Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[F:33][C:34]([F:44])([F:43])[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([C:34]([F:33])([F:43])[F:44])[CH:36]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 40.2 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-(trifluoromethyl)benzylamine (available from Aldrich Chemical Company, Inc.; 108 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-trifluoromethyl-benzylcarbamoyl)-biphenyl-2-carboxylic acid (53 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 9.20 (t, J=6.0 Hz, 1H), 8.46 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.2, 1.9 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.56-7.72 (m, 5H), 7.51 (d, J=8.3 Hz, 2H), 4.60 (d, J=5.8 Hz, 2H).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:15](=[O:16])[C:14]3[C:17]([CH3:24])=[C:18]([C:20]([O:22]C)=[O:21])[S:19][C:13]=3[N:12]=[CH:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[OH-].[Li+]>C1COCC1.CO>[CH:1]1([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:15](=[O:16])[C:14]3[C:17]([CH3:24])=[C:18]([C:20]([OH:22])=[O:21])[S:19][C:13]=3[N:12]=[CH:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1sc2ncn(CC(=O)NC3CCCCC3)c(=O)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncn(CC(=O)NC3CCCCC3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of methyl 3-(2-(cyclohexylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (3.6 g, 10 mmol) in THF (30 mL), MeOH (10 mL), and H2O (10 mL) was added lithium hydroxide monohydrate (1.26 g, 30 mmol). The reaction mixture was then stirred at RT overnight. The reaction mixture was concentrated, diluted with H2O (30 mL) and washed with DCM (2×30 mL). The aqueous layer was acidified (pH˜2) with 1M HCl and the resultant precipitate was filtered and dried to give 1.7 g of 3-(2-(cyclohexylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (yield: 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.C1COCC1.C(N(CC)CC)C.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>[Cu](I)I.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.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A 250 ml round bottom flask was charged with 5-chloro-3-iodo-pyridin-2-ylamine (1) (42 g, 165 mmol), THF (100 ml), copper iodide (315 mg, 1.65 mmol) and PdCl2(PPh3)2 (1.15 g, 1.65 mmol) under nitrogen. Triethylamine (70 ml, 0.5 mol), and trimethylsilyl acetylene (30 ml, 0.21 mol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then cooled to 0° C. and diethyl ether was added. The suspension was filtered through a celite and thoroughly washed with diethyl ether. The filtrate was concentrated and pre-absorbed onto silica gel and purified by column chromatography using as eluent, pentane/DCM 10% to 100%, to afford an off white solid (36 g, 100%). 1H NMR (CDCl3): 0.3 (9H, s), 5.0-5.1 (2H, brs), 7.6 (1H, s), 7.9 (1H, s). MS (ES+): 225, 227.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]([OH:23])=[O:22])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:27]1([C:33]([CH:35](Br)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C.S(=O)(=O)(O)O>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]([O:23][CH:35]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:22])=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1CCCCN1C(=O)c1cccc(OCc2ccccc2)c1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: O=C(c1ccccc1)C(OC(=O)C1CCCCN1C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 28.4 %

Procedure:
Sodium (54 mg) was dissolved in ethanol (8.0 ml), and then 1-(3-benzyloxybenzoyl)-2-piperidinecarboxylic acid (665 mg), conc. sulfuric acid (1 drop), and desyl bromide (539 mg) was successively dissolved thereto. The resulting mixture was stirred at 70° C. for 2 days, cooled to room temperature, and partitioned between ethyl acetate and 1N HCl. The organic layer was washed with 1N HCl, aqueous sodium bicarbonate, and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 2-oxo-1,2-diphenylethyl 1-(3-benzyloxybenzoyl)-2-piperidinecarboxylate (297 mg) as a pale yellow oil.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH:7]([CH3:9])[CH3:8])=[N:4][C:3]=1[CH3:10].[O:11]1[CH2:16]CC(C=O)C[CH2:12]1>>[I:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:9][CH2:16][O:11][CH2:12][CH2:8]2)=[N:4][C:3]=1[CH3:10]
Reactant: Cc1nc(C(C)C)[nH]c1I
Reactant: O=CC1CCOCC1
Product: Cc1nc(C2CCOCC2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 159.2, except tetrahydro-2H-pyran-4-carbaldehyde was used in place of isobutyraldehyde.
Reaction SMILES: C1C2C=CC=CC=2CCNC1.C(N1CCC2C=CC(S([Cl:29])(=O)=O)=CC=2CC1)(=O)C.C([N:33]1[CH2:39][CH2:38][C:37]2[CH:40]=[CH:41][C:42]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:43][C:36]=2[CH2:35][CH2:34]1)(=O)C.Cl>>[ClH:29].[CH3:47][S:44]([C:42]1[CH:41]=[CH:40][C:37]2[CH2:38][CH2:39][NH:33][CH2:34][CH2:35][C:36]=2[CH:43]=1)(=[O:46])=[O:45]
Reactant: CC(=O)N1CCc2ccc(S(C)(=O)=O)cc2CC1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2CC1
Agent: Cl
Agent: c1ccc2c(c1)CCNCC2
Product: CS(=O)(=O)c1ccc2c(c1)CCNCC2

Procedure:
Following the procedure of Examples 1 and 4, 2,3,4,5-tetrahydro-1H-3-benzazepine was converted to 3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine and then to 3-acetyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine which was hydrolyzed with hydrochloric acid to give 7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 275°-277° C.
Reaction SMILES: [CH2:1]([Si:9]([CH3:12])([CH3:11])Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:13][C:14]([CH3:25])([C:16](=[O:24])[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].C(N(CC)CC)C>C(OCC)C>[CH2:1]([Si:9]([CH3:12])([CH3:11])[O:24][C:16](=[CH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]([CH3:13])([CH3:15])[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Si](C)(C)Cl
Reactant: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCC[Si](C)(C)OC(=CC(=O)C(C)(C)C)C(C)(C)C

Procedure:
A dehydrating compound was prepared by the dropwise addition of octyldimethylchlorosilane to an equal molar solution of 2,2,6,6-tetramethyl-3,5-heptanedione and triethylamine in ethyl ether. The mixture was heated until it refluxed for a period of 6 hours, and filtered to remove salts. The solvent was removed under reduced pressure to yield 3-(octyldimethylsiloxy)-2,2,6,6-tetramethylhept-3-ene-5-one.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](=[N:26][OH:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[OH:27][N:26]=[C:20]([CH2:19][C:4]1[C:3]2[C:7](=[CH:8][C:9]([Br:11])=[CH:10][C:2]=2[Br:1])[NH:6][CH:5]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Brc1cc(Br)c2cc[nH]c2c1
Reactant: CCOC(=O)C(CBr)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1c[nH]c2cc(Br)cc(Br)c12)=NO

Procedure:
Mix 4,6-dibromoindole (2.09 g, 7.58 mmol), potassium carbonate (1.57 g, 11.4 mmol) and anhydrous methylene chloride (30 mL). Stir and add a solution of ethyl 3-bromo-2-hydroxyiminopropanoate (1.59 g, 7.58 mmol) in methylene chloride (20 mL). Stir under a nitrogen atmosphere for 48 hours. Take the solution up in ethyl acetate and wash with water (100 mL), saturated sodium hydrogen carbonate (100 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in in vacuo and purify by silica gel chromatography to give the title compound.
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:10][CH:9]=[CH:8][CH2:7][C@H:6]1[C:11]([OH:13])=[O:12])=O.C(N(CC)CC)C.ClC(OCC)=O>O1CCCC1>[C:11]1(=[O:12])[C@@H:6]2[C@@H:5]([CH2:10][CH:9]=[CH:8][CH2:7]2)[CH2:3][O:13]1
Reactant: COC(=O)[C@H]1CC=CC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC[C@@H]2CC=CC[C@H]12
Reaction time: 2 h
Yield: 62.3 %

Procedure:
In a stream of nitrogen gas, 20 g of (1R, 2S)-2-methoxycarbonylcyclohex-4-ene-1-carboxylic acid was dissolved in 120 ml of dry tetrahydrofuran, and to the solution, was added 18.2 ml of triethylamine while the solution being cooled by ice. A dry tetrahydrofuran (40 ml) solution of ethyl chloroformate (12.4 ml) was slowly added dropwise to the mixture. While the mixture was being cooled by ice, the mixture was stirred for 2 hours. After filtration of the resulting triethylamine hydrochloride, the filtrate was added dropwise to a H2O (100 ml) solution of NaBH4 (10.3 g) with ice-cooling and the mixture was stirred for 2 hours at room temperature. Then, 2N-HCl was added to the mixture to adjust the pH thereof to 4-5, and THF was distilled off under a reduced pressure. The residue was extracted by ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate solution and brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under a reduced pressure, and the residue was dissolved in 100 ml of toluene. 2.07 g of p-toluenesulfonic acid monohydrate was added to this solution, and the mixture was stirred for 5 hours at room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution and brine. Then, the organic layer was dried over anhydrous magnesium sulfate, and after filtration, the filtrate was concentrated under a reduced pressure. The residue was distilled under a reduced pressure, and thus 9.35 g of the titled compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[CH:5]=[N:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=1.[CH2:19]=[CH:20][C:21](=[CH2:23])[CH3:22]>CC#N.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:22][C:21]([CH3:23])([CH:20]=[CH2:19])[C:12]3[N:11]=[C:10]([C:13]#[N:14])[CH:9]=[CH:8][C:7]=3[NH:6]2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: N#Cc1ccc(N=Cc2ccc(F)c(Cl)c2)cn1
Reactant: C=CC(=C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: C=CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C#N)nc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
To a stirred solution 5-[(3-chloro-4-fluoro-benzylidene)-amino]-pyridine-2-carbonitrile (3.7 g, 14.3 mmol) in MeCN (36 mL) were added isoprene (5.8 mL, 57.1 mol) and scandium(III) trifluoromethanesulfonate (Sc(OTf)3) (1.4 g, 2.9 mmol). The resulting mixture was stirred at 80° C. for 16 hours in sealed tube. The mixture was extracted with diethyl ether (80 mL) and washed with water (100 mL) and brine (100 mL) and then dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 0-20% ethyl acetate in petroleum ether) to afford 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonitrile (0.25 g, 5.5%) as white powder. MS (ESI+) [(M+H)+] 328.2.
Reaction SMILES: CN[C:3]([O:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7]O)=O.[CH2:32]([S:48][CH2:49][CH:50]([O:72][C:73](=[O:76])[NH:74][CH3:75])[CH2:51][O:52][C:53]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].[CH2:77](SCC(OC)CN)CCCCCCCCCCCCCCC>>[NH2:74][CH2:73][C:6]1([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:77][CH2:3][O:5]1.[CH2:32]([S:48][CH2:49][CH:50]([O:72][C:73](=[O:76])[NH:74][CH3:75])[CH2:51][O:52][C:53]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)OC(=O)NC
Agent: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CN)CCCO1

Procedure:
2-Methylcarbamoyloxy-3-octadecylcarbamoyloxypropanol V c2 is allowed to react and worked up by the same procedure as described in (3) to give an amine IV c2 of m.p. 91°-92° C. The summary of the experimental condition and the physical data of the product are listed in the Table 5 and 6.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:7]2.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:7]3)=[CH:22][CH:21]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C1c2c(Cl)cccc2CC1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: Cc1ccc(-c2cccc3c2C(=O)C(CC2CCCCC2)C3)cc1
Temperature: 125 °C

Procedure:
24.16 g (91.9 mmole) 7-Chloro-2-cyclohexylmethyl-indan-1-one, 15.0 g (1.2 eq.) 4-methylphenyl boronic acid, 19.49 g sodium carbonate, 303 ml ethylene glycol and 57 ml water were placed in a 1 l—roundbottom flask equipped with a mechanical stirrer and a reflux condenser. The mixture was degassed three times by slight evacuation and recharging with argon. A premixed catalyst solution consisting of 41 mg (0.2 mole %) palladium acetate, 1.2 ml NaTPPTS (2.6 M in water, 0.8 mole %) and 2 ml of water was added and the mixture was refluxed at 125° C. until complete conversion (approx. 8 h). 100 ml of water were added and the mixture was extracted three times with 100 ml of toluene each. The combined organic layers were washed twice with 100 ml water and once with 100 ml of a saturated sodium chloride solution. Drying over magnesium sulphate and evaporation of the solvent in vacuo yielded 30.57 g (quant.) of the desired product as a yellow sticky oil. 1H-NMR (400 MHz, CDCl3): δ=7.60-7.19 (m, 7H, aromatic), 3.31 (m, 1H, (C═O)CH), 2.91-2.61 (m, 2H, benzylic), 2.38 (s, 3H, Ph-CH3), 1.80-0.85 (m, 10H, aliphatic) ppm.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[C@@H:6]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:5]([CH3:22])[O:4][C:3]1=[O:23].[OH:24][C:25]1[C:26]([C:33](O)=[O:34])=[N:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:24][C:25]1[C:26]([C:33]([NH:1][C@H:2]2[CH2:10][O:9][CH2:8][C@H:7]([O:11][C:12]([CH2:13][CH3:14])([CH3:15])[CH3:16])[C@@H:6]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:5]([CH3:22])[O:4][C:3]2=[O:23])=[O:34])=[N:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: CCC(C)(C)O[C@H]1COC[C@H](N)C(=O)O[C@@H](C)[C@@H]1OCC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C)(C)O[C@H]1COC[C@H](NC(=O)c2nccc(OC)c2O)C(=O)O[C@@H](C)[C@@H]1OCC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a mixture of (3S,7S,8S,9S)-3-amino-7-(1,1-dimethylpropoxy)-8-isobutoxy-9-methyl-1,5-dioxonan-2-one and 3-hydroxy-4-methoxypicolinic acid (79.0 mg, 0.466 mmol) in DCM (2.0 mL) were added 4-methylmorpholine (0.205 mL, 1.86 mmol) followed by HATU (189 mg, 0.497 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was directly purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to yield the title compound as a white solid (50.0 mg, 42%): mp 138-140° C.; IR (neat) 3370, 2926, 1750, 1650, 1529, 1243, 1085 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.98 (s, 1H), 8.73 (d, J=8.0 Hz, 1H), 8.01 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.08 (dq, J=9.1, 6.3 Hz, 1H), 5.00 (ddd, J=8.1, 6.1, 3.8 Hz, 1H), 4.00 (dd, J=12.1, 6.1 Hz, 1H), 3.94 (s, 3H), 3.95-3.89 (m, 2H), 3.79 (dd, J=8.6, 5.6 Hz, 1H), 3.56-3.45 (m, 2H), 3.07 (dt, J=12.6, 8.4 Hz, 2H), 1.90-1.78 (m, 1H), 1.56-1.43 (m, 2H), 1.45 (d, J=6.4 Hz, 3H), 1.15 (s, 3H), 1.14 (s, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.91-0.85 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 170.17, 169.09, 155.47, 148.89, 140.79, 130.47, 109.68, 85.26, 81.29, 81.18, 77.82, 75.32, 75.19, 73.37, 56.23, 53.07, 35.01, 29.10, 25.16, 25.08, 19.95, 19.60, 18.97, 9.06; HRMS-ESI (m/z) [M]+ calcd for C24H38N2O8, 482.2628; found, 482.2631.
Reaction SMILES: Br[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH:26](B1OC(C)(C)C(C)(C)O1)=[CH2:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]([C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1)=[CH2:27]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C

Procedure:
A suspension of tert-butyl N-[(1S,2S)-2-{[3-bromo-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (650 mg, 1.53 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS number 75927-49-0; 942 mg, 6.11 mmol), tetrakis(triphenylphosphine)palladium (177 mg, 0.15 mmol) and potassium carbonate (845 mg, 6.11 mmol) in 1,4-dioxane (5 ml) and water (0.8 ml) was subjected to microwave irradiation at 120° C. for 1 hour. The reaction was partitioned between ethyl acetate (10 ml) and water (10 ml). The aqueous layer was further extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine (20 ml), filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: S(=O)(O)[O-].[Na+].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[C-:21]#[N:22].[K+]>O.CO.O.CO>[CH:14]1([NH:20][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:21]#[N:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: [C-]#N
Reactant: O=Cc1ccccc1
Reactant: NC1CCCCC1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC(NC1CCCCC1)c1ccccc1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of 0.98 g (9.4 mmol) of sodium bisulfite in 4 ml of water was treated with 0.96 ml (9.4 mmol) benzaldehyde in 5 ml of methanol. The resulting mixture was cooled to 5°-10° C. and treated with cyclohexylamine, whereupon a thick precipitate was formed. With the reaction mixture still at approximately 5° C., solid potassium cyanide (0.61 g, 9.4 mmol) was added portionwise over 2 minutes. The precipitate became thick enough to halt stirring and 5 ml of 1:1 methanol water was added to facilitate stirring. The reaction mixture was allowed to warm to room temperature over a 16 hour period. The mixture was then filtered and the product was washed with methanol-water and dried in air. There were obtained 1.6 grams (79.6% yield) of the above titled product. 1H NMR (300 MHz, CDCl3) δ7.5-7.3 (m, 5H), 4.82 (s, 1H), 2.9-2.8 (m, 1H), 2.0 (d, 1H, J=12 Hz), 1.75-1.62 (m, 4H), 1.4-1.0 (m, 6H). 13C NMR (75 MHz, CDCl3) δ135.56, 128.99, 128.91, 127.29, 119.35, 54.87, 51.68, 33.87, 31.94, 25.95, 24.66, 24.27. IR CHCl3 λ 2220 cm-1. Mass Spectrum m/e 214 p+.