Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[C:16](=[O:17])[N:15]2[C@H:18]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:29])[CH2:12][CH2:11]1)(=[O:8])[C:2]1C=CC=CC=1.[K+].[Br-]>CO>[C:1]([NH:9][C@@H:10]1[C:16](=[O:17])[N:15]2[C@H:18]([C:22]([OH:24])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:29])[CH2:12][CH2:11]1)(=[O:8])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)c3ccccc3)C(=O)N12
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O

Procedure:
was prepared from 211e the same method as compound 212e as a white glassy solid (595 mg, 77%): mp >250° C.; [α]D24 −153 (c 0.10, MeOH); IR (KBr) 3280, 2942, 1742, 1697, 1675, 1650, 1616, 1548, 1470, 1443, 1281, 1249, 1202, 1187, 1171; 1H NMR (CD3OD) δ5.35-5.31 (1H, m), 4.81-4.71 (1H, m), 4.61-4.46 (1H, m), 3.59-3.44 (2H, m), 3.11-2.94 (1H, m), 2.58-2.39 (1H, m), 2.36-2.19 (2H, m), 2.11-1.83 (3H, m), 1.99 (3H, s), 1.78-1.56 (2H, m); Anal. Calcd for C12H17N3O5: C, 50.88; H, 6.05; N, 14.83. Found: C, 50.82; H, 6.02; N, 14.58; MS (ES−) 282 (M−1, 100%): Accurate Mass calculated for C12H18N3O5 (MH+): 284.1246. Found: 284.1258.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:13][C:12]=3[O:24][CH3:25])[NH:8][C:5]2=[N:6][CH:7]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(N(CC)CC)C>ClCCl>[C:37]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:9]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([NH:26][C@@H:27]5[C@H:32]6[CH2:33][C@@H:29]([CH:30]=[CH:31]6)[C@@H:28]5[C:34]([NH2:36])=[O:35])=[C:4]4[N:10]=3)=[C:12]([O:24][CH3:25])[CH:13]=2)[CH2:19][CH2:20]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(CN2CCNCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(C)=O)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@@H]3C4)c(Cl)cnc2[nH]1
Yield: 33.1 %

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(2-methoxy-4-piperazin-1-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Compound XLII) (254 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 mL) and treated with acetic anhydride (1 mL, 10.0 mmol) and triethylamine (1.0 mL, 7.2 mmol) for one hour at ambient temperature. The reaction was concentrated and the product was purified by reverse phase chromatography (Gilson) to afford following neutralization of desired fractions a pale yellow solid as the title compound (91 mg, 30%). Mp 109-113° C. 1H NMR (d-chloroform): 11.12 (br s, 1H), 8.34 (d, J=7 Hz, 1H), 7.99 (s, 1H), 7.11 (m, 2H), 6.37 (m, 3H), 5.72 (d, J=7 Hz, 1H), 5.36 (m, 1H), 5.22 (t, J=8 Hz, 1H), 4.10 (s, 3H), 3.66 (m, 2H), 3.59 (s, 2H), 3.50 (m, 2H), 3.17 (s 1H), 2.92 (s, 1H), 2.85 (d, J=7 Hz, 1H), 2.48 (m, 4H), 2.34 (d, J=8 Hz, 1H), 2.10 (s, 3H), 1.73 (d, J=7 Hz, 1H). MS: 550.2 (M+H). HPLC retention time: 1.70 minutes (G Method).
Reaction SMILES: [C:1]([C:4]1[C:12]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:7]=2[S:6][C:5]=1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[O:22])(=[O:3])[NH2:2].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[NH:20][C:5]2[S:6][C:7]3[CH2:8][NH:9][CH2:10][CH2:11][C:12]=3[C:4]=2[C:1]([NH2:2])=[O:3])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2

Procedure:
A stirred suspension of tert-butyl 3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (697 mg, 1.55 mmol) in 6 mL of DCM at rt was treated with 3 mL of TFA. The resultant solution was stirred at rt for 25 min whereupon it was concentrated in a rotary evaporator. The product was taken up in MeOH and the solution concentrated in vacuo (×2) to afford the title compound as a tan solid in quantitative yield. LRMS [M+H]351.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.P(=O)(O)(O)O.O>ClC1C=CC=CC=1Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[C:11]2[C:12]=1[CH2:1][CH2:2][C:3]2([CH3:5])[CH3:4]
Reactant: C=CC(=C)C
Reactant: Oc1cccc(Cl)c1
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CC1(C)CCc2c(Cl)cc(O)cc21
Reaction time: 8 h
Yield: 16.4 %

Procedure:
449 g of isoprene, stabilized with 1.35 g of phenothiazine, were added dropwise over the course of 5.5 hours to a solution of 771 g of m-chlorophenol, 77 g of 85% strength phosphoric acid and 6 ml of water in 1.44 liters of o-dichlorobenzene at 150° C. To complete the reaction, stirring was continued overnight at 150° C. After cooling, the acid phase was separated off and extracted by shaking with toluene. The combined organic phases were washed until neutral. Fractional distillation gives 194 g of 7-chloro-3,3-dimethyl-5-hydroxy-indane; boiling point 105°-110° C/0.5 mm Hg; melting point 86.5° - 87.5° C. ##STR38##
Reaction SMILES: [CH3:1][C:2]1[N:7]=C(C#N)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.[OH-:23].[Na+].Cl.[CH3:26][CH2:27][OH:28]>>[CH3:1][C:2]1[N:7]=[C:26]([C:27]([OH:23])=[O:28])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2
Reactant: [OH-]
Reactant: Cc1nc(C#N)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: Cc1nc(C(=O)O)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To 6-methyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)picolinonitrile (1.7 g, 5.62 mmol) in EtOH (20 mL) was added sodium hydroxide (14.06 mL, 28.1 mmol) and the resulting mixture was stirred for 16 hours at reflux. The mixture was subsequently cooled to room temperature and acidified with concentrated HCl. Volatiles were evaporated and the residue purified by CombiFlash® chromatography (5-40% MeOH in DCM over 120 minutes). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a white solid (1.6 g, 89%). ESI-MS m/z [M+H]+ calc'd for C15H10F3N3O2, 322.1. found 322.06.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:26])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:26])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH3:14]
Reactant: CCOC(=O)C=Cc1cccc(C)n1
Reactant: COc1n[nH]c2cc(Br)ccc12
Product: CCOC(=O)C=C(c1ccc2c(OC)n[nH]c2c1)c1cccc(C)n1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-3-(6-methyl-pyridin-2-yl)-acrylic acid ethyl ester CCLIII was prepared from 6-bromo-3-methoxy-1H-indazole and 3-(6-methyl-pyridin-2-yl)-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl esterLVIII (Example 14).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.O.ON1C2C=CC=CC=2N=N1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34]([OH:36])=O.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH:5]2[CH2:4][N:3]([CH3:2])[C:34](=[O:36])[CH2:33][C:29]1[S:28][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)Cc1cccs1
Reactant: CNCC1CCCc2c(OC)cccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CCCC2CN(C)C(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.5 %

Procedure:
The product from Example 17 (1.04 g), 1-hydroxybenzotriazole hydrate (1.51 g) and 2-thiopheneacetic acid (720 mg) in dry THF (30 ml) at 0° C. was treated with dicyclohexylcarbodiimide (1.16 g). The reaction was warmed to room temperature and stirred for 18 hr. The mixture was filtered and concentrated. The residue was dissolved into EtOAc (60 ml) washed with 5% aq. HCl (15 ml), water (15 ml), 10% aq. KOH (15 ml), dried (MgSO4) filtered and concentrated. Chromatography on SiO2 afforded 1.58 g of product as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26].O.Cl.CCOCC>CO>[ClH:1].[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[CH:11]=1
Reactant: NCC(O)CO
Reactant: Clc1cc(N2CCc3ccccc3C2)c2ccccc2n1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: OCC(O)CNc1cc(N2CCc3ccccc3C2)c2ccccc2n1
Temperature: 155 °C
Yield: 69.1 %

Procedure:
2-Chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline (0.44 g, 1.5 mmol) and (RS)-3-amino-1,2-propanediol (0.82 g, 9.0 mmol) were mixed and heated at 150-160° C. for 5 hours. The reaction mixture was cooled to room temperature and water (15 ml) was added. The resulting solid was filtered, dried and chromatographed over silica gel (CH2Cl2—MeOH, 19:1 then 9:1) to provide a white foam which was dissolved in MeOH. HCl—Et2O was added to provide (RS)-3-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-propane-1,2-diol hydrochloride (0.4 g, 69%) as an offwhite foam, MS: m/=349 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:16](O)(=[O:19])[CH:17]=[CH2:18]>>[Cl:1][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(Sc2ccnc(Cl)n2)c1
Reactant: C=CC(=O)O
Product: C=CC(=O)Nc1cccc(Sc2ccnc(Cl)n2)c1
Yield: 68 %

Procedure:
In a procedure analogous to Example 15, reaction of 3-(2-chloropyrimidin-4-ylthio)benzenamine (300 mg, 1.26 mmol) and acrylic acid (173 μL, 2.52 mmol) furnished the product (250 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+].O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[N:17][OH:18])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCCC2=O)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc(C2CCCCC2=NO)c1

Procedure:
2-(3-Methoxyphenyl)-cyclohexanone, as described in Step A above, (0.61 g, 3 mmol), hydroxylamine hydrochloride (0.40 g, 6 mmol) and sodium acetate (0.80, 6.2 mmol) were combined in EtOH (4 mL): H2O (2 mL) and heated at reflux for 3 h. The reaction mixture was concentrated, then partitioned between EtOAc (100 mL) and H2O (100 mL), the organic layer separated, washed with H2O, brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [CH2:1]([PH:5](=[O:9])[O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH3:4].[CH2:10]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH:23]=[O:24])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C>[CH2:10]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH:23]([P:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:9])[O:6][CH2:7][CH3:8])[OH:24])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CCCNC(=O)OCc1ccccc1
Reactant: CCCC[PH](=O)OCC
Solvent: CCN(CC)CC
Product: CCCCP(=O)(OCC)C(O)CCNC(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1.50 g of ethyl (n-butyl)phosphinate, 1.01 g triethylamine and 2.07 g 3-(N-benzyloxycarbonylamino)propionaldehyde is heated to 100° C. for 4 hours. After this time the mixture is cooled to 20° and the volatile components are removed in high vacuum. Chromatography of the residue on silica gel affords ethyl 3-(N-benzyloxycarbonylamino)-1-hydroxy-propyl(n-butyl)phosphinate as a viscous oil.
Reaction SMILES: CN(C=O)C.[C:6]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([CH3:9])([CH3:8])[CH3:7].Cl[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1Oc1cccc(C(C)(C)C)c1
Temperature: 60 °C
Yield: 89.2 %

Procedure:
A 50 ml two-necked round-bottomed flask equipped with a magnetic bar, a thermometer and a reflux condenser is charged with DMF (50 ml), 3-tert-butyl-phenol (1.5 g), 2-chloro-3-methyl-5-nitro-pyridine (1.73 g) and potassium carbonate (2.76 g). The reaction mixture is heated at 60° C. for 2 hours. After cooling the mixture to room temperature it is then poured into water (200 ml). The mixture is then extracted with ethylacetate (2×40 ml). The combined organic layers are dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification of this crude material by flash chromatography over silica gel with hexane/ethyl acetate 4:1 (v:v) gives 2.55 g of the compound as a yellow oil.
Reaction SMILES: [S:1](=[O:3])=[O:2].[Mg:4].[OH-:5].[OH-].[Mg+2]>>[S:1]([O-:5])([O-:3])=[O:2].[Mg+2:4].[S:1](=[O:5])([OH:3])[O-:2].[Mg+2:4].[S:1](=[O:5])([OH:3])[O-:2]
Reactant: O=S=O
Reactant: [Mg]
Reactant: [OH-]
Agent: [Mg+2]
Product: O=S([O-])O
Product: O=S([O-])[O-]

Procedure:
In lieu of a limestone or lime-based scrubbing system, flue gas containing sulfur dioxide may be treated by passing it through a scrubbing unit that utilizes a magnesium-containing scrubbing agent, e.g., a magnesium hydroxide slurry. The magnesium hydroxide reacts with sulfur dioxide to produce magnesium sulfite and magnesium bisulfite. The magnesium hydroxide slurry also reacts with hydrochloric acid in the flue gas, producing magnesium chloride, although there is very little hydrochloric acid in the flue gas compared to sulfur dioxide. The following chemical reactions occur in the scrubbing unit: SO2+Mg(OH)2→MgSO3+H2O  (1) H2O+SO2+MgSO3→Mg(HSO3)2  (2) Mg(HSO3)2+Mg(OH)2→2MgSO3  (3) 2HCl+Mg(OH)2→MgCl2→2H2O  (4)
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-:25].[K+].[K+].Cl>CN(C)C=O.O.C(OCC)C>[CH2:1]([O:25][C:22]1[CH:23]=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCOc1ccccc1C(=O)O

Procedure:
A solution of dodecylbromide (8.2 g, 4-hydroxybenzoic acid (5 g) and potassium carbonate (5 g) in dimethylformamide (100 ml) was stirred at 130° C. for two hours. The solution was poured in water and neutralized with dilute aqueous hydrochloric acid solution. Diethyl ether was added in order to effect extraction and the extracted layer was distilled to remove the solvent. The residue was added to a solution of sodium hydroxide (3 g). water (10 ml) and ethanol(50 ml) and the solution was refluxed for about one day. The solution was neutralized with dilute aqueous hydrochloric acid solution and distilled to remove the solvent and concentrated. Solid collected was recrystallized from water/ethanol to obtain the titled compound (4.9 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.N1C=CC=CC=1.[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([O:25][C:26]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1csc(NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylate (5 g), pyridine (3.36 ml) and dichloromethane (50 ml) was added benzyloxycarbonyl chloride (3.1 ml), and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium hydrogen bicarbonate (30 ml), dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with diisopropyl ether to give ethyl 2-{[(benzyloxy)carbonyl]amino}-1,3-thiazole-4-carboxylate (5.1 g)
Reaction SMILES: CS([CH:5]([OH:15])[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])(=O)=O.[I:16][C:17]1[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.CCCCCC>[I:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][CH:18]=1)[O:15][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: COCCOCCOCC(O)S(C)(=O)=O
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COCCOCCOCCOc1cccc(I)c1
Temperature: 68 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a solution of 1-[(methanesulfonyl)-oxyl-3,6,9-trioxadecane (11.6 g, 47.9 mmol) in dry DMF (145 ml) was added 3-iodophenol (10.6 g, 48.2 mmol) and potassium carbonate (6.6 g, 47.8 mmol). The reaction was immersed in an oil bath which was warmed to 68° C. over a period of 0.5 hr. The reaction was stirred at this temperature under an N2 atmosphere for 16 hrs and then at 82° C. for an additional 2 hrs. At the end of this period, the reaction was cooled, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up into ethyl acetate (500 ml), washed with water (200 ml), 1 N aqueous sodium hydroxide (200 ml) and brine (200 ml), dried (Na2SO4), filtered and evaporated in vacuo to provide a light brown oil. Flash column chromatography (silica, 1:3 to 1:2; EtOAc:hexane) provided 1 -(3-iodophenoxy)-3,6,9-trioxadecane as a light yellow oil (10.8 g, 37.1%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39]CCC[CH2:35]1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:35][CH2:34][CH2:39][C:8]3[CH:9]=[CH:10][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:4][CH:5]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CCCc3ccc(C(F)(F)F)cc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3-(4-(trifluoromethyl)phenyl)propanal for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.69-7.62 (m, 4H), 7.39 (d, J=8.0, 1H), 7.37-7.32 (m, 3H), 7.26 (t, J=7.3, 1H), 4.41-4.33 (m, 1H), 3.25 (d, J=10.5, 1H), 3.00 (dd, J=2.2, 9.0, 0.5H), 2.76-2.59 (m, 3H), 2.56-2.46 (m, 1H), 2.44-2.39 (m, 0.5H), 2.37 (dd, J=2.1, 8.9, 0.5H), 2.31 (dt, J=5.8, 14.1, 2H), 2.23-2.07 (m, 3H), 1.94-1.71 (m, 2.5H), 1.67 (ddd, J=5.6, 7.9, 11.8, 1H), 1.47-1.28 (m, 2H), 1.23 (dd, J=6.5, 13.1, 3H), 0.89 (dt, J=7.2, 24.8, 1H), 0.72 (dd, J=3.7, 6.7, 3H); MS (ESI+) m/z 473 (M+H)+.
Reaction SMILES: Br[C:2]([CH3:13])([CH3:12])[CH:3](OCCC)OCCC.C([CH:17]([CH:19]([C:21]([O-:23])=O)O)O)(O)=O.[K+].[OH2:25]>>[CH3:3][C:2]([O:23][CH2:21][CH2:19][CH3:17])([CH3:13])[CH2:12][OH:25]
Reactant: CCCOC(OCCC)C(C)(C)Br
Reactant: O=C([O-])C(O)C(O)C(=O)O
Reactant: O
Agent: [K+]
Product: CCCOC(C)(C)CO

Procedure:
2-Methyl-2-propoxypropanol was prepared according to a modified method described in U.S. Pat. No. 3,652,579. A slurry consisting of 2-bromo-2-methyl-1,1-dipropoxypropane obtained from Example 2(a) (6.5 g, 0.026 mol), potassium hydrogen tartrate (4.8 g, 0.026 mol) in water (75 mL) was heated at reflux for 7 h. A distillation set-up was mounted and the liquid that was distilled between 82-90° C. was collected. The organic phase was separated. The obtained crude product (1.9 g, 56%) was used without further purification.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][NH:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[C:19]([OH:28])[CH:20]=[CH:21][C:22]=3[OH:27])[C:17](=[O:29])[C:16]=2[C:15]([NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]2CO)=[CH:14][CH:13]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:60]([Cl:64])(Cl)(Cl)Cl.C(Cl)[Cl:66]>>[Cl:66][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][NH:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[C:19]([OH:28])[CH:20]=[CH:21][C:22]=3[OH:27])[C:17](=[O:29])[C:16]=2[C:15]([NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]2[CH2:60][Cl:64])=[CH:14][CH:13]=1
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCN3CCCCC3CO)ccc(NCCN3CCCCC3CO)c21
Reactant: ClCCl
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCN3CCCCC3CCl)ccc(NCCN3CCCCC3CCl)c21
Reaction time: 5 h
Yield: 78 %

Procedure:
The method follows that of CAQ39 using HAQ105 (60 mg, 0.109 mmol), Ph3P (171.5 mg, 0.654 mmol), CCl4 (190 μL, 1.96 mmol) and dry CH2Cl2 (5 mL). The reaction was stopped after 5 hours of reflux. The product (CAQ190M) was afforded as a dark blue powder (49.8 mg, 78%). M.p. decompose>300° C.; δH (250 MHz; DMSO); 1.5-1.65 (m, 4H, 4×ring-H), 1.75-2.15 (m, 10H, 10×ring-H), 3.4-3.8 (m, 8H, 2×HNCH2CH2N and 4×ring-H), 4-4.1 (q, 4H, 2×HNCH2CH2N), 4.15 (2×d, 4H, 2×NCHCH2Cl) 7.2 (s, 2H, C(2)H and C(3)H), 7.65 (s, 2H, C(6)H and C(7)H), 10.45 (t, 2H, C(1)NH and C(4)NH), and 13.45 (s, 2H, C(5)OH, C(8)OH); δC (62.9 MHz; DMSO), 26.11, 37.05, 42.78, 50.78, 51.83, 60.32, 62.26, 108.41, 114.33, 125.00, 126.56, 145.93, 154.69, 184.28; FAB MS, m/z(M+H)+589.