Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]#[CH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.C([Li])CCC.CCCCCC.Cl[C:25]([O:27][CH3:28])=[O:26]>>[CH:1]1([C:6]#[C:7][C:25]([O:27][CH3:28])=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cl
Reactant: C#CC1CCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C#CC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a stirred solution of cyclopentylacetylene (7, 17.49 mL, 150.0 mmol) in anhydrous tetrahydrofuran (THF, 200 mL, 2466 mmol) at −78° C. was added 2.50 M of n-butyllithium in hexane (66.0 mL, 165 mmol, 1.1 equiv). The resulting milky suspension was stirred at −78° C. for 30 min. Methyl chloroformate (17.6 mL, 225 mmol, 1.5 equiv) was then added. The reaction mixture became a clear solution. The cooling bath was then removed, and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture became a suspension again. When TLC (5% EtOAc/hexane, KMnO4 stain) showed the reaction was deemed complete, the reaction mixture was quenched with saturated aqueous NH4Cl solution (150 mL) and extracted with diethyl ether (Et2O, 2×200 mL). The combined organic layers were washed with saturated aqueous NaCl solution, dried over magnesium sulfate (MgSO4), filtered and concentrated under the reduced pressure. The residue was distilled under vacuum (99-101° C./16 mbar) to afford methyl 3-cyclopentylpropiolate (18, 21.856 g, 22.83 g theoretical, 96% yield) as a colorless oil. For 18: 1H NMR (CDCl3, 400 MHz) δ ppm 3.74 (s, 3H), 2.73 (m, 1H), 1.95 (m, 2H), 1.72 (m, 4H), 1.57 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:14][CH2:13][CH2:12][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][CH:7]=[CH:6]3.[C:15](OC(=O)C)(=[O:17])[CH3:16].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH2:12][CH2:13][N:14]1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C2N=c3ccccc3=C2CCN1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C1c2[nH]c3ccccc3c2CCN1C(C)=O

Procedure:
To a solution of harmalan (1 mmol) in pyridine (2 ml) is added acetic anhydride (1.1 eq). After acid hydrolysis and extraction with ethyl acetate, the crude product is flash-chromatographed (eluent: EtOAc/pet. ether; 50/50). The 1-methylene-2-acetyl-1,2,3,4-tetrahydro-β-carboline elutes off first.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH2:18])[CH:12]=[CH:13][CH:14]=2)C=1.[N:19]1C=CC(C#CC2C=C(CCCN)C=CC=2)=C[CH:20]=1.S1C=CC=C1C#CC1C=C(CCCN)C=CC=1.S1C=CC(C#CC2C=C(CCCN)C=CC=2)=C1>>[N:19]1[CH:20]=[CH:6][CH:5]=[CH:4][C:3]=1[C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH2:18])[CH:12]=[CH:13][CH:14]=1
Reactant: NCCCc1cccc(C#Cc2ccncc2)c1
Reactant: NCCCc1cccc(C#Cc2cccnc2)c1
Agent: NCCCc1cccc(C#Cc2cccs2)c1
Agent: NCCCc1cccc(C#Cc2ccsc2)c1
Product: NCCCc1cccc(C#Cc2ccccn2)c1

Procedure:
3-(3-(pyridin-3-ylethynyl)phenyl)propan-1-amine; 3-(3-(pyridin-4-ylethynyl)phenyl)propan-1-amine; 3-(3-(thiophen-2-ylethynyl)phenyl)propan-1-amine; and 3-(3-(thiophen-3-ylethynyl)phenyl)propan-1-amine.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([I:15])=[C:9]([CH2:11][C:12](Cl)=[O:13])[CH:10]=1.CCOC(C)=O>CCOCC>[CH3:1][N:2]([CH3:3])[C:12](=[O:13])[CH2:11][C:9]1[CH:10]=[C:5]([CH3:4])[CH:6]=[CH:7][C:8]=1[I:15]
Reactant: Cc1ccc(I)c(CC(=O)Cl)c1
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc(I)c(CC(=O)N(C)C)c1

Procedure:
Dimethylamine (200 ml of 2 M solution in THF) is added dropwise to a solution of 5-methyl-2-iodophenylacetyl chloride in Et2O (500 ml) which is cooled in an ice bath. After the addition is complete, EtOAc (350 ml) is added and the solution is washed with water (350 ml), brine (250 ml) and dried (MgSO4). Evaporation on a rotovap and trituration with 1:1 Et2O/hexanes gives N,N-dimethyl-5-methyl-2-iodophenylacetamide as a light tan solid, m.p. 47-49°.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1C(=O)N([Br:20])C(=O)C1>CO>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Br:20])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: COc1cc(Br)cc(C(=O)O)c1N
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a solution of 2-amino-3-methoxybenzoic acid (5 g, 29.9 mmol) in MeOH (35 mL) at −5° C., NBS (5.59 g, 31.4 mmol) was added and the resulting mixture was stirred at 0° C. for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the crude product (4 g, 54% yield). ESI-MS m/z: 244.2 [M−H]−.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:15])(=[O:13])=[O:12].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:15][N:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[S:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[C:6]([OH:8])=[O:7])(=[O:13])=[O:12]
Reactant: CN1CCNCC1
Reactant: CN(C1CCCCC1)S(=O)(=O)c1cc(C(=O)O)ccc1Cl
Product: CN1CCN(c2ccc(C(=O)O)cc2S(=O)(=O)N(C)C2CCCCC2)CC1

Procedure:
The reaction was carried out in a manner analogous to that of Example 31, using 33 g of 4-chloro-3-(N-methylcyclohexylaminosulfonyl)-benzoic acid and 30 g of N-methylpiperazine. The moist crude product, which had been washed with water, was freed from by-products by boiling with methanol.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][CH:11]2[CH:7]([N:8]=[C:9]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[S:10]2)[C@H:6]1[O:25]C(=O)C)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[OH:15][CH2:14][C@H:13]1[O:12][CH:11]2[CH:7]([N:8]=[C:9]([NH:19][CH2:20][C:21]([F:24])([F:22])[F:23])[S:10]2)[C@@H:6]([OH:25])[C@@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1OC2SC(NCC(F)(F)F)=NC2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC[C@H]1OC2SC(NCC(F)(F)F)=NC2[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
(5R,6S,7R)-5-(acetoxymethyl)-2-(2,2,2-trifluoroethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (0.328 g, 0.776 mmol) was dissolved in anhydrous MeOH. Solid K2CO3 was added to the solution until it was basic, and the reaction was stirred at room temperature (1 h). The reaction was filtered and then concentrated in vacuo. The final reaction mixture was purified via flash column chromatography with a solvent system of 5:1 DCM and MeOH, providing (5R,6S,7R)-5-(hydroxymethyl)-2-(2,2,2-trifluoroethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (39) (0.110 g, 47% yield). 1H NMR (500 MHz, methanol-d4) δ 3.47-3.50 (m, 1H), 3.61-3.69 (m, 2H), 3.81 (d, 1H, J=11.8 Hz), 3.92 (m, 3H), 4.03 (s, 1H), 4.10 (q, 1H, J=6.9 Hz), 6.35 (d, 1H, J=6.0 Hz). 13C NMR (125 MHz, methanol-d4) δ 61.94, 69.79, 74.31, 75.35, 123.82, 126.04, 175.25, 225.56.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:88]=[CH:89][CH:90]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH3:77])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:88]=[CH:89][CH:90]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH3:77])[CH2:75][CH2:76]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 59.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (90 mg, 0.144 mmol) was hydrolyzed with lithium hydroxide (12 mg, 0.289 mmol) in THF/methanol/water (5/2/1 mL) to yield 40 mg (47.6% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.566-8.560 (d, 1H), 8.49-8.45 (m, 2H), 8.24 (s, 1H), 8.09-8.06 (dd, 1H), 7.97 (s, 1H), 7.71 (s, 1H), 7.40-7.38 (q, 1H), 7.14-7.12 (d, 2H), 7.10-7.00 (m, 2H), 5.45 (s, 2H), 3.00 (s, 3H). MS: m/z=468.2 (M+1), HPLC: 99.02% in method B.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:33]([O:35]CC)=[O:34])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][C:40]=1[CH3:46].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Li+].[OH-].Cl>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CO>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[NH:17][C:16]([C:33]([OH:35])=[O:34])=[C:15]3[CH2:14][CH2:13][CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[C:40]([CH3:46])[CH:41]=1
Reactant: CCOC(=O)c1[nH]c2c(B3OC(C)(C)C(C)(C)O3)cccc2c1CCCOc1cccc2ccccc12
Reactant: Cc1cc(O)ccc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(O)ccc1-c1cccc2c(CCCOc3cccc4ccccc34)c(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 43A (50 mg) and 4-bromo-3-methylphenol (22 mg) in THF (2 mL) was added tris(dibenzylideneacetone)dipalladium(0) (4.6 mg), and tri-tert-butylphosphine tetrafluoroborate (1.45 mg). The mixture was stirred at ambient temperature overnight and partitioned between ethyl acetate (150 mL) and water (50 mL). The extract was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the concentrate was loaded on a silica gel cartridge and eluted with ethyl acetate (5%) in hexanes to provide a product which was dissolved in THF (2 mL), methanol (1 mL) and water (1 mL) and hydrolyzed with LiOH (100 mg) overnight. The mixture was acidified with 5% aqueous HCl and extracted with ethyl acetate. The exteact was washed with water and brine and dried (Na2SO4), filtered and concentrated. The concentrate was purified by reverse phase HPLC as described in Example 1D. 1H NMR (300 MHz, CDCl3) δ 8.39 (d, 1H), 8.35 (d, 1H), 7.77 (d, 1H), 7.72 (dd, 1H), 7.13-7.50 (m, 6H), 6.85 (d, 1H), 6.76 (t, 2H), 4.21 (t, 2H), 3.47 (t, 2H), 2.38 (m, 2H), 2.13 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].[N-:15]=[N+]=[N-].[Na+].CCOC(C)=O.[BH4-].[Na+]>CN(C)C=O.O>[NH2:15][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nc(Cl)cc(Cl)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)cc(N)c1OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
Methyl 4,6-dichloro-3-methoxypicolinate (320 mg, 1.4 mmol) was dissolved in dry N,N-dimethylformamide (DMF; 5 mL), treated with sodium azide (130 mg, 2.0 mmol) and heated at 50° C. for 5 h. After cooling, the mixture was shaken with EtOAc (20 mL) and H2O (10 mL). The organic phase was washed with H2O (2×10 mL) and satd aq NaCl (1×10 mL), dried (Na2SO4) and evaporated. This material was dissolved in methyl alcohol (CH3OH; 15 mL), treated with sodium borohydride (NaBH4; 55 mg, 1.4 mmol) and stirred at 20° C. for 1 h. The mixture was treated with H2O (10 mL), and the volatiles were removed under vacuum. The residue was taken up in EtOAc (25 mL), washed with H2O (10 mL) and satd aq sodium chloride (NaCl; 10 mL), dried (Na2SO4), and evaporated to give the desired product as a white solid (100 mg, 33%): mp 78-79° C.; 1H NMR (400 MHz, CDCl3) δ 6.76 (s, 1H), 4.84 (s, 2H), 3.95 (s, 3H), 3.87 (s, 3H); EIMS m/z 216.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)(Cl)Cl>[CH:14]1([N:11]2[CH2:12][CH2:13][CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:22](=[O:24])[CH3:23])=[CH:3][CH:4]=3)[CH2:10]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)NC2CCN(C3CCCCC3)C2)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)NC2CCN(C3CCCCC3)C2)cc1
Yield: 50 %

Procedure:
To a suspension of 8.6 g. (0.3 mole) of p-amino-N-(1-cyclohexyl-3-pyrrolidinyl)benzamide in 50 ml. of chloroform was added dropwise with stirring, 3.37 g. (0.03 mole) of acetic anhydride. The mixture was stirred for 30 minutes and the solution extracted with dilute sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in hot ethyl acetate and an equivalent amount of isopropyl ether added to precipitate the product. After recrystallizing from the same solvent, 5.1 g. (50%) of product melting at 184°-186°C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:37][O:38][C:39](=[O:45])[CH2:40][CH2:41][C:42](O)=[O:43].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:42]([O:35][C@@H:20]1[C:21]([CH3:34])=[CH:22][C@@H:23]2[C@:28]([OH:29])([C@H:27]([CH3:30])[CH2:26][CH2:25][C@@H:24]2[C:31]([CH3:33])=[CH2:32])[C@H:19]1[O:18][C:16]([C@H:14]1[NH:13][C@@H:8]2[O:9][N:10]([CH3:12])[C:11]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C@:7]2([OH:36])[CH2:15]1)=[O:17])(=[O:43])[CH2:41][CH2:40][C:39]([O:38][CH3:37])=[O:45]
Reactant: COC(=O)CCC(=O)O
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)[C@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(=O)CCC(=O)OC)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reaction time: 18 h
Yield: 19.1 %

Procedure:
A mixture of (1S,2R,4aS,5R,8R,8aR)-2,8a-dihydroxy-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 139, 100 mg, 0.19 mmol), commercially available 4-(methyloxy)-4-oxobutanoic acid (50 mg, 0.38 mmol), 4-dimethylaminopyridine (60 mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.58 mmol) and dichloromethane (5 ml) was stirred for 18 h and the reaction mixture concentrated in vacuo. The crude product was purified by chromatography on a Biotage® 12M column eluting with dichloromethane:diethyl ether (4:1). The pure fractions were combined and the solvent removed in vacuo to give the title product (23 mg, 18%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].Br[CH2:39][C:40]([O:42]C(C)(C)C)=[O:41].[OH-].[Li+]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][CH2:39][C:40]([OH:42])=[O:41])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:4])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NCC(=O)O)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) using tert-butyl bromoacetate. The final product was hydrolysed using lithium hydroxide to obtain the acid in 74% yield.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][CH:8]1[CH:12]=[CH:11][CH:10]([CH3:13])[NH:9]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:7][C@H:8]1[CH:12]=[CH:11][C@H:10]([CH3:13])[N:9]1[CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CBr
Reactant: CC1C=CC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1[C@@H](C)C=C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
Methyl bromoacetate (16.8 g, 0.11 mol) was added, dropwise, to a stirred mixture of 2,5-dimethyl-3-pyrroline (10 g, 0.1 mol), potassium carbonate (13.8 g, 0.1 mol), and dimethylformamide (25 cm3) maintained below 30° C. by ice cooling. After addition was complete the mixture was cooled in ice for a further 1 h, then stirred at room temperature overnight. The reaction mixture was then diluted with water (50 cm3) and the product extracted into ether. The ether extract was dried and evaporated to yield an oil* which was distilled under vacuum to give methyl (trans-2,5-dihydro-2,5-dimethyl-1H-pyrrol-1-yl)acetate (7 g) b.p. 89°-92° C./15 mm.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O:33][C:34]([C@H:36]1[CH2:40][C@@H:39](O)[CH2:38][N:37]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:35].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O>[C:45]([O:44][C:42]([N:37]1[CH2:38][C@@H:39]([O:3][S:2]([CH3:1])(=[O:5])=[O:4])[CH2:40][C@@H:36]1[C:34]([OH:35])=[O:33])=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CS(=O)(=O)O
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@@H]1C(=O)O
Temperature: 80 °C
Reaction time: 24 h
Yield: 104.5 %

Procedure:
To a suspension of 6.7 ml (103.3 mmol) methanesulfonic acid, 14.4 ml (103.3 mmol) triethylamine and 28.8 g (107.6 mmol) triphenylphosphine in 280 ml toluene was added a suspension of 21.12 g (86.12 mmol) (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [prepared according to “Synthesis of macrocyclic dilactones by cyclization of sulfonium salts”. T. Nakamura, H. Matsuyama, N. Kamigata, M. Iyoda, J. Org. Chem. (1992), 57(14), 3783-9] in 180 ml toluene. After adding 21.6 ml (112 mmol) of diisopropyl azodicaboxylate (exothermic!) the solution was heated for 2.5 h at 80° C. and was stirred at RT for 1 day. 300 ml water was added at RT and extracted with ethylacetate (3×300 ml). The organic phase was washed with aqueous 1M KHSO4 (2×100 ml), brine (2×150 ml), dried over Na2SO4 and evaporated to give 27.85 g (2R,4S)-4-Methanesulfonyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester as crude product which was dissolved in THF and treated with LiOH according to 5.2.to give (2R,4S)-4-Methanesulfonyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)OC)#[N:2].[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=[N:22][CH2:21][CH2:20][O:16][N+:17]([O-:19])=[O:18])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: COC(=NC#N)c1ccoc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccoc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 8.2 %

Procedure:
Methyl N-cyano-3-furancarboximidate (0.5 g, 3.3 mmol) was dissolved in methanol (10 ml), and 2 nitroxyethylamine nitrate (0.84 g, 5.0 mmol) and sodium methoxide (0.27 g, 5.0 mmol) were added. The mixture was stirred at room temperature for 26 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was extracted with chloroform (60 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C 200, 20 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.06 g, 0.27 mmol, yield: 8%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1([F:56])[C:6]2[N:7]([CH2:14][C:15]([NH:17][C@H:18]([C:28]3[C:33]([C:34]4[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=4)[C:39]([NH2:41])=[O:40])=[CH:32][C:31]([N:44]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:30][N:29]=3)[CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)=[O:16])[N:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:5]=2[C@H:4]2[CH2:55][C@@H:3]12.O.NN>C(O)C>[NH2:44][C:31]1[CH:32]=[C:33]([C:34]2[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=2)[C:39]([NH2:41])=[O:40])[C:28]([C@@H:18]([NH:17][C:15](=[O:16])[CH2:14][N:7]2[C:6]3[C:2]([F:56])([F:1])[C@@H:3]4[CH2:55][C@@H:4]4[C:5]=3[C:9]([C:10]([F:11])([F:12])[F:13])=[N:8]2)[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)=[N:29][CH:30]=1
Reactant: NC(=O)c1cc(-c2cc(N3C(=O)c4ccccc4C3=O)cnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)ccc1F
Agent: NN
Solvent: CCO
Solvent: O
Product: NC(=O)c1cc(-c2cc(N)cnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 30K (13 mg, 0.017 mmol) was dissolved in 1 ml of ethanol; 0.01 ml of hydrazine monohydrate was added and stirred at room temperature for 2 hours. The solvent was removed and the residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title compound. 1H NMR (400 MHz, CD3OD) δ 8.07 (d, 1H), 7.38 (m, 2H), 7.28-7.07 (m, 2H), 6.71 (t, 1H), 6.35 (m, 2H), 5.14 (m, 1H), 4.90 (s, 2H), 3.13 (m, 1H), 3.01-2.91 (m, 1H), 2.48 (m, 2H), 1.40 (m, 1H), 1.09 (m, 1H). MS (m/z) 650.94 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH3:24])=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]=2)=[CH:7][C:6]=1[F:29].[OH-].[Na+].C(O)C.O>C(#N)C>[C:19]([C:17]1[CH:18]=[C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[C:6]([F:29])[CH:7]=2)[CH:14]=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:16]=1[O:23][CH3:24])([CH3:20])([CH3:21])[CH3:22]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: COc1c(C(C)(C)C)cc(C#Cc2ccc(CC(=O)O)c(F)c2)cc1C(C)(C)C

Procedure:
Following General Procedure I and using [4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-acetic acid methyl ester (Compound 144, 0.122 g, 0.29 mmol), 5M aqueous sodium hydroxide solution (1 mL) and ethanol (4 mL), followed preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a white solid (0.077 g, 65%).