Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:21].[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32](O)[CH3:33])=[N:30][CH:31]=1.CCCCC>C(Cl)Cl>[Cl:21][CH:32]([C:29]1[CH:28]=[CH:27][C:26]([F:25])=[CH:31][N:30]=1)[CH3:33]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(O)c1ccc(F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: CC(Cl)c1ccc(F)cn1
Reaction time: 0.17 h
Yield: 3 %

Procedure:
A mixture of triphenylphospine (0.92 g, 3.5 mmol) and CCl4 (4 mL) was stirred for 10 min. and then a solution of 1-(5-fluoropyridin-2-yl)ethanol (0.25 g, 1.7 mmol) in DCM (2 mL) was added. After 18 h, pentane (20 mL) was added, the solid material was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluent heptane:ethyl acetate 3:1) affording the title compound (8 mg, 3% yield).
Reaction SMILES: Cl.O[CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9].S(=Cl)=O.[C-:21]#[N:22].[Na+]>C(Cl)(Cl)Cl.CS(C)=O>[C:21]([CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])#[N:22]
Reactant: COc1ccc(-c2nc(CO)c(C)[nH]2)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(CC#N)c(C)[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
To a stirred slurry of 15.3 g (0.06 mole) of 4-hydroxymethyl-2-p-methoxyphenyl-5-methyl-imidazole hydrochloride in 200 ml of chloroform are added 15 g (0.12 mole) of thionyl chlorine in CHCl3. Vigorous evolution of gas is observed during the addition. The reaction mixture is stirred at room temperature for 5 hours, during which time the slurry dissolves to form a pale pink solution. The solvent is then removed under reduced pressure and the solid residue taken up in fresh CHCl3. The solution is then filtered, ether is added until cloudy and then chilled. White crystals of 5-chloromethyl-2-p-methoxyphenyl-4-methyl-imidazole hydrochloride are precipitated, filtered and collected (91% yield), m.p. 203°-205° C (dec.). This chloromethyl derivative is dissolved in 75 ml of warm DMSO and added to a hot solution of 15 g (0.3 mole) of sodium cyanide in DMSO. The reaction mixture is stirred at room temperature for 16 hours and warmed to 60° C for 4 hours, then allowed to cool to room temperature and poured over 1 liter of ice and stirred. A yellow solid is precipitated, filtered and air-dried. Three recrystallizations from methylene chloride-hexane give the product, 4-cyanomethyl-2-(p-methoxyphenyl)-5-methyl-imidazole, as fluffy white crystals, m.p, 158°-160° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17]([N:35]3[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[CH2:37][CH2:36]3)=[C:18]([C@H:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:27]CC)=[O:26])[C:19]([CH3:23])=[N:20][C:21]=2[CH3:22])[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17]([N:35]3[CH2:36][CH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][CH2:40]3)=[C:18]([C@H:24]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[C:25]([OH:27])=[O:26])[C:19]([CH3:23])=[N:20][C:21]=2[CH3:22])[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(C)c(OCc3ccccc3)c2)c1N1CCC(C)(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c2N2CCC(C)(C)CC2)cc1OCc1ccccc1
Yield: 90.5 %

Procedure:
A solution of (S)-ethyl 2-(5-(3-(benzyloxy)-4-methylphenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0121 g, 0.021 mmol) and 1M NaOH (0.211 ml, 0.211 mmol) in EtOH (1 mL) was refluxed for 6 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(5-(3-(benzyloxy)-4-methylphenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid (0.0103 g, 0.019 mmol, 90% yield) as solid and ˜3:2 mixture of isomers by H-NMR. LCMS (M+H)=545.25.
Reaction SMILES: O[CH2:2][N:3]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([Cl:12])=[N:4]1.S(Cl)([Cl:15])=O>>[Cl:12][C:5]1[C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH3:8])[N:3]([CH2:2][Cl:15])[N:4]=1
Reactant: Cc1c([N+](=O)[O-])c(Cl)nn1CO
Reactant: O=S(Cl)Cl
Product: Cc1c([N+](=O)[O-])c(Cl)nn1CCl

Procedure:
A mixture of 13.58 g (0.0708 mole) 1-hydroxymethyl-3-chloro-5-methyl-4-nitropyrazole and 30 ml of thionyl chloride was heated under reflux overnight and concentrated in vacuo. Benzene was added and the solution was concentrated again. This was replicated two more times. This left 15.8 g of an amber liquid. This was distilled at 155°-170° (air bath temperature)/1.25 mm to obtain a colorless liquid which crystallized upon standing. Recrystallization from benzene-Skelly B solvent gave 9.52 g of white crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.CN(C)C=O>O>[Si:12]([O:1][CH2:2][C:3]1[NH:4][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: OCc1nc2cncnc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1nc2cncnc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A mixture of 1.81 g of 2-hydroxymethyl-3H-imidazo-[5,4-d]pyrimidine (prepared as described in Preparation 48), 2.71 g of t-butyldimethylsilyl chloride, 2.45 g of imidazole and 100 ml of dimethylformamide was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue thus obtained was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 1.89 g of the title compound, melting at 104-107° C.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([CH3:47])[CH2:43][CH2:44][NH:45][CH3:46])(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl.O>[F:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([N:42]([CH3:47])[CH2:43][CH2:44][N:45]([CH3:46])[C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([NH:14][C:8]3[C:7]4[C:12](=[CH:13][C:4]([C:3]([F:25])([F:24])[F:2])=[CH:5][CH:6]=4)[N:11]=[CH:10][CH:9]=3)=[CH:16][CH:17]=2)(=[O:40])=[O:41])=[CH:37][CH:38]=1
Reactant: CNCCN(C)S(=O)(=O)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(CCN(C)S(=O)(=O)c1ccc(F)cc1)C(=O)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
4-(7-Trifluoromethyl-4-quinolinylamino)benzoyl chloride hydrochloride (2.0 g) was added portionwise to a well-stirred mixture of sodium carbonate (8.0 g) and 4-fluoro-N-methyl-N-[2-(methylamino)ethyl]benzenesulphonamide (1.48 g) in chloroform (60 ml) and water (70 ml) at about 10° C. The mixture was warmed to room temperature and, after 1 hour, the chloroform layer was separated, dried (MgSO4) and evaporated under reduced pressure to give an oil, which crystallised on standing. Recrystallisation from ethanol/water gave a white solid, which was further purified by recrystallisation from ethanol, giving the pure title compound (1.4 g), m.p. 191°-3° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22]>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: OC[C@@H]1CCCN1
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC[C@H]1CO

Procedure:
Prepared analogously to Example 1.1.c. from 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and (S)-1-pyrrolidin-2-ylmethanol. Yield: 0.2 g (25% of theory); C14H20N2O5 (M=296.32); calc.: molecular ion peak (M+H)+: 297; found: molecular ion peak (M+H)+: 297; Rf value: 0.55 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>C(#N)C>[C:12]([NH:14][C:15]([NH:18][CH3:19])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: CN=C(NC#N)SC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (17.0 g.) and N-cyano-N',S-dimethylisothiourea (11.2 g.) in acetonitrile (500 ml.) was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was finally recrystallised from acetonitrile-ether to yield N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 141°-2°. (Found: C, 47.2; H, 6.4; N, 33.4; S, 12.4. C10H16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[F:18].[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>C1COCC1>[F:18][C:8]1[CH:9]=[C:10]([O:13][C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][C:7]=1[B:19]([OH:24])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cc(OC(F)(F)F)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC(F)(F)F)cc1F
Temperature: -98 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (2.5 M solution in hexanes, 14.1 mL) in THF (30 mL) at −98° C. was added a solution of 4-bromo-3-fluorotrifluoromethoxy-benzene in THF (3 mL). After stirring for 10 min. at −98° C., triisopropyl borate (4.88 mL, 3.98 g, 21 mmol) was added at a rate needed to keep the temperature below −97° C. The reaction mixture was allowed to warm to −30° C. over 30 minutes, re-cooled to −78° C. and stirred at this temperature for 30 min. Concentrated hydrochloric acid (2 mL) was added and the reaction mixture was concentrated under reduced pressure. Dilute hydrochloric acid (0.2 N, 15 mL) was added and the mixture was extracted with ether (3×20 mL). The combined ethereal layers were extracted with dilute sodium hydroxide (0.02 N, 3×30 mL). The combined aqueous extracts were cooled to 0° C., acidified to pH 3.5 using concentrated hydrochloric acid and extracted with ether (3×30 mL). The combined ethereal layers were then washed with water (15 mL) and brine (15 mL), dried over magnesium sulphate and concentrated under reduced pressure to leave 2.3 g of yellow solid. Recrystallisation from hexane afforded pink needles (1.25 g, 41%): mp 89-93° C.; 1H NMR (CDCl3) δ 7.89 (t, 1H), 7.07 (d, 1H), 6.94 (d, 1H), 5.11 (d, 2H); EI/MS 223 m/e (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH:26]3[CH2:30][O:29]C(C)(C)[O:27]3)[CH:21]=[CH:20][C:19]=2[CH3:33])=[O:17])=[C:12]([N+:34]([O-:36])=[O:35])[CH:11]=1>C(O)(C(F)(F)F)=O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH:26]([OH:27])[CH2:30][OH:29])[CH:21]=[CH:20][C:19]=2[CH3:33])=[O:17])=[C:12]([N+:34]([O-:36])=[O:35])[CH:11]=1
Reactant: Cc1ccc(OCC2COC(C)(C)O2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(OCC(O)CO)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 311 (48 mg, 0.01 mmol) was dissolved in TFA:H2O (3:1, 8 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:1) as the eluent, affording the title compound as a yellow oil. 13C NMR (DMSO-d6) δ 193.5, 156.3, 150.1, 148.8, 137.5, 132.5, 132.3, 129.3, 126.6 (dd), 123.9 (dd), 122.9, 117.3, 116.1, 115.6, 112.1 (dd), 108.6, 105.1 (dd), 69.8, 62.5, 19.0
Reaction SMILES: [OH:1][C:2]1[C:15]2[C@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[N:35][C:36]([O:39]C)=[N:37][CH:38]=2)=[CH:29][CH:28]=1)=[O:23].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>>[OH:1][C:2]1[C:15]2[C@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:34]=[N:35][C:36](=[O:39])[NH:37][CH:38]=2)=[CH:31][CH:32]=1)=[O:23]
Reactant: COc1ncc(-c2ccc(CCNC(=O)c3ccc4c(c3O)[C@]35CCN(C)[C@H](C4)[C@]3(O)CCC(=O)C5)cc2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1CC[C@]23CC(=O)CC[C@@]2(O)[C@H]1Cc1ccc(C(=O)NCCc2ccc(-c4cnc(=O)[nH]c4)cc2)c(O)c13
Temperature: 150 °C
Yield: 31.5 %

Procedure:
A mixture of 4,14-dihydroxy-N-{2-[4-(2-methoxypyrimidin-5-yl)phenyl]ethyl}-17-methyl-6-oxomorphinan-3-carboxamide (3) (0.5 g, 0.9 mmol) and pyridine hydrochloride (5 mL) was heated at 150° C. for 6 h. The reaction mixture was cooled, basified with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×40 mL). The aqueous phase was filtered and the collected brown solid was combined with the organic washes and evaporated to dryness. The residue was purified on silica eluting with dichloromethane/methanol (9:1) to dichloromethane/16% NH3 in methanol (9:1) to give 4,14-dihydroxy-17-methyl-6-oxo-N-{2-[4-(2-oxo-1,2-dihydropyrimidin-5-yl)pheyl]ethyl}morphinan-3-carboxamide (RDC6139) (0.15 g) as a white solid. This was dissolved in dichloromethane/methanol (3:1, 20 mL) and maleic acid (32 mg, 1 eq) added. The reaction mixture was stirred for 4 h and then the volatiles removed under vacuum at 40° C. The residue was freeze dried from water to give Compound 114,14-dihydroxy-17-methyl-6-oxo-N-{2-[4-(2-oxo-1,2-dihydropyrimidin-5-yl)phenyl]ethyl}morphinan-3-carboxamide maleate salt (0.17 g, 98%) as a white solid; LC/MS 529 (M+H)+; NMR (D2O): 1.15-1.21 (4H, m), 1.49-1.60 (1H, m), 1.65-1.90 (3H, m), 2.10-2.22 (1H, m), 2.29-2.41 (1H, m), 2.50-2.72 (5H, m), 2.90-3.00 (1H, m), 3.18-3.40 (3H, m), 3.45-3.60 (2H, m), 6.04 (2H, s), 6.95-7.05 (4H, m), 7.26 (1H, m), 8.11 (2H, bs).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[CH:7][S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(Br)sc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ncsc1-c1ccccc1
Yield: 12.8 %

Procedure:
A solution of 4-acetamido-2-bromo-5-phenylthiazole (U.S. Pat. No. 3,244,723) (5.5 g) and sodium acetate (1.55 g) in methanol (110 ml) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst until the theoretical uptake of hydrogen had occurred. The catalyst was removed by filtration and washed with methanol and the filtrate was evaporated to dryness. The residue was recrystallised three times from benzene-petroleum ether (b.p. 60°-80° C.) to give 4-acetamido-5-phenylthiazole (1.5 g) m.p. 105°-7° C. (Found: C, 60.3; H, 4.65; N, 12.7. C11H10N2OS requires: C, 60.5; H, 4.6; N, 12.8%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([CH3:28])[CH:30]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1cncc(B(O)O)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 36 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (5-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.87 min, m/z=459.1 [M+H]+, m/z=457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.79 (m, 1H) 1.85 (d, J=9.05 Hz, 1H) 2.39 (s, 3H) 2.88 (d, J=11.98 Hz, 1H) 3.15-3.30 (m, 2H) 3.37-3.49 (m, 1H) 4.15-4.25 (m, 0H) 4.83 (br. s, 0H) 7.35 (d, J=8.31 Hz, 2H) 7.67 (s, 1H) 7.85 (d, 2H) 8.02 (d, J=2.45 Hz, 1H) 8.39-8.49 (m, 2H) 8.77 (d, J=2.45 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([OH:32])=[O:31])[CH:18]=[C:17]3C(O)=O)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.O.C(=O)([O-])[O-].[Na+].[Na+]>N1C2C(=CC=CC=2)C=CC=1>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([OH:32])=[O:31])[CH:18]=[CH:17]3)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)O)cc(C(=O)O)c2c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 170 °C
Yield: 62.1 %

Procedure:
In 10 ml of quinoline were dissolved 44.2 mg of the 6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-2-(2-carboxyphenyl)-4-quinolinecarboxylic acid obtained in Example 9. After adding 100 mg of conc. sulfuric acid, the mixture was heated at 170° C. for 1 hour. Then the reaction mixture was poured into water, made alkaline by adding sodium carbonate and washed with toluene. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. Then the precipitate was collected by filtration and purified by flash chromatography on silica gel with the use of chloroform/methanol. Thus 25 mg of 2-{6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoic acid were obtained. NMR (270 MHz, CDCl3): δ 7.2-8.2 (m,9H); 5.4 (s,2H); 4.5 (s,2H); 2.6 (t,J=8Hz,2H); 1.2-1.8 (m,4H); 1.4 (m,2H); 0.8 (t,J=8Hz,3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:22]#[N:23])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]2[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:20])([CH3:19])[C:13]=2[CH:21]=1)([O-])=O.[Cl-].[NH4+].O>C(O)C.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:22]#[N:23])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]2[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:19])([CH3:20])[C:13]=2[CH:21]=1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3[nH]c(C#N)cc3[N+](=O)[O-])cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3[nH]c(C#N)cc3N)cc21
Temperature: 80 °C
Yield: 80.3 %

Procedure:
A solution of 4-nitro -5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (0.4 g, 1.28 mmol) in ethanol/water (5:1, 20 mL) was treated sequentially with zinc powder (2.5 wt, 1.0 g) and ammonium chloride (5 wt, 2.0 g). The suspension was heated at 80° C. or 30 min, cooled to room temperature, poured into water (30 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with ethyl acetate to give 4-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (0.29 g, 80%) as a yellow solid. 1H NMR (500 MHz, d6-DMSO) δ 1.63 (s, 6H), 4.29 (s, 2H), 6.39 (s, 1H), 6.89 (d, 1H, J=8.1 Hz), 7.49 (s, 1H), 7.52 (dd, 1H, J=8.1 and 2.3 Hz), 10.25 (s, 1H), 11.76 (s, 1H). MS (ESI (−)) m/z 281 (M−H)−. Anal. calcd for C15H14N4O2, C, 63.8, H, 5.00, N, 19.9. Found, C, 63.7, H, 5.10, N, 19.82
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH2:18]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH:32]=O)[CH:22]=1)[CH2:19][CH3:20]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:32][C:23]2[CH:22]=[C:21]([CH2:18][CH2:19][CH3:20])[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:24]=2)[CH2:13][CH2:14]1
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Product: CCCc1cc(CNCCN2CCN(c3cccc(C)c3C)CC2)nn1-c1ccccc1
Yield: 69.2 %

Procedure:
Compound 16 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]([CH:20]([CH3:22])[CH3:21])[C:5]=1[NH:23][CH2:24][C:25]([O:27]CC)=[O:26])([CH3:3])[CH3:2].[OH-].[Na+]>Cl>[C:25]([CH2:24][NH:23][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]([C:10]([OH:19])([C:15]([F:17])([F:16])[F:18])[C:11]([F:14])([F:12])[F:13])=[CH:7][C:6]=1[CH:20]([CH3:22])[CH3:21])([OH:27])=[O:26]
Reactant: CCOC(=O)CNc1c(C(C)C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C(C)C)c1NCC(=O)O

Procedure:
Stirr ethyl N-[2,6-diisopropyl-4-(hexafluoro-2-hydroxy-2-propyl)phenyl]glycinate (5.0 g, 12 mmol) with 50 ml 1.0 N NaOH for 1 hour. Neutralize the solution with 50 ml 1.0 N HCl. Filter the solid, dissolve in ether, dry and concentrate. Recrystallize from ether-hexane to obtain the title compound as a white solid, m.p. 130°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[NH2:31]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:28]([O:27][CH3:26])[CH:29]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1ccc(N)cc1OC
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(OC)c(OC)c3)nc21
Temperature: 160 °C

Procedure:
A mixture of 0.150 g (0.38 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.500 g (3.30 mmol) of 3,4-dimethoxyaniline was heated in a 160° C. oil bath for 5 minutes. The dark blue solution was cooled and dissolved in 2 mL of warm glacial acetic acid. This solution was diluted to 10 mL volume with water to precipitate a solid. The solid was filtered, washed well with water, and dried; wt 0.200 g. Purification was effected by filtration of an ethyl acetate (25 mL) solution through a layer of silica gel and washing the silica gel with ethyl acetate. The filtrate was concentrated to 3 mL volume. The crystals that separated on inducement were filtered and washed with 1 mL of ethyl acetate and then 1 mL of ether; wt 0.116 g; mp 221°-223° C.