Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:54][C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[CH:57]=[CH:58][N:59]([C@H:66]([CH3:70])[C:67]([NH2:69])=[O:68])[C:60]2=[O:65]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:54][C:55]2[CH:64]=[CH:63][CH:62]=[C:61]3[C:56]=2[CH:57]=[CH:58][N:59]([C@H:66]([CH3:70])[C:67]([NH2:69])=[O:68])[C:60]3=[O:65])=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: C[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(Cl)c(C(F)(F)F)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A round bottom flask was charged with 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (0.13 g, 0.00056 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0009 mol), N,N-diisopropylethylamine (0.2 mL, 0.0009 mol), N,N-dimethylformamide (3 mL, 0.04 mol) and (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)propanamide (0.1 g, 0.0004 mol). The reaction was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue purified by flash chromatography (12 g, 0-10% MeOH/DCM) to get the product as white solid. MS m/z=451.8(M+H). 1H NMR (400 MHz; DMSO-d6) δ 10.10 (s, 1H), 8.07(d, J=8.42 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J=8.47 Hz, 1H) 7.73-7.68 (m, 2H), 7.63 (s, 1H), 7.46 (d, J=7.57 Hz, 2H), 7.23 (bs, 1H), 6.68 (d, J=8.02 Hz, 1H), 5.50-5.45 (q, J=7.24 Hz, 1H), 3.92 (s, 2H), 1.54 (d, J=7.66 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([Mg]Br)[CH:19]=[CH2:20].Cl>O1CCCC1>[CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([CH:16]([OH:17])[C:19]([CH3:20])=[CH2:18])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)o1
Reactant: C=CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=C(C)C(O)c1ccc(C(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
5-Formyl-2-furancarboxylic acid benzyl ester (300 mg, 1.30 mmol) was dissolved in tetrahydrofuran (12 mL), 2-propenylmagnesium bromide (0.5 mol/L tetrahydrofuran solution, 2.6 mL, 1.3 mmol) was added at −78° C., and the mixture was stirred for 15 minutes. 1N Hydrochloric acid was added to the reaction mixture, the mixture was heated to room temperature and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30) to give the title compound (332 mg, 1.23 mmol, 94%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:15][CH2:16][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH2:20]3)[CH2:18][CH2:19]1)=[O:13])[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNc1ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
A 10-mL round-bottomed flask was charged with tert-butyl 1′-((2-adamantyl)carbamoyl)spiro[indoline-3,4′-piperidine]-1-carboxylate (50 mg, 0.107 mmol) and 20% trifluoroacetic acid in CH2Cl2 (2 mL). The mixture was stirred for 1 h at 0° C. The solution was concentrated under vacuum and the crude product was purified by preparative HPLC to provide N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (10 mg, 25%). 1H NMR (CD3OD, 400 MHz): δ=1.60˜2.00 (m, 18H), 3.00 (t, 2H), 3.86 (d, 3H), 4.08 (d, 2H), 7.40˜7.50 (m, 4H); LC-MS (4 min) tR=1.93 min, m/z=366 (M++1).
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([O:17][CH3:18])=[CH:7][C:6]=1C=O)[CH2:2][CH2:3][CH3:4].[C:21]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23]C)=[O:22].[OH-].[Na+].Cl[CH2:48]Cl>CO>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([O:17][CH3:18])=[CH:7][C:6]=1/[CH:48]=[CH:25]/[C:21]([OH:23])=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C=O)cc(OC)c2ccc(OC)cc12
Reactant: ClCCl
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1c(/C=C/C(=O)O)cc(OC)c2ccc(OC)cc12

Procedure:
As in Example 111, 1-butyl-4,7-dimethoxy-2-naphthalenecarboxaldehyde (1.35 g) and (carbomethoxymethylene)triphenylphosphorane (1.35 g) in dichloromethane (10 mL) was stirred at room temperature for 42 hours. The crude ester obtained from the usual work up was dissolved in methanol (25 mL) containing 1N sodium hydroxide solution (4 mL) and heated at reflux for 2 hours. The normal isolation procedure furnished 0.725 g of (E)-3-(1-butyl-4,7-dimethoxy-2-naphthalenyl)-2-propenoic acid. A portion was crystallized from diethyl ether-hexane to give the analytical specimen, mp 174°-176° C. Anal. Calcd for C19H22O4 : C, 72.59; H, 7.05 Found: C, 72.58; H, 7.18
Reaction SMILES: CC1C=C(COC2C=C(CCC(O)=O)C=CC=2)C=CC=1C1C=CC=C(OC)C=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([Mg]Br)[CH:34]=[CH:35][CH:36]=1.[CH3:39][C:40]1([CH3:51])[O:45][C:44](=[O:46])[C:43](=[C:47]([CH3:49])[CH3:48])[C:42](=[O:50])[O:41]1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:47]([CH:43]2[C:42](=[O:50])[O:41][C:40]([CH3:39])([CH3:51])[O:45][C:44]2=[O:46])([CH3:49])[CH3:48])[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: CC(C)=C1C(=O)OC(C)(C)OC1=O
Agent: COc1cccc(-c2ccc(COc3cccc(CCC(=O)O)c3)cc2C)c1
Product: COc1cccc(C(C)(C)C2C(=O)OC(C)(C)OC2=O)c1

Procedure:
The 5-(2-(3-methoxyphenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (85.C) was prepared via the procedure described in Huang, X.; et. al.; Tetrahedron Letters; 1982, (1); pp. 75-76. from (3-methoxyphenyl)magnesium bromide (1.0 M in THF solution from Aldrich) and 85.B. 1H NMR (400 MHz, CDCl3) ppm 7.26 (1H, t, J=8.0 Hz), 6.94 (1H, d, J=7.8 Hz), 6.89 (1H, t, J=2.2 Hz), 6.79 (1H, dd, J=8.2, 2.3 Hz), 3.81 (3H, s), 3.62 (1H, s), 1.67 (6H, s), 1.66 (3H, s), 1.34 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[N:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH:60]=O>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[CH2:60][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][N:54]=1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: O=Cc1ccccn1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1Cc1ccccn1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (40 mg) was treated with pyridine-2-carbaldehyde according to General Procedure D to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-pyridin-2-ylmethyl-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (42 mg). LCMS (m/z): 842. The methyl ester (25 mg) was hydrolyzed according to General Procedure B to give the title compound (20 mg). LCMS (m/z): 827.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21].[CH2:22](COC)OC.C(I)I>CCOCC.[Cu].[Zn]>[CH2:22]1[C@@H:13]2[C@H:12]([OH:20])[CH2:11][C:10]3[C@:15]([CH3:16])([C@H:14]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[C@@H:3]([OH:21])[CH2:4][CH2:5]2)[CH2:8][CH:9]=3
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)C=C[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: COCCOC
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: ICI
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)[C@H]5C[C@H]5[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C

Procedure:
To a stirred solution of 1,5-androstadiene-3β,17β-diol in a mixture of dry ether and glyme is added zinc-copper couple and methylene iodide. This reaction mixture is refluxed for 4 hours, cooled to room temperature, diluted with ether and filtered. The filtrate is washed with aqueous sodium chloride, water and dried over anhydrous magnesium sulfate. The ether is removed under reduced pressure and the residue crystallized from acetone-hexane to yield 1β,2β-methylene-5-androstene-3β,17β-diol.
Reaction SMILES: [Br:1][CH:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[C:4]([CH2:11][S:12]([OH:15])(=[O:14])=[O:13])([CH2:5][CH2:6]2)[C:3]1=[O:16].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([OH:41])([C:32]([C:34]1[CH:39]=[CH:38][C:37]([I:40])=[CH:36][CH:35]=1)=[CH2:33])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@:25]([OH:41])([C:32]([C:34]1[CH:35]=[CH:36][C:37]([I:40])=[CH:38][CH:39]=1)=[CH2:33])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1.[Br:1][CH:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[C:4]([CH2:11][S:12]([O-:15])(=[O:14])=[O:13])([CH2:5][CH2:6]2)[C:3]1=[O:16]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2Br
Reactant: C=C(c1ccc(I)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Product: C=C(c1ccc(I)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Product: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2Br
Reaction time: 20 h

Procedure:
A solution of (+)-3-bromocamphor-10-sulphonic acid (36.3 g, 0.110 moles) in IMS (40 ml) was added to a solution of the product of step (f) (50 g, 0.110 moles) in IMS (300 ml). After seeding, the resulting slurry was granulated for 20 hours at room temperature. A white solid (22 g, 0.03 moles) was collected by filtration after further granulating for 1 hour at low temperature. The chiral purity was assessed as 95% ee by chiral HPLC using a Chiralcel™ OD column and eluting with ethanol/hexane [40.60].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:10]([F:16])([F:15])[C:11](Br)([F:13])[F:12].N1C=CC=CC=1C1C=CC=CN=1>CS(C)=O.C(OCC)C.CCCCC.[Cu]>[F:15][C:10]1([F:16])[C:11]([F:13])([F:12])[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=2[O:9]1
Reactant: Fc1cccc(Br)c1OC(F)(F)C(F)(F)Br
Agent: [Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOCC
Solvent: CCCCC
Solvent: CS(C)=O
Product: Fc1cccc2c1OC(F)(F)C2(F)F
Temperature: 150 °C
Yield: 63.9 %

Procedure:
1-Bromo-2-(2-bromo-1,1,2,2-tetrafluoroethoxy)-3-fluorobenzene (14 g, 38 mmol), copper powder (12.2 g, 192 mmol) and 2,2′-bipyridine (610 mg, 3.9 mmol) were combined in dry DMSO (55 mL) and heated to 150° C. for 1.5 h. Vacuum (ca 20 mm) was applied to the reactor and distillate was taken overhead until the pot temperature reached 100° C. The distillate containing the product and DMSO was diluted with 1:1 diethyl ether-pentane (30 mL) and washed (3×5 mL) with water, dried, and distilled at 1 atmosphere (atm) through a 200 mm Vigreux column to remove the bulk of the solvents. Vacuum (ca 20 mmHg) was applied and the fraction boiling at 60-65° C. was collected to afford the title compound as a clear liquid (5.1 g, 64%): 1H NMR (400 MHz, CDCl3) δ 7.40-7.31 (m, 2H), 7.25-7.17 (m, 1H); EIMS m/z 210.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:3])=[O:2].Br[CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Nc1ccc(O)cc1
Reactant: CCOC(=O)C=C(OC)C(C)Br
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
Following the procedure of Example 1, 4-(2-nitro-4-trifluoromethylphenylamino) phenol is reacted with ethyl 4-bromo-3-methoxy-2-pentenoate to give ethyl 4-[4-(2-nitro-4-trifluoromethylphenylamino)phenoxy]-3-methoxy-2-pentenoate
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]1[S:3]2>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Yield: 83.7 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylate (517 mg.) in a mixture of dimethylformamide (3 ml.) and acetic acid (1 ml.) was added zinc powder (0.7 g.) under ice-cooling. After stirring for 1 hour at the same temperature, zinc powder was filtered off and washed twice with dimethylformamide (2 ml.). The filtrate was combined with the washings and the combined solution was poured into a mixed cooled solution of ethyl acetate and water, extracted with ethyl acetate, after which the extract was washed with water and dried over magnesium sulfate. Crystalline material (390 mg.) obtained by distilling off the solvent under reduced pressure was washed with ether and dried to give colorless crystals of 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylic acid (310 mg.) mp 112° to 118°C (dec.).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]([C:33](OC(C)(C)C)=O)[NH:25]C(OC(C)(C)C)=O.[C:40]([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:33]([CH3:40])=[N:24][N:25]=3)[C:11]=2[CH:10]=[C:9]1[C:18]1[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc(-c2cc3nc(Cl)ccc3n2Cc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1nnc2ccc3c(cc(-c4cn(C)cn4)n3Cc3ccccc3)n12
Temperature: 120 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
1-Benzyl-5-chloro-2-(1-methyl-1H-imidazol-4-yl)-1H-pyrrolo[3,2-b]pyridine (22 mg, 0.068 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (24 mg, 0.10 mmol) and Cs2CO3 (33 mg, 0.10 mmol) were combined in toluene (2.4 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (5.4 mg, 0.0068 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was stirred at 120° C. overnight. The mixture was diluted with DCM, filtered and concentrated. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded 5.6 mg of intermediate di-tert-butyl 1-[1-benzyl-2-(1-methyl-1H-imidazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate which was dissolved in acetic acid (1.1 mL) and heated in the microwave to 180° C. for 6 minutes. AcOH was removed in vacuo and the sample was reconstituted and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (3.0 mg 13%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].NC[C:24]1[CH:40]=[CH:39][CH:38]=[CH:37][C:25]=1[O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].[CH2:41]([N:43](CC)CC)[CH3:42]>C(OCC)(=O)C>[C:32]([O:31][C:30]([NH:29][CH2:28][CH2:27][O:26][C:25]1[CH:24]=[C:40]([CH:39]=[CH:38][CH:37]=1)[CH2:42][CH2:41][NH:43][C:6]1[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]([CH3:21])=[C:2]([Cl:1])[N:7]=1)=[O:36])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCOc1ccccc1CN
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NCCc2cccc(OCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 95.2 %

Procedure:
A mixture of benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (300 mg, 0.92 mmol), tert-butyl 2-[2-(aminomethyl)phenoxy]ethylcarbamate (preparation 128), (257 mg, 0.92 mmol) and triethylamine (140 ml, 1.0 mmol) in ethyl acetate (6 ml) was heated under reflux for 18 hrs. The cooled mixture was partitioned between ethyl acetate (80 ml) and hydrochloric acid (2N, 30 ml) and the phases separated. The organic layer was washed consecutively with hydrochloric acid (2N), saturated NaHCO3 solution, brine, then dried over MgSO4, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (50:50) as eluant to give the title compound as an orange foam, (500 mg, 95%).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].O.O[N:13]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O>[NH2:1][C@H:2]([C:8]([NH2:13])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: On1nnc2ccccc21
Reactant: NCCCC[C@H](N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: NCCCC[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
L-Lysine, N-E-(carbobenzoxy)-[N-α-[N-[4-[4-(2-methyl-1H-imidazol-1-yl)-butyl]phenyl]acetyl]-L-(O-benzyl)-seryl]-, (156.0 mg, 0.21 mmol), 1-hydroxy-benzotriazole hydrate (31.1 mg, 0.21 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40.1 mg, 0.21 mmol) were mixed in dimethylformamide (2.0 mL) at 0° C. for 15 minutes. Then N-methyl-morpholine (60.0 mg, 0.60 nmol) and methyl (R,S)-3-amino-3-cyclooctyl-propionate (46 mg, 0.21 mmol) were added, and the solution was stirred at room temperature for 16 hours. The solvent was removed at reduced pressure, and the residue taken up in methanol (1.00 mL) The product was isolated as a waxy solid by preparative HPLC to give 145 mg (76%) of L-lysinamide, N-[1-cyclooctyl-2-carbomethoxyethyl]-N-ε-(carbobenzoxy)-[N-α-[N-[4-[4-(2-methyl-1H-imidazol-1-yl)-butyl]phenyl]-acetyl]-L-(O-benzyl)-seryl]-, ±. HRMS calcd for C52H71N6O8 (M+H) 907.5333, found 907.5354.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.COP([CH2:24][C:25]([O:27][CH3:28])=[O:26])(OC)=O>O1CCCC1.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=[CH:24][C:25]([O:27][CH3:28])=[O:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
In tetrahydrofuran (40 ml), methyl dimethylphosphono-acetate (1.8 ml) was dissolved. To the resulting solution, 60% oily sodium hydride (450 mg) was added under ice cooling, followed by stirring under the same condition. After the addition of a solution of 1-(tert-butoxycarbonyl)-4-piperidone (2.05 g) in tetrahydrofuran (tetrahydrofuran: 10 ml) and stirring at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate. To the diluted solution, 2N hydrochloric acid was added. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and saturated aqueous saline, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=6:1), whereby the title compound (2.35 g, 92%) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C(N(C(C)C)CC)(C)C.Cl[C:19]1[N:24]([CH3:25])[C:23](=[O:26])[C:22]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[C:21]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([Cl:40])[CH:35]=2)[N:20]=1>ClCCl>[Cl:40][C:36]1[CH:35]=[C:34]([C:21]2[N:20]=[C:19]([N:5]3[CH2:6][CH2:7][CH2:8][CH:4]3[CH2:3][O:2][CH3:1])[N:24]([CH3:25])[C:23](=[O:26])[C:22]=2[C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[CH:39]=[CH:38][N:37]=1
Reactant: Cc1cccc(-c2c(-c3ccnc(Cl)c3)nc(Cl)n(C)c2=O)c1
Reactant: COC[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CCCN1c1nc(-c2ccnc(Cl)c2)c(-c2cccc(C)c2)c(=O)n1C
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (S)-2-methoxymethyl-pyrrolidine (0.172 g, 1.5 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 0.35 mL diisopropylethylamine (2.0 mmol) was added drop wise, and stirred for 10 min. 2-Chloro-6-(2-chloropyridin-4-yl)-3-methyl-5-m-tolyl-3H-pyrimidin-4-one (0.345 g, 1.0 mmol) was added in one portion, and stirred at 0° C. to rt for 12 h. The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.40 g as pale yellow solid. MS (ES+): 425 (M+H)+.
Reaction SMILES: [Cl-].[Li+].C(N([CH2:8][CH3:9])CC)C.[CH3:10][C:11]([CH3:26])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH:12]=O.[Cl-].[NH4+]>C(#N)C.O.CCOCC>[CH3:10][C:11]([CH3:26])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)/[CH:12]=[CH:25]/[C:20]([O:21][CH2:8][CH3:9])=[O:19]
Reactant: CC(C)(C=O)CCCCCOC1CCCCO1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)/C=C/C(C)(C)CCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of triethyl phosphonoacetate (1.62 mL) in acetonitrile (8 mL) was treated with lithium chloride (0.43 g) and then cooled to 0° C. and triethylamine (1.23 mL) added dropwise as a solution in acetonitrile (2.5 mL). The reaction mixture was stirred at 0° C. for 15 minutes then a solution of 2,2-dimethyl-7-(tetrahydro-pyran-2-yloxy)-heptanal (1.65 g) in acetonitrile (6 mL) was added. The resultant mixture was allowed to warm to room temperature and was stirred for 3 hours before treating with saturated aqueous ammonium chloride solution, ether and water. The layers were separated and the aqueous phase was extracted with ether (×2) and the combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated to afford the crude product. Purification was by silica gel chromatography eluting with 0 to 40% ethyl acetate in cyclohexane to afford the subtitled compound as a colourless oil. Yield 0.89 g.