Procedure:
The product from paragraph (a) (6.86 g) in ethanol (50 ml) was heated and stirred with a solution of sodium hydroxide (0.8 g) in water (10 ml) at 60°-70° C. for 4 hours. The mixture was then cooled and the ethanol removed under reduced pressure. The residue was diluted to 100 ml with water and brought to pH 2 with concentrated hydrochloric acid. The solid which separated was collected and recrystallised from toluene to give the required benzoic acid derivative (4.26 g) with a melting point of 192°-192.5° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[F:27][CH:28]([F:32])[C:29](O)=O.[Cl:33][C:34]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([Cl:45])[C:35]=1[NH2:36].C(Cl)(Cl)(Cl)[Cl:47]>>[Cl:33][C:34]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([Cl:45])[C:35]=1[N:36]=[C:29]([Cl:47])[CH:28]([F:32])[F:27]
Reactant: O=C(O)C(F)F
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: FC(F)C(Cl)=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
First, 31.4 g (120 mmol) of triphenylphosphine and 4.9 g (48 mmol) of triethylamine were added to 20 ml of carbon tetrachloride, to which 3.8 g (40 mmol) of difluoroacetic acid was added dropwise under ice cooling. After completion of the dropwise addition, the mixture was stirred under ice cooling for 10 minutes. Then, a solution of 9.2 g (40 mmol) of 2,6-dichloro-4-trifluoromethylaniline in 20 ml of carbon tetrachloride was added dropwise to the reaction mixture, which was heated at 80° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of hexane, and undissolved matter was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6.0 g of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2-difluoroacetimidoyl chloride.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[CH2:12]([OH:14])[CH3:13]>CCOCC>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[NH:11])[O:14][CH2:12][CH3:13])=[CH:5][CH:4]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)Cc1ccc(Cl)cc1
Reaction time: 72 h

Procedure:
Dry hydrogen chloride was passed into a mixture of 4-chlorophenylacetonitrile (50.5 g.) and dry ethanol (16.1 g., 20.1 ml.) until a weight increase of 14.6 g. was obtained. The mixture was allowed to stand at room temperature for 3 days; the resulting crystalline mass was broken up, digested thoroughly with dry ether, filtered, and dried in vacuo to give ethyl 4-chlorophenylacetimidate hydrochloride.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[N:28][C:27]=1[CH2:32][O:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2=[N:44][N:45]=[C:46]([C:47]3[CH:51]=[C:50]([CH3:52])[O:49][N:48]=3)[N:36]2[N:35]=1)(C)C.O>C1COCC1.CO>[CH3:31][N:30]1[C:26]([CH2:25][OH:24])=[C:27]([CH2:32][O:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]3=[N:44][N:45]=[C:46]([C:47]4[CH:51]=[C:50]([CH3:52])[O:49][N:48]=4)[N:36]3[N:35]=2)[N:28]=[N:29]1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)nn23)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CO)nn23)no1
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A solution of tetrabutylammonium fluoride (3.3 mmol) in THF (1.0 M, 3.3 ml) was added to a stirred solution of 6-({[5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-1-methyl-1H-[1,2,3]triazol-4-yl]methyl}oxy)-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (1.90 g, 3.3 mmol) in THF (50 ml) and MeOH (10 ml) at room temperature under N2 and the reaction mixture was stirred overnight. H2O (10 ml) was added and then the mixture was concentrated under reduced pressure to remove the organic solvents. The resulting solid was filtered off, washed with H2O (20 ml), then triturated with CH2Cl2 (100 ml), filtered and dried, to yield the desired hydroxymethyltriazole (672 mg, 56%). 1H NMR (400 MHz, d6-DMSO) δ 8.56 (1H, d, J=7.9 Hz), 8.17-8.04 (2H, m), 7.91 (1H, td, J=7.9, 0.9 Hz), 7.22 (1H, s), 5.71 (2H, s), 5.42 (1H, t, J=5.6 Hz), 4.72 (2H, d, J=5.6 Hz), 4.06 (3H, s), 2.59 (3H, s).
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O.[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][N:28]2[C:32](=[O:33])[N:31]([C:34]3[S:35][C:36]([C:40]([OH:42])=O)=[C:37]([CH3:39])[N:38]=3)[CH:30]=[N:29]2)=[CH:25][CH:24]=1.[NH2:45][CH2:46][C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[N:50]([CH3:52])[CH3:51]>>[CH3:51][N:50]([CH3:52])[C:49]1[CH:48]=[C:47]([CH:55]=[CH:54][CH:53]=1)[CH2:46][NH:45][C:40]([C:36]1[S:35][C:34]([N:31]2[C:32](=[O:33])[N:28]([CH2:27][C:26]3[CH:43]=[CH:44][C:23]([F:22])=[CH:24][CH:25]=3)[N:29]=[CH:30]2)=[N:38][C:37]=1[CH3:39])=[O:42]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: CN(C)c1cccc(CN)c1
Agent: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccc(N(C)C)c1
Yield: 50 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)-N,N-dimethylaniline, the title compound was obtained as a colourless solid in 50% yield: mp 149-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=5.9 Hz, 1H), 8.71 (s, 1H), 7.35 (dd, J=8.5, 5.6 Hz, 1H), 7.15 (d, J=8.9 Hz, 1H), 7.09 (dd, J=7.9, 6.9 Hz, 2H), 6.66 (s, 1H), 6.58 (dd, J=7.7, 7.7 Hz, 2H), 4.96 (s, 2H), 4.35 (d, J=5.8 Hz, 2H), 2.83 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ 163.7, 161.3, 160.5, 151.6, 151.2, 150.9, 150.1, 140.3, 132.7 (d, 3JC-F=11 Hz), 132.4, 130.4 (d, 2JC-F=33 Hz), 129.2, 123.1, 115.9 (d, 1JC-F=86 Hz), 115.6, 111.7, 111.4, 48.2, 43.6, 40.5, 17.3; MS (ES+) m/z 467.16 (M+1).