Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][C:7]=1[CH3:8])=O.Cl.[NH2:15]O>CCO.CN(C=O)C.O=S(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][C:7]=1[CH3:8])#[N:15]
Reactant: CCOC(=O)c1cc(C=O)c(C)[nH]1
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(C#N)c(C)[nH]1

Procedure:
Ethyl 4-formyl-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 15, 0.2 g, 1.1 mmol) and hydroxylamine hydrochloride (0.08 g, 1.1 mmol) were dissolved in EtOH (10 ml) and refluxed for 1.5 hours. The mixture was concentrated under vacuum to give yellow solid, which was dissolved in DMF (5 ml) before addition of SOCl2 (0.35 ml) at 0° C. The solvent was removed under vacuum after the completion of the reaction and the residue was partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc twice. The combined organic extracts were dried over MgSO4 and concentrated to give brown solid (0.16 g, crude).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].CO[N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[C:28](O)(=[O:30])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:22]2[CH2:23][CH2:24][CH:25]([O:30][CH3:28])[CH2:26][CH2:27]2)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CON1CCCCC1
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCN(Cc2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.59 mmol), 1-methoxypiperidine (68 mg, 0.59 mmol), acetic acid (0.051 mL, 0.89 mmol) and sodium triacetoxyborohydride (313 mg, 1.5 mmol) in THF (8 mL). MS (LC-MS): 387.0 [M]+
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1.[CH2:20]([CH2:22][NH2:23])[OH:21]>>[ClH:1].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([NH:23][CH2:22][CH2:20][OH:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: NCCO
Product: COc1ccc(-c2cc(NCCO)c3ccccc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 211-213° C. and MS: m/e=294 (M+), was prepared from 4-chloro-2-(4-methoxy-phenyl)-quinoline and ethanolamine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:3]=1N.N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:3]1[CH:5]=[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=[CH:8][C:2]=1[Cl:1]
Reactant: Br
Reactant: CS(=O)(=O)c1ccc(Cl)c(N)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a slurry of 2-chloro-5-methanesulfonyl-aniline (4.50 g, 21.9 mmol) in 48% HBr (12 mL) at 0° C. was added dropwise a solution of sodium nitrite (2.28 g, 33 mmol) in H2O (8 mL) at such a rate that the temperature never exceeds 5° C. The resulting yellow mixture was allowed to stir 20 min at 0° C. and then charged with copper(I) bromide (3.3 g, 23 mmol). After 30 min the resulting mixture was extracted with EtOAc (2×100 mL) and the combined extracts were washed successively with satd NH4Cl, 3N HCl and brine, then dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica, EtOAc/Hex, 0:100 to 50:50) to give the title compound (4.92 g, 83%) as a white solid. GC-MS (EI): 268, 270.
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Methyl 2-bromopropionate (60.12 g, 0.36 mol) is added to a mixture of 4-nitrophenol (25 g, 0.18 mol) and potassium carbonate (49.75 g, 0.36 mol) in acetonitrile. The reaction mixture is refluxed for 18 hours, cooled and poured into water. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and the organic extracts are combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a white powder, mp 79°-80° C.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C(N(CC)CC)C.[H][H]>C(OC(C)C)(=O)C.[Pd]>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C/C(=C\[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)C
Product: C[C@@H](C[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
To a suspension of (E)-(S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid 3(ii-b) (10 g, 26.2 mmol) and triethylamine (3.6 ml, 26.2 mmol) in isopropyl acetate is added palladium on carbon (1 g, 10% loading). Hydrogen atmosphere is then applied for 5 h. Upon filtering off the catalyst, the solvent is removed in vacuo to give the title compound {3(i-d): 3(i-c) 80:20 ratio; 3(i-d): 3(i-c) 99.9:0.1 ratio upon recrystallization; as determined by HPLC analysis}.
Reaction SMILES: [Li]CCCC.[CH:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1.Br[CH2:16][CH2:17][CH:18]([Br:20])[CH3:19].[NH4+].[Cl-]>C1COCC1>[Br:20][CH:18]([CH3:19])[CH2:17][CH2:16][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C1CCC1
Reactant: CC(Br)CCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCC(C)Br)CCC1
Temperature: -78 °C
Reaction time: 0.62 h
Yield: 41 %

Procedure:
To a 0° C. solution of DIPA (14.3 mL, 102 mmol) in THF (100 mL) was added n-BuLi (2.5M, 102 mmol). The Rx was stirred for 30-45 min then cooled to −78° C. Ethyl cyclobutane carboxylate (102 mmol, 1 equiv) was added slowly and the enolate was allowed to form for ˜30 min. At ˜78° C., above enolate was poured into 1,3-dibromobutane (2 equiv, 200 mmol) and Rx stirred at −78° C. for 1 h then warmed-up to RT. After 3 hours, NH4Cl was added and reaction extracted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated down to give 25 g of crude product. The residue was purified by silica gel chromatography (0% to 10% EtOAc in hexanes) to provide 11 g (42% yield) of racemic ethyl 1-(3-bromobutyl)cyclobutanecarboxylate 92.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH:21]=O)[CH2:13][C@H:12]1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:29]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33][C@H:32]2[OH:37])[CH2:30]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:21][N:34]2[CH2:35][CH2:36][C:31]3([CH2:30][CH2:29]3)[C@H:32]([OH:37])[CH2:33]2)[CH2:13][C@H:12]1[CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CNCCC12CC2
Reactant: COC(=O)[C@H](CC=O)N1C[C@@H](C)N(C(=O)OCc2ccccc2)CCC1=O
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)OCc2ccccc2)CCC1=O
Yield: 42 %

Procedure:
In analogy to the procedure described for example 58D, (R)-4-((S)-1-methoxycarbonyl-3-oxo-propyl)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 42% yield as yellow oil. MS: 488.4 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4](/[CH:7]=[CH:8]/[C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:3]1[CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.Cl>C1(C)C=CC=CC=1.CO>[CH3:25][O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][S:18][CH2:17][CH2:16][N:3]1[C:2](=[O:1])[CH2:6][CH2:5][C@@H:4]1/[CH:7]=[CH:8]/[C@@H:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(=O)/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)OC
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)OC
Temperature: -30 °C
Reaction time: 7 h
Yield: 29.6 %

Procedure:
A solution of methyl 4-[(2-{(5R)-2-oxo-5-[(1E)-3-oxooct-1-enyl]pyrrolidin-1-yl}ethyl)thio]-butanoate (0.039 g, 0.1 mmol) in 2 mL of anhydrous toluene was added dropwise to a −30° C. solution of (R)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 0.05 mL, 0.05 mmol) and borane-methyl sulfide complex (10 M, 0.01 mL, 0.1 mmol). The reaction was stirred for 7 hours at −30° C. and then a solution of hydrochloric acid in methanol (2 M, 1-2 mL) was added. The solution was warmed to room temperature and the solvents were removed via reduced pressure. The crude residue was purified via chromatography yielding 11 mg of 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxyoct-1-enyl]-5-oxopyrrolidin-1-yl}ethyl)thio]butanoic acid methyl ester as an oil. This was taken directly on to the next step.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([F:13])=[CH:5][C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:16]1=[O:27].Cl[C:29]1[N:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([N:24]2[CH2:23][CH2:22][CH:21]([N:17]3[CH2:18][CH2:19][CH2:20][C@H:15]([NH:14][C:4]4[CH:5]=[C:6]([F:13])[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=4[F:2])[C:16]3=[O:27])[CH2:26][CH2:25]2)=[N:34][CH:33]=1)(=[O:37])[CH3:36]
Reactant: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(N2CCC(N3CCC[C@H](Nc4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 68.5 %

Procedure:
(S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride (Example 45, Steps A-E; 0.4 g, 0.944 mmol), 1-(6-chloropyridin-3-yl)ethanone (0.220 g, 1.42 mmol) and DIEA (0.523 mL, 2.83 mmol) were dissolved in DMF (5 mL) and heated at 100° C. overnight. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes) to afford (S)-1′-(5-acetylpyridin-2-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.328 g, 0.647 mmol, 68.6% yield) as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31]([O:33]C)=[O:32])=[N:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1.O>[C:13]([O:12][C:11]([NH:10][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31]([OH:33])=[O:32])=[N:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])([CH3:14])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@@H](CCCCNC(=O)[C@@H](CCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of methyl ester 15 (2.15 g, 2.94 mmol) in MeOH/THF/H2O (30 mL/30 mL/15 mL) was charged with NaOH (589 mg, 14.7 mmol) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the pH was adjusted to 5 with 1 N HCl. The suspension was partitioned between CH2Cl2 (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to afford compound 16 (1.80 g, 86%) as a white solid, which was used directly in the next step: 1H NMR (400 MHz, CD3OD) δ 4.07-4.00 (m, 1H), 4.00-3.91 (m, 1H), 3.35 (t, J=7.2 Hz, 2H), 3.25-3.10 (m, 2H), 1.89-1.23 (m, 12H), 1.52 (s, 9H), 1.46 (s, 9H), 1.438 (s, 9H), 1.436 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:41])[CH2:31][C:32]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:33])=[CH:25][C:24]=3[F:42])[CH:14]=2)=[CH:9][CH:8]=1)[CH3:5].[N:43]([CH3:46])([CH3:45])[CH3:44]>COCCOC>[Cl-:1].[F:42][C:24]1[CH:25]=[C:26]([NH:29][C:30](=[O:41])[CH2:31][C:32](=[O:33])[NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:27]=[CH:28][C:23]=1[O:22][C:19]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][N:4]([CH3:5])[CH2:3][CH2:2][N+:43]([CH3:46])([CH3:45])[CH3:44])=[CH:8][CH:9]=3)[S:21][C:20]=12
Reactant: CN(CCCl)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)cc1
Reactant: CN(C)C
Solvent: COCCOC
Product: CN(CC[N+](C)(C)C)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)cc1
Product: [Cl-]
Temperature: 100 °C
Yield: 22.7 %

Procedure:
To a solution of 88 (80 mg, 0.133 mmol) in DME (1 mL) was added NMe3 (15.7 mg, 2 eq, 0.27 mmol) and the reaction mixture was heated to 100° C. in a sealed tube for an hour. The mixture was cooled to RT and concentrated. Purification (Gilson, 45 mins, 40% MeOH in water to 80% MeOH in water) afforded title compound 84 (20 mg, 9% yield). 1H NMR (DMSO-d6) δ (ppm): 10.85 (s, 1H), 10.41 (s, 1H), 8.47 (m, 2H), 8.05 (s, 1H), 7.85 (m, 3H), 7.59 (m, 2H), 7.42 (m, 5H), 7.32 (m, 2H), 7.05 (t, J=7.43 Hz, 1H), 6.63 (d, J=5.67, 1H), 3.60 (s, 2H), 3.51 (m, 2H), 3.1 (s, 9H), 2.81 (m, 2H), 2.20 (s, 3H). MS (m/z) 626.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7]2.Br[CH2:20][CH2:21][CH2:22][Cl:23].[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[ClH:23].[OH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:20][CH2:21][CH2:22][O:1][C:2]2[C:3]3[C:4](=[O:18])[CH:5]=[C:6]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[O:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:27][CH2:26]1
Reactant: ClCCCBr
Reactant: OC1CCNCC1
Reactant: O=c1cc(-c2ccccc2)oc2cccc(O)c12
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2cccc(OCCCN3CCC(O)CC3)c12

Procedure:
The compound was prepared by the method of Example 21 from 5-hydroxyflavone, 1-bromo-3-chloropropane, and 4-hydroxypiperidine: mp 213°-215° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:3]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:4]([C:5]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]2[CH2:24][NH:25][C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(F)c1-n1nccn1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)c(F)c2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described in Example A318, using 3,4-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-chloro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 481 [M+1]+.
Reaction SMILES: C(N1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=O.[OH:13][C@H:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:15][C:16]([OH:18])=[O:17].[Mg+].[CH2:31]([CH:37](C([O-])=O)[C:38](OC)=O)[CH2:32][CH2:33][CH2:34]CC>C1COCC1>[CH2:38]([C:15]1[C:16](=[O:18])[O:17][C@H:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:11][CH3:12])[CH2:19][C:14]=1[OH:13])[CH2:37][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)O
Reactant: CCCCCCC(C(=O)[O-])C(=O)OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Reaction time: 16 h
Yield: 34.3 %

Procedure:
6.81 g of 1,1'-carbonyldiimidazole were added under nitrogen and while stirring to a solution of 7.33 g of (R)-3-hydroxytetradecanoic acid (Example 4a) in 60 ml of THF. After stirring the reaction solution was added to the suspension of monomethyl n-hexylmalonate magnesium salt and the mixture was stirred at room temperature for 22 hours. The suspension was concentrated, whereby 60.35 g of resin remained behind. This was taken up in 200 ml of ethyl acetate, extracted with 200 ml of 3N hydrochloric acid and with 600 ml of 5 percent NaHCO3 solution. The ethyl acetate phase was separated and treated with 100 ml of 25 percent hydrochloric acid while stirring at 10°-15°. The mixture was stirred at 25° for 1.5 hours. The resulting, homogeneous phase was left to stand at room temperature for 16 hours. The suspension was stored at -20° for 4 hours, filtered, the filter cake was washed with water and the crystals were dried. There were obtained 3.63 g (34.3%) of (R)-5,6-dihydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one, m.p. 104.8°-106.2°, the product of Example 3f).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:11]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])[S:12][C:6]=2[S:5]1(=[O:22])=[O:21].C([N:25]([CH2:28][CH3:29])CC)C.[CH3:30]S(OS(C)(=O)=O)(=O)=O>C1COCC1.CN(C=O)C.C(N)CC>[CH2:28]([NH:25][CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:11]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])[S:12][C:6]=2[S:5]1(=[O:22])=[O:21])[CH2:29][CH3:30]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)N(CCO)C=C2
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCCN
Product: CCCNCCN1C=Cc2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Yield: 102.9 %

Procedure:
To a solution of the product from Example 7, Step B (1.02 g, 2.79 mmol) and triethylamine (0.84 g, 8.36 mmol) in anhydrous THF (50 mL) was added methanesulfonic anhydride (0.80 g, 4.18 mmol) with stirring under nitrogen. The volatiles were evaporated after 30 min and the residue dissolved in ethyl acetate (80 mL). This mixture was washed with a saturated aqueous solution of sodium bicarbonate (50 mL), dried (MgSO4) and evaporated to give a solid. The solid (1.55 g from two batches) was dissolved in a mixture of anhydrous DMF (40 mL) and 1-propylamine (6 mL) and heated at reflux temperature for 1 h followed by evaporation to a residue which was added to a saturated aqueous solution of sodium bicarbonate (100 mL). This mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts were dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 6% methanol/methylene chloride) to give a viscous oil (1.17 g, 84%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([OH:16])=O)[CH3:3].C(Cl)(=O)C([Cl:20])=O.CN(C)C=O.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[Cl:20][C:11]1[CH:12]=[CH:13][C:8]2[O:7][C:6]([C:14]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:16])=[C:5]([O:4][CH:2]([CH3:1])[CH3:3])[C:9]=2[CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccccc1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccccc12
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C(=O)Nc2ccccc2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 84 %

Procedure:
To 3-(1-methylethoxy)-2-benzofurancarboxylic acid (200 mg, 0.91 mmol) in 7 mL of dry tetrahydrofuran is added oxalyl chloride (0.095 mL, 1.09 mmol) followed by dimethylformamide (0.02 mL). The solution is stirred at room temperature for 1.75 hours, then aniline (0.50 mL, 5.46 mmol) is added. The solution is stirred at room temperature overnight then partitioned between ethyl acetate and 1N HCl . The organic layer is washed with saturated aqueous NaHCO3 and brine. The organic layer is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography eluting with 4:1 hexane:ethyl acetate to provide 5-chloro-3-(1-methylethoxy)-N-phenyl-2-benzofurancarboxamide in 84% yield; mp=82°-83° C.
Reaction SMILES: [N:1]1([CH2:10]O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C2C=CC=CC=2N=N1>CCO>[CH2:20]([N:19]([CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCn1nnc2ccccc21
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: c1ccc2[nH]nnc2c1
Solvent: CCO
Product: c1ccc(CN(Cc2ccccc2)Cn2nnc3ccccc32)cc1
Reaction time: 24 h
Yield: 99.7 %

Procedure:
1H-Benzotriazole-1-methanol (51.0 g, 0.342 mol) was weighed into a round bottom flask and solubilized in EtOH (800 mL). Dibenzylamine (67.5 g, 0.342 mol) was added slowly (over 5 min) to the rapidly stirred solution. Formation of a white precipitate was observed shortly after starting addition. The solution was abandoned to stir for 24 h. At this time the reaction is judged complete by NMR (product fragments on LCMS to show only benzotriazole). The majority of the solvent was removed by rotovap and diethyl ether (1 L) was added to the residue with vigorous stirring. This mixture was filtered, the filtrand washed with ether and dried under vacuum to yield the desired product as a fluffy white solid (112 g, quat. yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.80 (s, 4 H) 5.48 (s, 2 H) 7.21 (d, J=8.34 Hz, 1 H) 7.34-7.43 (m, 11 H) 7.49 (d, 1 H) 8.09 (d, J=7.83 Hz, 1 H).
Reaction SMILES: [Si](OCCC[C@H]1[C@H](OC(=O)[C@@H](C2C=CC=CC=2)OC)CO[C@H]1C1C=NC=CC=1)(C(C)(C)C)(C)C.[C:35]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:40]=[CH:39][C:38]([CH2:41][O:42][C@H:43]2[CH2:47][O:46][C@H:45]([C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)[C@@H:44]2[CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58][CH2:59][C:60]([OH:62])=[O:61])=[CH:37][CH:36]=1>CO>[C:35]1([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:36]=[CH:37][C:38]([CH2:41][O:42][C@@H:43]2[CH2:47][O:46][C@@H:45]([C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)[C@H:44]2[CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58][CH2:59][C:60]([OH:62])=[O:61])=[CH:39][CH:40]=1
Reactant: O=C(O)CC/C=C\CC[C@@H]1[C@@H](OCc2ccc(-c3ccccc3)cc2)CO[C@@H]1c1cccnc1
Agent: CO[C@@H](C(=O)O[C@@H]1CO[C@@H](c2cccnc2)[C@H]1CCCO[Si](C)(C)C(C)(C)C)c1ccccc1
Solvent: CO
Product: O=C(O)CC/C=C\CC[C@H]1[C@H](OCc2ccc(-c3ccccc3)cc2)CO[C@H]1c1cccnc1

Procedure:
(Z)-(2R,3R,4S)-7-[4-(biphenyl-4-ylmethoxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]hept-4-enoic acid having mp 94°-96° C. and [α]D25 =-83.75° (MeOH) is prepared from (2R,3R,4S)-3-(3-t-butyldimethylsilyloxypropan-1-yl)-4-[(R)-(-)-α-methoxyphenylacetoxy]-2-(3-pyridyl)tetrahydrofuran as described for the synthesis of (Z)-(2S,3S,4R)-7-[4-(biphenyl-4-ylmethoxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]hept-4-enoic acid in example 1.