Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)CCCNC(=N)N[S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10].[NH:48]([C:63]([O:65][CH2:66][CH:67]1[C:79]2[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=2)[C:73]2[C:68]1=[CH:69][CH:70]=[CH:71][CH:72]=2)=[O:64])[C@H:49]([C:60]([OH:62])=[O:61])[CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][CH:52]=1>C(O)(C(F)(F)F)=O>[NH:48]([C:63]([O:65][CH2:66][CH:67]1[C:68]2[C:73](=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:74]2[C:79]1=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:64])[C@H:49]([C:60]([OH:62])=[O:61])[CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][C:52]=1[S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:10])=[O:11]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)CC2
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C)c(S(=O)(=O)c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)CC2
Temperature: 30 °C

Procedure:
Fmoc-Arg(Pmc)-OH (0.5 g, 0.75 mmol) and Fmoc-Trp-OH (0.43 g, 0.1 mmol) was dissolved in 10 ml 100% TFA and heated at 30° C. for 1.5 hours. After evaporation of TFA, Fmoc-Arg-OH was removed by column chromatography on silica gel with heptane/ethyl acetate 2:1 as mobile phase. Fmoc-Trp(2Pmc)-OH was isolated by preparative HPLC (Cl8, 70-100% B in 15 min., tR 14.8 min, (A: H2O+0.1% TFA; B: CH3CN+0.1% TFA)). Isolated yield 130 mg (0.19 mmol, 25%).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:31]#[N:32].[Na+].[I-].[Na+].O>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][C:31]#[N:32])[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (80 mg, 0.173 mmol), sodium cyanide (17 mg, 0.35 mmol, 2.0 eq.), and sodium iodide (2.6 mg, 0.017 mmol, 0.1 eq.) in anhydrous DMF (1.7 mL) was stirred at 100° C. for 16 h. The reaction mixture was cooled to rt and poured into water. The aqueous layer was extracted with 3×25 mL of EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (47.5 mg, 67%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8.54 (s, 1H), 7.91 (s, 1H), 7.80 (d, 1H), 7.59 (s, 1H), 7.36 to 7.30 (m, 5H), 7.15 (dd, 1H), 6.65 (s, 1H), 5.65 (s, 2H), 3.00 (t, 2H), 2.59 (t, 2H), 2.04 to 1.96 (m, 2H); ES-MS m/z 408.3 [M+H]+, RT (min) 2.95.
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.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>[CH2:11]([O:10][C:8]([C:4]1[NH:5][C:6]([CH3:7])=[C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([F:26])([F:25])[F:14])[C:3]=1[CH3:13])=[O:9])[CH3:12]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1[nH]c(C)c(Br)c1C
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+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1[nH]c(C)c(-c2ccccc2C(F)(F)F)c1C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To a solution of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (3.42 g, 20 mmol) in carbon tetrachloride (40 mL) was added a solution of bromine in carbon tetrachloride (10 mL) dropwise at 20° C. After the addition was complete, stirring was continued for 2 h. The reaction mixture was diluted with DCM, washed with aqueous NaHCO3 and water, and then dried over Na2SO4. Evaporation of solvent gave ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate as a solid (4.8 g), which was used in the next step without purification. 1H-NMR (CDCl3): δ 9.36 (1H, s), 4.30 (2H, q), 228 (3H, s), 2.26 (3H, s), 1.36 (3H, t). To a solution of ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate (2.4 g, 10 mmol) in DMF (25 mL) was added tetrakis(triphenylphosphine)palladium (2.3 g, 1 mmol). After stirring 15 min, the reaction mixture was charged with 2-(trifluoromethyl)-benzeneboronic acid (2.4 g, 12.5 mmol) and sodium carbonate (in 5 mL of water). The reaction mixture was heated to reflux overnight with stirring. After cooling, the reaction mixture was then diluted with water and extracted with DCM. The combined extracts were washed with water and dried over Na2SO4. Evaporation of solvent gave a crude material, which was purified by chromatography on silica gel column eluting with EtOAc-hexane (1:1) to give the title compound (1.5 g). MS (ES): 312 (MH+);
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:28][C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)[C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccncc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 46.7 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (230 mg, 0.78 mmol, 1.0 eq), L-isoleucine pyridin-4-ylmethylamide (266 mg, 1.5 mmol) and dichloromethane (2 mL), was treated with triethylamine (660 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (1.0 mL, 2.0 eq), to provide 180 mg (46%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] pyridin-4-ylmethylamide.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[C@H:30]([OH:32])[CH3:31])[N:9]=3)[CH2:2]1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[OH:32][C@@H:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:4][N:1]([C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])[CH2:2]4)[N:7]3[CH3:33])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c([C@@H](C)O)nc5ccccc54)nc3n2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To a solution of (R)-1-[1-(8-azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-1H-benzoimidazol-2-yl]ethanol (57 mg, 0.13 mmol) in DCM (2 mL) was added DIPEA (24 μL, 0.14 mmol) and isobutyryl chloride (14 μL, 0.13 mmol) and the resulting mixture stirred at r.t. for 1 h. The reaction mixture was partitioned between DCM and H2O, the organic phase dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-8%) affording 860 (16 mg, 24%). LCMS (method I): RT 3.46 min, [M+H]+ 519.3. 1H NMR (DMSO, 400 MHz): δ 7.96-7.95 (1 H, m), 7.70-7.69 (1 H, m), 7.30-7.25 (2 H, m), 5.58-5.57 (1 H, m), 5.39 (1 H, d, J=6.34 Hz), 4.36-4.09 (4 H, brd s), 4.35 (1 H, t, J=8.22 Hz), 4.02 (1 H, t, J=8.79 Hz), 3.95-3.94 (1 H, m), 3.80-3.75 (4 H, m), 3.72 (3 H, s), 3.67 (1 H, dd, J=9.77, 5.28 Hz), 3.24-3.23 (3 H, m), 2.45-2.44 (1 H, m), 1.60 (3 H, d, J=6.49 Hz), 0.98 (3 H, d, J=1.77 Hz), 0.97 (3 H, d, J=1.79 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31](O)=[O:32].Cl.[NH:35]1[CH2:38][CH:37]([OH:39])[CH2:36]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31]([N:35]1[CH2:38][CH:37]([OH:39])[CH2:36]1)=[O:32]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N4CC(O)C4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid (1.00 g, 2.17 mmol) in 8 ml anhydrous DMF at RT was added azetidin-3-ol hydrochloride (0.475 g, 4.33 mmol) and N,N-diisopropylethylamine (1.84 ml, 10.8 mmol). 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.65 g, 4.33 mmol) was added and the mixture stirred at RT overnight. The mixture was filtered and purified by reverse-phase HPLC column chromatography (SunFire Prep C18 OBD Sum 19×100 mm column; 35-75% acetonitrile in 0.1% formic acid in water gradient) to afford the title compound. 1H NMR (CD3OD): δ 8.26 (s, 2H), 6.57 (d, J=9.4 Hz, 2H), 4.69 (t, J=12.5 Hz, 2H), 4.57-4.59 (m, 1H), 4.45-4.49 (m, 1H), 4.27 (s, 2H), 4.18-4.22 (m, 1H), 4.01-4.09 (m, 3H), 3.75-3.78 (m, 1H), 3.47 (s, 2H), 3.34 (s, 3H), 2.86-2.93 (m, 2H), 2.09-2.12 (m, 1H), 1.82-1.88 (m, 2H), 1.56-1.58 (m, 1H), 1.31-1.35 (m, 2H), 1.16-1.18 (m, 1H), 0.95-0.97 (m, 1H), 0.59-0.68 (m, 2H), −0.04 (m, 1H). LC/MS (m/z): 517.5 (M+H)+. Human EC50: 1.6 nM
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[C:15]([CH3:17])([CH3:16])[O:14][C:13](OC)=[N:12][S:11]2(=[O:21])=[O:20])[CH:5]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([NH2:32])[CH3:31]>ClCCl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[C:15]([CH3:17])([CH3:16])[O:14][C:13]([NH:32][C@H:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])[CH3:31])=[N:12][S:11]2(=[O:21])=[O:20])[CH:5]=1
Reactant: COC(=O)c1cccc(C2C(C)(C)OC(OC)=NS2(=O)=O)c1
Reactant: C[C@H](N)c1ccccc1F
Solvent: ClCCl
Product: COC(=O)c1cccc(C2C(C)(C)OC(N[C@@H](C)c3ccccc3F)=NS2(=O)=O)c1
Reaction time: 4 h
Yield: 69.5 %

Procedure:
A solution of 3-(2-methoxy-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl)benzoic acid methyl ester (1.3 g) and (S)-1-(2-fluorophenyl)ethylamine (713 mg) in dichloromethane (15 ml) was stirred under an argon stream and thus concentrated. The residue was left to stand for 4 h, dissolved in ethyl acetate, washed with 1 M HCl and sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (1.2 g) with a molecular weight of 434.5 g/mol (C21H23FN2O5S).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:14])[CH3:13])=[C:4]([OH:15])[CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.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>[OH:15][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([OH:16])=[CH:18][CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12](=[O:14])[CH3:13]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(=O)c1c(O)cc(Br)c2ccccc12
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1c(O)cc(-c2ccc(O)cc2)c2ccccc12
Temperature: 100 °C
Yield: 83.5 %

Procedure:
A mixture of 1-(4-bromo-2-hydroxynapthalen-1-yl)ethanone (0.255 g, 0.96 mmol), (4-hydroxyphenyl)boronic acid (0.140 g, 1.06 mmol), Pd(PPh3)4 (0.056 g, 0.048 mmol) and potassium carbonate (0.4 g, 2.88 mmol) in water (9.7 mL) in dioxane (32.0 mL) was flushed with nitrogen, sealed and heated for 2 h in a 100° C. oil bath. The solution was cooled to room temperature and partitioned between 200 mL of 10% methanol in ethyl acetate and 100 mL saturated aqueous sodium chloride. The layers were separated and the aqueous layer was extracted (2×50 mL 10% methanol in ethyl acetate). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (SiO2, 5:1 hexanes/ethyl acetate) gave 0.223 g (83%) of 1-[2-hydroxy-4-(4-hydroxyphenyl)napthalen-1-yl]ethanone. 1H NMR (400 MHz, d6-DMSO): 8.11 (d, 1H), 7.87 (d, 1H), 7.56 (dt, 1H), 7.33 (m, 3H), 7.07 (s, 1H), 6.99 (d, 2H), 2.89 (s, 3H); MS (EI) for C18H14O3: 279 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][N:13]([CH3:21])[C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH2:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:20][C@@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]2[N:13]([CH3:21])[CH3:12])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1ccc(C#N)cc1
Yield: 63 %

Procedure:
The titled amide was prepared according to general procedure B using p-cyanobenzoyl chloride (1.65 g.; 0.01 mole), the trans-2-(dimethylamino)cyclohexylamine (1.42 g.; 0.01 mole) and triethylamine (1.01 g.; 0.01 mole) but using CH2Cl2 for extraction. The crude solid was crystallized from ether to give colorless needles, 1.71 g. (63% yield), m.p. 160°-161°. uv λmax 236 nm (ε 17,900); sh 285 (2,550). ir NH 3320; N-alkyl 2780; C≡N 2220; C=O 1635; C=C 1610, 1500; amide II 1550; aromatic 860. NMR in CDCl3 (60 MHz) was in accord. Mass spectrum M+ 271.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:15](O)[C:16]3[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][C:17]=3[CH3:31])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>CO.[Pd].[C]>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:18][C:17]=2[CH3:31])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COc1ccc(C(O)c2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(Cc2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1Cc1ccc(F)cc1
Yield: 78.8 %

Procedure:
590 mg of tert-butyl 4-[[3-(4-fluorobenzyl)-4-methoxyphenyl](hydroxy)methyl]-3,5-dimethylphenylcarbamate (Example VIII), 24 mg of Pd/carbon (10%) and a drop of acetic acid are hydrogenated in 10 ml of methanol with hydrogen at atmospheric pressure for 4 h. The suspension is filtered through kieselguhr. The filtrate is concentrated in a rotary evaporator. Chromatography (cyclohexane/ethyl acetate=6:1) affords 449 mg (77%) of tert-butyl 4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenylcarbamate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC([O:24][CH:25](C)[CH3:26])=O.[CH:34]([C@H:47]1[N:52]2[CH2:53][C@H:54]([OH:56])[CH2:55][C@H:51]2[CH2:50][N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:48]1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[C:25]([O:56][C@@H:54]1[CH2:53][N:52]2[C@H:47]([CH:34]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:48][N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:50][C@@H:51]2[CH2:55]1)(=[O:24])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H](O)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](C(c3ccccc3)c3ccccc3)N2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triphenylphosphine (860 mg), acetic acid (159 mg) and diisopropyl azodicarboxylate were added successively into a solution of tert-butyl (4R,7R,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (670 mg) in tetrahydrofuran (10 ml) at room temperature. After being stirred for 1 hour at room temperature, the reaction mixture was poured into aqueous saturated sodium hydrogen carbonate. The whole was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (2:1-3:2) as an eluent to give tert-butyl (4R,7S,8aS)-7-acetoxy-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H+].[B-](F)(F)(F)F.[Br:19]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Br:19])[CH:6]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(O)c(Br)c1
Temperature: -15 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
This procedure is modified from the work of Oberhauser (J. Org. Chem, 1997, 62,4504). To a solution of 4-hydroxybenzoic acid ethyl ester (57.8 g, 348 mmol) in 480 mL of dry acetonitrile was added HBF4.EtO (54% in Et2O, 32.9 mL). The solution was cooled to −15° C. with an ice/methanol bath. N-bromosuccinimide (67.2 g, 378 mmol) was added portionwise at a rate where the temperature would not rise above −10° C. After addition was complete, the cooling bath was removed and the reaction mixture was allowed to stir overnight at room temperature. Worked up by pouring the reaction mixture into aqueous sodium bisulfite (38%, 200 mL) and extracting four times with ethyl acetate. The organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate/hexane gave 3-bromo-4-hydroxybenzoic acid ethyl ester (70.7 g, 83%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=6.7 Hz, 3H, —CO2CH2CH3), 4.34 (t, J=6.7 Hz, 2H, CO2CH2CH3), 7.02 (d, 1H, arom), 7.91 (dd, 1H, arom), 8.19 (d, 1H, arom).
Reaction SMILES: [C:1]([O:20][C:21](=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=O)[CH2:2]CCCCCCCCCCCCCCCC.C(O)C[OH:42].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:21]([O:20][CH2:1][CH2:2][OH:42])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: OCCO
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCCO
Reaction time: 1.5 h
Yield: 39.2 %

Procedure:
A solution of stearic anhydride (1.14 g, 2.06 mmol) in dichloromethane (30 mL) was cannulated into a stirred solution of ethylene glycol (1.10 mL, 19.7 mmol), DMAP (22 mg, 0.18 mmol) and triethylamine (0.300 mL, 2.16 mmol) in dichloromethane (20 mL). After stirring for 90 min. the reaction was quenched with the addition of H2O (100 mL). After separation of the phases the aqueous fraction was re-extracted with dichloromethane (2×50 mL) and the combined organic extract was washed with brine (70 mL). After drying (MgSO4) and filtration the solvent was removed at reduced pressure to give the crude product that was purified by chromatography on silica gel. Gradient elution with ethyl acetate/petroleum ether (10:90→30:70) afforded the title compound 48 (265 mg, 0.807 mmol, 39%) as an oil; 1H NMR (300 MHz, CDCl3) δ 4.25-4.20 (m, 2H), 3.83-3.78 (m, 2H), 2.38 (t, 2H, J 7.5 Hz), 2.00-1.97 (m, 1H), 1.62-1.55 (m, 2H), 1.35-1.20 (m, 28H), 0.87-0.81 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 174.6, 66.3, 61.7, 34.6, 32.3, 30.1, 29.8, 29.7, 29.6, 29.5, 25.3, 23.1, 14.5; HRMS-ESI (+ve) (Found: m/z 346.3323 (MNH4+). C20H44NO3 requires m/z 346.3316).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:34](=[O:36])[CH3:35])[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[CH3:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:18][CH2:19][C:20]1[N:21]=[C:22]([C:34](=[O:36])[CH3:35])[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:24]=1[CH3:25]
Reactant: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1nc(CO)c(C)n1COCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
The compound (11.7 g) obtained in (1) was dissolved in THF (100 mL), followed by addition of TBAF (1.0 M THF solution, 24.7 mL) under stirring, and the stirring was continued for 1 hour. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=10%→100%) using amino column (product name: Hi-Flash Column 3 L, manufactured by Yamazen Corporation) to afford the title compound (5.41 g).