Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[Cl:14][C:15]1[CH:20]=[N+:19]([O-])[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:19][C:20]=1[OH:4]
Reactant: CCOC(=O)c1ccc(Cl)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cl)c(O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Trifluoroacetic anhydride (147 mL) was added dropwise to a solution of ethyl 5-chloropyridine-2-carboxylate 1-oxide (36.8 g) in N,N-dimethylformamide (220 mL) under ice-cooling over 20 minutes, and the mixture was stirred at 50° C. for one hour. The reaction solution was ice-cooled and water was added. Sodium bicarbonate was slowly added to effect neutralization, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was suspended with ethyl acetate, stirred and then filtered. The filtrate was concentrated under reduced pressure. The same operation was further repeated twice. The resulting solids were combined and dried under reduced pressure to give ethyl 5-chloro-6-hydroxypyridine-2-carboxylate as a white solid (24.2 g, 75%). The filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give ethyl 5-chloro-6-hydroxypyridine-2-carboxylate as a white solid (1.84 g, 6%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([O:27][CH3:28])[C:6]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[CH3:13].I[CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].CCN(CC)CC>CCOCC>[CH3:28][O:27][C:5]1[C:6]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]2[C:12](=[C:3]([NH:2][CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]3[C:38](=[O:39])[C:37]4=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]4[C:35]3=[O:44])[CH:4]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH3:13]
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCCc1ccccc1
Reactant: CC(I)CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCCc1ccccc1
Reaction time: 4 h

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-(6-phenylhexoxy) quinoline hydrochloride (2.7 g, 0.007 mol), and 4-iodo-1-phthalimido-pentane (IPP) (3.0 g, 0.009 mol) was maintained at 100° C. while 1 ml of Et3N was added dropwise. After an additional 3 h of IPP and 1 ml of Et3N were added, heating was continued for 4 h and the mixture was allowed to cool, diluted with Et2O (100 ml), filtered, washed with saturated NaCl and dried (Na2SO4). Solvent removal provided a quantitative yield of 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-(6-phenylhexoxy) quinoline as a brown syrup which was used without further purification.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][C:10]([CH2:12]O)=O>C(O)C.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:12][C:10]1[C:2]2[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=2[O:7][CH:9]=1
Reactant: O=C1CCCC(=O)C1
Reactant: CC(=O)CO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1coc2c1C(=O)CCC2
Yield: 37.5 %

Procedure:
A mixture of 1,3-cyclohexanedione (3.36 g, 30 mmol), acetol (hydroxyacetone; 2.22 g, 30 mmol), and zinc chloride (4.09 g, 30 mmol) in ethanol (10 mL) was heated at reflux temperature for 3 hours. After cooling, the mixture was dissolved in ethyl acetate (100 mL). The whole was washed with water (100 mL), brine (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chlomatography eluting with ethyl acetate-hexane (1:10) to give the subtitle compound (1.69 g, 38% yield).
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])[CH:17]=2)=[C:10]([Cl:31])[CH:9]=1)=[O:6])C.Cl>O.CO.[OH-].[K+]>[Cl:14][C:12]1[CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]([OH:32])=[O:3])[CH:9]=[C:10]([Cl:31])[C:11]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])[CH:17]=1
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)N3CCCC3)c2)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)N3CCCC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-{3,5-dichloro-4-[4-hydroxy-3-(pyrrolidine-1-sulfonyl)-phenoxy]-phenyl}-oxamic acid ethyl ester (10 mg, 0.02 mmol) in a mixture of H2O (0.5 mL) and MeOH (0.5 mL) was added 2 drops of 3N KOH. The reaction mixture was stirred at RT for 2 h, acidified with 1N HCl and extracted with EtOAc (4×5 mL). The combined organic extracts were dried and concentrated to afford the title compound as an off-white solid. NMR (400 MHz, CD3OD) d 7.96 (s, 2H), 7.02-7.06 (m, 2H), 6.95-6.98 (d, 1H), 3.28-3.31 (m, 4H), 1.78-1.81 (m, 4H). MS Calc.: 474.3 Found: 473.1 (M−1).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C)C=CC=CC=1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([C:24]#[C:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Temperature: 70 °C

Procedure:
In an inert atmosphere glovebox, 4-bromo-4′-fluorobenzophenone (10 g, 35.8 mmol), PdCl2(PPh3)2 (250 mg), CuI (680 mg), phenylacetylene (4.02 g, 1.1 eq), triethylamine (3.6 g, 1 eq), and toluene (25 mL) were combined. The flask was closed and heated to 70° C. for 24 h. The mixture was poured over ice and extracted with methylene chloride, which was separated and evaporated. The residue was recrystallized twice from hot ethanol using decolorizing charcoal to give the title product as white crystals.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(C)C)c(CO)c(-c2ccc(F)cc2)c1/C=C/c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1nc(C(C)C)c(CCc2ccccc2)c(-c2ccc(F)cc2)c1CO

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-[2(E)-phenylethenyl]pyridine (Example 34) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.19 (m, 7 H), 6.86 (m, 2 H), 4.36 (d, J=5.5 Hz, 2 H), 3.44 (sept, J=6.6 Hz, 1 H), 3.35 (sept, J=6.6 Hz, 1 H), 2.58 (m, 4 H), 1.35 (d, J=6.6 Hz, 6 H), 1.34 (d, J=6.6 Hz, 6 H), 1.19 (t, J =5.5 Hz, 1 H). FAB-MS: calculated for (C26H30FNO) 391, found 392 (M+H). Anal. Calcd for C26H30FNO: C, 79.76; H, 7.72; N, 3.58. Found: C, 79.57; H, 7.61; N, 3.44. mp 158-159° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]1[N:30]=[CH:31][N:32](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]1[NH:30][CH:31]=[N:32][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(N2CCN(Cc3cnc[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
The intermediate (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(1-trityl-1H-imidazol-4-ylmethyl)-piperazine (90 mg, 0.13 mmol) was dissolved in CH2Cl2 (0.5 mL) and was treated with triethylsilane (0.5 mL) followed by trifluoroacetic acid (1.0 mL). The reaction mixture was stirred for 2 h then evaporated to a residue which was triturated with a 10% EtOAc/hexane solution (4×1 mL). The residue was then partitioned between EtOAc (1 mL) and a saturated aqueous K2CO3 solution (0.5 mL). The organic component was separated, dried over MgSO4, filtered, and evaporated to afford the title compound as a foam (50 mg, 83%). LC/MS (Method A) 4.50 min, [M+1]+ 447.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45]([C:48]1[C:49]([Cl:56])=[C:50]([C:53](O)=[O:54])[NH:51][CH:52]=1)(=[O:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:45]([C:48]1[C:49]([Cl:56])=[C:50]([C:53]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]3[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=3)[C:28]=2[F:44])=[O:54])[NH:51][CH:52]=1)(=[O:47])[CH3:46]
Reactant: CC(=O)c1c[nH]c(C(=O)O)c1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1c[nH]c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c1Cl
Reaction time: 8 h
Yield: 8.4 %

Procedure:
HATU (0.092 g, 0.241 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), 4-acetyl-3-chloro-1H-pyrrole-2-carboxylic acid (0.030 g, 0.161 mmol) and DIPEA (0.042 mL, 0.241 mmol) in DMF (2 mL). The resulting solution was stirred overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.0065 g, 7%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm ppm 11.46 (br. s., 1H), 7.88 (br. s., 1H), 7.79 (s, 1H), 7.63 (s, 1H), 7.36-7.50 (m, 4H), 4.73 (d, 2H), 2.41 (s, 3H). LCMS: m/z 480.0 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[N:10]1([C:16]2[N:17]=[C:18]([CH2:23][C:24](OCC)=[O:25])[NH:19][C:20](=[O:22])[CH:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C[Al](C)C>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:24](=[O:25])[CH2:23][C:18]1[NH:19][C:20](=[O:22])[CH:21]=[C:16]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[N:17]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: c1ccc2c(c1)CNC2
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1Cc2ccccc2C1
Yield: 23.5 %

Procedure:
The product is prepared according to the procedure described in example 70, using 250 mg of isoindoline, 267 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 1 and 1.15 ml of a 2M solution of trimethylaluminium, in a mixture of 20 ml of toluene and 10 ml of tetrahydrofuran. 80 mg of 2-[2-(1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14](OC)(=[O:19])[C:15]([O:17][CH3:18])=[O:16].[Li+].CC([N-]C(C)C)C>C1COCC1>[CH2:6]([O:5][CH:4]([C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])[C:3]([O:2][CH3:1])=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(=O)OC
Reactant: COC(=O)COCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(=O)C(OCc1ccccc1)C(=O)OC

Procedure:
A solution of methyl(benzyloxy)acetate (1 eq) and dimethyl oxalate (1.2 eq) in dry THF was cooled to −78° C. and LDA (2M in THF-heptane, 1.2 eq) was added dropwise. After stirring for an hour the cold bath was removed, and stirring was continued for an additional hour. The reaction was quenched at 0° C. by pouring into cold 1N aq HCl, and the aqueous phase was extracted with EtOAc; the organic layer was washed with brine, dried and concentrated to give a crude that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17]C)=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.Cl.C(O)(=O)C>O>[Cl:1][C:2]1[C:3]([F:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)c1cn2c3c(c(F)c(Cl)cc3c1=O)CCN2C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2c(F)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Yield: 81.8 %

Procedure:
To 600 mg (1.9 mmol) of the compound (133) obtained in Example 25, 5 ml of concentrated hydrochloric acid and 20 ml of acetic acid were added, and the solution was heated at reflux for 2 hours. After air-cooling, 20 ml of water was added to the solution, and solids were filtered off and washed with ethanol and ether in this order to obtain 461 mg of the subject compound (134) in a 80% yield.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12](Cl)=[O:13])[N:9]=[CH:8]2)[CH:2]=1.C(N(CC)CC)C.Cl.[CH3:29][NH:30][O:31][CH3:32]>ClCCl>[CH3:32][O:31][N:30]([CH3:29])[C:12]([C:10]1[N:9]=[CH:8][N:7]([C:3]2[CH:2]=[C:1]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[CH:5][CH:4]=2)[CH:11]=1)=[O:13]
Reactant: CNOC
Reactant: O=C(Cl)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
The above product (11a) was dissolved in dichloromethane (20 ml). Triethylamine (10 ml) and N,O-dimethylhydroxylamine hydrochloride (0.83 g, 8.3 mmol) were added and the resultant mixture was stirred at ambient conditions overnight. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by column chromatography on silica gel using a mixture of 0.8% methanol in chloroform as the eluent to afford 12a (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:22][C:23]([OH:25])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:12]2[NH:13][C:14]([CH3:16])=[N:15][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20].[CH3:26]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:12]2[NH:13][C:14]([CH3:16])=[N:15][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1nc2c([N+](=O)[O-])c(Oc3ccc(CC(=O)O)cc3Cl)ccc2[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)nc3c2[N+](=O)[O-])c(Cl)c1
Temperature: 25 °C

Procedure:
Under an N2 atmosphere, 2-(3-chloro-4-(2-methyl-4-nitro-1H-benzo[d]imidazol-5-yloxy)phenyl)acetic acid (0.331 0.915 mmol) was dissolved in methanol and concentrated sulfuric acid (3 drops) was added. The reaction was heated to reflux for 2.5 h, cooled to room temperature and concentrated in vacuo. The residue was partitioned between saturated NaHCO3 (aq) and ethyl acetate. The layers were separated and the aqueous layer washed with additional ethyl acetate (2×). The organics were combined, dried (Na2SO4), and concentrated in vacuo. Flash column chromatography of the residue, eluting 0% to 3% methanol in dichloromethane, afforded title compound. LC-MS ESI (pos.) m/z: 376.0 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1O[C:10](=O)[C:9]([C:13]#[N:14])=[C:8]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1.[H-].[Na+].[CH2:23]1[CH2:27]O[CH2:25][CH2:24]1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:4]2[C:3]3[C:24](=[CH:23][CH:27]=[CH:6][CH:2]=3)[CH2:25][C:10]=2[C:9]([C:13]#[N:14])=[C:8]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccco2)oc1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccco2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 6-(furan-2-yl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (270 mg), indanone-2 (132 mg) and NaH (28 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent White solid; mp 160-162° C.; ESIMS 341 (M++1); IR (KBr) 2218 cm−1 (CN).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH2:17][C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]N(C)C=O.S(Cl)(Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(OCc2ccccc2)c(CC(=O)O)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(C#N)ccc1OCc1ccccc1

Procedure:
10.0 g (0.037 mol) of (2-benzyloxy-5-cyano-phenyl)-acetic acid are refluxed for two hours in 65 ml dichloromethane, 0.1 ml of dimethylformamide and 8.1 ml (0.11 mol) of thionyl chloride. Then the mixture is concentrated by evaporation, the residue is combined with 55 ml of methanol and refluxed for one hour. After cooling the mixture is suction filtered, washed with ether/petroleum ether and dried at 50° C.
Reaction SMILES: [CH:1]1([O:4][CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC.Cl>C(Cl)Cl>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:6][CH2:5][O:4][CH:1]2[CH2:3][CH2:2]2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOC1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyclopropoxyethanol (400 mg, 3.92 mmol) in DCM (10 mL) were added TsCl (821 mg, 4.31 mmol) and Et3N (0.6 mL, 4.31 mmol). The reaction was stirred at room temperature overnight. Then, 1N HCl was added, and the reaction was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a yellow oil. The oil was purified by preparative TLC to obtain intermediate BP (50 mg) as a yellow oil.
Reaction SMILES: S(C)C.[CH:4]([NH:6][C:7]1[C:8]([Cl:25])=[CH:9][C:10]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][C@H:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[CH:24]=1)=O>C1COCC1>[CH3:4][NH:6][C:7]1[C:8]([Cl:25])=[CH:9][C:10]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][C@H:12]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:11]=2[CH:24]=1
Reactant: CN1CCc2cc(Cl)c(NC=O)cc2[C@@H](c2ccccc2)C1
Solvent: CSC
Solvent: C1CCOC1
Product: CNc1cc2c(cc1Cl)CCN(C)C[C@@H]2c1ccccc1
Reaction time: 8 h

Procedure:
Me2S in THF (13.25 ml) was added dropwise to the product obtained in Example III (2.55 g, 0.008 mol) dissolved in 30 ml of THF with stirring and cooling in an ice bath. The ice bath was removed and the mixture was heated to reflux for 3.5 hours. The mixture was left to stand at room temperature overnight. Ethanolic HCl was added dropwise to the mixture with cooling (ice bath) and stirring until a pH of 1.5 was reached. The mixture was heated to reflux for one hour and then the solvent was removed. The residue was stirred with ether and 1N NaOH. The dried ether solution was evaporated in vacuo. The residue was crystallized from isopropyl ether, m.p. 98°-100° C. [α]26D +67.3 (DMF, c=1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:29][CH:28]([NH2:30])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH:28]3[CH2:29][O:26][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC1COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=1.9 Hz, 1 H), 7.79 (d, J=1.9 Hz, 1 H), 7.72 (s, 1 H), 7.63 (t, J=3.8 Hz, 1 H), 7.44 (t, J=4.3 Hz, 2 H), 7.29 (d, J=2.1 Hz, 1 H), 5.72 (s, 1 H), 5.16 (t, J=3.3 Hz, 2 H), 5.12 (s, 2 H), 4.86 (m, 1 H), 4.72 (t, J=3.0 Hz, 2 H), 4.53 (brs, 2 H), 3.58 (t, J=2.3 Hz, 2 H), 2.43 (s, 3 H).
Reaction SMILES: [C:1]([Cl:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[Br:21]Br>>[Br:21][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:1]([Cl:20])=[O:19]
Reactant: BrBr
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)Cl
Product: CC(C)CCCCCCCCCCCCCC(Br)C(=O)Cl

Procedure:
Isooctadecanoyl chloride prepared as described in Example 5 (20.2 g) was stirred and heated to 100° and illuminated with a tungsten lamp (100 watts) whilst bromine (10.7 g) was added dropwise during 1.5 hours. Heating and stirring under illumination were continued and further additions of bromine were made until after 10 hours and the addition of a further 6 g of bromine, 95% of the starting material was shown by gas chromatography to be completely reacted. Excess bromine and hydrobromic acid were removed by applying vacuum (20 mm of mercury) to the heated liquid. The 2-bromoisooctadecanoyl chloride thus obtained was cooled and treated with 1,2,4-triazole (9.0 g) and drowned into water and extracted with petroleum ether (b.p. 60°-80° ). The organic solution was separated and washed with aqueous hydrochloric acid (2M) and water, and the solvent was distilled leaving 1-(2'-bromoiso- octadecanoyl)-1,2,4-triazole (25.3 g) as a pale brown oil. The nuclear magnetic resonance spectrum of the product as a solution in deuterated chloroform was compared with that of the product of Example 5, confirming that absorption at delta 3.4 ppm from tetramethylsilane, associated with a proton in the 2'-position of the side chain, had vanished. This compound was evaluated as an extractant for copper by the procedure of Example 1 and the results are presented in Table 1. The results show that the compound is a slightly "weaker" ligand than the products of Examples 1-7, and that it transfers only a small amount of acid.