Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].Cl.Cl.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCCC1>[OH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][NH:20][S:2]([C:5]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3])[CH2:24][CH2:25]1
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: NCCN1CCC(O)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (1.5 g, 5.4 mmol) in tetrahydrofuran (100 ml) was added over 1 hour to a stirred mixture of 1-(2-aminoethyl)-4-hydroxypiperidine dihydrochloride (1.2 g, 5.4 mmol) and triethylamine (2.3 ml, 16.5 mmol) in tetrahydrofuran (75 ml) cooled in an ice bath. After stirring at room temperature for 6 hours, solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium chloride solution. The ethyl acetate extract was dried (Na2SO4), filtered and concentrated. The residue was flash chromatographed on silica gel and eluted with 5% methanol-95% chloroform to give pure product, 1.0 g, as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[NH:17][N:16]=2)=[CH:11][CH:10]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]4[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=4)[NH:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Oc1ccc(/C=C/c2cc(-c3ccc(Cl)cc3)n[nH]2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CN1CCN(c2ccc(-c3cc(/C=C/c4ccc(O)cc4)[nH]n3)cc2)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 8.4 %

Procedure:
N-Methylpiperazine (50 μL, 0.49 mmol) was added to a suspension of 4-{(E)-2-[3-(4-chlorophenyl)-1H-pyrazol-5-yl]ethenyl}phenol (0.097 g, 0.33 mmol), NaOtBu (0.110 g, 1.14 mmol) and acetato(2′-di-tert-butylphosphino-1,1′-biphenyl-2-yl)palladium (0.015 g, 33 μmol, 10 mol %) in anhydrous toluene (1.5 mL) and heated to 80° C. After 24 hours, the reaction was cooled to room temperature, diluted with methanol and filtered though a celite pad. The filtrate was concentrated in vacuo and the residue purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the title compound (10 mg, 9% yield) as an off-white solid: 1H NMR (400 MHz, CD3OD): δ 7.71 (m, 2H), 7.40 (m, 2H), 7.20 (d, J=16.4 Hz, 1H), 7.10 (m, 2H), 6.87 (d, J=16.4 Hz, 1H), 6.84 (s, 1H), 6.79 (m, 2H), 3.95 (bd, J=14.4 Hz, 2H), 3.63 (bd, J=11.2 Hz, 2H), 2.28 (m, 2H), 3.10 (bt, J=13.2 Hz, 2H), 2.99 (s, 3H); MS (EI) for C22H24N4O: 361.2 (MH+).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])=[N:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cu][C:36]#[N:37]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[S:19][C:18]([CH3:28])=[N:17][C:16]=2[C:14]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][C:5]2[O:6][C:2]([C:36]#[N:37])=[C:3]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:4]=2)=[O:15])=[CH:22][CH:23]=1
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3)c(Br)o2)c(-c2ccc(F)cc2)s1
Reactant: N#C[Cu]
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3)c(C#N)o2)c(-c2ccc(F)cc2)s1
Yield: 13.5 %

Procedure:
The title compound (50 mg) was prepared by treating the compound of example 167 (0.410 g) with copper(I)cyanide (0.103 g) according to the method of example 96. Following column chromatography, further purification by HPLC was required (Supercosil ABZ+, 5-95% acetonitrile containing 0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid).
Reaction SMILES: S(O[CH:7]1[CH2:13][CH:12]2[N:14]([CH3:15])[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)(OC)(=O)=O.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.O>O1CCCC1>[CH3:15][N:14]1[CH:9]2[CH2:10][CH2:11][CH:12]1[CH2:13][CH:7]([S:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[CH2:8]2
Reactant: COS(=O)(=O)OC1CC2CCC(C1)N2C
Reactant: COc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(SC2CC3CCC(C2)N3C)cc1
Temperature: 30 °C
Yield: 103.7 %

Procedure:
To a solution of methyl 8-methyl-8-azabicyclo[3.2.1]oct-3-yl sulfate (Preparation 13, 35 g, 0.16 mol) in tetrahydrofuran (300 ml) was added with cooling to 0° C. sodium hydride (60% dispersion in oil, 7 g, 0.17 mol). After complete addition, 4-methoxybenzene thiol (23.8 g, 0.16 mol) was added in tetrahydrofuran (300 ml). The reaction mixture was heated under reflux for 2 h and then cooled to 30° C. and water (250 ml) was added. The tetrahydrofuran was removed in vacuo, dichloromethane was added and the layers separated. The organic layer washed with water, sodium hydroxide (1 M solution), water, and saturated brine before drying (Na2SO4). The organic extracts were concentrated in vacuo to give the title compound (43.7 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:30][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reaction time: 2 h
Yield: 42.3 %

Procedure:
A solution of [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (0.20 g, 0.58 mmol), iodomethane (Example 42, 0.14 g, 1.0 mmol) and K2CO3 (0.41 g, 3 mmol) in acetone (10 ml) was heated to reflux. After 2 hr, the reaction was cooled, filtered, concentrated to give an oil which was purified by column chromatography (eluent 10% EtOAc/hexane) to give a the desired product as a foam (0.10 g, Yield=48%); MS (ESI) m/z 408 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].[BrH:18].OO>>[NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([Br:18])=[CH:13][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5]
Reactant: Br
Reactant: CCCCCCOC(=O)c1cccc(C)c1N
Agent: OO
Product: CCCCCCOC(=O)c1cc(Br)cc(C)c1N
Yield: 795.6 %

Procedure:
The above-described method (Example 1) was repeated to react hexyl 2-amino-3-methylbenzoate (2.50 g, 10 mmol) with hydrogen bromide (2.21 g, 13 1 mmol, 48% in water) and hydrogen peroxide (1.72 g, 15.0 mmol, 30% in water). Following working up similar to Example 1 and additional column chromatography, hexyl 2-amino-5-bromo-3-methylbenzoate (2.5 g, 78.8% of theory, >99 area % LC) was obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10](I)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[F:16][C:17](I)([F:19])[F:18]>[Cu].N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C:17]([F:19])([F:18])[F:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: FC(F)(F)I
Reactant: COC(=O)c1cccc2c(I)cccc12
Agent: [Cu]
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c(C(F)(F)F)cccc12
Temperature: 130 °C
Yield: 60.4 %

Procedure:
A mixture of 5-iodo-1-naphthalenecarboxylic acid methyl ester [8.8 g, 28 mmoles, described by C. Seer and R. School, Justus Leibigs Ann. Chem., 398, 82 (1913)], trifluoromethyl iodide (12 g, 61.2 mmoles), freshly prepared copper powder (5.7 g, prepared according to the procedure of R. Q. Brewster and T. Groening, "Organic Syntheses", Coll. Vol. II, John Wiley and Sons, New York, N.Y., U.S.A., 1948, p. 445) and pyridine (45 ml) was charged into a stainless steel autoclave. The vessel was shaken and heated at 130° C. for 24 hr and cooled to room temperature. The mixture was filtered to remove insoluble material. The filtrate was washed with 1N aqueous HCl, water and brine, dried (MgSO4) and concentrated to dryness. The residue was crystallized from methanol to give 4.3 g of 5-(trifluoromethyl)-1-naphthalenecarboxylic acid methyl ester, NMR (CDCl3) δ 4.0 (s, 3H), 8.0 (m, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23].O>N1CCCCC1.C(O)C>[CH:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:25](/[S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)(=[O:24])=[O:23])\[C:26]#[N:27])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: N#CCS(=O)(=O)c1ccccn1
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccccn2)cc(C(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
The reaction mixture of 450.0 mg of 3,5-diisopropyl-4-hydroxylbenzaldehyde, 400.0 mg of 2-pyridinesulphonylacetonitrile and a few drops of piperidine in 10.0 mL of ethanol was refluxed for 3 h and then cooled to room temperature. To the above reaction mixture was added 5.0 mL of water until crystallization began. After standing at 0° C. for 2 h, the solid was filtered, washed with cold water and dried in oven at 40° C. overnight to provide 350.0 mg of the titled compound.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH:16]1[O:18][CH2:17]1
Reactant: BrCC1CO1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc(-c2ccc(OCC3CO3)cc2)cc1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
4.7 g of p-phenylphenol, 15.1 g of epibromohydrin, 13.6 g of potassium carbonate and 33.3 g of 2-butanone were introduced into a three-necked flask with reflux condenser and stirrer at 30° C. The mixture was heated to 70° C. and stirred for 16 hours. After filtration, the filtrate was freed from low-boiling components in a rotary evaporator. After addition of 2×30 ml of 2-butanone and redistillation, p-phenylphenol glycidyl ether was obtained as a crystalline solid having a melting range of 96-98° C. 1H-NMR (CDCl3, 400 MHz): 2.78 (dd, 1H), 2.90 (t, 1H), 3.36 (m, 1H), 4.02 (dd, 1H), 4.24 (dd, 1H), 7.00 (AA′BB′ system, 2H), 7.30 (t, 1H), 7.40 (t, 1H), 7.55 (m, 4H).
Reaction SMILES: ON=C[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].P(Cl)(Cl)(Cl)=O.[C:17](#[N:19])[CH3:18]>>[CH3:18][C:17]1[O:11][C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[N:19]=1
Reactant: ON=Cc1ccc(O)cc1O
Reactant: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2ccc(O)cc2o1

Procedure:
As depicted in Scheme 2 the known compound, for example 4-((hydroxyimino)methyl)benzene-1,3-diol (B), was cyclized with phosphorus oxychloride in acetonitrile, affording the corresponding 2-methylbenzoxazol-6-ol (B1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:28]4[CH:39]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:28]4[CH:39]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(-c5ccccc5)cccc4n3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3cn4c(-c5ccccc5)cccc4n3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (551 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (469 mg, yield: 90%). This was recrystallized from ethanol-hexane. Melting point: 160–161° C.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.CN1C(=O)CCC1>[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[C:7]([CH:8]3[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:29][CH:28]=1)=[O:26]
Reactant: CC(=O)N1CCC(c2cccnc2F)C1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 200 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(3-(2-fluoropyridin-3-yl)pyrrolidin-1-yl)ethanone (86 mg, 0.41 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (197 mg, 0.826 mmol), cesium carbonate (309 mg, 0.95 mmol), copper(i) iodide (79 mg, 0.413 mmol), and NMP (1.4 mL). The reaction mixture was degassed and flushed with N2 and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 200° C. for 1 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and 1 N NH4Cl. The aqeuous layer was back extracted with EtOAc (2×) and the combined organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The crude material was chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 5% MeOH in EtOAc, followed by trituration with ether, dried to provide 1-(3-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)pyrrolidin-1-yl)ethanone as off-white solid. MS (ESI, pos. ion) m/z: 427.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[CH2:54][CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:55])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[CH:16]=2)[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[CH2:54][CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:55])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:22][CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
Methanesulfonyl chloride (81μL, 1.05 mmol) was added to a stirred solution of Intermediate 95e (545 mg, 803 mmol) and DIPEA (420 μL, 2.41 mmol) in DCM (20 mL), under argon and the reaction mixture was stirred at RT for 1.5 h. A further 25 μL, 0.32 mmol of methanesulfonyl chloride was added and the reaction mixture continued to stir at RT for 2 h. Water (20 mL) was added and the two layers were shaken thoroughly before being separated. The aqueous layer was extracted with DCM (2×20 mL) and the combined organics were passed through a phase separator and concentrated in vacuo to afford the title compound as an orange glass (690 mg, >100%). LCMS (Method 3): Rt 3.89 min, m/z 757 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:19])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9](=[O:19])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[CH2:14][CH2:13]2)[CH3:11])=[CH:6][CH:7]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](O)CC1
Reactant: BrCCCCBr
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](OCCCCBr)CC1

Procedure:
In analogy to example 11.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester and 1,4-dibrombutane were reacted to yield trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester as yellowish oil, MS:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([OH:12])=O)=[N:6][CH:7]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])=[N:6][CH:7]=1
Reactant: O=C(O)C=Cc1ccc(Br)cn1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
3-(5-Bromo-pyridin-2-yl)-acrylic acid (1.3 g, 5.7 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (0.7 g, 6.8 mmol), HOBT (1.5 g, 11.4 mmol), EDAC (2.2 g, 11.4 mmol) and triethylamine (1.6 mL, 11.4 mmol) were added to dichloromethane (42.0 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with a saturated solution of ammonium chloride, and then extracted with dichloromethane. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to give 1.3 g of the titled compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=Cc1ccncc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccncc1
Yield: 95 %

Procedure:
Ethyl 3-(4-pyridyl)acrylate (16.62 g, 93.8 mmol) was hydrogenated in 80 ml of ethanol over 5% Pd on carbon (2 g) at 60 psi at room temperature for 16 hours. After evaporation, the residue was dissolved in 200 ml of diethyl ether and filtered through diatomaceous silica and concentrated to afford 15.97 g (95% yield) of the subtitle compound. D. Preparation of thyl 3-(4-(2-hydroxymethyl)pyridyl)propionate
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:36])[C@@H:15]([NH:32][C:33](=[O:35])[CH3:34])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([O:24]CC3C=CC=CC=3)[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C@@H:9]1[CH3:43])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:36])[C@@H:15]([NH:32][C:33](=[O:35])[CH3:34])[CH2:16][C:17]2[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([O:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C@@H:9]1[CH3:43])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(OCc2ccccc2)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Yield: 94.9 %

Procedure:
Stir (2R,3S,5R)-5-[(1S,2S)-2-acetylamino-3-(3-benzyloxy-5-fluoro-phenyl)-1-hydroxy-propyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (0.81 g, 1.34 mmol) and 10% palladium on carbon (0.50 g, 1.41 mmol) in ethanol (20 mL) under a hydrogen atmosphere for 3 hours. Filter and concentrate to give 0.652 g (94.7%) of the desired compound as a white solid.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[CH:23]1([CH:22]=[C:21]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:37])([CH3:35])[CH3:36])=[CH:30][CH:29]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(C(C)(C)O)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(C(C)(C)O)cc3)cc2c1
Yield: 85.7 %

Procedure:
A mixture of 2-{4-[1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-propan-2-ol (160 mg, 0.31 mmol) in ethanol (3 mL) and an aqueous sodium hydroxide solution (10%, 1.5 mL) was heated at reflux for 5 h. The mixture was acidified to pH 4-5 with a 2 N aqueous hydrochloric acid solution, diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 2-{4-[2-cyclopentyl-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-propan-2-ol (100 mg, 86.2%) as a light yellow solid: LC/MS m/e calcd for C24H28N2O2 [M+H]+ 377.5, observed 377.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][CH2:33][C@H:34]([OH:36])[CH3:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:36][C@H:34]([CH3:35])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@@H](O)CN
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Reaction time: 15 h
Yield: 83.9 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (51.4 g, 115 mmol) synthesized in Example (106c) was dissolved in methanol (600 mL), and (R)-(−)-1-amino-2-propanol (19.9 mL, 253 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (63.7 g, 230 mmol) were added, followed by stirring for 15 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and water (500 mL) was added, followed by extraction twice with ethyl acetate (500 mL). Subsequently, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=25%-67%) to afford the desired compound (48.7 g, yield 84%) as a white solid.