Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[N:14]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Cl:12][C:13]1[N:14]=[C:15]([C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccnc1Br
Reactant: CC1(C)OB(c2cccc(Cl)n2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccnc1-c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.49 g (0.70 mmol) of (Ph3P)2PdCl2 is added under argan to a solution of 3.0 g (13.9 mmol) of methyl 2-bromonicotinate in 10 ml of dioxane and the mixture is stirred for 30 min at room temperature. Thereafter, 3.33 g (13.78 mmol) of 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 5.76 g (41.68 mmol) of K2CO3 and 11 ml of H2O are added in succession to the mixture, and the mixture is stirred for 6 hours under reflux and subsequently allowed to stand overnight at room temperature (RT). For work-up, the reaction mixture is poured into 150 ml of H2O and extracted repeatedly with CH2Cl2. The combined organic phases are dried over Na2SO4 and subsequently concentrated. The crude product thus obtained is purified by chromatography on silica gel using heptane/ethyl acetate (7:3) as the mobile phase. This gives 2.50 g (72%) of product as a colorless oil; 1H NMR (CDCl3) δ 8.70 (dd, 1H), 8.15 (dd, 1H), 7.95 (dd, 1H), 7.80 (dd, 1H), 7.40 (dd, 1H), 7.37 (dd, 1H), 3.90 (s, 3H, COOMe).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=O.Cl.[NH2:24][OH:25].[OH-].[Na+].O>CO>[N:24](=[C:14]1[CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]34[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:19]2[CH2:20][C:7]2[CH:8]=[CH:9][C:10]([OH:22])=[C:11]([O:12][C@@H:13]13)[C:6]4=2)[OH:25]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=NO)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of oxymorphone (1.2 g, 4 mmol) and hydroxylamine hydrochloride (0.35 g, 5 mmol) in 20 mL of methanol was treated with 2 mL of 10% aqueous NaOH and stirred at room temperature for 15 h. The reaction mixture was poured into water and extracted with 150 mL CHCl3 (3×50 mL). The CHCl3 extract was dried (MgSO4), and evaporated. The residue was recrystallized from THF-petroleum ether yielding 600 mg (47.4%), mp 270°-71° C. IR: (KBr): No C=O absorption at 1720 cm-1. H NMR (d6DMSO) δ 4.83 (s, C5H), Rf: silica gel EtOAc-EtOH-NH4OH (100:1:1) 0.18. Anal. Calcd for C17H20N2O4C, 64.54; H, 6.37; N, 8.86. Found C, 64.76; H, 6.5; N, 8.58.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15]C)=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CO.O>[CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([OH:15])=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)CC2
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Temperature: 22.5 °C
Reaction time: 18 h

Procedure:
A mixture of Bicyclo[2.2.2]octane-1,4-dicarboxylic acid dimethyl ester (III Example 80, 20.4 g, 89.5 mmol), barium hydroxide octahydrate (14 g, 44.7 mmol) in methanol (160 ml) and water (40 ml) is stirred at 20-25° C. for 18 hour. The mixture is diluted with water (600 ml) and extracted with hexane (150 ml×2). The aqueous mixture is acidified (6 N hydrochloric acid) to pH=1-2 and extracted with chloroform (150 ml 2). The combined chloroform extracts are concentrated. The residue is dissolved in toluene, filtered and concentrated to give the title compound, mp 169-173° C.
Reaction SMILES: C(O[CH:5]1[CH:9]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH:7]([O:19][CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[O:6]1)(=O)C.[CH3:29][O:30][C:31]([C:33]1[N:37]=[CH:36][NH:35][N:34]=1)=[O:32].[N+](C1C=CC(OP([O-])(OC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1)([O-])=O>>[CH3:29][O:30][C:31]([C:33]1[N:37]=[CH:36][N:35]([CH:5]2[CH:9]([O:10][C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:8][CH:7]([O:19][CH2:20][P:21]([O:23][CH2:24][CH3:25])([O:26][CH2:27][CH3:28])=[O:22])[O:6]2)[N:34]=1)=[O:32]
Reactant: COC(=O)c1nc[nH]n1
Reactant: CCOP(=O)(COC1CC(OC(=O)c2ccccc2)C(OC(C)=O)O1)OCC
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Product: CCOP(=O)(COC1CC(OC(=O)c2ccccc2)C(n2cnc(C(=O)OC)n2)O1)OCC
Yield: 65 %

Procedure:
Benzoic acid 2-acetoxy-5-(diethoxy-phosphorylmethoxy)-tetrahydro-furan-3-yl ester (170 mg, 0.4 mmol), 1H-[1,2,4]Triazole-3-carboxylic acid methyl ester (51 mg, 0.4 mmol) and Bis-(p-nitrophenyl)phosphate were reacted according to literature procedure (J. Med. Chem. 2000, 43, 1019-1028). The desired product was isolated in 65% yield (150 mg). 1H NMR (CDCl3, 300 MHz) δ 8.60 (s, 1H), 8.00 (d, 2H, J=7.8 Hz), 7.60 (t, 1H, J=7.2 Hz), 7.45 (app t, 2H, J=7.7 Hz), 6.29 (d, 1H, J=1.5 Hz), 5.91-5.98 (m, 1H), 5.67-5.71 (m, 1H), 4.11-4.23 (m, 4H), 3.96-4.04 (m, 4H), 3.85-3.92 (m, 1H), 2.55-2.72 (m, 2H), 1.29-1.37 (m, 6H). 31P NMR (121.4 MHz, CDCl3) δ 19.8. LRMS (ESI) MH+ C20H27N3O9P requires 484.1 Found 483.8.
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:16][C@@H:17]([C@H:19]1[C:40](=[O:41])[N:21]2[CH:22]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])[C:23](=O)[C@H:24]([CH3:25])[C@H:20]12)[CH3:18].FC(F)(F)S(O)(=O)=O.[SH:50][C@@H:51]1[CH2:55][N:54]([CH3:56])[C@H:53]([C:57]([N:59]2[CH2:65][CH2:64][CH2:63][N:62]([C:66]([O:68][CH2:69][C:70]3[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=3)=[O:67])[CH2:61][CH2:60]2)=[O:58])[CH2:52]1>C(#N)C.C(N(C(C)C)CC)(C)C>[N+:76]([C:73]1[CH:74]=[CH:75][C:70]([CH2:69][O:68][C:66]([N:62]2[CH2:63][CH2:64][CH2:65][N:59]([C:57]([C@@H:53]3[CH2:52][C@H:51]([S:50][C:23]4[C@H:24]([CH3:25])[C@@H:20]5[C@@H:19]([C@H:17]([OH:16])[CH3:18])[C:40](=[O:41])[N:21]5[C:22]=4[C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=4)=[O:28])[CH2:55][N:54]3[CH3:56])=[O:58])[CH2:60][CH2:61]2)=[O:67])=[CH:71][CH:72]=1)([O-:78])=[O:77]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CCCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 0.67 h
Yield: 57.4 %

Procedure:
0.89 ml of diphenylphosphoryl chloride and 0.75 ml of diisopropylethylamine were simultaneously added dropwise, whilst ice-cooling, to a solution of 1.4 g of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 14 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 40 minutes. A solution of 2.68 g of (2S, 4S)-4-mercapto-1-methyl-2-[4-(4-nitrobenzyloxycarbonyl)-1-homopiperazinylcarbonyl]pyrrolidine trifluoromethanesulfonate (prepared as described in Preparation 49) in 14 ml of dry acetonitrile and 1.64 ml of diisopropylethylamine were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 5 hours, after which it was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The dilute solution was then washed with an aqueous solution of sodium hydrogencarbonate, with a phosphate buffer solution (pH 6.86), with water and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel (Merck Art No. 7734), using a gradient elution method with mixtures of ethyl acetate and methanol ranging from 85:15 to 80:20 by volume as the eluent, to give 1.7 g of the title compound, as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22]>>[CH3:17][CH:18]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCCC(C)C(C)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCCC(C)C(C)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
0.45 g of compound 22 was obtained in a similar manner to those described in the Examples 1 and 2 using 0.75 g of ethyl 4-(2-aminophenoxy)butyrate and 0.50 g of 3-[1-(1,2-dimethylpentyl)indol-5-yl]isocrotonic acid obtained according the procedures described in the Reference Examples 1-4.
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH2:64])[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1.[CH3:65][O:66][C:67]1[N:72]=[C:71]2[C:73]([CH2:76][C:77](O)=[O:78])=[CH:74][NH:75][C:70]2=[CH:69][CH:68]=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH:64][C:77](=[O:78])[CH2:76][C:73]3[C:71]4=[N:72][C:67]([O:66][CH3:65])=[CH:68][CH:69]=[C:70]4[NH:75][CH:74]=3)[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2n1
Reactant: NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: COc1ccc2[nH]cc(CC(=O)NC(Cc3cc(F)cc(F)c3)c3cnc(-c4ccc(Cl)cc4)o3)c2n1

Procedure:
The title compound (6.0 mg) was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 19E and 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 11.6 (br, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.40 (s, 1H), 8.01 (s, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.6 Hz, 3H), 7.03 (s, 1H), 6.83 (d, J=7.8 Hz, 3H), 5.08 (d, J=5.3 Hz, 1H), 3.82 (s, 3H), 3.44 (s, 2H), 3.23-3.06 (m, 1H), 3.04-2.91 (m, 1H). MS (m/z) 523.1 [M+H]+.
Reaction SMILES: CC(C)(C)[O-].[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[C:34]([CH:35]=O)=[N:33][N:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31](=[O:43])[C:26]=3[N:27]([CH3:30])[C:28]=2[CH:29]=1.CO>COCCOC>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[C:34]([CH2:35][C:17]#[N:18])=[N:33][N:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31](=[O:43])[C:26]=3[N:27]([CH3:30])[C:28]=2[CH:29]=1
Reactant: Cn1c2cc(Cl)ccc2c2c(C=O)nn(-c3ccccc3)c(=O)c21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: Cn1c2cc(Cl)ccc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
1.27 g (10.96 mmol) of potassium 1,1-dimethylethoxide are added, in small portions, to a solution of 2.14 g (10.96 mmol) of (4-methylbenzenesulphonyl)methyl isocyanide in 50 ml of 1,2-dimethoxyethane, the reaction mixture is stirred for 30 min at −60° C., 2.88 g (8.53 mmol) of 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxaldehyde are added and the reaction mixture is stirred for 3 hours 30 min at −60° C. 9 ml of methanol are added and the reaction mixture is further stirred for 30 min at room temperature and for 1 hour at reflux. The mixture is cooled and concentrated under reduced pressure, water, 5 ml of acetic acid and 200 ml of dichloromethane are added to the residue, the organic phase is separated by settling and the aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel. 1.87 g (5.36 mmol) of compound are isolated in the form of a white solid which is used as is in the following stage.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:14][C:11]([F:12])([F:13])[C:10]1[O:15][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:9]=1
Reactant: O=C(Nc1ccc(O)cc1O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc2nc(C(F)(F)F)oc2c1
Yield: 40.8 %

Procedure:
A stirred solution of 0.8 gram (0.0036) of N-(2,4-dihydroxyphenyl)-2,2,2-trifluoroacetamide and a catalytic amount of p-toluenesulfonic acid in 50 mL of toluene was heated at reflux during an 18 hour period while the theoretical amount of water by-product was collected in a Dean-Stark trap. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH:9](=O)[CH:10]([CH3:12])[CH3:11].O>C1C=CC=CC=1.S(=O)(=O)(O)O>[CH:10]([CH:12]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)([CH3:11])[CH3:9]
Reactant: CC(C)C=O
Reactant: Oc1ccccc1O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(C)C1Oc2ccccc2O1
Yield: 33.5 %

Procedure:
Catechol (22 g, 0.2 mole) and isobutyraldehyde (16 g, 0.24 mole) were dissolved in benzene (600 ml). A catalytic amount (5 drops) of sulfuric acid was added to the mixture. The mixture was heated under reflux and the water formed in the reaction was removed by use of a Dean-Stark trap. The reaction mixture was washed twice with aqueous sodium carbonate solution and dried. 2-Isopropyl-1,3-benzodioxole (11 g, 0.067 mole) was obtained by vacuum distillation. The 2-isopropyl-1,3-benzodioxole thus obtained boiled at 29-31° C. at 0.25 mm Hg. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([N:15]([CH3:35])[CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:24][CH2:23]4)[C:12]([C:36]([F:39])([F:38])[F:37])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[Li+].[OH-].O.[CH2:43]1COC[CH2:44]1>CO>[CH2:43]([CH:29]([C@H:25]1[C:26]2[C:22](=[CH:21][C:20]([O:19][CH2:18][CH2:17][CH2:16][N:15]([C:13]3[C:12]([C:36]([F:37])([F:38])[F:39])=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=4)[N:14]=3)[CH3:35])=[CH:28][CH:27]=2)[CH2:23][CH2:24]1)[C:30]([OH:32])=[O:31])[CH3:44]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1ccc(-c2ccc(C(F)(F)F)c(N(C)CCCOc3ccc4c(c3)CC[C@H]4C(CC)C(=O)O)n2)cc1

Procedure:
Following the procedure described in Example 308 and starting with ethyl ((1S)-5-[(3-{[6-(4-ethylphenyl)-3-(trifluoromethyl)-2-pyridinyl](methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 319, 10 mg, 0.018 mmol), LiOH (0.1 mg, 0.004 mmol) in THF (1 mL), MeOH (1 mL), and water (0.5 mL), the title compound was obtained (0.0024 g, 51%). 1H NMR (400 MHz, CD2Cl2) δ 7.98 (d, 2H), 7.85 (d, 1H), 7.35-7.25 (m, 3H), 7.01 (d, 1H), 6.72 (d, 1H), 6.65 (dd, 1H), 4.02 (t, 2H), 3.83 (t, 2H), 3.47 (qt, 1H), 3.08 (s, 3H), 2.90-2.68 (m, 5H), 2.42-2.30 (m, 2H), 2.15 (qt, 2H), 1.78-1.68 (m, 1H), 1.33 (m, 3H); LC-MS: RT=4.50 min, (M+H)+ 513.2.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=[O:5])=[O:4].[NH2:9][C:10]1[S:11][C:12]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:8])([F:7])[S:3]([NH:9][C:10]1[S:11][C:12]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:14]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COc1ccc(-c2nc(N)sc2-c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(NS(=O)(=O)C(F)(F)F)sc2-c2ccc(OC)cc2)cc1
Yield: 26.7 %

Procedure:
13.5 g of anhydrous trifluoromethanesulfonic acid was slowly dropped into a solution of 5.0 g of 2-amino-4,5-bis(4-methoxyphenyl)thiazole and 5.0 ml of triethylamine in chloroform under stirring in a nitrogen atmosphere at -20° to -15° C., and the resulting mixture was stirred as such for 2 hours. Then the reaction mixture was successively washed with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water in this order and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the reaction product was separated with a silica gel column by using chloroform/ethyl acetate as a developer. The crystals thus obtained were recrystallized from isopropyl ether/ethyl acetate to give 1.9 g of 2-trifluoromethanesulfonylamino-4,5-bis(4-methoxy-phenyl)thiazole. The melting point of this product was from 240° to 242° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(C(F)(F)F)c1
Reaction time: 18 h
Yield: 80.8 %

Procedure:
A mixture of 100 g (0.618 mole) of α,α,α-trifluoro-m-cresol, 106 g (0.632 mole) of ethyl bromoacetate, 87.5 g (0.632 mole) of potassium carbonate, and 1500 ml of acetone is stirred at reflux for 4 hours, and at room temperature for 18 hours. The mixture is filtered, evaporated under vacuum on a rotorary evaporator at 45° C and at 85° C (0.1 mm) to remove excess ethyl bromoacetate. The reaction mixture is taken up in 500 ml of ether, washed three times with 100 ml each of 0.1M potassium carbonate, once with 100 ml of water, 100 ml of 0.01M hydrochloric acid, and 100 ml of water. It is then dried with magnesium sulfate, filtered and evaporated, giving 142 g of the crude product. This is fractionally distilled at 73°-75° C (0.1 mm) to give 124 g of the purified subject product as a colorless liquid.
Reaction SMILES: O=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][C:13]3[CH:14]=[C:15]([C:19]4([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[NH:3]1.CCOC(C)=O.C([O-])(O)=O.[Na+].P(Cl)(Cl)([Cl:40])=O>>[Cl:40][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][C:13]3[CH:14]=[C:15]([C:19]4([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#CC1(c2cccc(Sc3ccc4[nH]c(=O)ccc4c3)c2)CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#CC1(c2cccc(Sc3ccc4nc(Cl)ccc4c3)c2)CCOCC1
Temperature: 90 °C

Procedure:
5g (4.52 g, 12.5 mmol) was dissolved in phosphorus oxychloride (23 mL) and heated to 90° C. for 1 hour. The reaction was cooled to room temperature, and ice was added slowly, followed by EtOAc and NaHCO3. The aqueous layer was extracted with CH2Cl2 twice, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product, 5h.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CC(C)=O.C1(C)C=CC=CC=1>[O:18]1[CH2:17][CH:16]1[CH2:14][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCC1CO1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: c1ccc(OCC2CO2)cc1
Yield: 59.9 %

Procedure:
A mixture of 9.4 gm (0.1 mole) of phenol, 28 gm (0.2 mole) of potassium carbonate and 30 mL (0.4 mole) of epichlorohydrin in 250 mL acetone was heated to reflux for 12 hours. The reaction medium was then filtered and evaporated leaving an oil which was taken up in toluene and successively washed with 100 mL water, 2×100 mL 1.0 N sodium hydroxide and 2×100 mL water. The toluene phase was dried with magnesium sulfate and evaporated to provide a clear oil which was chromatographed on a Prep-500 silica gel column employing hexane: ethyl acetate (9:1) as the mobile phase. Collection of the major peak and evaporation of solvent provided 9 gm (60%) of a clear oil whose NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: C(O[C:6](=[O:34])[NH:7][CH:8]([CH3:33])[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][CH:18]1[CH2:22][C:21](=[O:23])[O:20][CH:19]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:10])(C)(C)C.[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[N:45]([CH3:47])[CH3:46])C(O)=O.O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH2:25]([O:24][CH:19]1[CH:18]([NH:17][C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9](=[O:10])[CH:8]([NH:7][C:6](=[O:34])[C:38]2[CH:42]=[CH:43][C:44]([N:45]([CH3:47])[CH3:46])=[C:36]([Cl:35])[CH:37]=2)[CH3:33])=[O:32])[CH2:22][C:21](=[O:23])[O:20]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Reactant: CN(C)c1ccc(C(=O)O)cc1Cl
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N(C)C)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 44 %

Procedure:
Prepared from {2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert-butyl ester and 3-chloro-4-dimethylamino-benzoic acid according to the procedure used to prepare 98a to afford 82 mg of title compound (44% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.18-1.53 (m, 3H), 1.70-2.40 (m, 4H), 2.55-3.10 (m, 2H), 2.84 (s, 6H), 3.45-3.94 (m, 2H), 4.25-4.95 (m, 5H), 5.46 (s, 0.3H), 5.51 (s, 0.2H), 5.63 (d, 0.4H), 5.73 (d, 0.1H), 7.05 (d, 1H), 7.15-7.95 (m, 7H). Analytical HPLC: 11.85, 12.19 min. LC-MS (ES+): m/e=557.3 (M+H+).