Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28](=O)[CH3:29]>C(O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[C:28]([CH3:29])=[N:27][C:16]=2[CH:17]=1)=[O:22])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reactant: CC=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCO
Product: C=CCOC(=O)c1ccc2c(c1)nc(C)n2C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 36 h
Yield: 45.1 %

Procedure:
To a stirred solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (15.0 g, 39.95 mmol, 1.0 equiv) in ethanol (250 mL) were added copper(II) acetate (14.51 g, 79.90 mmol, 2.0 equiv) and acetaldehyde (44.1 mL, 0.20 mol, 5.0 equiv; 20% solution in water) and the reaction mixture heated to refluxe for 36 h. The solvent was evaporated, the residue diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water and a sat. solution of NaCl, dried over Na2SO4, concentrated by evaporation under reduced pressure and purified with silica column chromatography eluting with a gradient of hexane/ethyl acetate (3:7→1:9) to obtain 7.2 g (45%) of the title compound as a brown solid. 1H NMR (400 MHz, DMSO): δ 1.46 (s, 9H), 1.88-1.91 (m, 2H), 2.14-2.20 (m, 2H), 2.63 (s, 3H), 2.97 (br s, 2H), 4.13-4.15 (m, 2H), 4.58 (t, J=11.5 Hz, 1H), 4.81 (d, J=4.6 Hz, 2H), 5.28 (d, J=10.4 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 6.03-6.10 (m, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 8.14 (s, 1H). MS (ISP): 400.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1OCC(=O)c1ccccc1

Procedure:
A mixture of 1 mole of 2-methoxyphenol and 1 mole of potassium carbonate in acetone is heated at reflux while adding 1 mole of alpha-bromoacetophenone. The mixture is refluxed for several hours to provide alpha-(2-methoxyphenoxy)acetophenone.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Br:29])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Br:22])[C:4]=2[CH:3]=1.C([Li])(C)(C)C.C(O[B:39]1[O:43][C:42]([CH3:45])([CH3:44])[C:41]([CH3:47])([CH3:46])[O:40]1)(C)C>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([B:39]4[O:40][C:41]([CH3:46])([CH3:47])[C:42]([CH3:44])([CH3:45])[O:43]4)=[CH:7][C:6]=3[C:5]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Br:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Br:22])=[CH:13][CH:14]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: BrCCCCCCC1(CCCCCCBr)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC1(C)OB(c2ccc3c(c2)C(CCCCCCBr)(CCCCCCBr)c2cc(Br)ccc2-3)OC1(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
2,7-Dibromo-9,9-bis(6-bromohexyl)fluorene (2.00 g, 3.08 mmol, 1 eq.) was dissolved in diethyl ether (25 ml). The solution was cooled to −78° C. and t-butyllithium (2.0 mL of a 1.7 mole/L solution in hexanes, 3.38 mmol, 1.1 eq.) was added drop wise with strong stirring. The resulted white suspension was allowed to warm to −10° C. and stirred for 10 min. Then the solution was cooled to −78° C. again and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.69 mL, 3.38 mmol, 1.1 eq.) was added in one time. The mixture was stirring for another 1 h at −78° C. and was allowed to warm to 25° C. and stirred for 24 h, and then the reaction was quenched by 10 mL of water. The organic layer was washed thoroughly by water and was dried by anhydrous Na2SO4. After the solvent was removed under reduced pressure, the crude oil was separated by column chromatography with hexane/chloroform=3/1 (v/v) as eluent to give 1.18 g of white powder (yield=50%). 1H NMR (500 MHz, CDCl3) δ (ppm): 7.81 (d, J=7.55 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J=7.55 Hz, 1H), 7.58 (dd, J=1.90 and 6.70 Hz, 1H), 7.46 (dd, J=1.80 and 6.70 Hz), 3.27 (t, J=6.85 Hz, 4H), 2.03-1.95 (m, 2H), 1.94-1.91 (m, 2H), 1.67-1.62 (m, 4H), 1.39 (s, 12H), 1.19-1.14 (m, 4H), 1.09-1.04 (m, 4H), 0.61-0.55 (m, 4H). 13C NMR (500 MHz, CDCl3) δ (ppm): 153.19, 149.12, 142.97, 139.98, 134.06, 130.09, 128.75, 126.14, 121.64, 121.56, 119.14, 83.85, 55.35, 40.00, 33.88, 32.65, 28.97, 27.76, 24.98, 23.44.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][C:15]=2[OH:22])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CN(C)C=O.Cl[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31]>C1(C)C=CC=CC=1>[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][C:15]=2[O:22][CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: COC(=O)C(C)Cl
Reactant: CCc1ccc(CN2CCOCC2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1ccc(CN2CCOCC2)c(OC(C)C(=O)OC)c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 84.5 %

Procedure:
To a one liter round bottom flask equipped with a mechanical stirrer and a thermometer was added 157.13 grams (1.14 moles--1.3 equiv.) of potassium carbonate, followed by 215.27 grams (0.875 mole--1.0 equiv.) of 89.9% pure 2-(morpholin-4-ylmethyl)-5-ethylphenol, and 230 mL (%Wt/Vol. Phenol to Solvent--93.6%) of N,N-dimethylformamide. The mixture was vigorously stirred and heated to 110° C., and then 139.3 grams (1.14 moles--1.3 equiv.) of methyl 2-chloropropanoate was added during a one hour period. Upon completion of addition, the reaction mixture was analyzed by GC, which indicated the reaction was incomplete. The reaction mixture was heated at 110° C. for seven hours. After this time, the reaction mixture was again analyzed by GC, which indicated the reaction was complete. The reaction mixture was filtered, and the orange filtrate was kept under a nitrogen atmosphere for about 48 hours. After this time, the filtrate was concentrated under vacuum at 90° C. and 10 mm of mercury to yield a red, brown liquid. The liquid was taken up in 200 mL of toluene, and the resulting solution was washed with two 500 mL portions of an aqueous saturated sodium chloride solution. The organic layer was separated from the aqueous layer, dried with magnesium sulfate, and filtered. The filtrate was concentrated under vacuum at 90° C. and 10 mm of mercury, yielding 252.7 grams of 83.6% pure methyl 2-[2-(morpholin-4-ylmethyl)-5-ethylphenoxy]propanoate (78.6% yield). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[CH2:26]([N:8]1[C:9](=[O:11])[CH:10]=[C:5]([NH:4][C:3]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:2]=2[F:1])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]1)[CH:25]=[CH2:24]
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1cc(C(=O)OCC)c(Nc2ccc(I)cc2F)cc1=O

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and allyl bromide in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (50% EtOAc/hexanes as eluant). Ethyl 1-allyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was isolated as a white solid (78%), m.p. (EtOAc) 138-141° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.30 (s, 1H), 8.45 (s, 1H), 7.77 (dd, J=10.1, 1.9 Hz, 1H), 7.61 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.98-5.87 (m, 1H), 5.47 (d, J=1.3 Hz, 1H), 5.19 (ddd, J=10.4, 2.7, 1.3 Hz, 1H), 5.12 (ddd, J=17.2, 3.0, 1.5 Hz, 1H), 4.54 (br d, J=5.5 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H). Anal. Calcd for C17H16FIN2O3: C, 46.2; H, 3.7; N, 6.3. Found: C, 46.5; H, 3.6; N, 6.2.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:42]1(B(O)O)[CH2:44][CH2:43]1.[OH-].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([CH:42]4[CH2:44][CH2:43]4)[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(Br)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C2CC2)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (100 mg, 0.15 mmol) in 1,4-dioxane (0.5 mL) was added cyclopropylboronic acid (10 mg, 0.19 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (82 mg, 8 mol %), bis(tri-tert-butylphosphine)palladium (0) (10 mg, 13 mol %) and aqueous potassium hydroxide (78 μL, 3M, 1.5 eq.). The reaction mixture was purged with nitrogen and then sealed in a microwave vessel. The reaction vessel was subject to microwave irradiation at 150° C. for 30 min. An aliquot indicated complete consumption of starting material. Reaction crude was worked up with water. The resulting mixture was extracted with EtOAc and dried over Na2SO4. The titled compound was obtained as a glassy material after two preparative TLC plates using respectively 20% EtOAc in hexanes and 5% EtOAc in dichloromethane as the eluent. LC-MS: 610.26 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamers δ 7.84 (s, 1 H), 7.65-7.70 (m, 2 H), 7.21 (s, 0.5 H), 7.08-7.14 (m, 1.5H), 6.95-7.04 (m, 2 H), 6.61-6.67 (m, 1 H), 5.52 (d, J=8.5 Hz, 0.5H), 5.27 (d, J=8.0 Hz, 0.5H), 4.85 (d, J=15.5 Hz, 0.5H), 4.81 (d, J=15.5 Hz, 0.5 H), 4.00 (d, J=15.5 Hz, 0.5 H), 3.69-3.81 (m, 4.5 H), 3.13-3.24 (m, 1H), 1.90-1.99 (m, 1 H), 1.12-1.30 (m, 6 H), 0.98-1.15 (m, 2 H), 0.71-0.77 (m, 2 H), 0.48 (d, J=6.5 Hz, 1.5 H), 0.29 (d, J=6.5 Hz, 1.5 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:4][C:5]2[O:9][C:8]([CH:10]=O)=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[C:6]=2[CH:16]=1.Cl.[NH2:24][OH:25].N1C=CC=CC=1>CS(C)=O.O>[Br:1][C:2]1[C:3]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:4][C:5]2[O:9][C:8]([CH:10]=[N:24][OH:25])=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[C:6]=2[CH:16]=1
Reactant: NO
Reactant: CNC(=O)c1c(C=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: Cl
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CNC(=O)c1c(C=NO)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
A mixture of 5-bromo-2-formyl-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (700 mg, 1.8 mmol), hydroxylamine hydrochloride (280 mg, 4.05 mmol) and pyridine (284 mg, 3.6 mmol) in DMSO (5 mL) was stirred at room temperature for 2 h. The mixture was diluted with water, then filtered, the residue was crude product of 5-bromo-2-((hydroxyimino)methyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (650 mg, yield: 75%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.26 (s, 1H), 8.46 (s, 1H), 8.41 (d, J=4.4 Hz, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 3.20 (s, 3H), 3.19 (s, 3H), 2.83 (d, J=4.4 Hz, 3H). MS (M+H)+: 404/406.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:5]2[N:6]([C:8]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:19]([C:23]([OH:25])=[O:24])=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=3)[N:10]=2)[N:7]=1.C[O-].[Na+:40]>CO>[Na+:40].[Cl:1][C:2]1[CH:3]=[C:4]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[C:5]2[N:6]([C:8]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:19]([C:23]([O-:25])=[O:24])=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=3)[N:10]=2)[N:7]=1
Reactant: O=C(O)c1cccc2nc(/C=C/c3nc4c(N5CCOCC5)cc(Cl)nn4c3-c3cccnc3)ccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])c1cccc2nc(/C=C/c3nc4c(N5CCOCC5)cc(Cl)nn4c3-c3cccnc3)ccc12
Reaction time: 0.5 h

Procedure:
To compound 73g (31.3 mg, 0.061 mmol) in MeOH (0.6 mL) was added NaOMe (0.12 mL, 0.061 mmol). The resulting mixture was stirred for 30 min and the solvent was removed in vacuo to obtain a solid which was then dried at 70° C. under high vacuum to afford the title compound 140 as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.47 (d, J=8.8 Hz, 1H), 8.89 (s, 1H), 8.74 (d, J=3.9 Hz, 1H), 8.15 (d, J=7.6 Hz, 1H), 7.53-7.87 (m, 7H), 6.57 (s, 1H), 4.22 (br. s., 4H), 3.86 (br. s., 4H). Mass spectrum (LCMS, ESI pos.) Calcd. For C27H21ClN6O3: 513.1 (M+H). Found 512.8.
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[CH2:14]([Mg]Br)[CH2:15][CH3:16]>>[CH2:14]([CH:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1)[CH2:15][CH3:16]
Reactant: CCC[Mg]Br
Reactant: COC(=O)c1cc2c([nH]1)C(=O)CC2
Product: CCCC1CCc2cc(C(=O)OC)[nH]c21

Procedure:
The title compound was synthesized from methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.5 g, 2.79 mmol) and n-propylmagnesium bromide (3.5 mL, 6.97 mmol, 2.0 M in ether, 2.5 equiv) according to General Procedure 3 to give the exocyclic olefin-containing compound (E)-methyl 6-propylidene-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6, and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (t, J=7.1 Hz, 3H), 1.35-1.53 (m, 3H), 1.57-1.68 (m, 1H), 1.94-2.09 (m, 1H), 2.47-2.69 (m, 3H), 2.98-3.10 (m, 1H), 3.83 (s, 3H), 6.64 (d, J=1.61 Hz, 1H), 8.69 (br. s, 1H).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:21])[N:9]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:8]2=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(CC(OCC)=O)=C=O.C1(N2C(=O)CC(=O)N(C3CCCC3)C2=O)CCCCC1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:10]([OH:21])[N:9]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:8]2=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(C2CCCC2)c1=O
Agent: CCOC(=O)CN=C=O
Agent: O=C1CC(=O)N(C2CCCC2)C(=O)N1C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCC2)c(=O)n(C2CCCCC2)c1=O
Reaction time: 2 h
Yield: 49 %

Procedure:
N-[(1-Cyclohexyl-3-cyclopentyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine. Ethyl isocyanatoacetate (8.33 mL, 74.3 mmoles) was added to a mixture of 1-cyclohexyl-3-cyclopentyl-2,4,6(1H,3H,5H)-pyrimidinetrione (18.8 g, 67.54 mmoles) and diisopropylethylamine (23.53 mL, 135.08 mmoles) in dichloromethane (800 mL) and stirred for 2 hours. Reaction mixture from a prior run (approx 25% scale) was added. The combined reaction mixture was washed with 2 molar hydrochloric acid (2×1.0 L) and evaporated. The residue was dissolved in ethanol (200 mL) and treated with 3.0 molar sodium hydroxide (100 mL). The mixture was stirred for 2 hours. Ethyl acetate (500 mL) was added and the mixture acidified with 6 molar hydrochloric acid (200 mL), water (500 mL) was added and the layers separated. The aqueous layer was extracted with ethyl acetate (500 mL) and the organic solution was washed with 1 molar hydrochloric acid. The organic solution was dried and evaporated to a solid residue which recrystallized from acetic acid (300 mL) to afford the title compound (15.5 g, 49%). Mp 222-224° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.08 (s, 1H), 10.17 (t, J=5.43 Hz, 1 H), 5.08-5.33 (m, 1 H), 4.63 (t, J=12.25 Hz, 1 H), 4.12 (d, J=5.81 Hz, 2 H), 2.18-2.36 (m, 2 H), 1.93-2.06 (m, 2 H), 1.69-1.91 (m, 6 H), 1.46-1.68 (m, 5 H), 1.28 (q, J=12.88 Hz, 2 H), 1.12 (q, J=13.05 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:8]=[C:7]([Br:15])[C:6]=1[OH:16])[CH3:2].[CH:18](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[N:8]=[C:7]([Br:15])[C:6]=1[O:16][CH3:18])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1cc(C(C)(C)C)nc(Br)c1O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)c1cc(C(C)(C)C)nc(Br)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of the above bromopyridine (2.74 g, 9.07 mmol) in acetonitrile/methanol (9:1, 33 mL) was added N,N-diisopropylethylamine (2.50 mL, 14.2 mmol) followed by (trimethylsilyl)diazomethane (2.0M in hexane, 7.0 mL, 14.2 mmol). The red solution was stirred 0.5 h at room temperature then concentrated in vacuo. The residue was dissolved in methylene chloride, washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-bromo-6-tert-butyl-3-methoxy-isonicotinic acid ethyl ester (2.65 g, 93%) as a red oil which was utilized without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][OH:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14]([CH3:16])=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:14]([CH3:16])([CH3:13])[O:12][NH:11][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=C(NO)Nc1cccc(Cl)c1
Solvent: O
Product: CC1(C)ONC(=O)N1c1cccc(Cl)c1

Procedure:
18.6 g. (0.1 moles) of N-(3-chlorophenyl)-N'-hydroxy-urea are added to 130 g. of acetone. The mixture is stirred for 15 minutes at the temperature of the water bath under reflux. The reaction mixture is then evaporated to dryness and the residue is recrystallized from the mixture of acetone and water.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:6]1[CH:30]=[CH:29][C:9]([C:10]([C:12]2[C:16]3[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])=[CH:8][CH:7]=1)[CH:4]=[CH2:5].Cl>CO.O1CCOCC1.O>[CH2:3]([C:6]1[CH:30]=[CH:29][C:9]([C:10]([C:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])=[CH:8][CH:7]=1)[CH:4]=[CH2:5]
Reactant: C=CCc1ccc(C(=O)c2c(CCCC)oc3ccc(C(=O)OC)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: C=CCc1ccc(C(=O)c2c(CCCC)oc3ccc(C(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.7 g of NaOH pellets are added to 8.1 g of methyl 3-(4-allylbenzoyl)-2-butylbenzofuran-5-carboxylate in 40 ml of methanol, 200 ml of dioxane and 40 ml of water. The mixture is stirred at ambient temperature for 24 hours. It is neutralized to pH 7 with concentrated hydrochloric acid and then evaporated. Water is added and the acid is regenerated with concentrated hydrochloric acid. Extraction is carried out three times with ether and the extracts are washed with water and then with an aqueous NaCl solution. They are dried over Na2SO4 and then concentrated.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1.C(OCC)(=O)C.[Cu]>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: Oc1ccc(F)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Oc3ccc(F)cc3)cn2)CC1
Temperature: 120 °C
Yield: 26.7 %

Procedure:
A mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (684 mg, 2.0 mmol), 4-fluorophenol (1.1 g, 5.0 mmol), copper (650 mg, 10.0 mmol) and Cs2CO3 (6.5 g, 20.0 mmol) in pyridine (15 mL) was heated at 120° C. for 12 h. The mixture was cooled to RT, diluted with ethyl acetate (200 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to afford the title compound (200 mg, 27%) as a brown solid. MS (ES+) C19H23FN4O3 requires: 374. found: 319 [M−56+1]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:29][C@@H:28]3[CH3:41])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.O>C1COCC1.CO>[CH2:34]([N:30]1[C@H:31]([CH3:33])[CH2:32][N:27]([C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:42])[C@@H:28]([CH3:41])[CH2:29]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CN([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(C(=O)O)CC3)c2)[C@@H](C)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of 1-{3-[(R)-((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (365 mg, Example 122) in THF (4 mL) was added 1N NaOH solution (3 mL). The reaction was stirred at room temperature overnight. The reaction solution was neutralized by the addition of 1 N HCl solution (3 mL). The resulting solution was concentrated under vacuum to give crude product, which was subjected to reverse phase C-18 column chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% H2O to 100% MeOH) to give 1-{3-[(R)-((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid (228 mg; 66%). 1H NMR (300 MHz, CD3OD) δ 7.49 (m, 2H), 7.38 (m, 6H), 7.28 (m, 1H), 7.18 (dd, J=8.0, 8.0 Hz, 1H), 6.73 (m, 2H), 6.67 (s, 1H), 5.26 (s, 1H), 4.48 (m, 1H), 4.27 (d, J=13.0 Hz, 1H), 3.66 (m, 2H), 3.13 (m, 1H), 3.01 (m, 2H), 2.85 (m, 2H), 2.68 (m, 1H), 2.49 (m, 2H), 2.13 (dd, J=10.5, 10.5 Hz, 1H), 2.00 (m, 1H), 1.82 (m, 1H), 1.65 (m, 2H), 1.28 (d, J=6.5 Hz, 3H), 1.17 (d, J=6.0 Hz, 3H).