Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[C:33]1([CH2:32][CH2:31][CH2:30][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrCCCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCc3ccccc3)CC1)O2
Temperature: 70 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a solution of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.566 g, 1.88 mmol) in acetonitrile (30 mL) was added triethylamine (0.80 mL, 5.64 mmol) followed by (3-bromopropyl)benzene (0.747 g, 3.76 mmol). The reaction was stirred at 70° C. for 3 hours. The solvent was then evaporated under reduced pressure. The residue was dissolved in dichloromethane (30 mL) and the organic layer was washed with water (30 mL). The organic extract was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatorgraphy (SiO2, 8% CH3OH in dichloromethane). The product obtained after the chromatography was further purified by crystallization from hexanes and dichloromethane to give the desired product as a purple solid (0.405 g, 51%). M.p.=112-114° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (d, J=7.6 Hz, 1H), 7.78 (d, J=3.2 Hz, 2H), 7.58-7.54 (m, 1H), 7.29-7.22 (m, 2H), 7.21-7.14 (m, 3H), 3.07 (s, 2H), 2.74 (m, 2H), 2.60 (t, J=7.6 Hz 2H), 2.37-2.27 (m, 4H), 2.05-1-97 (m, 2H), 1.85-1.71 (m, 4H); LCMS: 420 [M+H]; Calc. for C25H25NO3S: C 71.51, H 6.005, N 3.338; Found C 72.08, H 5.35, N 3.43.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]([C:15]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH:16]1[CH2:18][CH:19]=O)=[O:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:11][O:12][C:13]([C:15]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH:16]1[CH2:18][CH:19]=[CH2:1])=[O:14]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CC=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1CC1(NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (4.6 mmol) was suspended in THF (10 mL) at room temperature. NaHMDS (1.0 M in THF, 4.1 mmol) was added dropwise at room temperature to produce a dark yellow turbid solution which was allowed to stir for 30 min. A THF (6 mL) solution of 1-tert-butoxycarbonylamino-2-(2-oxo-ethyl)-cyclopropanecarboxylic acid methyl ester was added dropwise to the ylide solution and allowed to age at room temperature for 30 min. The reaction was partitioned between EtOAc and saturated NH4Cl. The aqueous layer was extracted with EtOAc (3×10 mL) and the combined organics washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by column chromatography on SiO2 (0→10% EtOAc/hex) afforded 2-allyl-1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid methyl ester as a colorless film (0.070 g, 15%). (1H-NMR (300 MHz, CDCl3): δ 5.90-5.72 (m, 1H); 5.14 (br s, 1H); 5.08-4.94 (m, 2H); 3.71 (s, 3H); 2.34 (m, 2H); 1.55 (m, 2H); 1.45 (s, 9H), 1.37 (m, 1H)).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:21]COC)=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:18])/[C:15]([OH:17])=[O:16])[CH3:2].Cl.O>CC(C)=O>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:18])/[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(OCOC)c12
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
23 g of (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoic acid was dissolved in 230 ml of acetone and 15 ml of concentrated hydrochloric acid was added slowly at room temperature. After stirring at room temperature for 1.5 hours, the reaction mixture was gradually poured into 3.5 liters of water. The resultant crystals were filtered, washed with water and dried to obtain 19 g of the titled compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([CH2:14][NH:15][CH2:16][CH2:17][C@@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1.[Si:36]([O:43][CH2:44][CH2:45][CH:46]=O)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:43][CH2:44][CH2:45][CH2:46][N:15]([CH2:14][CH:12]1[C:11]2=[C:10]3[C:5](=[CH:4][CH:3]=[C:2]2[F:1])[CH:6]=[CH:7][C:8](=[O:35])[N:9]3[CH2:13]1)[CH2:16][CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C1CSc2ccc(N3C[C@H](CCNCC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Product: CC(C)(C)[Si](C)(C)OCCCN(CC[C@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1)CC1Cn2c(=O)ccc3ccc(F)c1c32
Yield: 87 %

Procedure:
Starting from the compound of Example 4 and 3-(tert-butyldimethylsilyloxy)-propionaldehyde and using procedure E, the title compound was obtained as a yellow foam (82 mg; 87% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]([OH:12])[CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].CO[C:22](OC)([CH3:24])[CH3:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[C@@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH:10]=[CH2:11])[O:12][C:22]1([CH3:24])[CH3:23])=[O:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(C)(C)OC
Reactant: C=C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: C=C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 82.5 °C
Reaction time: 3 h

Procedure:
(1S,2S)-(2-hydroxy-1-phenyl-but-3-enyl)carbamic acid t-butyl ester is dissolved in an aromatic solvent. 2,2-Dimethoxypropane is added at a temperature in the range of about 20-40° C. followed by addition of pyridinium p-toluene sulfonate. The reaction mixture is heated to about 70-95° C. and stirred at the same temperature for about 1-5 hours. The reaction mixture is cooled to about 30 to 45° C., neutralized with pyridine, and concentrated under reduced pressure to get (4S,5R)-2,2-dimethyl-4-phenyl-5-vinyl-oxazolidine-3-carboxylic acid t-butyl ester in a semi solid form, which is optionally further purified by column chromatography, such as using petroleum ether and ethyl acetate as solvents.
Reaction SMILES: [O:1]1[C:19]2[C:4](=[CH:5][C:6]3[CH:11]([CH2:12][C:13]([O:15]CC)=[O:14])[O:10][CH2:9][CH2:8][C:7]=3[CH:18]=2)[O:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[O:1]1[C:19]2[C:4](=[CH:5][C:6]3[CH:11]([CH2:12][C:13]([OH:15])=[O:14])[O:10][CH2:9][CH2:8][C:7]=3[CH:18]=2)[O:3][CH2:2]1
Reactant: CCOC(=O)CC1OCCc2cc3c(cc21)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC1OCCc2cc3c(cc21)OCO3
Temperature: 60 °C
Yield: 96.1 %

Procedure:
0.78 g of ethyl (7,8-dihydro-5H-1,3-dioxolo[4,5-g]-[2]benzopyran-5-yl)acetate was dissolved in 20 ml of ethanol. A solution of 0.35 g of sodium hydroxide in 4 ml of water was added thereto and the mixture was stirred under heating at 60° C. The solvent was distilled off and water was added to the residue. The mixture was washed with ethyl acetate and acidified with 1N hydrochloric acid. After extraction with chloroform, the extract was washed with a saturated aqueous common salt solution an dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was subjected to silica gel column chromatography (chloroform) to obtain 0.67 g of the intended compound in the form of colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NC(C)C)(C)C.[Si:29]([O:36][C:37]1[CH:42]=[C:41]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH:40]=[CH:39][C:38]=1[C@H:51]1[CH2:56][CH2:55][C@H:54](O)[CH2:53][CH2:52]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]([O:19][C@H:54]1[CH2:53][CH2:52][C@H:51]([C:38]2[CH:39]=[CH:40][C:41]([O:43][Si:44]([C:47]([CH3:49])([CH3:50])[CH3:48])([CH3:46])[CH3:45])=[CH:42][C:37]=2[O:36][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[CH2:56][CH2:55]1)=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O[C@H]1CC[C@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a round bottomed flask was added N-(tert-butoxycarbonyl)-L-phenylalanine (109 mg) and dichloromethane (10 ml). To the solution was added diisopropylcarbodiimide (64 μl), trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (150 mg) and 4-dimethyl aminopyridine (catalytic). The solution was stirred at room temperature for 15 hr. The reaction mixture was partitioned between water (20 ml) and dichloromethane (30 ml), the layers were separated and the aqueous phase was extracted with dichloromethane (2×30 ml). The combined organic phases were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether, 1:19 v/v) furnished the title compound (236 mg, 100%) as a yellow oil. δH (CDCl3): 0.18 (6H, s), 0.23 (6H, s), 0.97 (9H, s), 1.03 (9H, s), 1.35-1.47 (13H, m), 1.80-1.90 (2H, m), 1.95-2.07 (2H, m), 2.77-2.86 (1H, m), 3.05-3.12 (2H, m), 4.49-4.58 (1H, m), 4.73-4.82 (1H, m), 4.93-5.00 (1H, m), 6.28 (1H, d), 6.40 (1H, dd), 6.93 (1H, d), 7.15 (2H, d), 7.19-7.31 (3H, m).
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[OH-].[K+].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>O.O1CCOCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7]
Reactant: N[C@H](CCC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)O)C(=O)O

Procedure:
14.7 g (0.1 Mol) of H-D-Glu-OH was dissolved in 200 ml of distilled water, and the pH was adjusted to 10.2 with 0.1 M potassium hydroxide. 33.0 g (0.3 Mol) of BOC2O in dioxane was added with intensive mixing. The pH was controlled using a pH-stat. After completion of the reaction, the mixture was transferred to a separating funnel, and extraction was carried out from the alkaline solution with ethyl acetate (3×150 ml). The pH of the aqueous phase was adjusted to 3.0 using 0.2% sulphuric acid, and Boc-D-Glu-OH was extracted from the organic phase (3×200 ml). The organic phase was washed three times with 200 ml of Na2SO4 saturated solution to neutral pH, and dried over Na2SO4, and evaporated to oil under vacuum. The yield was 16.7 g (68%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:48][CH2:49][C:50]1[N:51]=[CH:52][N:53]([C:55]2[CH:60]=[CH:59][C:58]([N:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]3=[O:67])=[CH:57][CH:56]=2)[CH:54]=1>CN(C=O)C>[O:67]=[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][N:61]1[C:58]1[CH:59]=[CH:60][C:55]([N:53]2[CH:54]=[C:50]([CH2:49][NH:48][C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[O:12])[N:51]=[CH:52]2)=[CH:56][CH:57]=1
Reactant: NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1)c1ccc2[nH]ccc2c1
Reaction time: 0.08 h
Yield: 40.7 %

Procedure:
To a solution of indole-5-carboxylic acid (40 mg, 0.25 mmol) and triethylamine (0.150 mL, 1.08 mmol) in DMF (2 mL), BOP (135 mg, 0.30 mmol) was added. After 5 min of stirring, 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one hydrochloride (53 mg, 0.18 mmol) was added. The mixture was stirred at room temperature overnight. It was then purified by HPLC to give the titled compound (30 mg). MS 410.2 (M+H).
Reaction SMILES: Br[CH:2]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH:3](Br)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH3:23][O-:24].[Na+].[K+].[Br-]>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([CH:3]([O:24][CH3:23])[CH2:2][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C(c1ccc(Br)cc1)C(Br)C(Br)C(=O)c1ccc(Br)cc1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COC(CC(=O)c1ccc(Br)cc1)C(=O)c1ccc(Br)cc1

Procedure:
To a solution of 1,2-dibromo-1,2-di(4-bromobenzoyl) ethane (11.1 g, 0.02 mole) in 150 mL dry methanol was added a solution of sodium methoxide in methanol (0.92 g sodium in 50 mL methanol). The yellow brown mixture was refluxed for 1-1.5 hr. The solvent was removed by distillation, the residue was suspended in water and the mixture was extracted with 100 mL chloroform. The chloroform extract was washed with water, dried (Na2SO4) and concentrated. The residue obtained was titrated with dry methanol-ether (3:1) to yield off-white crystalline solid, 6.6 g (78%), mp 153°-154° C. IR (KBr): 3106, 3062, 2932, 1689, 1649, 1583, 1556, 1403, 1223, 1202, 1182, 1086, 1010, 1000, 857, 814, 738, 618, 472 cm-1. 1H (DMSO-d6 /40° C.): 7.95 (d, 2H, J=7.8), 7.77 (4H, J=8.8), 7.72 (d, 2H, J=7.8), 6.89 (s, 1H), 4.03 (s, 3H). 13C (DMSO-d6 /40° C.): 189.9, 187.2, 168.8, 139.9, 135.9, 133.1, 132.2, 131.8, 130.3, 128.1, 127.4, 98.6, 58.5. MS m/e 424 (M+).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:28]=1[CH:29]=[CH:30][C:31]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:32]
Reactant: O=C(O)C=Cc1cc(F)ccc1F
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1cc(F)ccc1F
Yield: 97.8 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (2.0 g), triethylamine (1.1 mL), 2,5-difluorocinnamic acid (1.5 g), WSC.HCl (1.6 g), and methylene chloride (80 mL), to give the captioned compound (2.9 g, 98%) as an oily product.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12](=[O:35])[C@H:13]([CH2:31][CH2:32][S:33][CH3:34])[NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>CN(C=O)C>[CH3:10][O:11][C:12](=[O:35])[C@H:13]([CH2:31][CH2:32][S:33][CH3:34])[NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:18][C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CBr)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
To a 0° C. suspension in DMF (2 mL) of sodium hydride (90% in mineral oil, 38 mg, 0.95 mmol) was added a solution of 3-hydroxypyridine (95 mg, 1.0 mmol) in DMF (2 mL) dropwise and the mixture was stirred for 0.5 hours. A solution of (4-bromomethyl-2-phenylbenzoyl)methionine methyl ester (218 mg, 0.5 mmol) in DMF (1 mL) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was poured into aqueous 2N sodium hydroxide and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were dried, filtered and concentrated in vacuo. Chromatography on silica gel (60% ethyl acetate-hexanes, then ethyl acetate) gave [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]methionine methyl ester (58 mg). 1H NMR (300 MHz, DMSO-d6) δ 12.66 (bs, 1H), 8.58 (d, 1H), 8.38 (d, 1H), 8.17 (dd, 1H), 7.30-7.56 (m, 10H), 5.29 (s, 2H), 4.29 (ddd, 1H), 2.23 (m, 2H), 1.98 (s, 3H), 1.84 (m, 2H). MS (CI NH3) m/e 454 (M+NH4)+, 437 (M+H)+. Anal calcd for C24H24N2O4S (+0.41 H2O): C, 64.94; H, 5.64; N, 6.31. Found: C, 64.94; H, 5.35; N,S 6.14.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[O:11][C@H:7]([S:8][CH2:9][CH3:10])[C@H:6]1[N:27]=[N+:28]=[N-:29])(=[O:3])[CH3:2]>C1COCC1>[C:1]([O:4][C@H:5]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([CH2:18][OH:19])[O:11][C@H:7]([S:8][CH2:9][CH3:10])[C@H:6]1[N:27]=[N+:28]=[N-:29])(=[O:3])[CH3:2]
Reactant: CCS[C@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Solvent: C1CCOC1
Product: CCS[C@H]1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To compound 23 (305 mg, 0.68 mmol) dissolved in THF (6 mL), TREAT-HF (0.55 ml, 3.38 mmol) was added. The mixture was stirred at rt overnight. Concentration and chromatography (10:1→0:1 toluene-EtOAc) gave 35 (171 mg, 0.51 mmol, 75%); 13C NMR δ 14.7 (SCH2CH3), 20.6, 20.8 (CH3CO), 25.4 (SCH2CH3), 61.3, 63.0, 66.6, 71.1, 71.3 (C-2-6), 82.2 (C-1), 170.0, 170.6 (CH3CO); 1H NMR δ 1.26-1.30 (t, 3H), 2.05 (s, 3H), 2.08 (s, 3H), 2.32 (s, 1H), 2.56-2.68 (m, 2H), 3.58-3.67 (m, 2H), 4.09-4.14 (m, 2H), 5.24-5.35 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]34[CH2:23][CH2:22][C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:20][CH2:21]3)[O:18][CH2:17]4)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.CCOC(C)=O.[H][H]>[OH-].[OH-].[Pd+2].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]34[CH2:21][CH2:20][C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:22][CH2:23]3)[O:18][CH2:17]4)=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc([N+](=O)[O-])cc4)cc3)(CC1)CO2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cc4)cc3)(CC1)CO2
Yield: 90 %

Procedure:
To a round bottom flask containing methyl 2-(4-(4′-nitrobiphenyl-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (716 mg, 1.88 mmol) was added Pd(OH)2 on activated carbon (395 mg, 2.82 mmol). EtOAc (15 ml) and MeOH (3 ml) were added and the mixture was stirred under 1 atm. of hydrogen at room temperature for 2 hours. The resulting mixture was filtered through a pad of celite and concentrated to afford a crude residue. Column purification affords the title compound as off-white solid after drying (595 mg, 90% yield). LC/MS, ESI-MS(+): 352.3, RT: 1.29 (Condition E).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CC(C)([O-])C.[K+].Cl[CH2:19][CH2:20][CH2:21][OH:22].O>CS(C)=O>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:19][CH2:20][CH2:21][OH:22])[CH:7]=[CH:8][CH:9]=1
Reactant: OCCCCl
Reactant: Oc1cccc2cccnc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: OCCCOc1cccc2cccnc12
Temperature: 70 °C

Procedure:
A solution of 8-hydroxyquinoline (36.0 g, 0.25 mole) and potassium tertbutoxide (28.0 g, 0.25 mole) in 80 ml of dimethyl sulfoxide was stirred for 1 hr at room temperature. 3-Chloro-1-propanol (242.0 g, 0.25 mole) was added and the solution was heated overnight at 70° C. The solution was poured into 500 ml of water. A brown solid/mass was obtained. The solid was washed with several portions of water and then triturated with acetone. The solid was filtered and dried in vacuo at 80° C. overnight to give 35.67 g (70.3%) of light brown solid, m.p. 126°-127° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][C@@H:15]3[C@@H:17]([NH2:20])[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40])([O-:32])=[O:31]>ClCCl>[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH:20][C@@H:17]1[C@@H:15]2[C@@H:14]([CH2:13][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:16]2)[CH2:19][CH2:18]1)(=[O:41])=[O:40])([O-:32])=[O:31]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3aR,4S,6aS)-2-(4-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (300 mg, 0.897 mmol) from Step A of Example 256 and triethylamine (0.313 mL, 2.243 mmol) were combined in dichloromethane (20 mL). 2-Nitrobenzene-1-sulfonyl chloride (258 mg, 1.166 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water, and the organic layer was separated and concentrated. The resulted crude material was triturated with 50% diethyl ether/hexane, collected by filtration, washed with water then hexane to yield a solid. The crude solid was purified using a 12 g silica gel cartridge with a gradient of 10-100% ethyl acetate/hexane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.69 (s, 1H), 8.31 (dd, J=6.0, 3.3, 1H), 8.12 (d, J=8.2, 2H), 7.92 (dd, J=8.6, 2.1, 3H), 7.67 (dd, J=5.9, 3.3, 2H), 4.94 (s, 2H), 3.84 (dd, J=15.0, 6.2, 1H), 3.58 (dd, J=10.0, 2.4, 1H), 3.17 (dd, J=9.7, 2.7, 1H), 2.94 (dd, J=10.0, 7.7, 1H), 2.87 (dd, J=9.6, 7.7, 1H), 2.71 (td, J=9.3, 2.4, 1H), 2.60-2.50 (m, 1H), 1.94-1.80 (m, 2H), 1.71-1.58 (m, 1H), 1.23 (tt, J=10.5, 6.5, 1H); MS (ESI+) m/z 518 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+].CO>O>[NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1scc(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1csc(C(=O)O)c1N
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To a solution of methyl 3-amino-4-methyl-2-thiophene carboxylate (5 g, 29 mmol) and sodium hydroxide (3.5 g, 88 mmol) in a mixed solution (methanol:H2O/30 ml:120 ml) was heated at 50° C. for over night. The solution was cooled to room temperature and extracted with methylene chloride. The aqueous phase was acidified with 6N HCl until pH equal to 5. The aqueous phase was extracted again with ethyl acetate, and solvent phase washed with brine and dried over by sodium sulfate. After filtered and dried over the solvent, evaporated solvent to give 3.85 g of 3-amino-4-methyl-thiophene-2-carboxylic acid as a white solid in 84% yield: 1H NMR (300 MHz, CDCl3) δ 7.05 (d, 1H), 3.12 (br, 2H), 2.16 (s, 3H); MS (m/e): 157.9 (M+1).