Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22]CS([O-])(=O)=O)([C:13]2[CH:18]=[CH:17][C:16](Cl)=[C:15](Cl)[CH:14]=2)[CH2:9]1)=[O:7].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(OCC)(=O)C>CO.C(OCC)(=O)C>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[C:13]1([C:10]2([CH2:21][CH2:22][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=3)[CH2:9]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: NC(=O)N1CCOCC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using 2-[1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid morpholine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with ethyl acetate and then 10% methanol/ethyl acetate, the title compound. HRMS calculated for C38H47N3O6 : 642.354312. Found: 642.356150.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][Br:20])[CH:8]=[CH:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cccc(Br)c2n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2cccc(Br)c2n1

Procedure:
To a solution of 2 (2.5477 g, 11.47 mmol) in carbon tetrachloride (40 mL) was added NBS (2.2461 g, 12.62 mmol) and a little bit of AIBN followed by refluxing overnight under UV light. The mixture was filtered to remove the solid and concentrated to give a yellow solid. Purification by chromatography (hexanes/DCM 80:20) yielded a white solid.(1.33 g, 39%) 1H NMR (400 MHz CDCl3) δ8.16 (1H, d, J=8.4 Hz), 8.05 (1H, d, J=7.2 Hz), 7.78 (1H, d, J=7.6 Hz), 7.65 (1H, d, J=8.4 Hz), 7.41 (1H, t, J=7.6 Hz), 4.78 (3H, s); 13C NMR (300 MHz CDCl3) δ158.3, 144.7, 138.0, 133.9, 128.9, 127.7, 127.6, 125.1, 122.4, 34.6; EIMS, m/z 299/300/301 (M/M+1/M+2).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-chlorobenzoyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (90%, white crystals). HPLC-MS m/z=366.1 (M+1), Rt: 5.19 min.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:32])[CH3:31])[CH2:27][CH2:28]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N[C@H]1CC[C@@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 24 h
Yield: 50 %

Procedure:
trans/cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine (27 mg) was dissolved in pyridine (0.5 ml). Acetyl chloride (6 μl) and 4-dimethylaminopyridine (2 mg) were added sequentially and the reaction mixture stirred for 24 hr. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (10 ml) and water (2 ml). The aqueous phase was extracted with ethyl acetate (2×5 ml) and the combined organic phases were washed with brine (10 ml), dried over anhydrous magnesium sulphate, and concentrated to give a brown oil. Purification via flash column chromatography (SiO2 eluting with ethyl acetate:petroleum ether, 7:3 v/v) afforded the title product as a white solid (15 mg, 50%) and a mixture of diastereoisomers. δH(CDCl3): 0.17 (3H, s), 0.19 (3H, s), 0.21 (3H, s), 0.22 (3H, s), 0.96 (9H, s), 1.02 (9H, s), 1.06-1.20 (2H, m), 1.36-1.54 (2H, m), 1.60-1.75 (2H, m), 1.80 -1.92 (2H, m), 1.95 (1.5H, s), 2.00 (1.5H, s), 2.75-2.90 (1H, m), 3.76-3.87 (1H, m), 5.34-5.39 (0.5H, d), 5.72-5.77 (0.5H, d), 6.26-6.29 (1H, m), 6.38-6.41 (1H, m), 6.93 (0.5H, d), 6.95 (0.5H, d); m/z (ES+) 478 (M+1)+.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(O)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Magnesium ribbon (0.11 g) is suspended in absolute ethanol (0.5 ml), and thereto is added carbon tetrachloride (0.05 ml). After 10 minutes, to the mixture is added dropwise a mixture of diethyl malonate (1.5 ml), absolute ethanol (0.9 ml) and anhydrous ether (3.8 ml) at a room temperature. After the addition, the mixture is refluxed for 3 hours. Thereafter, a solution of 2,3,4,5-tetrafluorobenzoyl chloride (2.0 g) in anhydrous ether (0.9 ml) is added dropwise under ice-cooling. After the addition, the mixture is stirred at room temperature for 3 hours, and then allowed to stand overnight. A mixture of ice-water (4 ml) and conc. sulfuric acid (0.24 ml) is added dropwise to the reaction mixture under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. The ether layer is separated, and the remaining reaction mixture is extracted with ether. The ether layers are combined, and are washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give diethyl 2,3,4,5-tetrafluorobenzoylmalonate (3.0 g).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:25][CH:26]1[C:43](=[O:44])[N:28]2[C:29]([C:40]([OH:42])=[O:41])=[C:30]([CH2:33][S:34][C:35]3[S:36][CH:37]=[N:38][N:39]=3)[CH2:31][S:32][C@H:27]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])[C:10]([NH:25][CH:26]2[C:43](=[O:44])[N:28]3[C:29]([C:40]([OH:42])=[O:41])=[C:30]([CH2:33][S:34][C:35]4[S:36][CH:37]=[N:38][N:39]=4)[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: [N-]=[N+]=NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Yield: 80.8 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-azidoethoxyimino)acetic acid (syn isomer, 0.70 g.), N,N-dimethylformamide (0.21 ml.), phosphoryl chloride (0.4 g.) and ethyl acetate (15.8 ml.) were treated in a similar manner to that of Example 1-(1) to give an activated acid solution. The solution was added to a solution of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (0.74 g.) and trimethylsilylacetamide (2.0 g.) in ethyl acetate (15 ml.) at -10° to -15° C. and stirred at the same temperature for an hour. After adding water (30 ml.) to the resultant solution, the organic layer was separated, washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate and evaporated in vacuo to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-azidoethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.08 g.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si]([C:25]#[CH:26])(C)C.CCN(CC)CC>[Cu]I.CN(C=O)C>[C:25]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[CH:26]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cc2)CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
A microwave vial was charged with tert-butyl 4-(4-iodophenyl)piperazine-1-carboxylate (300 mg, 0.773 mmol), trimethylsilylacetylene (0.22 mL, 1.54 mmol), NEt3 (3.0 mL), DMF (1.5 mL), CuI (15 mg, 0.080 mmol), and PdCl2 (PPh3)2 (27 mg, 0.039 mmol). The vial was capped and heated in the microwave at 100° C. for 1 h. After removing the NEt3 in vacuo, the residue was extracted with EtOAc (15 mL). The organic layer was then washed with NaHCO3 (sat.) (5 mL), H2O (5 mL), brine (5 mL) and then dried over MgSO4. The solvent was removed and then the material was dissolved into MeOH (4 mL) and THF (2 mL). K2CO3 (1.0 mL of a 1M solution) was added and the reaction stirred for 3 h. The solvent was removed and the residue extracted with EtOAc (15 mL). The organic layer was washed with brine (5 mL) and then dried over MgSO4. The solvent was removed and the product dried under high vacuum to give the title compound as a brown solid (212 mg, 96%); MS ESI 287.0 [M+H]+, calcd for [C17H22N2O2+H]+ 287.18.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[B:16](OCCCC)([O:22]CCCC)[O:17]CCCC.Cl>C1COCC1.CCOCC>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([B:16]([OH:22])[OH:17])[CH:7]=1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: COc1ccc(Cl)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(Cl)cc1B(O)O
Reaction time: 8 h

Procedure:
A solution of 2-bromo-4-chloroanisole (5.0 g, 22.6 mmol) in dry THF (60 ml) under nitrogen was cooled to −70° C. and n-butyl lithium (12.4 ml of a 2.0 M solution in hexanes, 24.8 mmol) was added. After 10 min. at −70° C. tributyl borate (8.5 ml, 31.4 mmol) was added and the temperature was allowed to rise to room temperature overnight. Aqueous hydrochloric acid (40 ml, 2 M) was added and the product was extracted with 2×60 ml ether. The ethereal phase was extracted with aqueous sodium hydroxide (2×40 ml, 1 M). Acidification with concentrated HCl during ice-cooling gave a precipitate that was dissolved in ether. Drying over magnesium sulfate and evaporation of the solvent gave the title compound. Yield 1.93 g, 46%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2C2CCCCO2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>CO>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[NH:12]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C

Procedure:
To a solution of 2-(butyloxy)-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.34 g) in methanol (100 ml) was added trifluoroacetic acid (10 ml). The mixture was stirred at ambient temperature over the weekend to give a suspension. The reaction mixture was concentrated to a small volume (thick slurry) before being diluted with ethyl acetate (50 ml). The resultant slurry was filtered and washed with a small volume of ethyl acetate until the filtrate was colourless. The solid remaining was dried by air and then in vacuo to give the title compound as a white solid (6.20 g). The filtrate obtained previously was concentrated to give a slurry which was diluted with a small volume of ethyl acetate (10 ml) and then filtered and dried as above. This second crop was isolated as a white solid (0.276 g). Both crops were identical by NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C@@H:13](O)[CH2:12]2)[C:7]1=[O:25].CCN(S(F)(F)[F:36])CC>C(Cl)Cl.C(=O)(O)[O-]>[F:36][C@@H:13]1[C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:15][CH2:16][N:11]([CH:8]2[CH2:9][CH2:10][N:6]([CH2:5][C:4]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:2]([F:1])[CH:3]=3)[C:7]2=[O:25])[CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccc(CN2CCC(N3CC[C@H](c4ccc(O)cc4)[C@@H](O)C3)C2=O)cc1F
Agent: O=C([O-])O
Solvent: ClCCl
Product: Cc1ccc(CN2CCC(N3CC[C@H](c4ccc(O)cc4)[C@@H](F)C3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of 1-(3-fluoro-4-methylbenzyl)-3-((3R,4R)-3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one (from step F, 1.9 g, 4.8 mmol) in DCM (35 mL) at 0° C. was added DAST (3.2 mL, 23.8 mmol) under nitrogen. The reaction mixture was allowed to warm to rt and stirred for 2 h, and then diluted with saturated bicarbonate solution and extracted with 200 mL of DCM. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to give a crude product which was purified via preparative HPLC (method J) to yield 3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (1.1 g, 2.6 mmol) as a pair of diastereomers. LCMS (Method F) RT: 2.13 min, m/z 401. (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@@H:31]([C:42](O)=[O:43])[CH2:32][C:33]3[CH:38]=[C:37]([CH3:39])[C:36]([OH:40])=[C:35]([CH3:41])[CH:34]=3)=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:14]=[C:15]1[N:21]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C@H:31]([CH2:32][C:33]3[CH:34]=[C:35]([CH3:41])[C:36]([OH:40])=[C:37]([CH3:39])[CH:38]=3)[C:42]([N:11]3[CH2:10][CH2:9][N:8]([C:2]4([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)[CH2:13][CH2:12]3)=[O:43])=[O:29])[CH2:26][CH2:27]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1
Reactant: CC1(N2CCNCC2)CCOCC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3(C)CCOCC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
50 mg (0.23 mmol) 1-(4-methyl-tetrahydropyran-4-yl)-piperazine (amine A1, used as the hydrochloride salt) were added to a solution of 90 mg (0.19 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 7h), 70 mg (0.22 mmol) TBTU and 70 μL (0.50 mmol) triethylamine in 1 mL DMF and the reaction mixture was stirred for 20 h at RT. Semisaturated NaHCO3 solution was added, the precipitate was filtered off and dried. The purification was carried out by chromatography (Alox, activity stage II-III, DCM/MeOH 30:1). After the solvent had been eliminated the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH3:1]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.O[CH2:24][C:25]1([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.S(=O)(O)[O-].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH:24]([C:25]1([CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][CH2:26]1)=[CH2:1]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(COCc2ccccc2)CC1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.6 %

Procedure:
1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.38 g, 3.3 mmol) was added to a solution of 1,1-dimethylethyl 4-(hydroxymethyl)-4-(phenylmethoxymethyl)-1-piperidinecarboxylate (Description 95, 1.06 g, 3 mmol) in dichloromethane (40 mL) and the mixture was stirred at room temperature for 4 hours. Aqueous sodium bisulfite (10%, 10 mL) was added and the mixture was stirred at room temperature for 5 minutes. Saturated aqueous sodium hydrogen carbonate (20 mL) was added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), and added to a stirred, cooled (0° C.) solution of triphenylphosphoranylidine (0.1M, 50 mL). The mixture was stirred at room temperature for 16 hours, then the solvent was evaporated under reduced pressure. Ethyl acetate (40 mL) and aqueous sodium hydrogen carbonate (10%, 40 mL) were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25) give the title compound (1.01 g, 99%). m/z (ES+) 332 (M+1).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][N:18]=[C:17]([CH3:20])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH:27]1[C:35]2[C:30](=[CH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:34]=2)[CH:29]=[CH:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[C:21]([N:6]1[C:5]2[CH:25]=[CH:26][C:2]([C:32]3[CH:31]=[C:30]4[CH:29]=[CH:28][NH:27][C:35]4=[N:34][CH:33]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][N:18]=[C:17]([CH3:20])[N:16]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: Cc1noc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccccc2-c2nc3cc(-c4cnc5[nH]ccc5c4)ccc3n2C(C)(C)C)n1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 10.2 %

Procedure:
To a solution of 5-bromo-1-tert-butyl-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-phenyl]-1H-benzimidazole (100 mg, 0.24 mmol) in DMF (5 mL) and H2O (1 mL) are added 7-azaindole-5-boronic acid pinacol ester (89 mg, 0.37 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol) and K2CO3 (34 mg, 0.24 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The mixture is stirred for 15 minutes and is filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is (MgSO4), filtered and concentrated and the residue is purified by preparative HPLC to afford the title compound (11 mg, 10%) as a white foam. LCMS (ESMS): m/z 449.77 (M++1)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[N+:7]([O-])[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1.C(OC(=O)C)(=[O:20])C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[CH:9]([OH:20])[CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cc(OCC(F)(F)F)cc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC1CCCc2cc(OCC(F)(F)F)cnc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
A mixture of 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinoline 1-oxide (530 mg, 2.1 mmol) and acetic anhydride (3 mL) was stirred at 100° C. for 2 hours. After cooling to room temperature, acetic anhydride was removed in vacuo. To the residue, methanol (5 mL) and potassium carbonate (1.77 g, 13 mmol) were added, and the mixture was stirred at room temperature for 20 hours. Then, methanol was evaporated in vacuo. To the residue was added ethyl acetate, and the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1-1:2) to give 193 mg (36% yield) of the title compound as a white solid:
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:6]=1OC.[OH-].[Na+]>CCO.O>[NH2:1][C:2]1[NH:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: N#CBr
Reactant: COc1cccc(N)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Cyanogen bromide (7.05 mmol, 0.74 g) was added to a solution of 2,3-diaminoanisole (4.7 mmol, 0.65 g) in EtOH (10 mL) and the reaction was stirred at room temperature for 14 h. The reaction was diluted with H2O and then basified (pH>12) using 4 M NaOH. The aqueous layer was extracted with CH2Cl2. The organic phase was then separated and washed with brine and then dried over MgSO4 and then concentrated to provide 2-aminobenzimidazole 37b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[ClH:24]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[ClH:24]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2cccc(F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(F)c1)C1CCNCC1
Temperature: 23 °C
Reaction time: 21 h

Procedure:
To a solution of tert-butyl 4-((3-fluorophenyl)sulfonyl)piperidine-1-carboxylate (756 mg, 2.201 mmol) in dioxane (5.0 mL) was added HCl (4 M in dioxane, 5.50 mL, 22.01 mmol) at 23° C. The reaction was stirred at 23° C. for 21 h to furnish a white suspension. The resulting solid was filtered, rinsed with dioxane and dried in vacuo to give the title compound as its HCl salt (582.6 mg, 95%) as a white solid. ESI-MS m/z [M+H]+ 243.9.