Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCN(C)CC4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(CCCOc2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 26.6 %

Procedure:
To a solution of methyl 6-chloro-5-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylate (80 mg, 0.22 mmol) in methanol (8 mL) was added 1.0 M aqueous NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (25 mg, 28% yield) as a white solid. MS (ES+) 428.1 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.41 (br. s, 1H), 8.03 (s, 1H), 7.97 (s, 1 H), 7.56 (s, 1 H), 7.34 (d, 2 H), 6.98 (d, 2 H), 4.12 (t, 2 H), 3.20-2.75 (m, 10 H), 2.70 (s, 3 H), 2.10-2.01 (m, 2 H).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:13]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1CCCCC1.N1C=CC=CC=1>[C:1]([N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1=[O:20])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2=[O:20])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: O=C1CCCCCCCCCCCN1
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: O=C1CCCCCCCCCCCN1C(=O)c1ccc(C(=O)N2CCCCCCCCCCCC2=O)cc1
Temperature: 0 °C

Procedure:
Terephthaloyl chloride (203 g, i mol) is added in the course of 30 minutes to a solution of ω-laurolactam (403 g, 2 mol) in 1600 ml of cyclohexane and 475 ml of pyridine at room temperature. The mixture is then refluxed for 3 h. After cooling, the flask contents are poured into 3 1 of ice water and the resulting light yellow precipitate is filtered off by suction and dried. Yield 498 g (95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=O.[CH3:14][CH:15]([CH2:20][CH3:21])[C:16](OC)=[O:17].O.[NH2:23][NH2:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:15]([CH2:20][CH3:21])([CH3:14])[C:16](=[O:17])[NH:23][N:24]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: CCC(C)C(=O)OC
Reactant: NN
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: O
Product: CCC1(C)C(=O)NN=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for the example C5 using 3,4-dimethoxybenzoyl chloride, methyl 2-methylbutanoate and hydrazine hydrate as starting compounds.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+:33].C(OCC)(=O)C.Cl>O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:9][C:3]=1[C:4]([O-:6])=[O:5].[K+:33]
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C#Cc2ccc(O)c(C(=O)[O-])c2)cc1
Yield: 54.4 %

Procedure:
Ethyl 2-hydroxy-5-[[4-[(3-methyl-2-pyridinylamino)sulfonyl]phenyl]ethynyl]benzoate (15.5g, 35 mmol) was refluxed in potassium hydroxide (10 g, 0.15 mol) in water (100 ml) for 1 h. After cooling to ca 70° C. ethyl acetate (50 ml) was added and hydrochloric acid was added to reach pH 7-8. Cooling with stirring and then filtration gave directly 8.5 g of the product (51%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]1([NH:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3B3OC(C)(C)C(C)(C)O3)[CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:33]1[N:38]=[C:37]([CH2:39][NH:40][C:41]2[C:46]([CH:47]([CH3:49])[CH3:48])=[CH:45][CH:44]=[CH:43][C:42]=2[CH:50]([CH3:52])[CH3:51])[CH:36]=[CH:35][CH:34]=1.C1(C)C=CC=CC=1>O.CO.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>[CH:47]([C:46]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:50]([CH3:52])[CH3:51])[C:41]=1[NH:40][CH2:39][C:37]1[N:38]=[C:33]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:22]=2[CH:14]([NH:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:15][CH2:16]3)[CH:34]=[CH:35][CH:36]=1)([CH3:48])[CH3:49]
Reactant: CC1(C)OB(c2cccc3c2C(Nc2ccccc2)CC3)OC1(C)C
Reactant: CC(C)c1cccc(C(C)C)c1NCc1cccc(Br)n1
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: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NCc1cccc(-c2cccc3c2C(Nc2ccccc2)CC3)n1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 2.21 g (21.0 mmol) of Na2CO3 in a mixture of 80 ml of water and 25 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 2.80 g (8.40 mmol) of N-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-amine, 2.90 g (8.40 mmol) of N-[(6-bromopyridin-2-yl)methyl]-2,6-diisopropylaniline, 0.48 g (0.40 mmol) of Pd(PPh3)4, and 120 ml of toluene. This mixture was stirred for 12 h at 70° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×50 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexane-ethyl acetate-triethylamine=100:5:1, vol.). Yield 2.00 g (50%) of a yellow oil. Anal. calc. For C33H37N3: C, 83.33; H, 7.84; N, 8.83. Found: C, 83.49; H, 7.66; N, 8.65. 1H NMR (CDCl3): δ 7.56-7.61 (m, 3H, 6-H in indane and 4.5-H in Py); 7.46-7.51 (m, 2H, 3,5-H in phenyl); 7.14-7.16 (m, 1H, 4-H in indane); 7.08-7.12 (m, 5H, 3-H in Py, 3,4,5-H in 2,6-diisopropylphenyl and 5-H in indane); 6.65 (m, 1H, 4-H in phenyl); 6.53 (m, 2H, 2,6-H in phenyl); 5.21-5.22 (m, 1H, 1-H in indane); 3.95-4.15 (m, 4H, CH2NH and NH-phenyl and NH-2,6-diisopropylphenyl); 3.31 (sept, J=6.8 Hz, 2H, CH in 2,6-diisopropylphenyl); 3.16-3.24 (m, 1H, 3- or 3′-H in indane); 2.91-2.97 (m, 1H, 3′- or 3-H in indane); 2.21-2.37 (m, 2H, 2,2′-H in indane); 1.19-2.21 (m, 12H, CH3 in 2,6-diisopropylaniline).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(NCCC#N)CC1C=CC=CC=1.Cl.CCCCCC>CCCCCC.C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@@H:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)C(CCNC(=O)OC(C)(C)C)CC3
Agent: CC(Cc1ccccc1)NCCC#N
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)c1c(C)nn2ccc3c(c12)[C@@H](CCNC(=O)OC(C)(C)C)CC3
Yield: 46.7 %

Procedure:
Ethyl 9-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (300 mg) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mm ID×500 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: A) hexane 100%, B) hexane/ethanol=70/30, mixing ratio: A/B=80/20, flow rate: 60 mL/min, column temperature: 30° C., sample concentration: 10 mg/mL (hexane/ethanol=95/5), injection amount: 300 mg). A fraction solution containing an optically active compound having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give the title compound (140 mg, 99.7% ee). The enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=95/5, flow rate: 0.5 mL/min, column temperature: 30° C., sample concentration: 0.25 mg/mL (hexane/ethanol=95/5), injection volume: 10 μL).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.C1COCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:12][C:10]2[O:11][C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2ccccc2)c2oc(N)nc12
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccccc2)c2oc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 16 h
Yield: 32.9 %

Procedure:
To a stirred solution of 100 mg (0.42 mmol) 4-methoxy-7-phenyl-benzooxazol-2-ylamine, 0.087 ml (0.62 mmol) triethylamine and 5.1 mg N,N-dimethyl-4-aminopyridine in 5 ml THF at room temperature was added dropwise a solution of 0.064 ml (0.54 mmol) 4-fluoro-benzoyl chloride in 2 ml THF and stirring continued at 65° C. for 16 h. The reaction mixture was then concentrated in vacuo. To the residue was added water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/4 then 4/1 ethyl acetate/hexane) followed by trituration in ether afforded 50 mg (33%) 4-fluoro-N-(4-methoxy-7-phenyl-benzooxazol-2-yl)-benzamide as a light yellow crystalline solid. EI-MS m/e (%): 362 (M+, 90), 123 ([FC6H4CO+, 100).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>CN(C=O)C.O>[CH2:1]([O:8][C@H:9]1[CH2:10][C@H:11]([C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:15])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CC(OCc2ccccc2)C1
Reactant: Nc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccccn1)[C@H]1C[C@@H](OCc2ccccc2)C1
Product: O=C(Nc1ccccn1)[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (2.21 g, 5.82 mmol) was added to a stirred mixture of 3-(benzyloxy)cyclobutanecarboxylic acid (0.80 g, 3.88 mmol), 2-aminopyridine (0.73 g, 7.76 mmol), and triethylamine (1.08 mL, 7.76 mmol) in DMF (15 mL). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was separated, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified via silica gel chromatography to give the separated diastereomers trans-3-(benzyloxy)-N-(pyridin-2-yl)cyclobutanecarboxamide and cis-3-(benzyloxy)-N-(pyridin-2-yl)cyclobutanecarboxamide.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[C:7]([Br:24])[CH:6]=1.[C:26]1([CH3:35])[CH:31]=[CH:30][CH:29]=[C:28]([C:32](Cl)=[O:33])[CH:27]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:24][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:25])[CH:10]=[C:9]([Br:11])[C:8]=1[O:12][C:13]1[CH:14]=[C:15]([CH:21]([CH3:22])[CH3:23])[C:16]([O:19][CH2:20][CH2:6][C:5]([CH3:10])=[CH2:4])=[CH:17][C:18]=1[C:32](=[O:33])[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH3:35])[CH:27]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)c(C(C)C)c2)c(Br)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C(C)CCOc1cc(C(=O)c2cccc(C)c2)c(Oc2c(Br)cc(CC(=O)O)cc2Br)cc1C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
TiCl4 (25.2 mL, 229 mmol) was added dropwise to a solution of 3,5-dibromo-4-(3-isopropyl-4 -methoxyphenoxy)phenylacetic acid methyl ester (31.0 g, 65.6 mmol) and m-toluoyl-chloride (35.4 g, 229 mmol) in CH2Cl2 (310 mL) at 0° C. The mixture was stirred at room temperature for 3 d, cooled to 0 C, and quenched with ice (300 g). The layers were separated and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phases were washed with NaHCO3 (aq., sat, 3×100 mL), concentrated and purified by chromatography on silica gel to give 18.5 9 (49%) of the title compound.
Reaction SMILES: C([NH:6][C@H:7]([C:9](O)=[O:10])[CH3:8])(=O)C(C)=C.N[C@H](C(O)=O)C.Cl.[NH2:19][C@H:20]([C:24]([NH:26][C@H:27]([C:29]([O:31][CH3:32])=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[NH2:6][C@H:7]([C:9]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:29]([O:31][CH3:32])=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:10])[CH3:8]
Reactant: C=C(C)C(=O)N[C@@H](C)C(=O)O
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@H](N)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](C)N)C(C)C

Procedure:
Using the Schotten-Bauman method of acylation, N-methacryloylalanine was prepared. Coupling of MA-Ala-OH (5.35 g; 0.034 mol) with HCl.Val-Ala-OMe (8.1 g) was performed in dimethylformamide by means of dicyclohexylcarbodiimide (7.0 g) in the presence of triethylamine (3.4 g). Recrystalization from CH2Cl2 /pentene gave 9.5 g of MA-Ala-Val-Ala-OMe.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.BrC1C=CC(N)=CC=1.[NH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]
Reactant: NCCCN1CCCC1=O
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Agent: Nc1ccc(Br)cc1
Product: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Yield: 87.8 %

Procedure:
6-Bromo-4-chloro-3-nitroquinoline (50.62 g, 177.8 mmol), prepared from 4-bromoaniline according to the methods described in Parts A-D of Example 1, was treated with 1-(3-aminopropyl)pyrrolidin-2-one (27.5 mL, 196 mmol) according to the method described in Part E of Example 1 to provide 61.41 g of 1-[3-(6-bromo-3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one as a solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:26]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:27]=[O:28])[CH2:10][O:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](Cl)Cl>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)C)(C)C>[CH2:1]([O:8][C@H:9]([C@@H:26]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@@H:27]([OH:28])[CH3:37])[CH2:10][O:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](COC[C@H](OCc1ccccc1)[C@H](C=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: ClCCl
Agent: CC(C)O[Ti](C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](COC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](C)O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of (S)-methyl 3-((2S,3R)-2,3-bis(benzyloxy)-4-oxobutoxy)-2-((tert-butoxycarbonyl)amino)propanoate (7.55 g, 15.05 mmol) in DCM (30 ml) and THF (30 ml) at −78° C. was added triisopropoxy(methyl)titanium, 1.0 M in THF (31.6 ml, 31.6 mmol) and the reaction was stirred at −78° C. for 2 h, warmed to −20° C., and stored at −20° C. overnight. The reaction was warmed to 0° C., stirred for 4 h between 0° C. and −10° C., and then quenched at this temperature with saturated aqueous NH4Cl. The reaction mixture was extracted with EtOAc, and the combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash chromatography (SiO2, hexanes/EtOAc) to yield the title compound as a colorless oil (4.59 g, 59%, diastereomer selectivity=6:1): 1H NMR (400 MHz, CDCl3) δ 7.45-7.14 (m, 11H), 5.45 (d, J=8.8 Hz, 1H), 4.67 (d, J=11.6 Hz, 1H), 4.61-4.51 (m, 3H), 4.50-4.41 (m, 1H), 3.90 (dd, J=9.4, 3.0 Hz, 1H), 3.84-3.78 (m, 1H), 3.74-3.61 (m, 6H), 3.31 (dd, J=6.8, 4.0 Hz, 1H), 2.85 (d, J=4.5 Hz, 1H), 1.45 (s, 9H), 1.20 (d, J=6.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.04, 155.45, 137.99, 137.76, 128.51, 128.44, 128.12, 128.00, 127.97, 127.87, 81.43, 80.05, 77.91, 73.55, 72.88, 71.60, 70.91, 67.53, 54.00, 52.47, 28.34, 19.89; ESIMS m/z 540.6 ([M+Na]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[F:10][C:11]1[CH:12]=[C:13]([CH:41]=[CH:42][CH:43]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[O:37][C:36]([CH:38]=O)=[CH:35][CH:34]=4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)=[CH:18][C:17]=1[Cl:40].CCN(C(C)C)C(C)C.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[Cl:40][C:17]1[CH:18]=[C:19]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[O:37][C:36]([CH2:38][NH:1][CH2:2][CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])=[CH:35][CH:34]=4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:13]1[CH:41]=[CH:42][CH:43]=[C:11]([F:10])[CH:12]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: COP(=O)(CCN)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COP(=O)(CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1)OC
Reaction time: 0.5 h

Procedure:
To a suspension of compound 6.2 (153 mg, 1 mmol) and the compound 1.7 (473 mg, 1 mmol) in DCE (5 mL) was added DIPEA (1.5 mmol) and HOAc (1.5 mmol). After stirring the mixture for 30 minutes, 2.0 mmol of NaBH(OAc)3 was added followed by Stirring the mixture overnight. 1.0 mL of 5M NaOH was added and the mixture was extracted with DCM (2×20 mL). Combined organics was washed with brine and dried over MgSO4. Filtration and concentration followed by purification through flash column chromatography on silica gel (10% methanol in DCM) to get pale brown powder. LCMS ESI(+) m/z: 612 (M+1). 1H NMR (CD3OD, 300 MHz) δ 8.64 (s, 1H), 8.45 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.38 (m, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.23 (d, J=5.4 Hz, 1H), 7.05 (m, 1H), 6.90 (d, J=2.7 Hz, 1H), 6.44 (d, J=2.7 Hz, 1H), 5.20 (s, 2H), 3.73 (s, 3H), 3.70 (s, 3H), 2.90 (m, 2H), 2.10 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:25][CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[N:34](CC=C)[C:33]([Cl:41])=[N:32][C:31]=2[N:30]([CH2:42][CH2:43][CH2:44][C:45]([F:48])([F:47])[F:46])[C:29]1=[O:49])(=O)=O.N1CCOCC1>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>[Cl:41][C:33]1[NH:34][C:35]2[C:36](=[O:37])[N:28]([CH2:27][CH2:26][CH2:25][N:11]3[N:12]=[N:13][C:9]([CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:10]3)[C:29](=[O:49])[N:30]([CH2:42][CH2:43][CH2:44][C:45]([F:48])([F:46])[F:47])[C:31]=2[N:32]=1
Reactant: Fc1ccc(Cc2nnn[nH]2)cc1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCOS(C)(=O)=O)c(=O)n2CCCC(F)(F)F
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: C1COCCN1
Solvent: CN(C)C=O
Product: O=c1c2[nH]c(Cl)nc2n(CCCC(F)(F)F)c(=O)n1CCCn1nnc(Cc2ccc(F)cc2)n1
Temperature: 60 °C

Procedure:
5-[(4-Fluorophenyl)methyl]-1H-tetrazole (75 mg, 0.4 mmol) was treated with potassium carbonate (100 mg, 0.7 mmol) and DMF (3 ml). The mixture was treated with a solution of 3-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate (100 mg, 0.2 mmol) in DMF (0.5 ml). The mixture was stirred and heated at 60° C. 3 hours then cooled and evaporated. The residue was partitioned between chloroform (4 ml) and water (2 cm3). 1 cm3 of saturated aqueous sodium bicarbonate (3 ml) was added to each. The mixture was separated and the organic phase evaporated. The residue was dissolved in anhydrous THF (3 ml) and the mixture degassed by the cautious successive application of vacuum and nitrogen pressure to the mixture. The mixture was treated with tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.008 mmol) and morpholine (0.2 ml, 2.3 mmol) and then stirred in a nitrogen atmosphere for 2 h. The mixture was evaporated and partitioned between chloroform (4 ml) and saturated aqueous ammonium chloride (3 ml). The mixture was separated, and the aqueous phase re-extracted with chloroform. The organic phase was evaporated and the residue dissolved in MeOH (3 ml). The solution was added to the top of a 2 g aminopropyl SPE and washed with MeOH (15 ml). The desired product was eluted from the cartridge with a 3% v/v solution of AcOH in MeOH (20 ml). Product containing fractions were combined and evaporated and the residue subjected to purification by flash column chromatography (gradient elution from 10:1 cyclohexane/EtOAc to EtOAc). Product-containing fractions were combined and evaporated to yield the product as a colourless oil. Trituration in minimal diethyl ether caused the product to solidify and this was thoroughly dried to yield the title compound as a white solid (18.7 mg, 18%).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[CH:16])[CH:14]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH:14]=1
Reactant: Fc1ccc(I)cc1
Reactant: C#Cc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cncc(Br)c2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sequentially add triethylamine (161 mL, 1156 mmol), bis(triphenylphosphine)palladium(II) dichloride (2 g, 2.89 mmol) and copper (I) iodide (1.1 g, 5.78 mmol) to a solution of 3-bromo-5-ethynylpyridine (52.7 g, 289 mmol), (prepared essentially as described in PREPARATION 23), and 1-fluoro-4-iodobenzene (58.4 g, 262.7 mmol) in acetonitrile (1000 mL). Purge the system with nitrogen and heat the reaction mixture at 50° C. for 16 h. Concentrate, dissolve the residue in 10:1 hexanes:dichloromethane (1000 mL), filter and concentrate. Stir the residue in 150 mL of hexanes at room temperature for 30 min to produce a slurry. Cool the slurry at 0° C. and filter to give the title compound. From the filtrate, a second crop of the title compound can be isolated (45.5 g, 63%).