Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:27])[C:14]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[CH:21]=2)([OH:19])[C:15]([F:18])([F:17])[F:16])=[C:9]([Cl:28])[CH:8]=1)C.[OH-].[Na+].O.Cl>C1COCC1>[Cl:28][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:29])=[O:3])[CH:12]=[CH:11][C:10]=1[CH:13]([CH3:27])[C:14]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[CH:21]=1)([OH:19])[C:15]([F:16])([F:18])[F:17]
Reactant: CCOC(=O)CCc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(CCC(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-{3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl}-propionic acid ethyl ester (118 mg) was dissolved in THF (1 mL). To the solution was added 1M aq. NaOH (1 mL) to give a cloudy, light yellow mixture. The reaction was allowed to stir at RT for 2.5 hours; a clear solution was obtained at that time. Water was added and the pH was adjusted to pH=3 with dilute aqueous HCl. A colorless precipitate was formed. The mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried over Na2SO4 and evaporated. The title compound was obtained as a colorless solid (78 mg). MS (neg. ion, m/e)=420.1 (M−H)−.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Cl-].[Na+].[OH2:15].[OH2:16]>CN(C=O)C>[O:15]=[C:1]1[NH:5][CH2:4][C@H:3]([CH2:2][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[O:16]1
Reactant: O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC[C@H](CN2C(=O)c3ccccc3C2=O)O1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of Example IA (22.16 g) in DMF (163 mL) at room temperature was treated with potassium phthalimide (16.7 g), heated to 80° C., stirred for 5 hours, poured into 1:1 brine/water (200 mL), and extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was treated with ethyl acetate (200 mL), cooled to 5° C., and filtered. The mother liquor was concentrated, treated with ethyl acetate (100 mL), cooled to 5° C., filtered, and combined with the first crop to provide the desired product. MS (ESI(+)) m/e 247 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.88 (m, 2H), 7.75 (m, 2H), 4.98 (m, 1H), 4.10 (dd, 1H), 3.90 (dd, 1H), 3.73 (t, 1H), 3.49 (dd, 1H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])=[CH:10][CH:11]=1)[CH2:26][C:27]([OH:29])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)CC(C(=O)OCc1ccccc1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(CC(=O)O)C(=O)OCc2ccccc2)cc1

Procedure:
A suspension of 1-benzyl 4-tert-butyl 2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)succinate (1.00 g, 2.12 mmol) and silica gel (10.6 g) in toluene (50 mL) was heated at reflux for 3 h. The crude mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane/methanol (8:2; 2×100 mL) then the organic filtrates were combined and evaporated to dryness to give the title compound as a while solid (0.83 g, 94%). LC/MS: 4.03 min; z/e 432, calcd (M+18) 432. 1H NMR (400 MHz: DMSO-d6): 7.05 (7H), 6.60 (2H), 4.95 (2H), 3.85 (1H), 2.85 (1H), 2.40 (1H), 0.80 (9H), 0.00 (6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.Cl.[CH3:35][NH:36][O:37][CH3:38].CN(C)C=O>CCOC(C)=O>[Cl:33][C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([C:10]3[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=3)[OH:9])[CH:17]=2)[N:22]=[C:21]([N:36]([O:37][CH3:38])[CH3:35])[C:20]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: CNOC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)c1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1-c1ccccc1
Temperature: 100 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (250 mg, 0.505 mmol, Example 65), N,O-dimethylhydroxylamine hydrochloride (1.01 g, 10.1 mmol), and dimethylformamide (2 mL) were combined in a reaction tube, which was then sealed and heated to 100° C. for 48 hours. The contents were then cooled, transferred to a reparatory funnel, diluted with EtOAc and extracted with saturated, aqueous NH4Cl solution, followed by deionized water (4×). The organic phase was separated and dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C28H24Cl2N4O2, 518.1; m/z found, 519.2 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 8.14 (d, J=1.9 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.8, 2.1 Hz, 1H), 7.67 (s, 1H), 7.47 (dd, J=11.4, 4.3 Hz, 2H), 7.39 (dt, J=4.4, 1.8 Hz, 1H), 7.36 (d, J=4.1 Hz, 4H), 7.26 (dd, J=8.2, 1.3 Hz, 2H), 6.28 (s, 1H), 3.46 (s, 3H), 3.05 (s, 3H), 2.76 (s, 3H).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:9][CH:8]=1>C(O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[NH:23][CH:24]2[CH2:25][CH2:26][N:27]([CH2:4][CH2:3][C:2](=[O:5])[CH3:1])[CH2:28][CH2:29]2)=[CH:9][CH:8]=1
Reactant: C=CC(C)=O
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Solvent: CCO
Product: CC(=O)CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 42 %

Procedure:
A mixture of 2.1 parts of 3-buten-2-one, 9.7 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine and 120 parts of ethanol was stirred for 3 hours at reflux temperature. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 5 parts (42%) of 4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-butanone; mp. 131.3° C. (intermediate 91).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=2[F:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(F)c(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-5-methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 90° C. for 1 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 475 mg, about 100%).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([OH:24])[CH:23]=2)[O:20][C:19]([CH3:26])([CH3:25])[CH2:18][C:17]3([CH3:28])[CH3:27])=[CH:8][CH:7]=1)[CH3:5].[OH-].[K+]>CO.O1CCCC1>[OH:24][C:22]1[CH:23]=[C:14]([C:13]#[C:12][C:9]2[CH:10]=[CH:11][C:6]([CH:4]([CH3:5])[C:3]([OH:29])=[O:2])=[CH:7][CH:8]=2)[CH:15]=[C:16]2[C:21]=1[O:20][C:19]([CH3:26])([CH3:25])[CH2:18][C:17]2([CH3:27])[CH3:28]
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C(=O)O)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A solution of 2-[4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-propionic acid methyl ester (Intermediate 22, 0.018 g, 0.046 mmol) in methanol (1 mL) and tetrahydrofuran (0.5 mL) was treated with a 2M solution of potassium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at 80° C. for 2 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over-anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow solid (0.017 g, 100%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH:2][S:33]([CH3:32])(=[O:35])=[O:34])[CH:5]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride ((for a preparation see Intermediate 4) 51 mg, 0.10 mmol) in dry DCM (3 mL) was added methanesulfonyl chloride (8 μL, 0.1 mmol), followed by pyridine (1 mL). The resultant pale yellow solution was stirred at room temperature overnight. LCMS showed only 19% of required product. Triethylamine (14 μL, 0.10 mmol), followed by more methanesulfonyl chloride (8 μL, 0.1 mmol) were added and stirring was continued for a further 30 min. The reaction mixture was then concentrated in vacuo and the residue dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was evaporated in vacuo to give the title product (10.7 mg, 19%) as a white solid. LCMS (System A) RT=1.13 min, ES+ve m/z 541/543 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=O.[N+]([O-])(O)=O.[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:21])[F:20]>>[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[CH:11]=[CH:10][S:9][CH:8]=3)[CH:4]=[CH:3][N:31]=2)[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:20])[F:21]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: CN(C)C=CC(=O)c1ccsc1
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccsc3)n2)c1

Procedure:
In accordance with the general procedure described in Example 1, reaction of 10 g (0.055 mol) of 3-dimethylamino-(3-thienyl)-2-propen-1-one [described in EP-A-0 233 461] and 15 g (0.060 mol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(3-thienyl)-2-pyrimidine-amine; FAB-MS:370 (M+ +1), m.p. 110°-111°, Rf =0.8 (ethyl acetate:hexane=1:1).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f14) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[NH:10][CH:9]1[CH2:18][NH2:19])=O)(C)(C)C>Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]2[NH:10][C:9]([CH2:18][NH2:19])=[N:8][C:12]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)ccc2NC1CN
Agent: Cl
Product: NCc1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.62 g (16.398 mmol) N′-tert-butoxycarbonyl-C-(5-chloro-1H-benzimidazol-2-yl)methylamine are dissolved in 100 mL saturated ethanolic hydrogen chloride solution and stirred for 2 hours at ambient temperature. Then all the volatile constituents are removed under reduced pressure and the crude product is further reacted. Yield: quantitative; Rf value: 0.35 (silica gel; petroleum ether/ethyl acetate=8:2).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:9]([CH3:10])[S:8][CH2:7][C:6]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:3])[CH3:2].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:4][C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][S:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=C(OC(C)=O)C(C)SC1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1csc(C)c1OC(C)=O
Temperature: 25 °C

Procedure:
To methyl 4-acetoxy-2,5-dihydro-5-methyl-3-thiophene-carboxylate (68.3 g) in anhydrous methylene chloride (143 ml) was added sulphuryl chloride (30.4 ml) dropwise over 30 minutes. The black solution was stirred at room temperature over night.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH2:7][CH3:8])[CH2:4][NH2:5].Br[CH2:10][CH:11]1[O:16][CH2:15][CH2:14][CH2:13][O:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:15][O:16][CH:11]([O:12][CH2:13][CH3:14])[CH2:10][NH:5][CH2:4][CH:3]1[O:2][CH2:1][CH2:8][CH2:7][O:6]1
Reactant: CCOC(CN)OC
Reactant: BrCC1OCCCO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CNCC1OCCCO1)OC
Temperature: 25 °C

Procedure:
2-Methoxy-2-ethoxyethylamine (0.11 mole), 2-bromomethyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]5[NH:23][C:24]([NH:32][C:19]=5[CH:18]=4)=[C:25]4[CH:31]=[CH:30][C:28](=[O:29])[CH:27]=[CH:26]4)[NH:16][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[C:33](O)(=O)[CH2:34]CC(O)=O>C(Cl)(Cl)Cl>[CH3:33][CH2:34][O:29][C:28]1[CH:30]=[CH:31][C:25]([C:24]2[NH:32][C:19]3[CH:18]=[C:17]([C:15]4[NH:16][C:10]5[CH:9]=[C:8]([N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)[CH:13]=[CH:12][C:11]=5[N:14]=4)[CH:22]=[CH:21][C:20]=3[N:23]=2)=[CH:26][CH:27]=1
Reactant: CN1CCN(c2ccc3nc(-c4ccc5c(c4)NC(=C4C=CC(=O)C=C4)N5)[nH]c3c2)CC1
Reactant: O=C(O)CCC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(-c2nc3ccc(-c4nc5ccc(N6CCN(C)CC6)cc5[nH]4)cc3[nH]2)cc1
Yield: 80 %

Procedure:
In this step, synthesis of an active ester of a binding enhancer is described, which can then be easily conjugated to both the photoreactive ligand and the linker. A solution of bisbenzimidazole (6 g, 0.01 mol) dicyclohexylcarbodiimide (0.05 mol) and succinic acid (0.01 mol) in 100 mL of chloroform is stirred overnight ( 18-24 hrs). During this time, a white precipitate is formed. The precipitate is filtered of and washed with chloroform (2×50 mL). The combined chloroform is concentrated under vacuum in a rotary evaporator and the residue purified by flash column chromatography. The fractions containing the product is combined and concentrated under vacuum in a rotary evaporate to afford bisbenzimide succinnate ester (80%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:9])[C@@H:4]([CH3:8])[C:5]([OH:7])=[O:6].[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=3)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C>O1CCCC1>[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([O:6][C:5](=[O:7])[C@H:4]([CH3:8])[C@@H:3]([O:2][CH3:1])[CH3:9])=[CH:36][CH:35]=3)=[O:32])=[CH:29][CH:30]=2)=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CO[C@@H](C)[C@@H](C)C(=O)O
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(O)cc3)cc2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(OC(=O)[C@H](C)[C@H](C)OC)cc3)cc2)cc1

Procedure:
(2R, 3S)-3-methoxy-2-methylbutyric acid prepared in the above i) (0.79 g), 4-hydroxyphenyl 4'-octyloxy-4-biphenylcarboxylate (2.5 g) and tributylamine (2.66 g) were dissolved in dehydrated tetrahydrofuran (40 ml) and 2-chloro-1-methylpyridinium iodide (1.84 g) was added thereto. The mixture was heated under reflux for 7 hours. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography [eluent:chloroform:n-hexane (4:1)] and recrystallized from ethanol to obtain the title compound (0.36 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C1(C)C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:8]([CH3:9])[N:17]([CH:14]3[CH2:16][CH2:15]3)[N:11]=2)[CH:7]=1
Reactant: CC(=O)c1cc(Br)ccc1[N+](=O)[O-]
Reactant: NC1CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1c2cc(Br)ccc2nn1C1CC1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a solution of 1-(5-bromo-2-nitrophenyl)ethanone (4.0 g) in toluene (41 ml) were added cyclopropylamine (2.3 ml) and titanium(IV) tetraisopropoxide (14.4 ml) at room temperature, and the mixture was stirred at 60° C. for 17 hr. The reaction mixture was concentrated, triethyl phosphite (8.4 ml) was added to the residue, and the mixture was stirred at 150° C. for 5 hr. The reaction mixture was cooled, and diluted with ethyl acetate, and 1 M aqueous sodium hydroxide solution was added. The resulting insoluble solid was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.6 g).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1I.C[O:16][B:17](OC)[O:18]C.Cl>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[B:17]([OH:18])[OH:16]
Reactant: COB(OC)OC
Reactant: Fc1ccc(I)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 23.5 mmol, 14.7 mL) was added to 2-chloro-4-fluoro-1-iodobenzene (19.6 mmol, 5.0 g) in THF (120 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (76.6 mmol, 8.7 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming (2-chloro-4-fluorophenyl)boronic acid as a white precipitate. The white precipitate (1.10 g, 33%) was filtered and dried. 1H NMR (CDCl3, 300 MHz): 7.96 (1H, t, J 8.1 Hz), 7.11 (1H, dd, J 8.8 and 2.5 Hz), 7.04 (1H, td, J 8.4 and 2.5 Hz), 5.28 (2H, s.)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH:18][C@H:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[N:10][C:11]=2[NH2:17].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[NH2:17][C:11]1[N:10]=[C:9]([NH:18][C@H:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: CCC[C@@H](C)Nc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Product: CCC[C@@H](C)Nc1nc(N)c2[nH]c(=O)n(CCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-N2-[(1R)-1-methylbutyl]-8-(methyloxy)-9H-purine-2,6-diamine and piperidine.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[C:12]1([CH2:18][C:19]([O:21][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][O:22]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1=COCCC1
Reactant: O=C(O)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)OC1CCCCO1

Procedure:
To a saturated solution of anhydrous p-toluenesulphonic acid in dry dichloromethane (25 ml), phenylacetic acid (E4) (0.581 g, 4.26 mmol) and 3,4-dihydro-2H-pyran (3 ml, 32.9 mmol) were successively added, and the resultant solution was stirred for 1 hour at room temperature. To the reaction mixture, triethylamine (1 ml, 7.2 mmol) was added, and the volatiles were evaporated. The crude title compound was obtained and was immediately utilized in the next step of the synthesis.