Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:10]([C:11]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])=[C:4]2[C:3]=1[F:29].[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[C:16]([O:15][C:14]([N:13]([CH3:21])[C:11]([C:10]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:8][N:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:31]=3[CH3:30])[C:35]([OH:37])=[O:36])=[C:3]([F:29])[C:4]=12)=[O:12])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)c(F)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1ccn2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1F
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a degassed solution containing tert-butyl 5-chloro-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate (0.10 g, 0.24 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.078 g, 0.30 mmol), sodium carbonate (0.075 g, 0.71 mmol), dioxane (2.0 mL) and water (0.40 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.008 g, 0.007 mmol). The mixture was stirred at 95° C. for 18 h. The solution was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1 N aqueous hydrochloric acid (2.0 mL). Water was added (10 mL) and the aqueous portion was extracted with ethyl acetate (2×15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated to afford 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as a residue which was used without further purification. LCMS retention time: 2.467 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 522 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>CO.C1COCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ccc([N+](=O)[O-])cn2)cc1OC
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(N)cn2)cc1OC
Reaction time: 15 h

Procedure:
To a mixture of 2-(3,4-dimethoxyphenyl)-5-nitropyridine (Interchim, Montlucon, France, 2.85 g, 10.95 mmol) in MeOH (27 ml) and THF (27 ml), Ra/Ni catalyst (1.10 g, 10.95 mmol) was added and shaked under hydrogen at rt for 15 h. After that, the RM was filtered over celite, the catalyst was washed with MeOH and the filtrate was evaporated to dryness to give the title compound as an off-white solid. (HPLC: tR 2.22 min (Method A); M+H=231 MS-ES)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]1[CH3:12].Br[C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].C([O-])(=O)C.[K+].C>CN(C)C(=O)C.[Pd].ClCCl>[Cl:22][C:20]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([C:6]2[N:2]([CH3:1])[C:3]([CH3:12])=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=2)[CH:21]=1
Reactant: CCOC(=O)c1ccn(C)c1C
Reactant: O=Cc1ccc(Cl)cc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(-c2cc(Cl)ccc2C=O)n(C)c1C
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
To a solution of 10.5 g of the compound obtained in Step A (62.8 mmol) in 65 mL of N,N-dimethylacetamide there are successively added 15.2 g of 2-bromo-4-chlorobenzaldehyde (69 mmol), 12.3 g of potassium acetate (125.6 mmol) and then the batch is stirred under argon for 20 minutes. There are then added 2.2 g of palladium catalyst PdCl2(PPh3)2 (3.14 mmol). The reaction mixture is then heated at 130° C. overnight. The mixture is allowed to return to ambient temperature and it is then diluted with dichloromethane. Animal charcoal is added (30 g) and the batch is stirred at ambient temperature for 1 hour and then filtered. The organic phase is then washed with water, dried over magnesium sulphate and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel (petroleum ether/AcOEt gradient). The title product is obtained in the form of a solid.
Reaction SMILES: [CH2:1]([C@@H:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[N:14][C:6]=2[NH:5]1)[C:2]#[CH:3].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.CCOC(C)=O>N1C=CC=CC=1>[CH2:1]([C@@H:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[N:14][C:6]=2[N:5]1[S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[C:2]#[CH:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CC[C@H]1Nc2ncccc2NC1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C#CC[C@@H]1C(=O)Nc2cccnc2N1S(=O)(=O)c1ccc(C)cc1
Reaction time: 7 h
Yield: 67.9 %

Procedure:
To (R)-3-(prop-2-ynyl)-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one (0.42 g, 2244 μmol) in pyridine was added p-toluenesulfonyl chloride (642 mg, 3365 μmol). The reaction mixture was stirred for 7 h and then EtOAc was added. The organic layer was separated, washed with brine, brine/5mL 10% HCl, dried, evaporated to give 0.52 g of solid. Purification by column chromatograph (DCM to 20% EtOAc/DCM) gave the title compound. MS 342 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[N:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:25]3[CH:26]=[N:21][CH:22]=[N:23][CH:24]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncnc1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cncnc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-pyrimidinecarboxylic acid as starting materials, MS (LC/MS): 409.0 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1.Cl[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:21][O:20][C:18]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1)=[O:19]
Reactant: COC(=O)Cl
Reactant: NCCOc1cc(-c2ccccc2)on1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NCCOc1cc(-c2ccccc2)on1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
3-(2-Aminoethoxy)-5-phenylisoxazole hydrochloride (240 mg) was suspended in anhydrous tetrahydrofuran (5 ml), and the suspension was cooled to 5° C. Then, methyl chloroformate (113 mg) and triethylamine (243 mg) were added thereto, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the reaction mixture was added to ice-cold water (40 ml) and extracted with ethyl acetate (40 ml×2). Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The crystals thus obtained were recrystallized from a mixture of ethyl acetate and ether to obtain the title compound (233 mg, 89%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)=[N:6][C:7]=1[Br:8].[CH3:14][N:15](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]([NH:15][CH3:14])=[O:13])=[N:6][C:7]=1[Br:8]
Reactant: Nc1ncc(CCC(=O)O)nc1Br
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CCc1cnc(N)c(Br)n1
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 3-(5-amino-6-bromopyrazin-2-yl)propanoic acid (32 mg, 0.130 mmol) in DMF (1300 μL) was added TBTU (62.6 mg, 0.195 mmol), DIEA (68.1 μL, 0.390 mmol), and methanamine hydrochloride (9.66 mg, 0.143 mmol). The reaction mixture was stirred for 3 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude 3-(5-amino-6-bromopyrazin-2-yl)-N-methylpropanamide (74%) was obtained and was used for the next step without further purification. LCMS (m/z): 259/261 (MH+), 0.35 min.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=[C:14]1[C:21](O)=[O:22].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:21]([C:14]3[S:13][C:17]4[S:18][CH:19]=[CH:20][C:16]=4[CH:15]=3)=[O:22])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cc2ccsc2s1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccsc2s1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thieno[2,3-b]thiophene-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.32 (d, J=5.4 Hz, 1H), 7.53-7.58 (m, 1H), 8.06 (s, 1H). MS (DCI/NH3) m/z 319. Anal. Calculated for C16H18N2OS2.HCl: C, 54.15; H, 5.40; N, 7.89. Found: C, 54.19; H, 5.25; N, 7.72.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:25][CH2:26]2)=[CH:17][CH:16]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)ncn2CCCCN1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(4-pyridyl) piperazine (4.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.3 g compound (I-13) with a yield of 62.1%. ESI-MS [M+H]+: m/z 336.2.
Reaction SMILES: [OH-:1].[Li+].[C:3]([O:7][C:8]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=2)[C:13]([CH3:22])([CH3:21])[CH2:12][C:11]1=[O:23])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:19]1[CH:18]=[CH:17][C:16]([F:20])=[CH:15][C:14]=1[C:13]([CH3:22])([CH3:21])[CH2:12][C:11]([OH:23])=[O:1])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC(C)(C)c2cc(F)ccc21
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1C(C)(C)CC(=O)O
Reaction time: 24 h

Procedure:
375 ml (0.75 mol) of an aqueous 2 M lithium hydroxide solution is added to a solution of 44 g (0.15 mol) of 1-tert-butoxycarbonyl-3,4-dihydro-4,4-dimethyl-6-fluoro-2-quinolone in 1l of THF. After 24 hours at room temperature, the batch is concentrated by evaporation, brought to pH 4 with 10% citric acid and extracted with ether. The combined organic extracts are washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography of the residue on silica gel with hexane-ethyl acetate yields 34.0 g of 3-(2-tert-butoxycarbonylamino-5-fluorophenyl)-3-methylbutyric acid [1H-NMR (CDCl3), δ (ppm)=1.62 (br.s, 15H), 2.77 (s, 2H), 6.41 (br, 1H), 6.93 (td, 1H), 7.07 (dd, 1H), 7.20 (br, 1H)], which dissolves in 1 l of THF and is mixed at 0° C. with 17 ml (121 mmol) of triethylamine and 11.5 ml (121 mmol) of ethyl chloroformate. After 10 minutes at 0° C., 20.7 g (546 mmol) of sodium borohydride is added to it, and 1 l of MeOH is slowly added in drops to it. The batch is stirred for another 30 minutes at 0° C., concentrated by evaporation and diluted with ethyl acetate. It is washed with saturated NaCl, dried on Na2SO4 and purified by column chromatography on silica gel with hexane-ethyl acetate. Yield: 6.7 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:17][CH2:16]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Reactant: C=CC(=O)NCCC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)NCCC1CCN(C(=O)CNc2cc(Cl)c(Cl)cc2O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To a stirred solution of 2-((4,5-dichloro-2-hydroxyphenyl)amino)acetic acid (200 mg, 0.85 mmol) in DMF (30 mL) at room temperature, N-(2-(piperidin-4-yl)ethyl)acrylamide (222.8 mg, 1.02 mmol) was added followed by HOBt (172.9 mg, 1.28 mmol), EDCI.HCl (244.7 mg, 1.28 mmol) and Et3N (257.9 mg, 2.55 mmol). The reaction mixture was stirred at room temperature for 1 h and then partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-3% methanol/dichloroethane) to afford the desired product (120 mg, 29% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 10.15 (s, 1H), 8.07 (t, J=5.2 Hz, 1H), 6.78 (s, 1H), 6.72 (s, 1H), 6.18 (dd, J=10.0, 17.2 Hz, 1H), 6.06 (dd, J=2.4, 17.2 Hz, 1H), 5.56 (dd, J=2.4, 10.4 Hz, 1H), 5.34 (t, J=4.0 Hz, 1H), 4.36 (d, J=12.8 Hz, 1H), 3.94-3.87 (m, 3H), 3.20-3.15 (m, 2H), 2.98-2.92 (m, 1H), 2.63-2.57 (m, 1H), 1.74-1.69 (m, 2H), 1.57-1.52 (m, 1H), 1.41-1.35 (m, 2H), 1.12-0.95 (m, 2H). ESI-MS m/z: 400.4[M+H]+.
Reaction SMILES: [S:1]([O:5][C:6]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](C(=O)NCCCCCCC)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1)(=[O:4])(=[O:3])[NH2:2].OC1C=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H]([NH:53][C:54](=[O:62])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])CC4)CCC=2C=1>>[S:1]([O:5][C:6]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([NH:53][C:54](=[O:62])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: CCCCCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Reactant: CCCCCCCC(=O)N[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Product: CCCCCCCC(=O)N[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Yield: 50 %

Procedure:
Sulfamates 11a (50%) were prepared by using the procedure outlined in Example 1 for the synthesis of sulfamate (5a), but using compound 10a instead of compound 4a.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][N:8]([C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester, (400 mg, 1.03 mmol) in chloroform (10 ml) was added triethylamine (416 mg, 4.12 mmol), benzoyl chloride(144 μl, 1.24 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 375 mg (80%) of the product as a solid. MS-ES: m/z 456.1 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH:11]2[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]2)[C:5]([F:18])=[C:4]([F:19])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]#[N:31]>CC#N>[F:8][C:7]1[C:2]([O:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=2[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:30]#[N:31])=[N:3][C:4]([F:19])=[C:5]([F:18])[C:6]=1[O:9][CH2:10][CH:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: CC1(C)OCC(COc2c(F)c(F)nc(F)c2F)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OCC(COc2c(F)c(F)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)O1
Reaction time: 24 h
Yield: 56.1 %

Procedure:
To 2,3,5,6-tetrafluoro-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridine (3.2 g, 11 mmol) in CH3CN (20 mL) was added Cs2CO3 (3.8 g, 12 mmol) and 3-hydroxy-4-(benzyloxy)benzonitrile (2.5 g, 11 mmol). After stirring for 24 hours the reaction was partitioned with water and ethyl acetate. The layers were separated, washed with water and brine, dried (Na2SO4), and the solvent was removed in vacuo. The residue was triturated with hexane/ethyl acetate (1/1) and the resulting solid was collected by filtration to give 3-[[3,5,6-trifluoro-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile (3.0 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[F:34]>>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([F:34])[C:27]=1[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: Fc1cccc(F)c1OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3c(F)cccc3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.820 g of 2-(3-bromopropoxy)-1,3-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.70 (1:1 EtOAc-heptane); Rt=5.26.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:32]([O:39][C:40](=[O:43])[CH2:41][NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH2:32]([O:39][C:40](=[O:43])[CH2:41][NH:42][C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 77.4 %

Procedure:
11.57 g (50 mmoles) of tert.-butoxycarbonyl-D-norleucine and 5.6 ml (50 mmoles) of N-methylmorpholine are dissolved in 50 ml of dimethyl formamide. The solution is cooled to -10° C., and 6.6 ml (50 mmoles) of isobutyl chloroformate are added with stirring. After 10 minutes the mixture is cooled to -20° C., and a solution of 18.6 g (55 mmoles) of glycine benzyl ester p-toluolsulfonate and 6.1 ml (55 mmoles) of N-methylmorpholine in 80 ml of dimethyl formamide, cooled to -20° C., is added. The reaction mixture is stirred at -10° C. for 10 minutes, at 0° C. for one hour and then at room temperature overnight. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is dissolved in a mixture of 300 ml of ethyl acetate and 100 ml of water. The ethyl acetate phase is separated, washed successively with 5% aqueous sodium hydrocarbonate solution (2×60 ml), water (2×60 ml), 1 n hydrochloric acid cooled with ice water (2×60 ml) and water (2×60 ml) again, dried over sodium sulfate, decolourized with carbon, filtered, and the filtrate is evaporated under reduced pressure. The crystalline residue is triturated with diisopropyl ether, the solid is filtered off, washed with diisopropyl ether and dried. 14.65 g (76.9%) of tert.-butoxycarbonyl-D-norleucyl-glycine benzyl ester are obtained; m.p.: 85°-86° C., Rf13 =0.75-0.85, [α]D20 =+12.2° (c=1%, in dimethyl formamide).
Reaction SMILES: [I:1]I.C(=O)(O)[O-].[Na+].[F:8][C:9]([F:18])([F:17])[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.NC(N)=S>C1COCC1.O>[F:8][C:9]([F:17])([F:18])[C:10]1[CH:11]=[C:12]([I:1])[C:13]([OH:16])=[CH:14][CH:15]=1
Reactant: II
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(C(F)(F)F)cc1I
Reaction time: 8 h

Procedure:
A mixture of iodine (91.6 mmol, 23.2 g) and sodium bicarbonate (91.6 mmol, 7.7 g) was added to a solution of α,α,α-trifluoro-p-cresol (83.3 mmol, 13.5 g) in THF (90 mL) and H2O (90 mL) and the reaction mixture was allowed to stand at room temperature overnight. Sufficient thiourea (5% solution) was added to remove the excess iodine as indicated by the color change of the reaction from deep violet to brown. The reaction mixture was extracted with ether (3×100 mL), the extract was dried, filtered and the filtrate was concentrated to obtain a brown oil. This oil was distilled (bp 105° C. at 44 mm Hg) to obtain α,α,α-trifluoro-o-iodo-p-cresol (4.1 g, 75% pure, admixed with the starting α,α,α-trifluoro-p-cresol).
Reaction SMILES: [N].N1C=CC=C1.[C:7]([C:9]1[C:10]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[S:27][CH:28]=[CH:29][C:30]=3[N+:31]([O-:33])=[O:32])=[CH:22][CH:21]=2)=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([CH3:14])[CH:13]=1)#[N:8].[Br:34]NC(=O)CCC(N)=O>C(Cl)Cl>[Br:34][C:13]1[N:12]([CH3:14])[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[S:27][CH:28]=[CH:29][C:30]=3[N+:31]([O-:33])=[O:32])=[CH:24][CH:25]=2)[C:9]=1[C:7]#[N:8]
Reactant: CCOC(=O)c1c(-c2ccc(-c3sccc3[N+](=O)[O-])cc2)c(C#N)cn1C
Reactant: NC(=O)CCC(=O)NBr
Agent: [N]
Solvent: c1cc[nH]c1
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(-c3sccc3[N+](=O)[O-])cc2)c(C#N)c(Br)n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound is prepared in a manner analogous to the procedure set forth in Scheme XXIII, step A wherein the starting pyrrole nitrogen is already methylated. For example, to a solution of ethyl 4-cyano-1-methyl-3-[4-(3-nitro(2-thienyl))phenyl]pyrrole-2-carboxylate, prepared directly above (1.0 mmol) in methylene chloride in an ice bath add N-bromo-succinamide (1.5 mmol). Allow the reaction to warm to room temperature and stir for 18 hours. After this time, wash reaction with water while extracting with ethyl acetate. Dry organic layer with sodium sulfate, filter and concentrate in vacuo to provide the title compound. Use as crude in the next step.