Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33](/[CH:36]=[CH:37]/[CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:25]([C@H:30]1[CH2:31][CH2:32][C@H:33](/[CH:36]=[CH:37]/[CH2:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:5][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:10]([F:11])[C:2]=3[F:1])=[CH:44][CH:45]=2)[CH2:34][CH2:35]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)O)c(F)c1F
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CCc2ccc(O)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(CC/C=C/[C@H]3CC[C@H](CCCCC)CC3)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.7 g of 2,3-difluoro-4-dodecyloxybenzoic acid, 1.5 g of 4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]phenol and 0.1 g of 4-(dimethylamino)pyridine were dissolved in 250 ml of dichloromethane and the solution was treated portionwise within 10 minutes while stirring with 1/2 g of N,N'-dicyclohexylcarbodiimide. The mixture was stirred at room temperature overnight and then filtered. The filtrate was diluted with dichloromethane, washed twice with 50 ml of saturated sodium carbonate solution each time and then with 100 ml of water, dried over magnesium sulphate, filtered and then concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from ethanol gave 2 g of 2,3-difluoro-4-dodecyloxybenzoic acid 4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]phenyl ester with m.p. (C-SC) 51° C., SC -N 115° C. and cl.p. (N-I) 133° C.
Reaction SMILES: N#N.I[C:4]1[N:5]=[N+:6]([O-:17])[C:7]2[CH:16]=[C:12]3[CH2:13][CH2:14][O:15][C:11]3=[CH:10][C:8]=2[N:9]=1.[CH2:18]([OH:21])[CH:19]=[CH2:20].C([O-])(O)=O.[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[O-:17][N+:6]1[C:7]2[CH:16]=[C:12]3[CH2:13][CH2:14][O:15][C:11]3=[CH:10][C:8]=2[N:9]=[C:4]([CH2:20][CH2:19][CH:18]=[O:21])[N:5]=1
Reactant: [O-][n+]1nc(I)nc2cc3c(cc21)CCO3
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Pd(OAc)2 (53 mg, 0.24 mmol) was added to a N2-purged solution of iodide 213 (1.50 g, 4.8 mmol), allyl alcohol (0.91 mL, 13.3 mmol), nBu4NBr (1.38 g, 4.3 mmol) and NaHCO3 (880 mg, 10.5 mmol) in dry DMF (40 mL) and the solution was stirred at 60° C. for 24 h under N2. The mixture was quenched with saturated aqueous NH4Cl solution (150 mL) and filtered. The filtrate was extracted with EtOAc (5×50 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (20-50%) of EtOAc/pet. ether, to give aldehyde 214 as a dark oil, which was crystallised from MeOH to give a pale purple solid (532 mg, 45%): mp 140-142° C.; 1H NMR δ 9.92 (s, 1H, CHO), 8.26 (t, J=1.5 Hz, 1H, H-9), 7.10 (s, 1H, H-5), 4.80 (t, J=8.4 Hz, 2H, H-7), 3.43 (dt, J=8.4, 1.5 Hz, 2H, H-8), 3.29-3.33 (m, 2H, CH2), 3.06-3.10 (m, 2H, CH2); 13C NMR δ 200.4, 166.5, 165.0, 150.3, 135.2, 129.0, 116.2, 104.0, 73.1, 40.5, 29.4, 29.0; HRMS (FAB+) calcd for C12H12N3O3 (MH+) m/z 246.0879, found 246.0881.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH:5]=1.[NH3:18]>O>[N:12]1([CH2:11][O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:18])=[O:2])[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: N
Reactant: COC(=O)c1cccc(OCn2cccn2)c1
Solvent: O
Product: NC(=O)c1cccc(OCn2cccn2)c1
Temperature: 110 °C
Yield: 19 %

Procedure:
3-(Pyrazol-1-ylmethoxy)-benzoic acid methyl ester (250 mg, 1.1 eq.) was taken in a pressure vessel along with 5 ml of aq. ammonia, heated at 110° C. for 12 hr. reaction mass was then poured in water (25 ml), extracted with dichloromethane (25 ml×4). Organic layer was dried over sodium sulphate and concentrated to obtain crude solid. Product was purified by column chromatography using 80% EtOAc-DCM as an eluent over 230-400 mesh silica gel. Pure product was obtained as solid powder (50 mg, 19%). 1H NMR (DMSO-d6, 400 MHz with D2O): δ 6.12 (s, 2H), 6.33 (m, 1H), 7.25 (m, 1H), 7.37 (m, 1H), 7.41 (m, 1H), 7.51 (m, 1H), 7.56 (m, 2H), 7.95 (br s, 1H), 7.99 (m, 1H). MS ES+ (218.0, 235.0—Ammonium adduct), HPLC (method 7) Rt=9.08 min.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([F:13])=[C:8]([Br:14])[C:7]=1[O:15][CH3:16])[CH3:5])=[N+]=[N-].CP(C)C>C1COCC1.O.CCOC(C)=O>[Br:14][C:8]1[C:7]([O:15][CH3:16])=[C:6]([CH:4]([NH2:1])[CH3:5])[CH:11]=[C:10]([Cl:12])[C:9]=1[F:13]
Reactant: COc1c(C(C)N=[N+]=[N-])cc(Cl)c(F)c1Br
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(C(C)N)cc(Cl)c(F)c1Br
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To the stirred solution of 1-(1-azidoethyl)-3-bromo-5-chloro-4-fluoro-2-methoxybenzene (3.3 g, 11 mmol) in THF (50 mL) and water (10 mL) was added 1.0 M trimethylphosphine in THF (13 mL) at room temperature and the mixture was stirred for 1 hour. The mixture was diluted with EtOAc, washed with saturated sodium bicarbonate solution, water, brine, dried over magnesium sulfate and concentrated to give the desired compound (2.9 g, 95%). LCMS calculated for C9H8BrClFO (M−NH2)+: m/z=264.9, 266.9. found: 265.0, 267.0.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[C:23]3[C:22]4[C:17](=[CH:18][C:19]([C:24]#[N:25])=[CH:20][CH:21]=4)[NH:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:26]([Sn](CCCC)(CCCC)CCCC)=[N+:27]=[N-:28].Cl.O1CCOCC1>FC(C1C=CC=CC=1)(F)F.C(OCC)C>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[C:23]3[C:22]4[C:17](=[CH:18][C:19]([C:24]5[N:26]=[N:27][NH:28][N:25]=5)=[CH:20][CH:21]=4)[NH:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc2c(c1)[nH]c1ncnc(NCCCN3CCCCC3)c12
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: FC(F)(F)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1nc(NCCCN2CCCCC2)c2c(n1)[nH]c1cc(-c3nn[nH]n3)ccc12
Temperature: 180 °C
Reaction time: 16 h
Yield: 104.5 %

Procedure:
In a 2-5 mL microwave vial was added 4-((3-(piperidin-1-yl)propyl)amino)-9H-pyrimido[4,5-b]indole-7-carbonitrile (47.5 mg, 0.142 mmol) and azidotributyltin (409 μl, 1.491 mmol) in (trifluoromethyl)benzene (2 mL) to give a tan suspension. The vial was placed in the microwave and heated to 180° C. for 30 minutes. The mixture was concentrated to dryness and MeOH (3 mL) followed by HCl 4M in Dioxane (1.07 mL, 4.26 mmol) was added to get a yellow solution. To the resulting solution was added diethyl ether (3 mL) Stirred at 20° C. for 16 hours. The solid obtained was collected on a Buchner. The cake was washed with diethyl ether (3×1 mL) and with Hexane (3×1 mL) and the solid dried at 30° C. under high vacuum until constant weight to afford 56 mg of the title compound as the HCl salt. LCMS m/z 378.2 (M+H)+, retention time (on analytical HPLC)=1.30 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[C:31](Cl)=O>COCCOC>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:31]2[CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: O=C(Cl)C1CCCCO1
Solvent: COCCOC
Product: Cc1c(Cl)cccc1Cn1c(C2CCCCO2)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in 1,2-Dimethoxyethane (DME) (1000 ul) was added tetrahydro-2H-pyran-2-carbonyl chloride (81 mg, 0.545 mmol) in 1,2-Dimethoxyethane (DME) (400 ul). The mixture was stirred at room temperature for 3 h, then irradiated (uwave) for 20 min at 90° C. The mixture was quenched with methanol, concentrated, and purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-(tetrahydro-2H-pyran-2-yl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (17 mg, 14%); LC/MS: MS (ES*) m/e 461 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (br. s., 3H), 1.62-1.72 (m, 1H), 1.78-1.98 (m, 2H), 2.45 (s, 3H), 3.45-3.57 (m, 5H), 3.66 (t, J=4.8 Hz, 4H), 3.81 (d, J=11.6 Hz, 1H), 4.28 (m, 1H), 5.51-5.66 (m, 2H), 6.49 (d, J=7.8 Hz, 1H), 7.13 (m, 1H), 7.36 (d, J=7.8 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12](=O)[CH2:13][CH2:14][N:3]1[C:4]=23.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>CO>[O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]([NH:30][CH2:27][CH:28]=[CH2:29])[CH2:13][CH2:14][N:3]1[C:4]=23
Reactant: O=C1CCN2C(=O)OCc3cccc1c32
Reactant: C=CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C=CCNC1CCN2C(=O)OCc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6,7-dihydro-3,7-dioxo-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (6.10 g) in methanol (100 ml) were added molecular sieve 3A (12 g), p-toluenesulfonic acid (catalytic amount) and allylamine (50 ml), and the mixture was refluxed overnight. After cooling the reaction mixture, molecular sieve 3A was filtered off and sodium borohydride (1.70 g) was added to the filtrate under ice-cooling, then the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added a small amount of water, and methanol was distilled off. The residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (3:1)]to give 6,7-dihydro-3-oxo-7-allylamino-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (5.89 g).
Reaction SMILES: [Cl:1][C:2]([Cl:32])([Cl:31])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:30])[C@@H:14]([NH:22]C(OC(C)(C)C)=O)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:8]1)=[O:6].FC(F)(F)C(O)=O.C(N(CC)C(C)C)(C)C.[NH:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:50]([C:54](O)=[O:55])[CH:51]([CH3:53])[CH3:52].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[Cl:32][C:2]([Cl:31])([Cl:1])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:30])[C@@H:14]([NH:22][C:54](=[O:55])[C@@H:50]([NH:49][C:57]([O:59][C:60]([CH3:61])([CH3:63])[CH3:62])=[O:58])[CH:51]([CH3:53])[CH3:52])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of (S)-1-((S)-2-tert-butoxycarbonylamino-3-phenyl-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.0 g, 2.0 mmol) in anhydrous dichloromethane (7 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (1.5 mL, 19.7 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h before concentrating in vacuo. The residue was dissolved in anhydrous acetonitrile (11 mL), cooled to 0° C. and under an atmosphere of nitrogen was added N,N-diisopropylethylamine (1.8 mL, 9.8 mmol), N-Boc-Val-OH (428 mg, 2.0 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.1 g, 2.8 mmol). After 16 h at room temperature the reaction was diluted with ethyl acetate and quenched with hydrochloric acid (1 M). The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was then dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 to give the title compound (1.0 g, 84%) as a viscous oil. 1H NMR (300 MHz, CDCl3) δ 0.89 (d, J=6.7 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 1.47 (s, 9H), 1.47-1.56 (m, 1.72-1.94 (m, 2H), 2.08-2.20 (m, 1H), 2.23-2.36 (m, 1H), 2.67-2.84 (m, 1H), 2.91 (dd, J=12.9, 9.4 Hz, 1H), 3.05 (dd, J=12.9, 5.4 Hz, 1H), 3.53 (d, J=10.9 Hz, 1H), 3.90-4.03 (m, 1H), 4.23-4.36 (m, 1H), 4.70, 4.84 (ABq, J=12.0 Hz, 2H), 5.00-5.14 (m, 1H), 5.73-5.86 (m, 1H), 6.55 (d, J=8.3 Hz, 1H), 7.16-7.34 (m, 5H). LCMS (m/z) 607.1 [M+H], Tr=3.24 min.
Reaction SMILES: O([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[N:14]([CH3:17])[C:12](=[O:13])[C:11]2=[CH:18][CH:19]=1)C1C=CC=CC=1.C1(=O)OC(=O)C2=CC=CC=C12>>[CH3:17][N:14]1[C:12](=[O:13])[C:11]2=[CH:18][CH:19]=[CH:8][CH:9]=[C:10]2[C:15]1=[O:16]
Reactant: CN1C(=O)c2ccc(Oc3ccccc3)cc2C1=O
Agent: O=C1OC(=O)c2ccccc21
Product: CN1C(=O)c2ccccc2C1=O
Yield: 46 %

Procedure:
The above results show that an exchange occurred between 4-phenoxy-N-methylphthalimide and phthalic anhydride, resulting in a 46% yield of N-methylphthalimide and a 64% yield of 4-phenoxyphthalic anhydride or acid. This conversion of 4-phenoxy-N-methylphthalimide to 4-phenoxyphthalic anhydride was achieved in a direct manner without any requirement for converting the 4-phenoxy-N-methylphthalimide to the corresponding hydrazide or the base hydrolysis thereof, resulting in the production of metal salt requiring the neutralization and heating of the resulting phthalic acid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:17]O>C[Re](=O)(=O)=O.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][N+:12]([O-:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(-c2ccncc2)cc1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 4-(4-trifluoromethyl-phenyl)-pyridine (5.0 g, 22 mmol) and methyltrioxorhenium (VII) (Aldrich) (110 mg, 0.45 mmol) in a 100-mL, round-bottomed flask was added CH2Cl2 (10 mL). Hydrogen peroxide (5 mL, Aldrich) was added drop-wise, and the reaction was stirred at room temperature under N2 for 48 h. The mixture was partitioned between CH2Cl2 and brine, and the aqueous layer was extracted with CH2Cl2 (40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 240 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16]Br.CCOCC>CS(C)=O>[C:3]1([C:9]2([C:10]#[N:11])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCBr
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccccc2)CCCC1
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a suspension of sodium hydride (60%) (7.5 g, 187.79 mmol) in dimethyl sulfoxide (100 mL) was added dropwise a mixture of phenyl acetonitrile (10 g, 85.36 mmol) and 1,4-dibromobutane (18.43 g, 187.79 mmol) dissolved in dimethyl sulfoxide: ether (120 mL, 1:1) at 0° C. Stirring was continued for 30 min at same temperature and at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with 1N HCl (10 mL) and water (100 mL) was added. This mixture was extracted with ethyl acetate (3×100 mL), and the organic part separated and washed with water (3×100 mL) and brine (100 mL). The organic part was dried over sodium sulfate and concentrated to get a crude product which was purified on a CombiFlash column (eluted at 3% ethyl acetate in hexane) to afford 1-phenyl-cyclopentanecarbonitrile (276) (11.5 g, 78.68%) as a colorless liquid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32]([OH:34])=O)[CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[O:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)[C:32](=[O:34])[N:48]3[CH2:47][CH2:46][N:45]([CH:42]4[CH2:43][CH2:44][O:39][CH2:40][CH2:41]4)[CH2:50][CH2:49]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Reactant: C1CN(C2CCOCC2)CCN1
Product: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)N3CCN(C4CCOCC4)CC3)cc(C)c2[nH]1

Procedure:
Prepared analogously to Example 1h from 90 mg (0.16 mmol) (R)-1-carboxy-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 40 mg (0.24 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](I)=[CH:12][N:13]=[C:7]2[CH:6]=1)=O.O.[NH2:16][NH2:17]>C(O)C>[N:13]1[CH:12]=[CH:11][N:8]2[CH:9]=[CH:10][C:5]([C:3]([NH:16][NH2:17])=[O:2])=[CH:6][C:7]=12
Reactant: COC(=O)c1ccn2c(I)cnc2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccn2ccnc2c1
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a suspension of methyl-3-Iodo-imidazo[1,2-a]pyridine-7-carboxylate (0.3 g, 1.7 mmol, 1.0 equiv) in ethanol (3 ml) was added hydrazine hydrate (0.414 ml, 8.52 mmol). The mixture was heated to 70 deg C. for 1 h then allowed to cool. The solid was filtered off and washed with ethyl acetate and ether then dried to afford 0.209 g of product. 1H NMR (400 MHz, DMSO-d6): 9.95 (1H, s), 8.60 (1H, d), 8.05 (2H, d), 7.70 (1H, d), 7.30 (1H, dd), 4.58 (2H, s).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.CC1CCC(C(C)C)C(=O)C=1>>[CH3:1][C@H:2]1[CH2:8][C@@H:6]([OH:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Agent: CC1=CC(=O)C(C(C)C)CC1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O

Procedure:
0.04 % of menthone, piperitone; and
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@@:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=5)=[CH:22][CH:21]=4)(O)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:4].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+].Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=5)=[CH:22][CH:21]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:4]
Reactant: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@](O)(c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-3-hydroxy-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (122 mg) in DCM (10 mL) were added TFA (1 mL) and triethylsilane (3 eq) at −10° C. and the reaction mixture were stirred and allowed to warm up to room temperature within 3 h. Then the reaction mixture was concentrated in vacuo. To this residue di-tert-butyl dicarbonate (2 eq) and sodium bicarbonate (3.0 eq) were added in the presence of ethyl acetate (25 mL) and stirred at r.t. for 4 h. After t-boc protection was complete the reaction mixture was then slowly acidified with dilute HCl (25 mL, 1.0 M solution), extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with 1 N HCl (25 mL), water (25 mL) and brine (25 mL) dried over sodium sulfate, filtered, and concentrated to provide a yellow solid. The residue was then purified by silica gel chromatography (10/90 to 30/70 ethyl acetate/hexanes in 10% increments) to obtain a white solid of (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (73 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10]>C(O)(=O)C>[N+:9]([C:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[OH:8])([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(I)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of p-iodophenol (2.2 g, 10 mmol) in 18 mL acetic acid was added a solution of HNO3 (0.7 mL, 70%) in 5 mL acetic acid dropwise over 10 minutes. The resulting mixture was stirred at ambient temperature. After 30 minutes, the reaction mixture was diluted by 100 mL ice-water. The precipitate was collected, washed with 100 mL water. Purification by flash column chromatography afforded 1.2 g of 2-nitro-4-iodophenol.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:11][Si:12]([CH2:15][CH2:16][O:17][CH2:18]Cl)([CH3:14])[CH3:13]>C1COCC1>[CH3:11][Si:12]([CH3:14])([CH3:13])[CH2:15][CH2:16][O:17][CH2:18][O:7][CH:4]1[CH2:5][CH2:6][CH:1]([OH:8])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: OC1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOC1CCC(O)CC1
Yield: 24.5 %

Procedure:
Cyclohexane-1,4-diol (4 g, 34.8 mmol) was dissolved in THF (200 mL). To this solution was added 95% NaH (0.922 g, 36.6 mmol). The mixture was heated to reflux for 1 hour. Then 10 the reaction was cooled down. SEMCl (6.44 mL, 36.6 mmol) was added dropwise. The reaction mixture was heated to reflux again overnight. THF was removed. The residue was purified by flash chromatography to give the desired product (2.10 g, 16%). MS (DCI/NH3) m/z 247 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.02 (s, 9H) 0.87-0.95 (m, 2H) 1.30-1.38 (m, 2H) 1.57 (m, 1H) 1.64-1.70 (m, 2H) 1.80 (m, 1H) 1.91-2.01 (m, 2H) 3.50-3.70 (m, 4H) 4.69 (s, 2H).
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[Br:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][NH:20]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.O>O1CCCC1.C(OCC)(=O)C>[C:8]([O:7][C:1]([N:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([Br:13])[CH:22]=2)[CH2:18][CH2:19]1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: Brc1ccc2c(c1)NCC2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc21
Yield: 71.6 %

Procedure:
Di-t-butyl carbonate (6.7 g) was added to a solution of 6-bromoindoline (5.1 g) and triethylamine (3.1 g) in tetrahydrofuran (50 ml) followed by stirring the resultant mixture at room temperature overnight. After adding water and ethyl acetate thereto, the layers were separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was then purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (5.5 g) as a colorless oil (yield: 71%).