Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]1([CH2:36][O:37][C:38](=[O:49])[C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([N+:46]([O-:48])=[O:47])[CH:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C)C=O>[C:30]1([CH2:36][O:37][C:38](=[O:49])[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:9]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:41]([N+:46]([O-:48])=[O:47])[CH:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)c([N+](=O)[O-])c1
Yield: 81.6 %

Procedure:
A mixture of 5.8 g (0.013 mol) of 1-(6-bromohexyl)-2,3-bis(phenylmethoxy)benzene, 3.5 g (0.013 mol) of 4-hydroxy-3-nitrobenzoic acid phenylmethyl ester, 3.5 g (0.026 mol) of potassium carbonate and 2.9 g (0.019 mol) of sodium iodide in 125 mL of acetone and 13 mL of dimethylformamide was stirred and heated at reflux for 5 days. Workup as described in Example 16 and purification by HPLC using 50% methylene chloride-hexane gave 6.85 g (83% yield) of 3-nitro-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid phenylmethyl ester as an oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:27])[N:10]2[CH2:28][CH2:29][CH2:30][CH:9]2[CH:8]1[O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)=[O:6])[CH:2]=[CH2:3].CCN=C=NCCCN(C)C.Cl.[NH2:50][C:51]1[CH:52]=[C:53]([C:57]([O:59]C)=[O:58])[N:54]([CH3:56])[CH:55]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:21][CH2:22][CH2:23][C:24]([NH:50][C:51]3[CH:52]=[C:53]([C:57]([OH:59])=[O:58])[N:54]([CH3:56])[CH:55]=3)=[O:25])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:27])[N:10]2[CH2:28][CH2:29][CH2:30][C@H:9]2[C@@H:8]1[O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)=[O:6])[CH:2]=[CH2:3]
Reactant: COC(=O)c1cc(N)cn1C
Reactant: C=CCOC(=O)N1c2cc(OCCCC(=O)O)c(OC)cc2C(=O)N2CCCC2C1OC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1c2cc(OCCCC(=O)Nc3cc(C(=O)O)n(C)c3)c(OC)cc2C(=O)N2CCC[C@H]2[C@@H]1OC1CCCCO1
Reaction time: 6 h

Procedure:
A solution of Alloc-THP protected PBD acid 13 (1.85 g, 3.57 mmol, 1.2 equivalent) was dissolved in DMF. EDCl (1.24 g, 6.48 mmol, 2.0 eq) and DMAP (0.99 g, 8.1 mmol, 2.5 eq) were added to the stirred solution of 13 at room temperature and the mixture was allowed to stir for 30 minutes after which methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate (0.5 g, 3.243 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for a further 6 hours at which point TLC showed completion of reaction. The reaction was quenched by pouring it onto a mixture of ice/water mixture and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were sequentially washed with citric acid (200 mL), saturated aqueous NaHCO3 (250 mL), water (250 mL), brine (250 mL) and finally dried over MgSO4. Excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product (1.88 gm) was used for hydrolysis reaction to afford 14a. For hydrolysis, Lithium hydroxide (0.24 g, 5.71 mmol, 3 eq) was added to the crude product (1.88 g, 2.87 mmol) in aqueous dioxane (75 ml dioxane, 11.5 ml water) at room temperature. The reaction mixture was stirred for 3 hours at which point TLC showed completion of reaction. Dioxane was evaporated under high vacuum and the residue was diluted with water. The resulting solution was acidified with 1 M citric acid followed by extraction with ethyl acetate (2×100 mL). The organic layer combined and washed with brine (100 mL), dried over MgSO4 and finally concentrated using a rotary evaporator under reduced pressure to obtain 14a as a white solid (yield, 1.68 gm, 74.0% over 2 steps). 1H-NMR δ 9.09 (1H, s, NH), 7.39 (1H, d, J=2.0 Hz), 7.14 (1H, s, H-6), 7.12 (1H, s, H-6), 6.96 (1H, s, H-9), 6.76 (1H, d, J=2.0 Hz, Py-H), 5.86-5.75 (2H, m, H-11), 5.13-4.84 (3H, m), 4.61-4.21 (2H, m), 4.06-3.88 (3H, m, side-chain H-1, pyran H-6), 3.87 (3H, s, O/NCH3), 3.87 (3H, s, O/NCH3), 3.86 (3H, s), 3.53-3.44 (3H, m), 2.55-2.45 (2H, m), 2.13-1.88 (6H, m), 1.70-1.39 (6H). m/z (+EI) calc. for C32H40N4O10 (M)+ 640.68. found 641.57 ([M+H]+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH2:9](Cl)[C:10]#[CH:11]>CS(C)=O>[CH2:11]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[C:10]#[CH:9]
Reactant: C#CCCl
Reactant: Oc1ccc(O)cc1
Solvent: CS(C)=O
Product: C#CCOc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
Hydroquinone (75.0 grams, 0.681 moles) is dissolved in 395 milliliters dimethylsulfoxide. The flask is purged with nitrogen, and aqueous sodium hydroxide (275 milliliters of a 5N solution, 1.375 moles) and water (210 milliliters) are added. Propargyl chloride (50.0 milliliters, 51.5 grams, 0.691 moles) is then added and the solution is stirred at room temperature overnight. The aqueous solution is washed twice with toluene, and then is acidified with 65 milliliters concentrated hydrochloric acid. The solution is extracted ten times with 100 milliliters toluene. The combined organic extracts are washed with 200 milliliters water and dried. Solvent is evaporated off and the crude product is distilled under vacuum. The boiling range of a fraction collected is between about 100° C. and about 109° C. at pressures between about 0.4 and 0.5 millimeters of mercury. The yield of monopropargyl ether is about 53 grams reflecting a yield of about 52 percent. Gas chromatography analysis shows no other products present.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][CH2:5][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH2:2][CH3:3]
Reactant: CCCOCc1ccccc1Oc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCc1ccccc1Oc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 65 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
Into a solution of methyl 7-(2-propoxymethylphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.37 g) in THF-methanol (10-5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (1.8 ml), and the resulting mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, 1 N hydrochloric acid (10 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-(2-propoxymethylphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (229 mg) as light yellow crystals.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][CH:10]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[F:11].C(P(C([Li])(F)F)(CC)=O)C.[C:30]1([CH2:36][O:37][C@@H:38]([C@@H:42]([C@@H:51]([CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)O)[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]([OH:41])=[O:40])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.C(O)(=O)C>[CH2:17]([O:16][P:12]([O:13][CH2:14][CH3:15])([C:10]([F:11])([F:9])[C:39]1([O:41][C@H:51]([CH2:53][O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C@@H:42]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:38]1[O:37][CH2:36][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[OH:40])=[O:19])[CH3:18]
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: O=C(O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]C(F)(F)P(=O)(CC)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
In accordance with M. Obayashi et al., Tetrahedron Letters, 2323-2326 (1982), to a solution of lithium diisopropylamide (prepared from 17.2 ml of 1.6M n-butyllithium in hexane and 2.78 g of diisopropylamine in 50 ml of tetrahydrofuran) at -78° C., was added a solution of 4.70 g of diethyl difluoromethylphosphonate in 10 ml of tetrahydrofuran during 10 minutes, thereby forming (diethylphosphinyl)difluoromethyllithium. After 15 minutes, a solution of 2,3,5-tris-O-(phenylmethyl)-D-arabinonic acid, gamma-lactone [Y. Rabinsohn & H. G. Fletcher, J. Org. Chem., 32, 3452-3457 minutes. The solution was stirred at -78° C. for 1 hour, warmed to -15° C. during 15 minutes, recooled to -78° C. and treated with 3 ml of glacial acetic acid. The mixture was partitioned with ether and water. The ether layer was washed with water, sodium bicarbonate solution and brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (heptane-ethyl acetate) giving the desired compound as an oil; CMR δ 100.7 (major anomer) and 104.0 (minor anomer); (multiplets, anomeric carbon atom).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10][CH:11](Br)[CH3:12].O>[OH-].[Na+]>[Br:10][CH2:11][CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CC(Br)Br
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccc(OCCBr)cc1
Temperature: 70 °C
Yield: 19 %

Procedure:
4-hydroxy benzaldehyde (700 mg, 5.7 mmol) and dibromoethane (1.2 ml, 0.46 mmol) were taken in 10% NaOH solution (0.7 ml) and TBAS (2.5 g, 13.7 mmol) and heated at 70° C. for 16 h when TLC indicated completion of reaction. The reaction mixture was cooled to rt and poured into water and extracted with ethyl acetate. The combined organic extracts was washed with water, dried and purified by column chromatography using silica gel (100-200 mesh) to afford the pure product as colorless oil in 19% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[O:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:26]
Reactant: COC(=O)c1ccc(OC)cc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC)cc1Oc1ccc(C(F)(F)F)cc1N
Reaction time: 4 h

Procedure:
Methyl-2-(nitro-4-trifluoromethylphenoxy)-4-methoxybenzoate (21.65 g 0.058 mol) was dissolved in ethyl acetate and a palladium on carbon catalyst was added under argon. The mixture was hydrogenated in a parr bottle, at 50 psi, for 4 h The mixture was filtered through Celite® and washed with ethyl acetate and methanol. The solvent was evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, CDCl3) δ7.92 (d, 1H), 7.03 (d, 1H) 6.90 (dd, 1H) 6.68-6.81 (m, 2H) 6.50 (d, 1H) 4.22 (s, 2H) 3.75 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:16]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[CH2:18]([N:17]([CH2:20][CH3:21])[C:16]1[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:3][C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[NH:6][C:5]=2[CH:15]=1)[CH3:19]
Reactant: CCN(CC)c1cc2[nH]c(C3CCCCC3)nc2cc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCN(CC)c1cc2[nH]c(C3CCCCC3)nc2cc1NC(=O)c1ccc(OC)cc1
Yield: 78.5 %

Procedure:
5-Amino-6-diethylamino-2-(cyclohexyl)-1H-benzo[d]-imidazole (28 mg, 0.1 mmol) was reacted with 4-methoxybenzoyl chloride (17 mg, 0.1 mmol) in the same manner as that described above to give the desired product (33 mg, 79% yield) as white powder: 1H-NMR (300 MHz, CDCl3) δ 0.97 (t, 6H, J=7.2 Hz), 1.16 (m, 3H), 1.57-1.70 (m, 5H), 1.98 (m, 2H), 2.87 (m, 1H), 3.01 (q, 4H, J=7.2 Hz), 7.05 (d, 2H, J=8.7 Hz), 7.57 (s, 1H), 7.96 (d, 2H, J=8.7 Hz), 8.94 (s, 1H); ESI MS m/z 421.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[S:21])[NH2:6]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: NC(=S)c1c(F)cccc1F
Yield: 99 %

Procedure:
A solution of 2, 6 difluorobenzamide (1 eq) and Lawesson's reagent (0.5 eq.) in toluene (0.2 M) was heated at 90° C. for 14 hours. Upon cooling the volatiles were removed in vacuo and purified by SiO2 chromatography (25% EtOAc/hexanes) yielding 2,6-difluorobenzothioamide as a light yellow solid (99%). LCMS (m/z): 174.1 (MH+); LC Rt=2.19 min.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:26]=[CH:25][CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH2:36]([O:38][C:39]([C:41]1[O:45][C:44](Br)=[N:43][C:42]=1[CH3:47])=[O:40])[CH3:37].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:36]([O:38][C:39]([C:41]1[O:45][C:44]([C:23]2[CH:24]=[CH:25][CH:26]=[C:16]([N:10]3[N:9]=[CH:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=4)[C:11]3=[O:15])[C:17]=2[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[N:43][C:42]=1[CH3:47])=[O:40])[CH3:37]
Reactant: CCOC(=O)c1oc(Br)nc1C
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)ccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1oc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2COC(C)=O)nc1C
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Under N2, acetic acid 2-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (preparation described in intermediate-4, 72 mg, 0.153 mmol), 2-bromo-4-methyl-oxazole-5-carboxylic acid ethyl ester (34 mg, 0.146 mmol), Pd(dppf)Cl2 (36 mg, 0.0438 mmol) and K2CO3 (61 mg, 0.438 mmol) were dissolved in dioxane/H2O (5:1, 6 mL). The reaction mixture was stirred at 100° C. for about 1.5 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=2:1) to give 2-[2-acetoxymethyl-3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-phenyl]-4-methyl-oxazole-5-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][C:3]1=[O:16].C([O-])=O.[NH4+]>[Pd].CO>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]2[N:2]([CH3:1])[C:3](=[O:16])[CH2:4][CH2:5][CH2:6][C:7]=2[CH:12]=1
Reactant: CN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1C(=O)CCCc2cc(N)ccc21
Temperature: 80 °C
Yield: 105.2 %

Procedure:
In a microwave tube, 275 mg of 1-methyl-7-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are introduced into 26 ml of methanol. 473 mg of ammonium formate and 398 mg of Pd/C (10%) are added. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure, so as to give 250 mg of 7-amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a purple gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[OH-].[Na+].[CH3:13]OS([O-])(=O)=O.C([S+](C)C)CCCCCCCCCCC.C1(C)C=CC=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]1[O:7][CH2:13]1
Reactant: COc1cccc(C=O)c1
Reactant: COS(=O)(=O)[O-]
Agent: CCCCCCCCCCCC[S+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(C2CO2)c1

Procedure:
A mixture of 3-methoxybenzaldehyde (13.4 g, 0.098 mol), a solution of sodium hydroxide (200 g) in water (200 ml), dodecyl-dimethylsulfonium methyl sulfate (51 g, 0.15 mol) and toluene (150 ml) is stirred for 17 hours. Ice is then added and the organic phase is separated, washed with water (3×50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The above product is recovered from the thus obtained residue by distillation at 135°-140° C. and 30 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:15][C:14](=[O:16])[O:13][C:8]3([CH2:12][CH2:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[CH:4][C:5]3[NH:15][C:14](=[O:16])[O:13][C:8]4([CH2:12][CH2:11][CH2:10][CH2:9]4)[C:6]=3[CH:7]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1Nc2ccc(Br)cc2C2(CCCC2)O1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C2(CCCC2)O1

Procedure:
Prepared from 6-bromo-spiro-[4H-3,1-benzoxazine-4,1′-cyclopentane]-2-(1H)-one and 3-chlorophenyl boronic acid according to Procedure A. Off-white solid: mp 140-145° C. 1H-NMR (DMSO-d6) δ10.27 (s, 1H), 7.75 (t, 1H, J=1.8 Hz), 7.53-7.63 (m, 3H), 7.44 (t, 1H, J=7.9 Hz), 7.36 (m, 1H), 6.95 (d, 1H, J=8.6 Hz), 2.09-2.15 (m, 4H), 1.81-1.89 (m, 4H). MS (ESI) m/z 314 [M+H]+. Anal. Calc. For C18H16ClNO2: C, 68.90; H, 5.14; N, 4.46. Found: C, 60.94; H, 4.94; N, 3.78.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH:7]([Br:26])[CH:8]1[O:25][C@H:11]2[CH2:12][C@@H:13]([OH:24])[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH:7]([Br:26])[CH:8]1[O:25][C@H:11]2[CH2:12][C@@H:13]([OH:24])[C@H:14]([CH2:15][CH2:16][C@@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCC[C@H](O)CC[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1O
Yield: 59.7 %

Procedure:
350 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-bromo-6,9-epoxy-11,15-dihydroxyprost-13-enoic acid methyl ester (prepared as described in Example 2) were hydrogenated at a pressure of one atmosphere in 6 ml of ethanol containing 120 mg of 5% palladium on charcoal at room temperature. The reduction was stopped after the absorption of one equivalent of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:1) as eluent to give 210 mg of the title compound having the following physical characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([CH2:28][O:29]C2CCCCO2)[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([CH2:28][OH:29])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[O:15])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CNS(=O)(=O)c2ccc(Cl)cc2)COC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCOC(=O)c1ccc(NC(=O)C(CO)CNS(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
After (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (10.8 mg) was dissolved in methanol (5 ml), the mixture was acidified with p-toluenesulfonic acid to pH less than 4, and the whole was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with saturated NaHCO3 and saturated NaCl and dried over Na2SO4 and concentrated to give (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (8.1 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][NH:20]2)[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[CH:10][CH:9]=1.[CH3:34][C:35]([O:38][C:39]([NH:41][C@H:42]([C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)[CH3:43])=[O:40])([CH3:37])[CH3:36]>>[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][N:20]2[C:50]([C@H:47]2[CH2:46][CH2:45][C@H:44]([C@@H:42]([NH:41][C:39](=[O:40])[O:38][C:35]([CH3:37])([CH3:36])[CH3:34])[CH3:43])[CH2:49][CH2:48]2)=[O:51])[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:16][CH3:17])=[O:18])=[CH:10][CH:9]=1
Reactant: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)nc2Cl)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)[C@H]3CC[C@H]([C@H](C)NC(=O)OC(C)(C)C)CC3)nc2Cl)cc1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 67 was treated with trans-4-[(1S)-1-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)ethyl]cyclohexanecarboxylic acid to give the title compound as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][CH2:26][CH2:25][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCCN1CCCCC1
Product: O=C(NCCN1CCCCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(2-piperidin-1-ylethyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 2.5 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 4.0 mmol of 2-piperidin-1-ylethylamine. LC/MS [5.40 min; 469 (M+1)]
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[CH:12]([CH2:14][C:15]([OH:17])=[O:16])[O:11][B:10]([OH:18])[C:9]=2[CH:8]=[C:7]([O:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:6]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[C:13]2[CH:12]([CH2:14][C:15]([OH:17])=[O:16])[O:11][B:10]([OH:18])[C:9]=2[CH:8]=[C:7]([O:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:6]=1
Reactant: [N-]=[N+]=NCc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a mixture of [4-azidomethyl-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (100 mg, 0.29 mmol) was treated with PPh3 on resin (140 mg, about 0.42 mmol) in THF/water (5/1 mL). The reaction mixture was stirred at r.t overnight and filtered off. The filtrate was purified by HPLC, yielded 25 mg of the desired product. 1H NMR (300 MHz, CD3CN) δ 8.44 (s, 1H), 8.30 (d, 1H), 8.12 (s, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 5.71 (m, 1H), 4.24 (s, 2H), 3.04-3.10 (m, 1H), 2.50-2.58 (m, 1H).