Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]1([C:28]2[CH:32]=[CH:31][NH:30][N:29]=2)[CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:30]3[CH:31]=[CH:32][C:28]([CH:25]4[CH2:27][CH2:26]4)=[N:29]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: c1cc(C2CC2)n[nH]1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C4CC4)n3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (93 mg, 0.25 mmol), 3-cyclopropyl-1H-pyrazole (54 mg, 0.50 mmol) and DMAP (92 mg, 0.75 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 30 mg (27% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.62-0.75 (m, 2 H), 0.87-0.99 (m, 2 H), 1.43-1.59 (m, 4 H), 1.61 (s, 9 H), 1.81-1.96 (m, 1 H), 2.24-2.42 (m, 1 H), 3.31-3.39 (m, 2 H), 3.91 (m, 2 H), 4.43 (d, J=7.42 Hz, 2 H), 6.18 (d, J=2.73 Hz, 1H), 7.91 (d, J=8.8 Hz, 1 H), 7.95 (dd, J=8.7, 1.5 Hz, 1 H), 8.15 (d, J=2.73 Hz, 1 H), 8.28 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=442.8; Anal. Calcd for C23H30N4O3S+1.10 TFA+0.10H2O (569.31): C, 53.12; H, 5.54; N, 9.83. Found: C, 53.13; H, 5.62; N, 9.76.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([OH:13])[CH:4]=1.[CH2:14]([C:23]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(O)[C:24]#[CH:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C1(C)C=CC=CC=1>CCCCCC>[CH2:14]([C:23]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[O:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:12]3[C:7]([C:6]=2[CH:25]=[CH:24]1)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1
Reactant: COc1cc(O)cc2ccccc12
Reactant: C#CC(O)(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(CC2(Cc3ccc(OC)cc3)C=Cc3c(cc(OC)c4ccccc34)O2)cc1
Reaction time: 1.5 h

Procedure:
A mixture of 4-methoxy-2-naphthol (0.26 g; 0.015 mol). 1,1-dianisylprop-2-yn-1-ol (0.40 g g;0.0015 mol), acidic alumina Brockmann 1 (3.5 g) and toluene (40.0 ml) was heated and stirred for 1.5 h, cooled, filtered. The filtrate was washed with 2M NaOH then water, dried and evaporated to give an orange gum. Trituration with hexane yielded 3,3-dianisyl-6-methoxy-3H-naphtho[2,1-b]pyran of formula (1) below as an off-white solid (41%). Crystallisation from hexane and ethylacetate gave the pyran as white micro-platelets, m.pt. 158°-160° C. ##STR8##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([NH:19]C(=O)C)=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cccc2cc(OCc3ccccc3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cccc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C

Procedure:
A solution of N-(6-benzyloxy-naphthalen-1-yl)-acetamide (5.0 grams, 17 mmol) and potassium hydroxide (2.88 grams, 51 mmol) in EtOH (35 mL)/H2O (25 mL) was heated at 93° C. for 17 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with saturated aqueous NaCl (25 mL) and extracted with EtOAc (5×100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using 30% ethyl acetate/hexanes. 1H NMR (250 MHz, CDCl3): d 7.78 (d, 1 H), 7.50 (s, 1 H), 7.38 (m, 3 H), 7.20 (m, 4 H), 6.67 (d, 1 H), 5.18 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17]=O)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.ClCCCl.[C:29]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:29]([N:33]1[CH2:38][CH2:37][N:36]([CH2:17][C:7]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]3[C:5]([N:6]=2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=[C:2]([Cl:1])[N:10]=3)[CH2:35][CH2:34]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Reactant: CC(C)(C)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
2-Chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-8-carbaldehyde (0.148 g, 0.422 mmol) was dissolved in 1,2-dichloroethane (3.7 mL, 0.047 mol). 1-tert-butylpiperazine (0.060 g, 0.42 mmol) was added followed by micronized 4 Å molecular sieves (0.450 g). After 2 hours sodium triacetoxyborohydride (0.179 g, 0.844 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was filtered. The filter cake was washed with additional DCM and MeOH. The combined organics were concentrated to dryness. The crude was purified by flash column chromatography (Si—PPC; MeOH:DCM gradient 0:100 to 10:90) to give 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (126 mg, 62%). [M+H]+=478.3
Reaction SMILES: [C:1]([NH:9][CH:10]([C:44]([O:46][CH:47]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH2:24]Cl)[CH2:22][S:23][C@H:18]12)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:60]1([P:66]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.[I-:79].[Na+].C(O)(C)C>CN(C)C=O>[I-:79].[C:1]([NH:9][CH:10]([C:44]([O:46][CH:47]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH2:24][P+:66]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH2:22][S:23][C@H:18]12)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCC(NC(=O)c1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: O=C(CCCC(NC(=O)c1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a solution of benzhydryl 7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-chloromethyl-3-cephem-4-carboxylate (102 g) in N,N-dimethylformamide (150 ml) were added triphenylphosphine (48.5 g) and sodium iodide (18.4 g), and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was added dropwise to isopropyl alcohol (5000 ml), and the precipitated material was collected by filtration and washed with diisopropyl ether to obtain [7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-4-benzhydryloxycarbonyl-3-cephem-3-yl]methyl-triphenyl-phosphonium iodide (123.5 g), mp 165°-175° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S([O-])(=O)(=O)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35]O)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[N:14]([CH2:35][CH2:34][CH2:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: OCCCc1ccc(F)cc1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Agent: CS(=O)(=O)[O-]
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CCCc2ccc(F)cc2)c1=O
Yield: 90.1 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and the mesylate derivative of 3-(4-fluorophenyl)-1-propanol {J. Med. Chem., 19, 461 (1976)} were reacted to yield the title compound as a yellow oil (yield: 90.1%). The mesylate derivative was prepared in accordance with the procedure of Example 1(9).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH:41]([Mg]Br)([CH3:43])[CH3:42].O1CCCC1>O1CCCC1.CN1CCCC1=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Fe]>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH:41]([CH3:43])[CH3:42])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: CC(C)[Mg]Br
Agent: [Fe]
Agent: CC(=O)/C=C(/C)O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1cc2nc(C(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Yield: 47 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (200 mg, 0.33 mmol) and iron (III) acetylacetonate (6 mg, 0.017 mmol) in anhydrous tetrahydrofuran/1-methyl-2-pyrrolidinone (5 mL/0.5 mL) at 0° C. was added 2.9 M in tetrahydrofuran isopropylmagnesium bromide (0.149 mL, 0.431 mmol) drop wise. The reaction was let warm to room temperature over three hours, quenched with water and extracted with ethyl acetate and concentrated. The crude reaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (77 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H39ClNO3: 496.25. found: 496.83.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N+:18]([O-])=O)=[CH:6][C:7]([F:17])=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:9]=1)[CH3:2].[C:21]([CH2:23][C:24](OCC)=O)#[N:22]>CO.[Pd]>[CH2:1]([N:3]1[C:4]2[CH:9]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:7]([F:17])=[CH:6][C:5]=2[N:18]=[C:24]1[CH2:23][C:21]#[N:22])[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: CCNc1cc(N2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCn1c(CC#N)nc2cc(F)c(N3CCN(C)CC3)cc21
Yield: 38.8 %

Procedure:
1-[5-(Ethylamino)-2-fluoro-4-nitrophenyl]-4-methylpiperazine (2.8 g, 10 mmol) is dissolved in methanol (200 ml) and hydrogenated with 5 percent palladium/carbon under hydrogen at normal pressure. The palladium/carbon is filtered off and the filtrate is evaporated under reduced pressure. The residue is dried in a high vacuum, dissolved in diethyl glycol ethyl ether (10 ml) and then treated with ethyl cyanoacetate (2.26 g, 20 mmol). The solution is heated to 160° for 4 hours. The solvent is then distilled off and the residue is taken up in an acetic acid/ether mixture (100 ml, 1:2). The crystals obtained are filtered off, dissolved in an ethyl acetate/methanol mixture (6:4 and chromatographed on silica gel (eluent: ethyl acetate/methanol 6:4). The product is recrystallized from an ethyl acetate/acetonitrile mixture (9:1). There are obtained 1.17 g (39%) of 1-ethyl-5-fluoro-6-(4-methyl-1-piperazinyl)-2-benzimidazoleacetonitrile with a m.p. of 204°-206°.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1>>[CH3:19][C:15]1[CH:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: Cc1cccc(-c2ccc(C=O)cc2)c1

Procedure:
Scheme 43, Example 1 depicts the coupling reaction of 4-formylbenzeneboronic acid 43.1 with 3-bromotoluene 43.9 to afford 3′-methylbiphenyl-4-aldehyde 43.10. The product is then reacted with N-bromosuccinimide, as described above, to afford the bromomethyl product 43.11. This material is reacted with a sodium dialkyl phosphonate 43.5 to afford the phosphonate ester 43.12.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:4]2[N:3]=1.[H-].[Na+].Br[CH:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].O>CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:1][CH:26]4[CH2:30][CH2:29][NH:28][C:27]4=[O:31])[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(O)nn23)cc1
Reactant: O=C1NCCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nnc3c4ccccc4c(OC4CCNC4=O)nn23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
6-Hydroxy-3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazine, (9.8 g), is suspended in N,N-dimethylformamide (100 ml) and added of 50% sodium hydride in mineral oil (1.7 g). The mixture is heated to 50°-60° C. and stirred for about 2 hours. After cooling to room temperature the mixture is added portionwise with 3-bromo-2-pyrrolidone (5.5 g). [This product is prepared according to F. Korte, H. Wanholf, Ber. 97, 1976 (1964)]. Then stirring is continued for about 5 hours at a temperature of about 70° C. The mixture is then cooled to room temperature and poured into water (800 ml). The residue, which is collected by filtration, is then crystallized from ethanol/chloroform. (Yield=82%). M.p. 290°-293° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[Br:12]Br.N>CC(O)=O>[CH3:1][N:2]1[C:6]2[C:7]([Br:12])=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: BrBr
Reactant: Cn1cnc2ccc(N)cc21
Agent: N
Solvent: CC(=O)O
Product: Cn1cnc2ccc(N)c(Br)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 3-methyl-5-aminobenzimidazole (0.27 g, 1.8 mmol) in 10 ml of AcOH was added Br2 (0.10 ml). The reaction mixture was stirred for 1 h at 25° C. and concentrated in vacuo, yielding an oil which was subjected to column chromatography (NH3 sat'd 3% MeOH/CHCl3) to yield 0.14 g (0.62 mmol, 35%) of the desired product.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[O:16][C:17]1[CH:18]=[C:19]([CH3:31])[C:20]2[CH:24]([CH2:25][C:26]([OH:28])=[O:27])[O:23][B:22]([OH:29])[C:21]=2[CH:30]=1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[O:16][C:17]1[CH:18]=[C:19]([CH3:31])[C:20]2[CH:24]([CH2:25][C:26]([OH:28])=[O:27])[O:23][B:22]([OH:29])[C:21]=2[CH:30]=1
Reactant: Cc1cc(Oc2cccc(OCCCNC(=O)OC(C)(C)C)c2)cc2c1C(CC(=O)O)OB2O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Oc2cccc(OCCCN)c2)cc2c1C(CC(=O)O)OB2O
Yield: 45.7 %

Procedure:
A solution of {6-[3-(3-tert-butoxycarbonylamino-propoxy)-phenoxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid (0.5 g, 1.06 mmol) in 4M HCl in dioxane (5 mL) was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC to give {6-[3-(3-amino-propoxy)-phenoxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid (0.18 g, 45%). 1H NMR (400 MHz, DMSO): δ 8.36 (s, 1H), 7.24 (t, J=8.4 Hz, 1H), 6.99 (s, 1H), 6.85 (s, 1H), 6.66 (d, J=8.0 Hz, 1H), 6.51 (t, J=8.0 Hz, 2.0H), 5.37 (d, J=6.0 Hz, 1H), 3.98 (t, J=5.6 Hz, 2H), 2.85 (d, J=12.0 Hz, 2H), 2.22 (s, 3H), 2.05-1.93 (m, 4H). MS (ESI) m/z=372 [M+H]+.
Reaction SMILES: COB(OC)OC.CSC.B.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:25][CH:24]3[N:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]([CH2:22][CH2:23]3)[CH2:20]2)=[C:15]([C:32](=[O:35])[CH2:33][CH3:34])[CH:14]=1.Cl>O1CCCC1.CCOC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:25][CH:24]3[N:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]([CH2:22][CH2:23]3)[CH2:20]2)=[C:15]([CH:32]([OH:35])[CH2:33][CH3:34])[CH:14]=1
Reactant: CCOC(=O)N1C2CCC1CC(c1ccc(Cl)cc1C(=O)CC)C2
Agent: B
Agent: COB(OC)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)N1C2CCC1CC(c1ccc(Cl)cc1C(O)CC)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S) (−)-α,α-dephenyl-2-pyrrolidinemethanol (0.724 g, 2.86 mmol) in anhydrous tetrahydrofuran (25 mL) was added trimethylborate (0.446 g, 4.29 mmol) all at once and stirred at room temperature for 1 h. The borane dimethylsulfide complex (7.15 mL, 14.3 mmol, 2.0 M in THF) was added dropwise over a period of 1 h. The mixture was then cooled to 0° C. with an ice-bath and a solution of ethyl 3-(4-chloro-2-propionylphenyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (2-7) (5.00 g, 14.9 mmol) in 15 mL of anhydrous tetrahydrofuran was added dropwise over a period of 3 h (keeping the reaction temperature below 4° C.). The reaction mixture was allowed to warm slowly up to room temperature and stirred overnight. After the reaction was complete, the mixture was added portionwise to a stirring mixture of 2 N HCl (125 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification of the crude residue by flash chromatography over silica gel (5% ethyl acetone/dichloromethane as eluent) afforded (2-8) as a colorless oil.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([Br:20])[CH:19]=1)[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CN(C)[CH:23]=[O:24].C(O)(=O)C>CCCCCC.CCOCC.O>[Br:20][C:18]1[CH:19]=[C:7]([CH:8]=[C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:17]=1)[CH:23]=[O:24]
Reactant: Brc1cc(Br)cc(Cc2cccnc2)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: O=Cc1cc(Br)cc(Cc2cccnc2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
A 1.3M solution of s-butyllithium in hexane (27.7 ml) was added dropwise to a stirred suspension of 3-(3,5-dibromobenzyl)pyridine (Preparation 3; 9.81 g) in dry ether (300 ml) at -78° C. under an atmosphere of dry nitrogen. The resulting mixture was stirred at -78° C. for 15 minutes and then N,N-dimethylformamide (6.60 g) was added dropwise. This mixture was stirred at -78° C. for a further 30 minutes, allowed to warm to -20° C. and the glacial acetic acid (12 ml) was added. After 10 minutes, water (150 ml) was added and the organic phase separated. The aqueous layer was washed with ethyl acetate, then the combined organic solutions washed with saturated aqueous sodium bicarbonate solution and dried (MgSO4). Evaporation under vacuum of the solvent gave a solid which was crystallised from ether-hexane to give the title compound (5.25 g), m.p. 97°-98° C. Found: C,56.21; H,3.71; N,5.19. C13H10BrNO requires C,56.54; H,3.65; N,5.07%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[C:17](=[S:22])([O:19][CH2:20][CH3:21])[S-:18].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH:11]=[C:12]([S:22][C:17]([O:19][CH2:20][CH3:21])=[S:18])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: CCOC(=S)[S-]
Reactant: Cc1c(Cl)cc(C(=O)C=CC(=O)O)cc1Cl
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCOC(=S)SC(=CC(=O)c1cc(Cl)c(C)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
A suspension of 2.59 g (0.01 mole) of 4-(3,5-dichloro-4-methylphenyl)-4-oxo-2-butenoic acid and 1.60 g (0.01 mole) of potassium O-ethyl dithiocarbonate in 40 ml of water was stirred at room temperature for 3 hours. At the end of this time, the mixture was ice-cooled, acidified by the addition of concentrated hydrochloric acid and then extracted with diethyl ether. The extract was subjected to column chromatography through silica gel, to give 3.60 g (yield 94.5%) of the desired 4-(3,5-dichloro-4-methylphenyl)-2-ethoxythiocarbonylthio-4-oxobutenoic acid, melting at 126°-128° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O1CCOCC1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylate (1.017 g) in MeOH (3 mL) and dioxane (3 mL) was added 1N NaOH aq solution (5.8 mL), and the mixture was stirred at ambient temperature for 2 hours. To the mixture was added 1N NaOH aq solution (5.8 mL) and heated at 50° C. for 2 hours. The pH value of the mixture was adjusted to 7 with 1N HCl, and the solvent was removed in vacuo. Obtained solid was suspended in toluene and the residual water was geotropically removed to give (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylic acid and the crude product was used in next reaction without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[CH3:17][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Yield: 93.6 %

Procedure:
Amine preparation: To a solution of 1-BOC-3-piperidine carboxylic acid (3.0 g) in DMF (25 mL) was added potassium carbonate (3.62 g) followed by iodomethane (4.07 mL). After 2.5 h the reaction was diluted with water and extracted into diethyl ether. The organic layer was washed with brine, separated and dried (MgSO4). The solvent was evaporated to give piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.98 g).