Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH3:5])C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].O>ClCCl.CO>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:16]([C:18]3[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:17]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Reactant: CCOC(C)=NC(=O)c1ccc(Br)cc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2ccc(Br)cc2)n(-c2ccc(S(N)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 53 %

Procedure:
N-(1-ethoxy-ethylidene)-4-bromo-benzamide 565 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(4-bromo-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (437 mg, yield: 53%) was obtained as a solid phase.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3S(C3C=CC=CC=3)(=O)=O)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:48][CH2:47][N:46]5[CH2:49][CH2:50][CH2:51][C@H:45]5[CH2:44]4)=[N:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:11])=[O:10].[OH-].[Na+]>O1CCOCC1.CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:48][CH2:47][N:46]5[CH2:49][CH2:50][CH2:51][C@H:45]5[CH2:44]4)=[N:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:11])=[O:10]
Reactant: COc1ncc(-c2cc(-c3nnc(CN4CCN5CCC[C@H]5C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COc1ncc(-c2cc(-c3nnc(CN4CCN5CCC[C@H]5C4)o3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.5 %

Procedure:
2,4-Difluoro-N-[5-[4-{5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylmethyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]benzenesulfonamide (84 mg, 0.110 mmol) was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 0.110 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was dried down under a stream of nitrogen and the residue partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml). The organic layer was separated, dried by passing through a hydrophobic frit and the solvent removed in vacuo to give a brown gum. This was dissolved in DMSO (1 ml) and purified by high pH MDAP (Method E, extended run). The product-containing fraction was dried under a stream of nitrogen to give the title compound as a cream solid (2.4 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH:11][CH:12]([CH2:20][OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>O1CCOCC1>[OH:11][CH:12]([CH2:20][OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:16][CH2:15]1
Reactant: OCC(O)CN1CCNCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCN(CC(O)CO)CC2)nc1

Procedure:
Operation was carried out in a manner similar to the one previously described in Example 5, using 1.6 g of 6-chloronicotinic acid and 3.2 g of 1-(2,3-dihydroxypropyl)piperazine in 50 ml dioxane. Grams 1.95 of 6-[4-(2,3-dihydroxypropyl)piperazin-1-yl]nicotinic acid were obtained, which, recrystallized from hot water, melted at 244°-246° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].Br[CH2:12][CH2:13][C:14](O)=[O:15].Cl>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[O:8][CH2:12][CH2:13][C:14]2=[O:15]
Reactant: Oc1ccccc1F
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCOc2c(F)cccc21
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
A solution of 2-fluorophenol (Compound 1-1, 3.0 g) in N,N-dimethylformamide (7.0 ml) was added to a solution of 50% sodium hydride (3.22 g) in N,N-dimethylformamide (100 ml) in a nitrogen atmosphere with cooling in an ice bath. After stirring at the same temperature for 30 minutes, a solution of 3-bromo-propionic acid (4.91 g) in N,N-dimethylformamide (8.0 ml) was added. The mixture was returned to room temperature and stirred at the same temperature for 24 hours. The pH was adjusted to 1 to 2 with 1 N hydrochloric acid (100 ml) to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized by adding a mixed solvent of 20% ethyl acetate-hexane to obtain the title compound (1.53 g). (1-2) The title compound was synthesized by the following alternative method.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:14])C)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH-].[Na+].Cl[O-].[Na+].S(S([O-])=O)([O-])(=O)=[O:22].[Na+].[Na+]>O1CCOCC1>[CH3:15][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:22])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)CCOc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 1.0 g (4.9 mmol) of 4,4-dimethyl-6-acetyl chroman (Compound 38), 2.0 g (50 mmol) of NaOH, 60 ml of 10% aqueous sodium hypochlorite solution and 18 ml of dioxane was heated at 60° C. with stirring for 3 hours. The reaction mixture was cooled to room temperature and then treated with sodium metabisulphite until the mixture was negative to the potassium iodide/starch test. The reaction mixture was then acidified with conc. HC1 and the resultant precipitate was collected by filtration. The residue was washed with water and dried under vacuum to give the title compound as a white solid. PMR (CDCl3): & 1.25 (6H, s), 1.81-1.90 (2H, m), 4.22-4.30 (2H, m), 6.83 (1H, d, J~8.1 Hz), 7.84 (1H, dd, J~8.1 Hz, 1.8 Hz), 8.07 (1H, d, J~1.8 Hz). MS exact mass, m/e 206.0939 (calcd. for C12H14O3, 206.0943).
Reaction SMILES: [CH3:1][C:2]1([NH:18][C:19](=[O:21])[CH3:20])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:4][CH2:3]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][N:36]=2)=[N:32][C:31]=1[C:42](O)=[O:43])=O)(C)(C)C>>[C:19]([NH:18][C:2]1([CH3:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[NH:15][C:42]([C:31]2[N:32]=[C:33]([C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][N:36]=3)[S:34][C:30]=2[NH2:29])=[O:43])[CH2:4][CH2:3]1)(=[O:21])[CH3:20]
Reactant: CC(=O)NC1(C)CCCN(c2c([N+](=O)[O-])cnn2C)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ncccc2F)nc1C(=O)O
Product: CC(=O)NC1(C)CCCN(c2c(NC(=O)c3nc(-c4ncccc4F)sc3N)cnn2C)CC1
Yield: 29 %

Procedure:
Following the procedures in Example 378, starting from N-(4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide and 5-(tert-butoxycarbonylamino)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxylic acid gave 384 as an off-white foam (80 mg, 29% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.41 (d, J=4.3 Hz, 1H), 7.90 (s, 1H), 7.52 (t, J=9.7 Hz, 1H), 7.31 (dt, J=8.4, 4.3 Hz, 1H), 6.32 (s, 2H), 5.75 (s, 1H), 3.74 (s, 3H), 3.33-3.15 (m, 4H), 2.38-2.21 (m, 2H), 2.02-1.84 (m, 4H), 1.82-1.74 (m, 3H), 1.51 (s, 3H). LCMS (ES+) m/z 487 (M+1)
Reaction SMILES: C([N:8]1[C:12]([CH2:13][CH:14]2[C:20](=[O:21])[N:19]([CH2:22][C:23]([N:25]([CH:34]([CH3:36])[CH3:35])[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[O:24])[C:18]3[CH:37]=[CH:38][CH:39]=[CH:40][C:17]=3[N:16]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:15]2=[O:47])=[CH:11][C:10]([CH3:48])=[N:9]1)C1C=CC=CC=1>C(O)=O.C(O)C.[Pd]>[CH:34]([N:25]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:23](=[O:24])[CH2:22][N:19]1[C:20](=[O:21])[CH:14]([CH2:13][C:12]2[NH:8][N:9]=[C:10]([CH3:48])[CH:11]=2)[C:15](=[O:47])[N:16]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:17]2[CH:40]=[CH:39][CH:38]=[CH:37][C:18]1=2)([CH3:35])[CH3:36]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cc(C)nn3Cc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cc(C)n[nH]3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
To a stirring solution of 194 mg (0.30 mmol) of 2-[3-(2-Benzyl-5-methyl-2H-pyrazol-3ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Example 54, in 10 mL of 5% formic acid (v/v) in absolute ethanol is added 190 mg of 10% palladium on carbon. The resulting mixture is heated to reflux for 2 h, then cooled to RT and filtered through a pad of Celite to remove the catalyst. The filtrate is concentrated, then poured into 50 mL of EtOAc and washed successively with 1N NaOH (1×50 mL) and H2O (1×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel MPLC using EtOAc/chloroform 8/1 as eluent afforded 112 mg of the title compound as a white solid: mp 156°-159° C.; 1H NMR (CDCl3, 400 MHz) δ7.38-7.18 (m, 9H), 7.14 (d, 1H, J=8.7), 7.06 (t, 1H, J=7.3), 6.96 (m, 2H), 6.86 (d, 1H, J=7.6), 5.81 (s, 1H), 5.02 (m, 1H), 4.18 (dd, 2H, J=16.5, 86.1), 3.83 (s, 3H), 3.59 (t, 1H, J=6.8), 3.32 (ddd, 2H, J=7.5, 15.2, 34.3), 2.19 (s, 3H), 1.08 (m, 6H); low resolution MS (FAB)m/e 552 (MH+), 551 (M+), 387; Anal. (C32H33N5O4) Calcd. C, 69.67; H, 6.03; N, 12.70 Found C, 69.61; H, 6.11; N, 12.44.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:17](O)[CH2:18][OH:19]>O>[OH:19][CH2:18][CH2:17][O:12][C:11](=[O:13])[CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:16][CH:15]=1)[CH3:14]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: OCCO
Agent: Cl
Solvent: O
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCO
Yield: 56.8 %

Procedure:
Dry HCl gas was passed through a mixture of 2-(4-nitrophenoxy)-propionic acid 29 (45 g, 213 mol) and ethylene glycol (135 ml) for 1½ hours. During HCl gas bubbling the temperature rose to 60° C. The crude reaction mass was poured onto cold water (600 ml). Crude 30 was extracted into chloroform, dried over Na2SO4, distilled and purified by column chromatography on silica gel using hexane as eluant to give pure 30 (28 g, 56.8%) as a syrup.
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1)[NH2:2].[CH3:13][C:14](OC(C)=O)=[O:15]>O1CCOCC1>[CH3:9][C:8]1[C:3]([NH:1][NH:2][C:14](=[O:15])[CH3:13])=[N:4][CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1NN
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)NNc1ncc([N+](=O)[O-])cc1C
Temperature: 25 °C
Yield: 100 %

Procedure:
To a suspension 2-hydrazinyl-3-methyl-5-nitropyridine (Step 67.1) (33.2 g, 198 mmol) in dioxane (175 mL) was added Ac2O (20.5 mL, 217 mmol) and the reaction was stirred at RT for min. The reaction mixture was poured onto ice-water and stirred for 1 hr at 0° C. The precipitate was collected by filtration, washed with H2O and Et2O, and dried under reduced pressure at 50° C. to afford the title product (41.5 g, 198 mmol, 99.5% yield) as light beige solid. tR: 0.45 min (LC-MS 2); ESI-MS: 211 [M+H]+; ESI-MS: 209 [M−H]− (LC-MS 2).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.CCN(CC)CC.[CH:20]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21]1>CCO>[CH:20]1([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[O:3][C:4]4[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=4[N:6]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21]1
Reactant: N#Cc1ccc2oc(Cl)nc2c1
Reactant: C1CN(C2CC2)CCN1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Yield: 52.6 %

Procedure:
To a solution of 2-chlorobenzooxazole-5-carbonitrile (1.69 g, 9.5 mmol) in EtOH (34 mL) was added Et3N (4.8 g, 47.5 mmol), followed by 1-cyclopropylpiperazine (1.44 g, 11.4 mmol) and the mixture was heated at reflux for 12 h. Then the volatiles were evaporated to remove EtOH and water (120 mL) was added. The mixture was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (elute: 10% ethyl acetate in petroleum ether, 0.1% NH4OH added) to give 1.34 g (53%) of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carbonitrile.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:24][O:25]C1CCCCO1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([NH:21][CH:22]=O)[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.B#B.O.Cl>O1CCCC1>[NH2:8][CH:9]([CH2:24][OH:25])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([NH:21][CH3:22])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(COc1noc2ccc(NC=O)cc12)COC1CCCCO1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc2onc(OCC(N)CO)c2c1

Procedure:
3-[2-tert-Butoxycarbonylamino-3-(2,3,4,5-tetrahydropyranyloxy)propoxy]-5-formylamino-1,2-benzoisoxazole is dissolved in 9 ml of tetrahydrofuran, and at 5°-10° C., 3.2 ml of a tetrahydrofuran solution (1M) of diborane is added, after which they are subjected to reaction at 20°-25° C. for one hour. Subsequently, 9 ml of water is added and the pH is adjusted to 0 with 6N hydrochloric acid, after which they are subjected to reaction at 20°-25° C. for one hour. The reaction mixture is concentrated under reduced pressure, ethyl acetate is added, and, after shaking, the aqueous layer is separated. Ethyl acetate is added again to the separated aqueous layer and the pH is adjusted to 11 with potassium carbonate, after which the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure, to obtain 0.22 g of brown, oily 3-(2-amino-3-hydroxypropoxy)-5-methylamino-1,2-benzoisoxazole.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[O:28]=[C:29]1[N:36]2[C@H:31]([CH2:32][O:33][C:34]([CH:49]3[CH2:53][CH2:52][CH2:51][O:50]3)=[C:35]2[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[O:38])[C@@H:30]1[NH:54]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([NH:54][C@@H:30]2[C:29](=[O:28])[N:36]3[C@@H:31]2[CH2:32][O:33][C:34]([CH:49]2[CH2:53][CH2:52][CH2:51][O:50]2)=[C:35]3[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)=[O:38])=[O:10])[N:6]=1
Reactant: COc1ccc(COC(=O)C2=C(C3CCCO3)OC[C@@H]3[C@H](NC(c4ccccc4)(c4ccccc4)c4ccccc4)C(=O)N23)cc1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(C3CCCO3)OC[C@H]12)c1csc(N)n1
Reaction time: 0.5 h

Procedure:
A stirred mixture of 2-(Z)-methoxyimino-2-(2-aminothiazol-4-yl)acetic acid (III) (54 mg) and N,N-diisopropylethylamine (0.047 ml) in dimethylformamide (0.3 ml) was cooled to -55° to -60° C. and methanesulphonyl chloride (0.021 ml) was added. The mixture was stirred at the same temperature for 0.5 h and then a solution of 4-methoxybenzyl (6S,7S)-7-amino-8-oxo-3-(tetrahydrofuran-2-yl)-1-aza-4-oxabicyclo[4.2.0]oct-2-ene-2-carboxylate (II) (91 mg) in dimethylformamide (1 ml) was added, followed by p-ndine (0.022 ml). The mixture was then stirred at 0° C. for 1 h and then at room temperature for 0.5 h. The mixture was partitioned between ethyl acetate and aqueous citric acid solution and the organic phase was washed twice with water, then brine, dried over magnesium sulphate and evaporated. Column chromatography (silica gel, ethyl acetate as eluent) gave the title compound (88 mg. νmax (CHCl3) 1769, 1709, 1679 and 1613 cm-1 ; δ(CDCl3) 1.72-2.12 (4H, m), 3.35 (3H, s), 3.68-3.96 (4H, m), 3.76 (3H, s), 4.64 (1H, dd, J 9.19 and 15.89 Hz), 5.13 (3H, s), 5.20 (1H, t, J 6.77 Hz), 5.72 (1H, dd, J 4.14 and 8.91 Hz), 6.80 (1H, s), 6.93 (2H, d, J 8.68 Hz), 7.24 (2H, s), 7.37 (2H, d, J 8.66 Hz), 9.23 (1H, d, J 9 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)(=[O:17])=[O:16].B(Br)(Br)[Br:25].CCOC(C)=O.C([O-])(O)=O.[Na+]>ClCCl>[Br:25][CH2:20][CH2:19][N:18]([CH2:23][CH2:22][OH:21])[S:15]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=2)[NH:8][C:7]=1[C:12]([NH2:14])=[O:13])(=[O:17])=[O:16]
Reactant: COc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reactant: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N(CCO)CCBr
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5-methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (416 mg, 1.23 mmol) in 15 mL of dichloromethane at −78° C. was added boron tribromide solution (1 M in dichloromethane, 6.13 mmol). After 10 minutes the mixture was allowed to warm to room temperature, and stir for an additional 60 hours. The reaction was poured into a mixture of EtOAc and saturated aqueous NaHCO3 solution. The organic phase was washed with water and brine, dried with Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography through silica gel (3-10% MeOH/dichloromethane) provide the titled product, along with 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C13H17BrN3O5S (M+H+): 406.0067. Found 406.0081.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][C:9]1([CH3:14])OCC[O:10]1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>CC(C)=O.O>[OH:1][C@H:2]([CH2:8][C:9](=[O:10])[CH3:14])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C[C@H](O)CC1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C[C@H](O)CC(C)=O
Temperature: 60 °C
Yield: 84.9 %

Procedure:
To a solution of Methyl(3R)-3-hydroxy-4-(2-methyl-1,3-dioxolan-2-yl)butanoate (3) (5 g, 24.5 mmol) (as prepared in Experiment 15) in a mixture of acetone/water (2:1, 30 mL), pyridiniumtosylate (1.84 g, 7.34 mmol) was added and the reaction mixture was refluxed (60° C.) for 1-2 hours. After removing the solvent under vacuum, a 10% NaHCO3 solution was added and extracted with dichloromethane (3×30 mL). The combined organic phases was evaporated under reduced pressure to give methyl(3R)-3-hydroxy-5-oxohexanoate (6) as an oil (3.33 g, 85%).
Reaction SMILES: C[O-].[Na+].[C:4](OC(C)(C)C)(=O)C.C(O[C:15]([C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][O:23][C:20]2=[CH:21][N:22]=1)=[O:16])C.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[C:15]([C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][O:23][C:20]2=[CH:21][N:22]=1)(=[O:16])[CH3:4]
Reactant: CCOC(=O)c1cc2ccoc2cn1
Reactant: CC(=O)OC(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)c1cc2ccoc2cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
As 405 mg (7.5 mmol) of sodium methoxide was stirred in 5 mL of toluene, 1.16 g (10.0 mmol) of tert-butyl acetate was added dropewise at room temperature to the solution. Then, 956 mg (5.0 mmol) of 5-ethoxycarbonylfuro[2,3-c]pyridine dissolved in 5 mL of toluene was added dropwise at room temperature to the above solution. After all the solution had been added, the reaction mixture was heated to 60° C., a reaction was carried out for 3 hours. The resulting reaction mixture was then neutralized with 450 mg (7.5 mmol) of acetic acid, the solution was stirred for 30 minutes, 1.5 mL (7.5 mmol) of 5 N hydrochloric acid was then added, and the solution was stirred for 5 hours at 60° C. to carry out a reaction. The solution was then returned to room temperature, the organic layer was separated, the aqueous layer was extracted twice with 5 mL of methylene chloride, and the combined organic layer was dried with anhydrous magnesium sulfate and then concentrated in a rotary evaporator. The resulting solids were recrystallized from a mixed solvent of toluene-hexane, giving 580 mg (72% yield) of 5-acetylfuro[2,3-c]pyridine in a purity of 99% by HPLC.
Reaction SMILES: Cl.C([NH:9][C@@H:10]([C@@H:44]1[C@H:48]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[O:47]C(C)(C)[O:45]1)[CH2:11][O:12][C@H:13]1[C@H:19]([O:20]CC2C=CC=CC=2)[C@@H:18]([O:28]CC2C=CC=CC=2)[C@@H:17]([O:36]CC2C=CC=CC=2)[CH:16]=[CH:15][CH2:14]1)C1C=CC=CC=1.C1CCCCC=1>CO.C(Cl)(Cl)Cl.[Pd]>[NH2:9][C@@H:10]([C@@H:44]([OH:45])[C@@H:48]([OH:47])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:11][O:12][C@@H:13]1[CH2:14][CH2:15][CH2:16][C@H:17]([OH:36])[C@H:18]([OH:28])[C@H:19]1[OH:20]
Reactant: CCCCCCCCCCCCCC[C@@H]1OC(C)(C)O[C@@H]1[C@@H](CO[C@@H]1CC=C[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC[C@H](O)[C@H](O)[C@H](N)CO[C@@H]1CCC[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1M solution of HCl (150 μL, 0.15 mmol) and Pd—C (10% wt, 32 mg, 0.03 mmol) were added to a solution of ether 71 (130 mg, 0.15 mmol) and cyclohexene (2 mL) in MeOH (10 mL) and heated under reflux. After stirring overnight the reaction mixture was cooled to rt and diluted with a 5:1 solution of CHCl3:MeOH, before being filtered thought a bed of celite. The filtrate was concentrated under reduced pressure to provide the crude amine 72, which was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[CH2:3][NH:4][C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]#[C:17][Si](C)(C)C)[CH:13]=2)[N:8]1[C:22](=[O:34])[C@@H:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH3:25])=[O:6].C(=O)([O-])[O-].[K+].[K+]>CO>[F:36][C:2]([F:1])([F:35])[CH2:3][NH:4][C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]#[CH:17])[CH:13]=2)[N:8]1[C:22](=[O:34])[C@@H:23]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:24][CH3:25])=[O:6]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(C#C[Si](C)(C)C)cc2CC1C(=O)NCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)CC(C(=O)NCC(F)(F)F)N2C(=O)[C@H](CC)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the solution of 1-[N-t-butoxycarbonyl-2(S)-aminobutyryl]-5-(trimethylsilyl)ethynylindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide (0.43 g, 0.81 mmol) in anhydrous methanol (7ml), potassium carbonate (0.02 g) was added under an atmosphere of nitrogen and stirred at room temperature for several hours. The solvent was evaporated in vacuo.