Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:42])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[CH:12][C:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[NH:28][C:27]([C@@H:29]6[CH2:33][CH2:32][CH2:31][N:30]6C(OC(C)(C)C)=O)=[N:26][CH:25]=5)=[CH:20][CH:19]=4)[S:15][C:14]=3[CH:41]=2)[O:4]1.CN1CCOCC1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[CH3:77][O:78][C:79]([NH:81][C@H:82]([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[C:83](O)=[O:84])=[O:80]>O1CCOCC1.ClCCl.C(OCC)(=O)C>[O:84]=[C:83]([N:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[C:27]1[NH:28][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[S:15][C:14]4[CH:41]=[C:10]([B:5]5[O:6][C:7]([CH3:9])([CH3:8])[C:3]([CH3:42])([CH3:2])[O:4]5)[CH:11]=[CH:12][C:13]=4[CH:17]=3)=[CH:23][CH:22]=2)=[CH:25][N:26]=1)[C@H:82]([NH:81][C:79](=[O:80])[O:78][CH3:77])[C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4ccc(B5OC(C)(C)C(C)(C)O5)cc4s3)cc2)[nH]1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4ccc(B5OC(C)(C)C(C)(C)O5)cc4s3)cc2)[nH]1)c1ccccc1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
A solution of hydrogen chloride in dioxane (4 N, 5 mL) was added to a solution of (S)-tert-butyl 2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (328 mg, 0.56 mmol) in dichloromethane (5 mL). Gas evolution was observed. After 20 min the solvent was removed under reduced pressure and the residue was placed under high vacuum for 30 min. The solid was taken up in N,N-dimethylformamide (3 mL) and N-methylmorpholine (158 μL, 1.43 mmol) was added to the solution. In a separate vessel, COMU (258 mg, 0.605 mmol), and N-methylmorpholine (158 μL, 1.43 mmol) were added to a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (126 mg, 0.604 mmol) in dichloromethane (3 mL). This was stirred for 5 minutes and both solutions were combined. After 15 minutes the mixture was diluted with ethyl acetate (20 mL) and washed with water (5 mL) and brine (5 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography with eluant of (10% methanol in ethyl acetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide methyl (R)-2-oxo-1-phenyl-2-((S)-2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethylcarbamate (261 mg, 0.39 mmol, 69%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[O:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:22]([OH:23])=[C:19]([O:20][CH3:21])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:22]=1[O:23][CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8])[CH:16]=[O:15]
Reactant: Cc1sc(N2CCOCC2)nc1CCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A mixture of 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)morpholine (5.0 g), vanillin (3.27 g), potassium carbonate (2.97 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as crystals (7.25 g, yield 96%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [NH2:1][C@H:2]1C[CH2:5][C@H:4](O)[CH2:3]1.[CH3:8][C@@H:9]([C@@H:15]1[C@@:19]2([CH3:35])[C@@H:20]([OH:34])[CH2:21][C@@H:22]3[C@@:27]4([CH3:33])[CH2:28][CH2:29][C@@H:30]([OH:32])[CH2:31][C@H:26]4[CH2:25][CH2:24][C@H:23]3[C@@H:18]2[CH2:17][CH2:16]1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH3:36][OH:37]>>[NH2:1][C@H:2]1[C@H:36]([OH:37])[CH2:5][CH:4]=[CH:3]1.[CH3:8][C@@H:9]([C@@H:15]1[C@@:19]2([CH3:35])[C@@H:20]([OH:34])[CH2:21][C@@H:22]3[C@@:27]4([CH3:33])[CH2:28][CH2:29][C@@H:30]([OH:32])[CH2:31][C@H:26]4[CH2:25][CH2:24][C@H:23]3[C@@H:18]2[CH2:17][CH2:16]1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: N[C@H]1CC[C@H](O)C1
Reactant: CO
Agent: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Product: N[C@@H]1C=CC[C@H]1O

Procedure:
A 49.5 g (0.50 M) quantity of dl trans-3-amino-hydroxycyclopentane dissolved in about 100-200 ml of methanol and 98 g (0.25M) of deoxycholic acid dissolved in about 200-300 ml of methanol are mixed and allowed to crystallize for several hours. The crystals of trans-3-amino-4-hydroxycyclopentene are collected by filtration and washed three times with some portions of methanol. There is obtained 105 g of trans-3-amino-4-hydroxycyclopentene deoxycholate as light beige crystals, m.p. 195°-197° (dec). The mother liquors are saved for Step 2.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[NH:8][C:7]=1[CH3:14])=[O:5])C.[OH-].[K+].Cl>CO.O>[CH:12]([C:9]1[NH:8][C:7]([CH3:14])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[CH3:11])=[O:13]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)O
Temperature: 25 °C
Yield: 95.7 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid which formed was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[C:13]([O:21][CH3:22])(=[O:20])[CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:28]([O:27][C:25](=[O:26])[CH2:24][CH:14]([C:13]([O:21][CH3:22])=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)CCCC(=O)[O-]
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CCC(=O)O)CC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of n-BuLi (2.5 M, 2.6 mL, 71.5 mmol) in anhydrous THF (200 mL) was added anhydrous diisopropyl amine (9.6 mL, 68.30 mmol) at −78° C. After 20 minutes of stirring, a solution of monomethyl glutarate (5 g, 32.5 mmol) in anhydrous THF (20 mL) was added drop wise under controlled temperature. After 30 minutes, a solution of tert-butyl bromoacetate (4.9 mL, 32.50 mmol) in anhydrous THF (20 mL) was slowly added followed by the addition of HMPA (8 mL). The reaction mixture was stirred at −78° C. for an additional 2 h followed by 24 h at room temperature. The reaction mixture was partitioned between HCl (2N, excess) and ethyl acetate. The organic phase was separated and the aqueous phase was extracted several times with ethyl acetate. The recombined organic layer was extracted with brine, dried over sodium sulfate, filtered, and evaporated. The residue was first flashed with chloroform and then with 2-5% methanol in chloroform. The product was obtained as a light yellow oil. 1H-NMR(CDCl3, 400 MHz: 1.42(s, 9H); 1.89(m, 2H); 2.24(m, 2H); 2.64(m, 2H); 2.84(m, 1H); 3.69(s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][C@H:20]([CH2:22][C:23]([O:25]CC)=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1.[OH-].[Na+]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][C@H:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Reaction time: 18 h
Yield: 96.2 %

Procedure:
A mixture of ethyl (R)-10,11-dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (0.4 g, 0.93 mmole) and 1.0 N NaOH (1.1 mL, 1.1 mmole) in absolute EtOH (10 mL) was warmed in an oil bath set at 50° C. After 18 hr, the reaction was concentrated on the rotavap and the residue was dissolved in H2O. The aqueous solution was adjusted to pH 4 with 3 N HCl, and the solid precipitate was collected and washed with H2O. The material was dried in high vacuum at 40° C. to afford the title compound (0.36 g, 96%) as a nearly colorless solid: [α]D +50.8° (c=0.12, CH3OH); MS (ES) m/e 403 (M+H)+. Anal. Calcd for C25H26N2O3.0.5 H2O: C, 72.97; H, 6.61; 6.80. Found: C, 73.09; H, 6.38; N, 6.58.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:48])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51].[CH2:53]([OH:55])[CH3:54]>O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:48])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51].[CH2:53]([O-:55])[CH3:54]
Reactant: CCO
Agent: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Solvent: O
Product: CC[O-]
Reaction time: 4 h

Procedure:
Ten g of azithromycin crude was introduced into a 0.25 liter three-necked flat flanged jacketed vessel equipped with a mechanical stirrer, a condenser and thermometer and containing 30 ml of absolute ethanol at 20° C. Three ml of water at 20° C. were added and the solution was heated at a constant temperature gradient so as to reach 55° C. after 4 hours. Between 35° C. and 55° C., additional water having a total volume of 11 ml was slowly added at regular time intervals. When 55° C. was reached, the resulting suspension was maintained at this temperature for 2 hours, during which an additional 49 mL of water was added. The suspension was then cooled from 55° C. to 20° C. over 2 hours. The precipitate was filtered. After drying, 9 g of azithromycin ethanolate were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=4)[C@@H:19]([NH:21][C:22](=[O:33])[C@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[NH2:25][C@H:23]([CH3:24])[C:22]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)=[O:33]
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@@H](C)N)c1

Procedure:
Tert-butyl (R)-1-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-ylamino)-1-oxopropan-2-ylcarbamate (303a, 25 mg, 0.04 mmol) in DCM/TFA 1:1 (1 ml) was shaken for 1 h and then evaporated. Yield 25 mg (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]([NH:19][C:20](=[O:29])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[O:18])[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[Cl:11].[OH-].[K+].I[CH3:33]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]([N:19]([CH3:33])[C:20](=[O:29])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[O:18])[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]([F:13])([F:14])[CH:10]([Cl:11])[Cl:12]
Reactant: CI
Reactant: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(Cl)Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C(=O)Nc1cc(Cl)c(OC(F)(F)C(Cl)Cl)c(Cl)c1)C(=O)c1c(F)cccc1F

Procedure:
N-(((3,5-Dichloro-4-(2,2-dichloro-1,1-difluoroethoxy)phenyl)amino)carbonyl)-2,6-difluorobenzamide (9.9 g, 0.02 mole) and KOH (1.4 g, 87 percent purity, 0.02 mole) were added to 50 ml dimethylformamide with stirring, giving a clear solution. Iodomethane (3.2 g, 0.022 mole) was added and the resulting solution was stirred at room temperature for about 24 hours. The precipitated product was collected by suction filtration and dried. The product was purified by recrystallization from isopropanol. The purified product was a white solid melting at 153°-155° C. NMR spectral features support the structural assignment.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].C(=O)(O)[O-].[Na+].[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>C(OCC)(=O)C>[NH2:30][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([N:15]([CH2:17][C:18]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][N:21]([C:39]([CH:36]3[CH2:38][CH2:37]3)=[O:40])[CH2:22][CH2:23]2)[CH3:16])[N:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(C(=O)C4CC4)CC3)nc(N)c2cc1OC
Reaction time: 0.5 h

Procedure:
A mixture of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (125 mg), ethyl acetate (10 ml) and aq. sodium bicarbonate (10 ml) was stirred vigorously while 40 μL of cyclopropylcarbonyl chloride were added slowly via syringe. After 30 min., the reaction mixture was worked up as usual to yield 1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-1-cyclopropyl-methanone 12, MS: 476 ([M+H]+) The crude base was converted to the hydrochloride salt as a white powder (120 mg).
Reaction SMILES: [OH:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[C:9](Cl)(=[O:12])[O:10][CH3:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:10][C:9]([O:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1)=[O:12]
Reactant: O=C1C=CC(O)OC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)OC1C=CC(=O)CO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.2 %

Procedure:
12 g of 6-hydroxy-2H-pyran-3(6H)-one was dissolved in 100 ml of methylene chloride, and the solution was cooled to 0° C. Then, 9.4 g of methyl chlorocarbonate was added thereto, and a solution comprising 10.6 g of triethylamine and 20 ml of methylene chloride was dropwise added thereto. The mixture was stirred for 3 hours, and the reaction mixture was poured into ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure, and the residue was subjected to distillation under reduced pressure to obtain 10.3 g (yield: 60%) of the above-identified compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[C:19]([CH2:24]OC)=[CH:20]N(C)C)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:28][C:29]([NH2:31])=[S:30].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:24])=[CH:20][N:31]=[C:29]([SH:30])[N:28]=2)[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(N)=S
Reactant: COCC(=CN(C)C)C(=O)c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cnc(S)nc1-c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Temperature: 90 °C
Yield: 48.1 %

Procedure:
4-(3-Dimethylamino-2-methoxymethyl-acryloyl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (17.6 mmol, 6.0 g) was combined with thiourea (39 mmol, 3.0 g) and potassium carbonate (53 mmol, 7.3 g) in ethanol (50 mL) and the resulting suspension was heated at 90° C. for 24 hrs. The solvent was removed in vacuo and the resulting black solid was diluted with water and the solid was removed by filtration. The solid was washed with ethyl acetate twice and the aqueous solution was acidified to pH 5-6 with HCl (2N). The solid formed was removed by filtration and the aqueous solution was then extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate. The solvent was removed under vacuum to afford the title compound as a brown solid (3.0 g, 48% yield). HPLC Method B, Rt=3.7 minutes, 1H NMR consistent with structure.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([OH:32])([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([O:30]C)[CH:24]=[CH:23]4)=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.BrC1C=CC(C2C=C3C(=CC=2)N=C(OC)C=C3)=CC=1.N1C=CC=CC=1.C[Si](I)(C)C>CO.C(Cl)(Cl)Cl>[OH:32][C:10]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([OH:30])[CH:24]=[CH:23]4)=[CH:18][CH:19]=2)[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COc1ccc2cc(-c3ccc(C4(O)CCCN(Cc5ccccc5)C4)cc3)ccc2n1
Agent: COc1ccc2cc(-c3ccc(Br)cc3)ccc2n1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: Oc1ccc2cc(-c3ccc(C4(O)CCCNC4)cc3)ccc2n1
Temperature: 55 °C

Procedure:
By the method described in Preparation 7, 1-benzyl-3-hydroxy-3-(4-(2-methoxyquinolin-6-yl)phenyl)piperidine is prepared from 6-(4-bromophenyl)-2-methoxyquinoline. This material (0.20 g, 0.471 mmol) is placed in a sealed tube under nitrogen with chloroform (5 mL), pyridine (0.02 ml, 0.075 mmol). and trimethylsilyliodide (0.107 ml, 0.754 mmol). The mixture is heated slowly to 55° C. in an oil bath for fifteen hours with stirring. The sealed tube is cooled to 0° C., opened and the contents diluted with methanol (50 ml). The solution is concentrated to dryness and the crude residue is purified by flash column chromatography using 10% methanol in methylene chloride to yield of 1-benzyl-3-hydroxy-3-(4-(2-hydroxyquinolin-6-yl)phenyl)piperidine as a yellow solid (0.1 g, 51%). The debenzylation is carried out as in preparation 1 to yield 3-hydroxy-3-(4-(2-hydroxyquinolin-6-yl)-phenyl)-piperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].C1(C)C=CC(S([CH2:22][N+:23]#[C-:24])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[C:6]1[O:7][CH:24]=[N:23][CH:22]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1cnco1

Procedure:
To a solution of 2-nitro-4-chlorobenzaldehyde (2.2 g, 11.8 mmol) and p-toluenesulfonyl-methylisocyanide (2.8 g, 14.2 mmol) in methanol (50 mL) was added potassium carbonate (8.2 g, 59 mmol) solid. The heterogeneous mixture was heated to reflux for 2.5 hours. Upon moving to room temperature, the reaction was filtered and concentrated in vacuo. The residue was dissolved in 0.1N sodium hydroxide and extracted with methylene chloride two times. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give crude 5-(2-nitro-4-chlorophenyl)oxazole.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:20][CH2:21][C:22]([O:24]C)=[O:23])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:26](=[O:28])[NH2:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:26](=[O:28])[NH2:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2CC1CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2CC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of [9-[(cyclopentyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (20 mg, 0.065 mmol) in 0.3 mL of THF and 0.1 mL of MeOH was treated with 0.1 mL of 1 N aq LiOH (0.1 mmol), and the mixture stirred at room temperature for 2 hours. The reaction was acidified with 0.2 N HCl, and the organics were removed in vacuo. The white precipitate was filtered away from the aqueous layer and rinsed with Et2O to afford 15 mg (0.0409 mmol; 63%) the title acid as a white powder. MS (ES) m/e 367 (M+1), 350 (M+H—NH3), 365 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:27]=[C:26]([CH:33]=O)[CH:25]=2)=[CH:20][CH:19]=1>>[C:29]([N:28]1[C:24]([C:21]2[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=2)=[CH:25][C:26]([CH2:33][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12]2)=[N:27]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Reactant: NCCN1CCN(c2ccccc2F)CC1
Product: CC(C)(C)n1nc(CNCCN2CCN(c3ccccc3F)CC2)cc1-c1ccc(Cl)cc1
Yield: 74.2 %

Procedure:
Compound 70 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: O1C2=CN=CC=C2C(=O)C1.C(OC([C:16]1[O:25][C:19]2=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=[C:18]2[C:17]=1[OH:26])=O)C>>[CH3:24][C:21]1[N:20]=[C:19]2[O:25][CH2:16][C:17](=[O:26])[C:18]2=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1oc2nc(C)ccc2c1O
Agent: O=C1COc2cnccc21
Product: Cc1ccc2c(n1)OCC2=O

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridin-3(2H)-one (A.2.4.3), 3-hydroxy-6-methylfuro[2,3-b]pyridine-2-carboxylic acid ethyl ester replacing 3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester;
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:18])([F:19])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: NCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NCC(F)(F)F
Yield: 79 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.81 ml (0.013 mol) of triethylamine, 1.1 ml (0.013 mol) of 2,2,2-trifluoroethylamine in 30 ml of DMF were reacted at 40° C. for 48 hours affording 4.71 g of oil. This oil was kugelrohr distilled at 53 Pa, pot temperature 110°-120° C. to give 2.82 g (47.3%) of product as a yellow oil, N25D 1.4496.