Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10](O)[C:9]1=[O:16])=[O:5].P(Br)(Br)([Br:19])=O.N#N.[OH-].[NH4+]>ClCCl.C(Cl)(Cl)Cl.O>[CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([Br:19])[C:9]1=[O:16])=[O:5]
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)CCn1c(C)cnc(O)c1=O
Agent: N#N
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CCn1c(C)cnc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a stirred slurry of 1-[(2-ethoxycarbonyl)ethyl]-3-hydroxy-6-methylpyrazinone (2-6) (3.8 g, 16.8 mmol) in 20 mL of dichloromethane, phosphorous oxybromide (5.8 g, 20.2 mmol) was added at 50° C. under a steady stream of N2. The resulting mixture was stirred for 2 hours. The reaction mixture was allowed to cool to room temperature and stirring was continued overnight. The mixture was diluted with 30 mL of chloroform and 30 mL of cold water, basified with ammonium hydroxide, and extracted with 30 mL of chloroform (3×). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the title compound (3.8 g, 80%) as an orange solid; the product was verified by NMR. 1H NMR (CDCl3): δ 7.01 (s, 1H), 4.26 (q, 2H), 4.16 (q, 2H), 2.83 (t, 2H), 2.38 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[C:14]([N:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([Br:42])[CH:33]=3)[C:25]3[C:20](=[CH:21][C:22]([O:45][CH3:46])=[C:23]([O:43][CH3:44])[CH:24]=3)[C:19]2=[O:47])[CH:15]=[CH:16][CH:17]=1.O>C(OCC)(=O)C>[CH3:44][O:43][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:45][CH3:46])[C:19](=[O:47])[N:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][CH:1]=[O:2])[CH:13]=1)[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([Br:42])[CH:33]=1
Reactant: O=CO
Reactant: COC(=O)c1c(-c2cc(Br)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1-c1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(-c2cc(Br)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1-c1cccc(NC=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To formic acid (3 ml) is added acetic anhydride (3 ml), and the mixture is stirred at room temperature for four hours. To the reaction mixture is added the compound obtained in Example 176 (500 mg), and the mixture is stirred at room temperature overnight. The mixture is further stirred at 60° C. overnight. After the reaction is complete, to the reaction mixture are added water and ethyl acetate. The ethyl acetate layer is separated, washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform:acetone=10:1) to give 6,7-dimethoxy-2-[3-(formylamino)phenyl]-4-(3-bromo-4,5-dimethoxyphenyl)-3-methoxycarbonyl-1(2H)-isoquinolinone as listed in Table 16.
Reaction SMILES: C(O[CH:4](OCC)/[CH:5]=[CH:6]/[CH3:7])C.[C:11]([C@H:17]([C@@H:19]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[OH:20])[OH:18])([O:13][CH:14]([CH3:16])[CH3:15])=[O:12]>C1C=CC=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>[CH:5](/[CH:4]1[O:20][C@H:19]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C@@H:17]([C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])[O:18]1)=[CH:6]\[CH3:7]
Reactant: CC(C)OC(=O)[C@@H](O)[C@H](O)C(=O)OC(C)C
Reactant: C/C=C/C(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: C/C=C/C1O[C@H](C(=O)OC(C)C)[C@@H](C(=O)OC(C)C)O1
Temperature: 25 °C
Reaction time: 7 h
Yield: 55.3 %

Procedure:
A solution of (2E)-1,1-diethoxybut-2-ene (32.20 g, 223.27 mmol), (−)-diisopropyl D-tartrate (64.64 mL, 245.60 mmol) and pyridinium tosylate (2.24 g, 8.93 mmol) in 100 mL benzene was heated to 95° C. to distill off the solvent and EtOH produced. After 7 h at 95° C., the reaction was cooled to rt and concentrated in vacuo. Purification by normal phase chromatography (10->30% EtOAc/hexanes) yielded 35.37 g (55%) of diisopropyl (4S,5S)-2-[(1E)-prop-1-enyl]-1,3-dioxolane-4,5-dicarboxylate as an orange oil. 1H NMR (CDCl3, 400 MHz) 6.03 (m, 1H); 5.86 (m, 2H); 5.12 (m, 2H); 4.71 (d, J=3.84 Hz, 1H); 4.63 (d, J=3.84 Hz, 1H); 1.78 (m, 3H); 1.30 (d, J=6.23 Hz, 12H); LC/MS [M+H]+=287.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:14][C:15](=[O:28])[C@@H:16]([NH:18][C:19](=[O:27])[CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH3:17])[C:11](O)=[O:12])=[CH:5][CH:4]=1.[NH2:29][C@@H:30]([CH2:37][C:38]1[CH2:42][CH2:41][CH2:40][CH:39]=1)[C:31]([C@@:33]1([CH3:36])[CH2:35][O:34]1)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[C:38]1([CH2:37][C@H:30]([NH:29][C:11](=[O:12])[C@@H:10]([NH:14][C:15](=[O:28])[C@@H:16]([NH:18][C:19](=[O:27])[CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH3:17])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:31]([C@@:33]2([CH3:36])[CH2:35][O:34]2)=[O:32])[CH2:42][CH2:41][CH2:40][CH:39]=1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2=CCCC2)CO1
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a solution of (S)-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoic acid (850 mg, crude) and (S)-2-amino-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-one (TFA salt, 200 mg, 0.680 mmol) in DCM (10 mL) was added HATU (283 mg, 0.750 mmol). The mixture was cooled to 0° C. and basified with DIEA to pH=8. The reaction mixture was stirred at ambient temperature for 30 min and water (30 mL) was added. The resulting mixture was extracted with DCM (30 mL×2) and the extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=2:1 to 1:2, then DCM/methanol=70:1) to afford (S)-N-((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide (170 mg, 18%) as a colorless solid. 1H NMR (300 MHz, CDCl3): δ7.29 (br. s, 1H), 7.16 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 6.74 (d, J=7.2 Hz, 1H), 6.10 (d, J=7.2 Hz, 1H), 5.33 (s, 1H), 4.56-4.44 (m, 2H), 3.80 (s, 3H), 3.75-3.73 (m, 4H), 3.29 (d, J=4.8 Hz, 1H), 3.00-2.91 (m, 5H), 2.53-2.47 (m, 5H), 2.27-2.16 (m, 5H), 1.90-1.81 (m, 1H), 1.73 (s, 3H), 1.37 (d, J=7.2 Hz, 3H). MS (EI) for C30H42N4O7, found 571.4 (MH)+.
Reaction SMILES: Cl(O)(=O)(=O)=O.[OH:6][CH:7]([C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1)[C:8]([O:10][CH3:11])=[O:9].C(O[C:22]([CH3:25])([CH3:24])[CH3:23])(=O)C>>[C:22]([O:6][CH:7]([C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1csc(C)n1
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1csc(C)n1
Reaction time: 1 h
Yield: 21 %

Procedure:
Under a nitrogen atmosphere, perchloric acid (70%, 3.75 mL) was added at −10° C. to a solution of methyl 2-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)acetate (15b) (590 mg, 3.15 mmol) in tertbutyl acetate (25 mL). After 1 hour, the reaction was quenched with a saturated aqueous solution of sodium carbonate and extracted with dichloromethane (2×20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 75/25) to afford the desired product (15c) as a white solid (160 mg, 0.66 mmol, 21%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9]C)=O)[N:6]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CO>[NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1nc(N)sc1-c1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nc(N)sc1-c1ccccc1
Yield: 45.1 %

Procedure:
5.0 g (21.3 mmol) of methyl 2-amino-5-phenyl-4-thiazolecarboxylate (which was prepared as described in J. Chem. Soc. Perk. Trans. I (1982) 159-164) and 6.84 g (42.7 mmol) of t-butyl (2-aminoethyl)carbamate were heated under reduced pressure for 2 hours at a bath temperature of 140°, whereby the methanol formed was distilled off continuously. After cooling the residue was dissolved in 50 ml of methylene chloride and chromatographed on 200 g of silica gel with a 9:1 mixture of methylene chloride and methanol as the eluting agent. The fractions which were pure according to the thin-layer chromatogram were combined and evaporated under reduced pressure, whereby there were obtained 4.5 g of a red, crystallizing oil. Crystallization from methanol and an ether/hexane mixture yielded 3.48 g (45%) of t-butyl [2-(2-amino-5-phenyl-4-thiazolecarboxamido)ethyl]carbamate as beige crystals which were used without further purification.
Reaction SMILES: C(O[C:6](=[O:23])[CH2:7][CH:8]([NH:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH:9]([O:13]CC)[O:10][CH2:11][CH3:12])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[NH:16][CH:8]1[CH2:7][C:6](=[O:23])[O:13][CH:9]1[O:10][CH2:11][CH3:12])[CH:21]=[CH2:22]
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(OCC)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)NC1CC(=O)OC1OCC
Yield: 85 %

Procedure:
A solution of the crude 3-Allyloxycarbonylamino-4,4-diethoxy-butyric acid tert-butyl ester, 103, obtained in the procedure above, in CH2Cl2(50 mL) is treated with triflouroacetic acid (50 mL). After the consumption of starting material, the organics are reduced under vacuum. The residual triflouroacetic acid is removed with ethyl acetate by azeotroping conditions. The final residue is purified over silica (hexanes/ethyl acetate 80:20) to afford 10.1 g (85% yield) of the desired product as a slightly yellow oil. 1H-NMR, (300 MHz, CDCl3): δ 1.23 (m, 3H), 2.41–2.54 (m, 1H), 2.82–3.06 (m, 2H), 3.61–3.73 (m, 1H), 3.82–3.98 (m, 1H), 4.06–4.25 (m, 1H), 4.61 (br s, 2H), 5.24–5.53 (m, 3H), 5.86–6.01 (m, 1H); MS (ESI): m/e=230.03 (M+H).
Reaction SMILES: ClC1N=C(NC2CCCCC2)C(C)=C(C)N=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([CH2:25][CH3:26])=[C:20]([CH3:27])[N:19]=1.ClC1N=C(Cl)C(C)=C(C)N=1.[F:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1>>[Cl:17][C:18]1[N:23]=[C:22]([NH:43][C:42]2[CH:44]=[CH:45][C:39]([F:38])=[CH:40][CH:41]=2)[C:21]([CH2:25][CH3:26])=[C:20]([CH3:27])[N:19]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCc1c(C)nc(Cl)nc1Cl
Agent: Cc1nc(Cl)nc(Cl)c1C
Agent: Cc1nc(Cl)nc(NC2CCCCC2)c1C
Product: CCc1c(C)nc(Cl)nc1Nc1ccc(F)cc1

Procedure:
The titled compound was synthesized according to the procedure described for preparation of 2-chloro-N-cyclohexyl-5,6-dimethylpyrimidin-4-amine (Example 1, Step D) using 2,4-dichloro-5-ethyl-6-methylpyrimidine instead 2,4-dichloro-5,6-dimethylpyrimidine and 4-fluoroaniline instead of cyclohexylamine. The titled compound was obtained as a white solid. MS (ESI) m/z 266.7, 268.7 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[NH2:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.O=[C:16]([CH2:23][CH2:24][CH3:25])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH2:23][CH2:24][CH3:25])[NH:9][C:10]2=[N:11][NH:12][CH:13]=[C:14]12
Reactant: Cc1ccsc1C=O
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2sccc2C)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 3-methylthiophene-2-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [CH3:1][Zn]C.[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:1])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: O=Cc1ccc(I)cc1[N+](=O)[O-]
Reactant: C[Zn]C
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CC(O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 48.2 %

Procedure:
Titanium(IV) isopropoxide (1.2 mL, 4.04 mmol) was dissolved in anhydrous dichloromethane (8 mL) under a nitrogen atmosphere. The solution was cooled to 0° C. and dimethylzinc (2 M in toluene, 8.67 mL, 17.34 mmol) was added dropwise. The mixture was stirred at 0° C. for 45 minutes followed by addition of 4-iodo-2-nitrobenzaldehyde (800 mg, 2.89 mmol). The mixture was stirred at 0° C. for 36 hours, then quenched by 1 M HCl (CAUTION: vigorous gas evolution!) and extracted with ethyl either (50 mL) three times. The combined organic phase was washed with water (50 mL), saturated NaHCO3 solution (50 mL) and brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by column chromatography to yield racemic (RS)-1-(4-Iodo-2-nitrophenyl)ethanol (408 mg, 48%). 1H NMR (400 MHz, CDCl3): δ 8.21 (dd, 1H, J=1.8 and 5.3 Hz, Ph-H), 7.96 (m, 1H, Ph-H), 7.58 (d, 1H, J=8.3 Hz, Ph-H), 5.38 (q, 1H, J=6.1 Hz, Ph-CH), 2.34 (br s, 1H, OH), 1.54 (d, 3H, J=6.1 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 147.98 (C), 142.49 (CH), 140.68 (C), 132.77 (CH), 131.31 (CH), 91.60 (C), 65.40 (CH), 24.28 (CH3).
Reaction SMILES: [Mg].[CH3:2][CH2:3][O:4][C:5]([C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].O.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]>O1CCCC1>[C:16]([O:15][C:13]([NH:8][C@H:7]([CH2:11][CH2:10][C:9]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])=[O:12])[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium (736 mg) in tetrahydrofuran (20 mL), 1-bromo-2,4-difluorobenzene (3.42 mL) was added dropwise at 45° C. over five minutes, and the reaction solution was stirred at room temperature for one hour. This solution was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (6.0 g) in tetrahydrofuran (50 mL) at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 7.5 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:27]([C:31]#[CH:32])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.N#N>CN(C=O)C.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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:32]#[C:31][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1
Temperature: 80 °C
Yield: 78.8 %

Procedure:
A solution of 2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 1.56 mmol), TMS-acetylene (1.11 mL, 7.79 mmol) and triethylamine (1.1 mL, 7.8 mmol) in DMF (8 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (180 mg, 0.16 mmol) and CuI (14.8 mg, 0.078 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back-extracted two times then the organic phases were combined and dried over Na2SO4. After concentration, the crude material was purified by silica gel chromatography (10-50% EtOAc-hexanes gradient) to afford 4,4-difluoro-2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (547 g, 1.23 mmol, 79% yield). LCMS-ESI+: calc'd for C23H30F2N3O2Si: 446.2 (M+H+). Found: 445.8 (M+H+).
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[C:7](OCC)(=[O:10])[C:8]#[CH:9]>CN(C=O)C>[CH3:1][C:2]1[NH:6][C:7](=[O:10])[CH:8]=[CH:9][C:3]=1[C:4]#[N:5]
Reactant: C#CC(=O)OCC
Reactant: C/C(N)=C\C#N
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
(Synthesis 1991, 894-896.) 3-Aminocrotonitrile (29, 2.9 g, 36 mmol) and ethyl propiolate (30, 3.0 mL, 36 mmol) were dissolved in dry DMF (17 mL). The reaction mixture was stirred for 1 h at room temperature, and the mixture was heated at reflux for 3 d. The precipitate formed after cooling to room temperature was collected, washed with methanol (5 mL), ether (10 mL), and dried to yield 131 (1.5 g, 31%): mp >300° C. 1H NMR (300 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.58 (d, J=9.6 Hz, 1H), 6.23 (d, J=9.6 Hz, 1H), 2.37 (s, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([OH:16])=[O:15])[CH2:3]1.[C:17](O[K])(C)(C)C.[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[C:31]2Cl)=[CH:26][CH:25]=1.C[Si](C=[N+]=[N-])(C)C>CS(C)=O.CO>[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[C:31]2[O:1][C@H:2]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CC(C)(C)O[K]
Reactant: Clc1nccc2ccc(Br)cc12
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2nccc3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0.2 mM solution of trans 4-hydroxy L-BOC-proline (1 eq) in DMSO at RT was added tBuOK (3 eq) in a single portion. The reaction mixture was stirred at RT for 30 min, cooled to 10° C. and 7-bromo-1-chloroisoquinoline was added (1 eq). The resulting mixture was allowed to warm to RT and stirred overnight. The organic layer was washed with sat. aq. citric acid solution, water and brine and the aqueous phases were back extracted with EtOAc. The combined organic phases were dried (Na2SO4) and the solvent evaporated under reduced pressure to give a dark solid. The solid was dissolved in MeOH and to the stirred solution an excess (4 eq) of 2.0 M trimethylsilyldiazomethane in hexanes was added dropwise at 15° C. The resulting mixture was stirred for 15 min after gas evolution has ceased. Volatiles were removed by rotary evaporation and the residue was purified by flash chromatography (SiO2, PE/EtOAc 8/2 v/v as eluent) to give title product as a solid. MS (ES+) C20H23BrN2O5 requires 451. Found: 452 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:49])[CH:7]([CH2:25][C:26]1([C:32](=[O:48])[NH:33][CH:34]([C:44](=[O:47])[NH:45][CH3:46])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])(C)(C)C.CCOCC>FC(F)(F)C(O)=O>[O:19]=[C:18]1[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11](=[O:24])[N:10]1[CH2:9][CH2:8][CH:7]([CH2:25][C:26]1([C:32](=[O:48])[NH:33][CH:34]([C:44](=[O:47])[NH:45][CH3:46])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:6]([OH:49])=[O:5]
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCN2C(=O)c3cc4ccccc4cc3C2=O)C(=O)OC(C)(C)C)CCCCC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCN2C(=O)c3cc4ccccc4cc3C2=O)C(=O)O)CCCCC1

Procedure:
A solution of 4-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethylcarbamoyl]cyclohexylmethyl}butyricacidtert-butyl ester (diastereomer A) (50 mg, 0.075 mmol) in trifluoroacetic acid (1 mL) was stirred overnight at room temperature. The solvent was evaporated under vacuum leaving a white foam which was titrated with ether to afford 4-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl) ethylcarbamoyl]-cyclohexylmethyl}butyric acid (diastereomer A) as a white solid, 40 mg (87%). High Resolution Mass Spectrum M+ calculated for C35H39N3O7 : 613.2788; found: 613.2746.
Reaction SMILES: C(O)(=O)C.[ClH:5].C([NH:13][C@H:14]([C:23]([NH:25][C@@H:26]([C:31]([NH:33][CH2:34][C:35]([NH:37][C@H:38]([C:46]([CH:48]1[C:55]2([NH2:57])[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:58][C:49]1([C:59]([O:61][CH3:62])=[O:60])[CH2:50]3)[CH2:54]2)=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36])=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(OC(C)(C)C)=O>O1CCOCC1>[ClH:5].[NH2:13][C@H:14]([C:23]([NH:25][C@@H:26]([C:31]([NH:33][CH2:34][C:35]([NH:37][C@H:38]([C:46]([CH:48]1[C:55]2([NH2:57])[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:58][C:49]1([C:59]([O:61][CH3:62])=[O:60])[CH2:50]3)[CH2:54]2)=[O:47])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:36])=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C2
Reaction time: 0.5 h

Procedure:
To a mixture of 5.0 ml acetic acid, 5.0 ml dioxane and 10.0 ml of a 6 M solution of hydrogen chloride in dioxane is added 1.0 g of methyl Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate. The reaction mixture is allowed to stand for 30 minutes at room temperature then the solvent is removed by vacuum distillation. The residue is dissolved in a mixture of 2.0 ml methanol and 20 ml water and the solution is lyophilized to give methyl L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride which is represented by the following formula ##STR20##