Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[N:38]1([CH2:44][CH2:45][NH2:46])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[CH:4]=[N:3][C:2]([NH:46][CH2:45][CH2:44][N:38]6[CH2:43][CH2:42][O:41][CH2:40][CH2:39]6)=[CH:7][N:6]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Reactant: NCCN1CCOCC1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(NCCN5CCOCC5)cn3)C4)n[nH]c2c1
Yield: 23.7 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (100 mg, 193 μmol) and 2-morpholin-4-yl-ethylamine, (30 mg, 347 μmol) using the method of Example 32. The crude material was purified by HPLC Method F to afford (28 mg, 28%) of the title compound as off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:24]([C:25]2[C:26]([CH3:52])=[CH:27][C:28]3[C:38]([CH:39]([CH3:41])[CH3:40])=[C:37]([O:42]C(C)=O)[C:36]([O:46]C(C)=O)=[C:35]([CH:50]=[O:51])[C:29]=3[C:30]=2[O:31]C(C)=O)=[C:23]([O:53]C(C)=O)[C:5]2=[C:6]([CH:21]=[O:22])[C:7]([O:17]C(C)=O)=[C:8]([O:13]C(C)=O)[C:9]([CH:10]([CH3:12])[CH3:11])=[C:4]2[CH:3]=1.S(=O)(O)[O-].[Na+]>>[CH3:52][C:26]1[C:25]([C:24]2[C:2]([CH3:1])=[CH:3][C:4]3[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([OH:13])[C:7]([OH:17])=[C:6]([CH:21]=[O:22])[C:5]=3[C:23]=2[OH:53])=[C:30]([OH:31])[C:29]2=[C:35]([CH:50]=[O:51])[C:36]([OH:46])=[C:37]([OH:42])[C:38]([CH:39]([CH3:40])[CH3:41])=[C:28]2[CH:27]=1
Reactant: CC(=O)Oc1c(OC(C)=O)c(C=O)c2c(OC(C)=O)c(-c3c(C)cc4c(C(C)C)c(OC(C)=O)c(OC(C)=O)c(C=O)c4c3OC(C)=O)c(C)cc2c1C(C)C
Agent: O=S([O-])O
Agent: [Na+]
Product: Cc1cc2c(C(C)C)c(O)c(O)c(C=O)c2c(O)c1-c1c(C)cc2c(C(C)C)c(O)c(O)c(C=O)c2c1O
Temperature: 50 °C

Procedure:
Gossypol acetic acid was obtained from the U.S. Department of Agriculture. Analytically pure gossypol was prepared from the acetic acid adduct by the method of Campbell et al., J. Amer. Chem. Soc. 59, 1723-38(1937). In the process, the adduct is dissolved in peroxide-free ether, mixed with aqueous sodium bisulfite solution (0.4%) and heated at 50° C. The resultant solid is further purified by repeating the process and by crystallization of the final solid from a mixture of ether and petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](/[C:8](=[C:11](/OC)\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.C(/C(=C(/OC)\C)/[C:26]#[N:27])(=O)C1C=CC=CC=1>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](/[C:8](=[C:11](/[NH:27][CH3:26])\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccccc1
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1
Product: CN/C(C)=C(\C#N)C(=O)c1ccc(F)cc1

Procedure:
The procedure of Example 15 is repeated substituting an equimolecular amount of 2-(p-fluorobenzoyl)-3-methoxycrotononitrile for the 2-benzoyl-3-methoxycrotononitrile employed in that example. There is thus obtained the title compound after purification by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:11]2[O:12][C:13]=1[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:27]([CH2:33][CH2:34][CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH:27]([O:19][C:15]1[C:16]([CH3:18])=[N:17][N:10]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:13]([CH3:14])[O:12][C:11]=12)[CH2:33][CH2:34][CH3:35])[CH3:32]
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1O
Reactant: CCCC(Br)C(=O)OCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCC(Oc1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12)C(=O)OCC

Procedure:
A solution of 3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazol-7-ol (Intermediate IC) (100 mg, 0.337 mmol), cesium carbonate (132 mg, 0.404 mmol) and ethyl 2-bromovalerate (0.069 ml, 0.404 mmol) in DMF (3.365 ml) is stirred at 45° C. for 2 hours. The reaction mixture is poured into sat NaHCO3 (50 ml) and the product is extracted with EtOAc (2×50 ml) (brine is used to aid the phase separation). The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the resultant oil by ISCO combiflash chromatography, eluting with 0 to 100% (iso-hexane/EtOAc) on a 12 g SiO2-column affords the title compound as a solid; MS: m/z 425.21 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:10]([OH:12])=[O:11])[C:7]([OH:9])=O)=[CH:2]1.[NH2:13][CH:14]1[C:27](=[O:28])[N:16]2[CH:17]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)[C:18]([CH3:21])([CH3:20])[S:19][C@H:15]12.[Na][Na]>>[C:10]([CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([NH:13][CH:14]1[C:27](=[O:28])[N:16]2[CH:17]([C:22]3[NH:23][N:24]=[N:25][N:26]=3)[C:18]([CH3:20])([CH3:21])[S:19][C@H:15]12)=[O:9])([OH:12])=[O:11]
Reactant: O=C(O)C(C(=O)O)c1ccsc1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Agent: [Na][Na]
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)O)c3ccsc3)C(=O)N2C1c1nnn[nH]1
Yield: 67 %

Procedure:
(2.69 mmole) of 2-(3-thienyl)malonic acid (British Pat. No. 1,125,557) with 645 mg. (2.69 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, according to the procedure of Example CXLVII, affords 810 mg, (67% yield) of 6-(2-carboxy-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as its disodium salt. The infrared spectrum of the product KBr disc) shows absorptions at 1775 cm-1 (β-lactam), 1670 cm-1 (amide I), 1620 cm-1 (carboxylate) and 1525 cm-1 (amide II). The NMR spectrum (D2O) shows absorptions at 7.80-7.00 ppm (multiplet, thienyl hydrogens), 5.88 ppm (doublet, C-6 hydrogen), 5.65 ppm (doublet of doublets, C-5 hydrogen), 5.40 ppm (doublet, C-3 hydrogen), 1.60 ppm (doublet, C-2 methyl hydrogens) and 1.00 ppm doublet, C-2 methyl hydrogens).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([N:9]2[CH2:18][CH2:17][C:16]3[C:15]([CH:19]=[O:20])=[C:14]([O:21][CH3:22])[CH:13]=[CH:12][C:11]=3[CH2:10]2)=[O:8])=[CH:5][N:6]=1.CN(C)C=O.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][O:21][C:14]1[CH:13]=[CH:12][C:11]2[CH2:10][N:9]([C:7]([C:4]3[S:3][C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:6][CH:5]=3)=[O:8])[CH2:18][CH2:17][C:16]=2[C:15]=1[CH:19]=[O:20]
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(c1C=O)CCN(C(=O)c1cnc(Br)s1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1C=O)CCN(C(=O)c1cnc(N3CCN(C)CC3)s1)C2
Yield: 38.3 %

Procedure:
To a solution of 2-(2-Bromo-thiazole-5-carbonyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde (229 mg, 0.60 mg) in abs. N,N-dimethylformamide (4 mL), N-methyl piperazine (133 μL, 120 mg, 1.20 mmol) and dry potassium carbonate (248 mg, 1.80 mmol) was added. The resultant mixture was stirred under nitrogen at 100° C. for 2 h in a closed vial. The reaction was cooled, water (10 mL) was added, and the resultant solution was extracted with ethyl acetate (3×15 mL) The combined organic layers were dried (MgSO4) and evaporated to afford title compound (92 mg, 0.23 mmol, 38%) as a pale yellow crystalline solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C:14]2([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(#N)C.CN(C)CC>C(=O)=O>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1=NC2(c3ccccc3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Agent: CCN(C)C
Agent: O=C=O
Solvent: CC#N
Solvent: CO
Product: O=C(NC1=N[C@@]2(c3ccccc3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Yield: 37.4 %

Procedure:
Racemic benzyl 2-benzamido-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (30 g, 63 mmol) is chirally purified by SFC: (Column: Chiralpak IC 2.1×25 cm; eluent: 40% methanol/acetonitrile (8/2) with 0.2% dimethylethyl amine in CO2; flow: 70 mL/min at UV 284 nm). The second eluting isomer is the title compound (11.1 g, 37%, >98% ee). Chiral analysis of the isolated isomer 2: Chiralpak IC 0.46×10 cm, 5 μm; eluent: 40% methanol/acetonitrile (8/2) with 0.2% dimethyl ethyl amine in CO2; flow: 5 mL/min at UV 215 nm. Rt=3.2 minutes. [α]D20=−88 (C=1.0, methanol), ES/MS (m/e) 372 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([OH:33])[CH2:15][C@H:16]([CH2:20][CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2C=CC([C@@H](O)C[C@H](CCN3C(=O)C4=CC=CC=C4C3=O)C(O)=O)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([OH:33])[CH2:15][CH:16]([CH2:20][CH2:21][N:22]3[C:23](=[O:32])[C:24]4=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]4[C:26]3=[O:27])[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](CCN1C(=O)c2ccccc2C1=O)C[C@@H](O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=C(O)[C@@H](CCN1C(=O)c2ccccc2C1=O)C[C@H](O)c1ccc(-c2ccc(Cl)cc2)cc1
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)CC(O)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
the more active of the compounds [2S, 4R]-4-[4-(4-chlorophenyl)phenyl]-4-hydroxy-2-(2-phthalimidoethyl)-butanoic acid and [2S, 4S]-4-[4-(4-chlorophenyl)phenyl]-4-hydroxy-2-(2-phthalimidoethyl)-butanoic acid;
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>ClCCl>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:8]([C:7]2[C:2]([Cl:1])=[N:3][C:4]([S:11][CH3:12])=[N:5][CH:6]=2)=[O:9])=[CH:16][CH:15]=1
Reactant: CSc1ncc(C(=O)Cl)c(Cl)n1
Reactant: Nc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Reaction time: 0.25 h

Procedure:
To a mixture of 4-chloro-2-methylsulfanylpyrimidine-5-carbonyl chloride prepared above (113 mg, 0.54 mmol) in dichloromethane was added 4-fluoroaniline (56 μL, 0.59 mmol). This was followed by the dropwise addition of DIPEA. The mixture was stirred for 15 min, the mixture was diluted with dichloromethane, washed with water and saturated aqueous sodium bicarbonate and was dried over sodium sulfate. Filtration and concentration afforded a residue that was purified by trituration from ethyl acetate with hexanes. The resulting off-white solid (122 mg, 0.41 mmol, 76%) was sufficiently pure to use without further purification. 1H NMR (300 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.86 (s, 1H), 7.69 (m, 2H), 7.23 (m, 2H), 2.56 (s, 3H); MS (EI) m/z 296.2 (M−H)−.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(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: [Na+]
Product: CN(Cc1cc(-c2ccccc2Cl)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-chlorophenyl)boronic acid (218 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-blue oil (yield 171 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[C:10]([C:18]([OH:20])=[O:19])[C:9]=2[O:21][CH3:22])=[O:7])=[CH:4][CH:3]=1.Cl.[CH2:26](O)[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:26][CH3:27])=[O:16])=[C:10]([C:18]([OH:20])=[O:19])[C:9]=2[O:21][CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: CCO
Reactant: COc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=O)Cc1c(C(=O)O)c(OC)c(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
5-(p-Chlorobenzoyl)-3-hydroxycarbonyl-4-methoxy-1-methylpyrrole-2-acetic acid (478 mg) is suspended in 5 ml of absolute ethanol under nitrogen and heated to reflux. Concentrated hydrochloric acid (75 ml) is subsequently added and the reaction mixture is heated for another 20 minutes until all the solids are dissolved. The resulting solution is heated for an additional 10 minutes. Upon cooling, the product crystallizes out and is filtered, and dried in vacuo to afford 260 mg of ethyl 5-(p-chlorobenzoyl)-3-hydroxycarbonyl-4-methoxy-1-methylpyrrole-2-acetate, m.p. 190 (dec.)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][PH:12]([CH2:14][O:15]CC)=[O:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([CH2:11][PH:12]([CH2:14][OH:15])=[O:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC[PH](=O)Cc1c(Cl)cccc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(Cl)c1C[PH](=O)CO
Yield: 89 %

Procedure:
10.4 grams (0.34 moles) of the ethyl ester of 3-chloro-2-[(ethoxymethylphosphinyl)methyl]-benzoic acid prepared as described in Part B Step A of Example 1 was admixed with 20 ml of concentrated hydrochloric acid and 80 ml of dioxane. The resulting composition was saturated with hydrochloric acid (gas) and refluxed for 12 hours. The composition was concentrated, extracted with ether and the ether solution was dried over magnesium sulfate. The ether was evaporated and the residue was recrystallized from acetone/CH2Cl2 to give 7.5 grams (89% yield) of 3-chloro-2-[(hydroxymethylphosphinyl)methyl]-benzoic acid having a melting point of 219°-220° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:26][C:24]1[CH:25]=[C:20]([NH:1][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH2:9]3)[CH:5]=[CH:4][CH:3]=2)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: C=CC(=O)N[C@H]1CCCN(c2cccc(N)n2)C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC(=O)N[C@H]1CCCN(c2cccc(Nc3cc(Br)cn(C)c3=O)n2)C1
Temperature: 95 °C
Reaction time: 7 h
Yield: 28.4 %

Procedure:
A mixture of 114e (440 mg, 1.79 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (534 mg, 2.0 mmol), Pd2(dba)3 (83 mg, 0.091 mmol), Xantphos (105 mg, 0.182 mmol) and Cs2CO3 (1.48 g, 4.55 mmol) in DMF (10 mL) was stirred at 95° C. under N2 for 7 h. The mixture was diluted with EA and filtered. The filtrate was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EA=1/2) to give (S)—N-(1-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yl)piperidin-3-yl)acrylamide 114f (220 mg, 28%) as yellow solid. MS-ESI: [M+H]+ 433.3
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:23][NH2:24]>CO.O1CCOCC1>[C:12]1([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:23][NH2:24])=[O:2])[CH2:6][CH2:7]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cccc3ccccc23)CC1
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2cccc3ccccc23)CC1
Temperature: 80 °C

Procedure:
A mixture of trans-4-(naphthalen-1-yloxy)-cyclohexanecarboxylic acid methyl ester (0.130 g, 0.457 mmol) and hydrazine hydrate (0.022 ml, 0.45 mmol) in methanol (0.5 ml) was heated at 80° C. for 16 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a 3:1 mixture of the crude title compound and starting material. This mixture (0.12 g) and hydrazine hydrate (0.022 ml, 0.45 mmol) were dissolved in 1,4-dioxane (0.4 ml) and heated at reflux for 18 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.120 g, 83%) as yellow solid with a purity of 90%, which was used in the next step without further purification. MS m/e: 285 (M+H+)
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[C:19]([OH:24])(=[O:23])[CH:20]([CH3:22])[CH3:21].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>C1COCC1>[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]([OH:29])[C:20]([CH3:22])([CH3:21])[C:19]([OH:24])=[O:23]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)C(O)c1ccccc1F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
To a solution of diisopropylamine (3.31 mL, 23.22 mmol) in THF (5 mL) was added n-BuLi/hexane (9.29 mL, 23.22 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 5 min and then stirred in ice bath for 20 min. The reaction mixture was added dropwise with a solution of isobutyric acid (1.055 mL, 11.61 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and 60° C. for 2 h. The flask was recooled to 0° C., and a solution of 2-fluorobenzaldehyde (1.441 g, 11.61 mmol) in THF (5 mL) was added dropwise. Then the solution was allowed to warm to rt and stirred for 16 h. The reaction was quenched with 1 N HCl until pH˜3 and extracted with EtOAc. The combined organic layers were washed with 1 N NaOH. The combined basic washes were acidified with HCl and extracted with EtOAc. Then organic phase was washed with sat. NaCl, dried over anhydrous MgSO4, and concentrated to yield 3-(2-fluorophenyl)-3-hydroxy-2,2-dimethylpropanoic acid (1.5 g, 60.9% yield) as Cap N-9. 1H NMR (400 MHz, DMSO-d6) ppm 7.50 (td, J=7.5, 1.8 Hz, 1H), 7.32 (tdd, J=7.7, 5.4, 1.8 Hz, 1H), 7.22 (td, J=7.5, 1.0 Hz, 1H), 7.14 (ddd, J=10.5, 8.3, 1.3 Hz, 1H), 5.28-5.11 (m, 1H), 3.33 (br. s., 1H), 1.06-0.97 (m, 3H), 0.93 (d, J=2.8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCO[Si](C)(C)C(C)(C)C)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCO)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)pyridin-2-yl]methyl}-L-glutamate (140 mg, 0.23 mmol) in tetrahydrofuran (7 ml) was added acetic acid (80 μl, 1.40 mmol). The solution was cooled to 0° C., and tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 674 μl) was added dropwise. The cooling bath was removed and the reaction was stirred overnight, then mixed with 1 N aqueous sodium hydrogen carbonate solution (20 ml), and extracted with dichloromethane (3×20 ml). The organic phases were washed with brine (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude material was used without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([C:28]2[S:32][C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:30][CH:29]=2)(=[O:27])=[O:26])[CH:20]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:36]1[CH2:35][CH2:34][N:33]([C:31]2[S:32][C:28]([S:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)(=[O:27])=[O:26])=[CH:29][N:30]=2)[CH2:38][CH2:37]1)=[O:9])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1cccnc1)c1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3cccnc3)s2)CC1
Yield: 87 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 87%). MS (m/e): 551.3 (M+H+, 100%).
Reaction SMILES: [C:1]1([S:7]([CH3:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[P:21](Cl)([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[CH2:24]([O:23][P:21]([CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])(=[O:22])[O:26][CH2:27][CH3:28])[CH3:25]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CS(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)c1ccccc1)OCC
Temperature: -78 °C
Yield: 47.8 %

Procedure:
A stirred solution of methyl phenyl sulfone (20 g, 0.128 mol) in dry THF (200 mL) was cooled at −78° C. in an acetone/dry ice bath. Lithium bis(trimethylsilyl)amide (Li HMDS; 134 mL, 1 M solution in THF, 0.134 mol) was added dropwise over 1 h. The resulting white suspension was stirred for an additional hour at −78° C. and diethyl chlorophosphate (18.5 mL, 128 mmol) in THF (20 mL) was added. The reaction mixture was stirred at −78° C. for 0.5 h, then allowed to slowly warm to room temperature and left stirring for 4 h. The reaction mixture was next concentrated under reduced pressure, the residue was dissolved in EA (500 mL), washed with brine (100 mL),dried over anhydrous Na2CO3 and concentrated under reduced pressure. The resultant crude material was purified by flash chromatography on silica gel (EA:H, 3:1 to 1:1) to afford the desired product as white solid (17.9 g, 48%).