Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[CH2:27][N:26]([C:29]1[N:34]=[C:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:32](Br)=[CH:31][CH:30]=1)[CH2:25][CH2:24]2)=[O:18].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH2:85]([O:88][C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)[C:86]#[CH:87]>CC#N.CC#N.Cl[Pd]Cl>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[CH2:27][N:26]([C:29]1[N:34]=[C:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:32]([C:87]#[C:86][CH2:85][O:88][C:89]3[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=3)=[CH:31][CH:30]=1)[CH2:25][CH2:24]2)=[O:18]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)ccc1Br
Reactant: C#CCOc1ccccc1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)ccc1C#CCOc1ccccc1
Temperature: 105 °C
Yield: 46.3 %

Procedure:
To pre-dried Cs2CO3 (378 mg, 1.16 mmol) was added compound 121C (180 mg, 0.26 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (18 mg, 0.04 mmol) and bis(acetonitrile)dichloropalladium(II) (3.2 mg, 0.012 mmol). The atmosphere was purged with nitrogen and following the addition of propionitrile (3.0 mL) the mixture was stirred at room temperature for 10 min. before phenyl propargyl ether (205 mg, 1.54 mmol) was added. The mixture was heated at 105° C. for 1 hr, cooled to room temperature, concentrated, diluted with saturated NH4Cl and extracted with EtOAc (3×). The organic phases were washed with brine (1×), dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel using a gradient of PE:EtOAc 100:0-85:15, to give the product (90 mg, 47%): 1H NMR (300 MHz, CDCl3) δ 8.28 (d, 1H), 7.69 (d, 1H), 7.57 (m, 2H), 7.47 (t, 1H), 7.38-7.26 (m, 5H), 6.99 (m, 3H), 6.82 (d, 1H), 5.98 (s, 2H), 5.24 (s, 2H), 4.92 (s, 2H), 4.07 (t, 2H), 3.74 (t, 2H), 1.60 (s, 9H), 0.97 (t, 2H), −0.09 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[N+:31]([C:34]1[CH:39]=[CH:38][C:37](OC(ON=C(C#N)C(OCC)=O)=O)=[CH:36][CH:35]=1)([O-:33])=[O:32]>C(Cl)Cl>[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:36][CH:35]=1)([O-:33])=[O:32]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NOC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CCN1CCOCC1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Yield: 47.5 %

Procedure:
to a solution of N-benzyloxycarbonyl-L-phenylalanine (1.5 g) and 4-ethylmorpholine (0.63 ml) in dry methylene chloride (20 ml), ethyl 2-p-nitrophenyloxycarbonyloxyimino-2-cyanoacetate (1.55 g) is added at room temperature while stirring. The resulting mixture is stirred for 3 hours and extracted with ethyl acetate. The extract is washed with water, dried and concentrated. The residue is triturated with ethanol, and the obtained powder is collected by filtration and dried to give N-benzyloxycarbonyl-L-phenylalanine p-nitrophenyl ester (1.0 g). M.P. 124° - 126°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[S:8][C:9]([C:16]([OH:18])=O)=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:28][NH2:29])=[CH:23][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCOC(C)=O>C(#N)C.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:28][NH:29][C:16]([C:9]2[S:8][C:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:11][C:10]=2[C:12]([F:13])([F:14])[F:15])=[O:18])=[CH:25][CH:26]=1
Reactant: CC(C)CC(CN)c1ccc(Cl)cc1
Reactant: O=C(O)c1sc(-c2ncccn2)nc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)CC(CNC(=O)c1sc(-c2ncccn2)nc1C(F)(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-pyrimidin-2-yl-4-trifluoromethyl-thiazole-5-carboxylic acid (15 mg), 2-(4-chloro-phenyl)-4-methyl-pentylamine hydrochloride (14 mg), BOP (25 mg) and TEA (20 mg) in ACN (1 mL) is stirred at RT overnight. EtOAc and water added to the mixture and the organic layer is separated, washed twice with water and concentrated in vacuo. The residue is purified by PTLC (1:1 EtOAc/Hexane) to give the title compound. MS (M+1)=469.11; RT=1.36 min. *IC50.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Si]([O:29][C@H:30]([CH2:41][CH3:42])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32])(C(C)(C)C)(C)C.O.CCOC(C)=O>C1COCC1>[OH:29][C@H:30]([CH2:41][CH3:42])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32]
Reactant: CC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@H](O)C(=O)Nc1ccc(C)cn1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Tetrabutylammoniumfluoride trihydrate (3.21 g, 10.19 mmol) was added to a stirred solution of (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-N-(5-methylpyridin-2-yl)butanamide (Step 2) (2.00 g, 6.79 mmol) in THF (20 mL). The reaction mixture was kept at ambient temperature for 2 hrs. Water and EtOAc were added and the two phases were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined and washed with water, dried over MgSO4 and concentrated in vacuo. The residue was recrystallised from diethyl ether to give the title compound as colourless crystals (1.14 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:12](/[N:16]=[CH:4]/[C:3]1[C:6]([F:11])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=1[Cl:1])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN
Reactant: O=Cc1c(F)ccc(F)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC/N=C/c1c(F)ccc(F)c1Cl

Procedure:
Butyl-[1-(2-chloro-3,6-difluoro-phenyl)-meth-(E)-ylidene]-amine was prepared from 2-chloro-3,6-difluorobenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 191a): yellow oil; MS (ISP): 234.1 ([M+H]+, 30%), 232.3 ([M+H]+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH3:12])=[C:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[CH:3]=1.O=S(Cl)Cl.[CH3:19]O>>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH3:12])=[C:7]([C:9]([O:11][CH3:19])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: Cc1c(C(=O)O)oc2cc(Br)ccc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1oc2cc(Br)ccc2c1C
Temperature: 25 °C

Procedure:
To a suspension of 6-bromo-3-methylbenzofuran-2-carboxylic acid (5 g, 19.6 mmol) in 196 mL of MeOH was added SOCl2 (2.9 mL, 39.2 mmol). After the mixture was heated to reflux for 1 hr, the reaction solution became clear, and the color changed to green. The mixture was concentrated to remove part of solvent, and the color of the solution changed to yellow. After cooling to room temperature a white PPT formed, and the suspension was filtered, and the solid was washed with small amounts of EtOAc. The solid was dried under vacuum at 50° C. to give pure methyl 6-bromo-3-methylbenzofuran-2-carboxylate (3.56 g). LCMS retention time=1.58 minutes (LC method 3); MS (m+1)=270.9. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.59 (s, 3H), 3.99 (s, 3H), 7.41-7.47 (m, 1H), 7.48-7.53 (m, 1H), 7.72 (d, J=1.5 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:24]#[N:25])C2C=[CH:7][N:8]([C:11]3[N:12]([CH2:22][CH3:23])[C:13](=[O:21])[NH:14][C:15](=[O:20])[C:16]=3[CH:17]([CH3:19])[CH3:18])[C:9]=2[CH:10]=1.N1C2C=CC=CC=2NC=1>>[N:8]1([C:11]2[N:12]([CH2:22][CH3:23])[C:13](=[O:21])[NH:14][C:15](=[O:20])[C:16]=2[CH:17]([CH3:19])[CH3:18])[C:9]2[CH:10]=[CH:2][CH:3]=[CH:4][C:24]=2[N:25]=[CH:7]1
Reactant: CCn1c(-n2ccc3c(C#N)cc(Cl)cc32)c(C(C)C)c(=O)[nH]c1=O
Agent: c1ccc2[nH]cnc2c1
Product: CCn1c(-n2cnc3ccccc32)c(C(C)C)c(=O)[nH]c1=O

Procedure:
This compound was made by a procedure similar to that used to prepare 6-chloro-1-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-1H-indole-4-carbonitrile (90), except that benzoimidazole was used instead of 6-chloro-1H-indole-4-carbonitrile. LC-MS shows 299.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.32 (br, 1H), 7.97 (m, 2H), 7.43 (m, 2H), 7.30 (m, 1H), 3.60 (m, 1H), 3.20 (m, 1H), 1.98 (m, 1H), 1.10 (m, 9H).
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=3)[C:24]([OH:26])=[O:25])[CH:17]=2)[O:12][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5]1.[CH:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41](N2C=CN=C2)=[O:42])[CH:37]=[C:36]3[O:48][CH3:49])[CH2:30][CH2:29]1.Cl>CN(C=O)C.O>[CH:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41]([N:9]2[CH2:10][CH2:11][C:6]4([CH2:5][C:4](=[O:3])[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([C:19]6[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=6)[C:24]([OH:26])=[O:25])[CH:17]=5)[O:12]4)[CH2:7][CH2:8]2)=[O:42])[CH:37]=[C:36]3[O:48][CH3:49])[CH2:29][CH2:30]1
Reactant: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: COc1cc(C(=O)n2ccnc2)nc2c(C3CC3)cccc12
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)nc2c(C3CC3)cccc12
Temperature: 70 °C
Reaction time: 19 h

Procedure:
5-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid di-hydrochloride (4.93 g, 12.0 mmol), TEA (5.14 mL, 36.9 mmol) were suspended in DMF (49 mL) and (8-cyclopropyl-4-methoxy-quinolin-2-yl)-imidazol-1-yl-methanone (2.70 g, 9.22 mmol) was added thereto at room temperature, and the reaction mixture was stirred at 70° C. for 19 h. After cooled to room temperature, the mixture was poured into 1N HCl aq. (27.7 mL, 27.7 mmol) in H2O (367 mL) solution and the suspension was stirred for 2 h. The resulting precipitate was filtered, washed with H2O to give crude intended compound as a pale brown solid. This solid was washed with EtOAc-MeOH (1:1), then EtOH, and dried to afford the intended compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 9.08 (1.0H, d, J=2.4 Hz), 9.03 (1.0H, d, J=2.0 Hz), 8.41 (1.0H, dd, J=2.0, 2.4 Hz), 8.07-8.03 (2.0H, m), 7.94 (1.0H, dd, J=8.3, 1.5 Hz), 7.49 (1.0H, dd, J=8.3, 7.6 Hz), 7.30-7.23 (2.0H, m), 7.20 (1.0H, s), 4.40-4.33 (1.0H, m), 4.07 (3.0H, s), 3.94-3.87 (1.0H, m), 3.57-3.48 (1.0H, m), 3.39-3.24 (1.0H, m), 3.11-3.04 (1.0H, m), 2.98 (2.0H, s), 2.15-2.07 (1.0H, m), 2.03-1.79 (3.0H, m), 1.10-1.04 (2.0H, m), 0.87-0.72 (2.0H, m). MS [M+H]+=564.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:19][C:20]1[C:21]([C:26]2[N:30]([CH:31]([CH3:33])[CH3:32])[N:29]=[CH:28][CH:27]=2)=[N:22][CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:19][C:20]2[C:21]([C:26]3[N:30]([CH:31]([CH3:33])[CH3:32])[N:29]=[CH:28][CH:27]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)n1nccc1-c1ncccc1CCl
Reactant: O=Cc1c(O)cccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1nccc1-c1ncccc1COc1cccc(O)c1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
A mixture of 2,6-dihydroxybenzaldehyde (1.58 g, 11.47 mmol, 2 eq.) and K2CO3 (2.4 g, 17.22 mmol, 3 eq.) in DMF (150 mL) was stirred at rt for 10 min. To this mixture was added 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (1.56 g, 5.74 mmol, 1 eq.) at rt. The mixture was heated at 50° C. for 2 h, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (1.71 g, 88%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J=4.8, 1.5 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.49-7.34 (m, 2H), 6.59 (d, J=8.5 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 6.29 (d, J=8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J=6.7 Hz, 1H), 1.50 (d, J=6.6 Hz, 6H). LRMS (M+H+) m/z 338.1
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>S(=O)(=O)(O)O.O>[C:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([CH3:3])=[CH2:2])=[CH:5][CH:6]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(C)c1ccc(OC(C)=O)cc1
Yield: 85 %

Procedure:
A mixture of 12 g. (0.09 mole) of p-isopropenylphenol (prepared as described in Preparation 1) and 12 g. (0.118 mole) of acetic anhydride was stirred at ambient temperature (circa 20° C.) while two drops of concentrated sulfuric acid were added. Stirring was continued until the exothermic reaction subsided and the reaction product was then poured into an excess of water. The organic material was extracted with a mixture of ether and n-hexane and the extract was dried over anhydrous sodium sulfate and evaporated to dryness. There was thus obtained 16.5 g. of acetylated product which was found by nuclear magnetic resonance spectral analysis to be a mixture of 20% w/w of p-isopropenyl-phenol acetate and 80% w/w of the dimer diacetate. The product was subjected to pyrolysis by adding 0.1 g. of p-toluenesulfonic acid and heating to a temperature of 200°-240° C. under reduced pressure (circa 18 mm. mercury) to yield a distillate which was found to be 13.44 g. (85% yield) of monomeric p-isopropenylphenol acetate. The latter was mixed with a small amount of chloroform and hydrogen chloride gas was bubbled into the mixture until saturated. There was thus obtained a solution of p-(2-chloroisopropyl)phenol acetate.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH2:10])[CH2:3]2.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:12]=[O:13]>CN(C=O)C.C(N(CC)CC)C>[CH2:14]([NH:11][C:12]([NH:10][CH:4]1[CH:5]2[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]2)[CH2:3]1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1CN2CCC1CC2
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)NC1CN2CCC1CC2
Yield: 548.3 %

Procedure:
To a stirred solution of quinuclidin-3-amine hydrochloride (324 mg, 0.199 mmol) in DMF (30 ml) was added triethylamine (3 drops) followed by (isocyanatomethyl)benzene (275 mg, 2.10 mmol) carefully. The resultant mixture was stirred at 25° C. for 18 h. After HPLC separation, 1-benzyl-3-(quinuclidin-3-yl)urea (283 mg, 55%) was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][NH:19]1.N1CCCCC1>C(O)C>[O:16]=[C:11]1[C:10](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:22]=2[CH2:21][CH2:20][NH:19][C:18]3=[O:17])[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:12]1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(-c3ccccc3)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 5-phenyl-1,3-dihydro-indol-2-one (41.8 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:36]CC1C2C=CC=CC=2C2C1=CC=CC=2)[C:14]([N:16]([C@@H:27]([CH3:35])[CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[CH2:17][C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:36][C@H:13]([C:14]([N:16]([CH2:17][C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20][CH:19]=1)[C@@H:27]([CH3:35])[CH:28]([O:29][CH2:30][CH3:31])[O:32][CH2:33][CH3:34])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
6-tert-butoxycarbonylamino-2-(S)-(9H-fluoren-9-yl)methylamino-N—((S)-1,1-diethoxypropan-2-yl)-N-(benzothiophen-3-ylmethyl)hexanamide (Compound III-15) 20.1 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 11.7 g, (yield 83%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][OH:17].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:9])[CH2:7][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCC1CCCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN1CCCCC1CO
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Bromo-acetic acid tert-butyl ester (0.39 g, 2 mmol) was dissolved in DMF (1 mL). A solution of piperidin-2-yl-methanol (0.25 g, 2.2 mmol) in DMF (1 mL) and diisopropylethylamine (0.38 mL, 2.2 mmol) was added. The reaction mixture was stirred at 50° C. for 16 h. The solvent was removed in vacuo. EtOAc (20 mL) and water (7 mL) was added. The two phases were separated. The aqueous phase was extracted twice with EtOAc (20 mL). The combined EtOAc phases were dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The product was isolated as an oil. Yield: 0.37 g, 80%.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl.[N+]([O-])([O-])=O.[Na+].B(O)(O)O.[FH:31]>O>[F:31][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Reactant: F
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: OB(O)O
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 44.2 g. (0.15 moles) of ethyl 3-amino-4-cyclohexylphenylglyoxylate is added at 0° C. 44 ml. of 1.5 moles of concentrated hydrochloric acid. The reaction is maintained at 0° C. and the diazonium salt is prepared with 23.2 g. (0.32 moles) of 95% sodium nitrate in 80 ml. of water. To this mixture is rapidly added a solution of 10.4 g. (0.17 moles) of boric acid dissolved in 22 g. (0.66 moles) of 60% hydrofluoric acid. The reaction mixture is then stirred for 1/2 hour and filtered, washed with 3×25 ml. of water, 2×25 ml. of methanol and 25 ml. of ether. The residual cake is then treated in vacuo. The treated cake is then placed in a distilling flask and heated to permit spontaneous decomposition. After the decomposition, the residue is then fractionally distilled to obtain ethyl 3-fluoro-4-cyclohexylphenylglyoxylate.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C:11](=[O:32])[CH2:12][N:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[C:1]([NH:9][CH:10]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])[CH:11]([OH:32])[CH2:12][N:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC(=O)C(CCCCNC(=O)OCc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: CN(CC(O)C(CCCCNC(=O)OCc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
The ester product from part (c) is treated with sodium borohydride according to the procedure of Example 1(f) to yield (±)-1-[[[3-(benzoylamino)-7-[[(phenylmethoxy)carbonyl]amino]-2-hydroxyheptyl]methylamino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [OH:1][CH2:2][N:3]1[CH:6]([C:7]#[C:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][C:4]1=[O:13].C(OC=C)(=O)C>ClCCl>[OH:1][CH2:2][N:3]1[C@@H:6]([C:7]#[C:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][C:4]1=[O:13]
Reactant: C[Si](C)(C)C#CC1CC(=O)N1CO
Solvent: ClCCl
Solvent: C=COC(C)=O
Product: C[Si](C)(C)C#C[C@H]1CC(=O)N1CO
Temperature: 37 °C
Reaction time: 32 h
Yield: 76.8 %

Procedure:
To a solution of N-hydroxymethyl-4-(2-trimethylsilylethynyl)-2azetidinone (250 g) in dichloromethane (6.5 L) was added vinyl acetate (350 ml) and Lipase PS (trademark; Amano Pharmaceutical Co., Ltd.) (190 g). The mixture was warmed to 37° C. and stirred for 32 hours. Catalyst was filtered off and washed with dichloromethane. Solvent was evaporated in vacuo. The residue was subjected to silica gel column chromatography eluting with (n-hexane:EtOAc=8:2 to 0:1) to give (R)-N-hydroxymethyl-4-(2-trimethylsilylethynyl)-2-azetidinone (192 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:19]C)[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH+]1C=CC=CC=1>>[C:1]1([C:7]2[CH:8]=[C:9]([OH:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Yield: 84.3 %

Procedure:
A mixture of 4.7 g of 3,5-diphenyl-anisole and 5.3 g of pyridinium hydrochloride was heated for 5 hours to 185° C. After cooling, the residue was partitioned between 100 cc of diethyl ether and 120 cc of water. The organic layer wes then washed with water, dried (Na2SO4) and evaporated. The resultant residue was suspended in 50 cc of n-hexane and filtered to give 3.75 g (85%) of 3,5-diphenyl-phenol as a white solid. (m.p.=97° C.)
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1.[N:18]#[C:19][NH2:20]>CCOCC>[ClH:1].[NH:2]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:5][CH:4]=1)[C:19]([NH2:20])=[NH:18]
Reactant: N#CN
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=N)N)cc1
Temperature: 25 °C

Procedure:
4-Amino-N-tert-butoxycarbonylbenzylamine hydrochloride (25.77 g, 99.6 mmol.) and cyanamide (55 g, 1.3 mol.) were heated neat at 65° C. over 1.5 hours. The mixture was then cooled to room temperature and ether (250 mL) was added. The insoluble yellow oil was repeatedly washed with additional ethyl ether to remove traces of cyanamide and dried in vacuo to give 4-guanidino-N-tert-butoxycarbonylbenzylamine hydrochloride as an amorphous yellow material which was carried on without further purification.