Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(CNC([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2O)=[CH:17][C:16](C(O)=O)=[CH:15][C:14]=3F)=O)=CC=1.C1(P([N:41]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[NH2:41][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:19]2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Solvent: CC(C)(C)O
Product: Nc1ccc2ncccc2c1

Procedure:
Compounds of the present invention may also be prepared by following the procedures described in Chart T. In CHART T, 3-{[(4-Chlorobenzyl)amino]-carbonyl}-8-fluoro-4-hydroxy-6-quinolinecarboxylic acid of example t-1 is converted to the 6-tert-butyl carbamate t-2 by treatment with diphenylphosphoryl azide in tert-butanol with heating. The carbamate is removed with trifluoroacetic acid to afford the 6-aminoquinoline t-3. The amine is sulfonylated with 4-methoxyphenylsulfonyl chloride in pyridine to yield the 6-sulfonamide t-4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([O:46][CH2:47][CH3:48])=[C:28]([C:30]2[NH:35][C:34](=[O:36])[C:33]3=[C:37]([CH3:45])[N:38]=[C:39]([CH:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[N:32]3[N:31]=2)[CH:29]=1)=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH2:47]([O:46][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([CH:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[O:22])=[CH:29][C:28]=1[C:30]1[NH:35][C:34](=[O:36])[C:33]2=[C:37]([CH3:45])[N:38]=[C:39]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[N:32]2[N:31]=1)[CH3:48]
Reactant: CCOc1ccc(NC(=O)C2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)C2CNCCN2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
132 mg (0.198 mmol) of the compound from example 48 are treated with 5 ml of trifluoroacetic acid for 90 minutes the solution is then concentrated dichloromethane and 10% strength NaHCO3 solution are added to the residue and the organic phase is dried and concentrated under reduced pressure.
Reaction SMILES: [C:1]([C:3]1([C:16]2[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>[Ni]>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:2][CH2:1][C:3]1([C:16]2[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:30]
Reactant: COCOc1cccnc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Ni]
Product: COCOc1cccnc1C1(CNC(=O)c2ccc(Cl)cc2Cl)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl 4-cyano-4-[3-(methoxymethoxy)pyridin-2-yl]piperidine-1-carboxylate was reduced using Raney nickel and acylated using 2,4-dichlorobenzoyl chloride using the method exemplified in example 8-1 to afford the desired product: tert-butyl 4-{[(2,4-dichlorobenzoyl)amino]-methyl}-4-[3-(inethoxymethoxy)pyridin-2-yl]piperidine-1-carboxylate: 1H NMR δ (ppm)(CDCl3): 8.18 (1 H, dd, J=1.3, 4.5 Hz), 7.50-7.46 (2 H, m), 7.33 (1 H, d, J=1.9 Hz), 7.25 (1 H, dd, J=8.3, 2.0), 7.15 (1 H, dd, J=4.6, 8.3 Hz), 6.70 (1 H, m), 5.25 (2 H, s), 4.01 (2 H, br s), 3.68-3.62 (2 H, m), 3.49 (3 H, s), 3.44-3.38 (2 H, m), 2.75-2.69 (2 H, m), 1.66-1.60 (1 H, m) 1.46 (9 H, s).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:8]=[C:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]2[CH:21]=1)=[O:5])[CH3:2].[Cl:22]N1C(=O)CCC1=O>O1CCCC1>[Cl:22][C:21]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][C:9]2=[N:8][C:7]=1[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5]
Reactant: CCNC(=O)Nc1cn2ccc(-c3cccnc3)cc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)ccn2c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Ethyl-3-(7-pyridin-3-yl-imidazo[1,2-a]pyridin-2-yl)-urea (1) (196 mg, 0.70 mmol), prepared as in Example 1, was dissolved/suspended in tetrahydrofuran (80 mL) and cooled to 0° C., (ice/water). N-chlorosuccinimide (102 mg, 0.77 mmol) was added and the mixture stirred at 0° C. for 2 h. All solids had dissolved and the reaction was complete by LCMS after this time. The solvent was removed under reduced pressure to give a residue which was purified by chromatography on silica gel (2% methanol/dichloromethane), followed by recrystallization from ethyl acetate/methanol to afford 1-(3-chloro-7-pyridin-3-yl-imidazo[1,2-a]pyridin-2-yl)-3-ethyl-urea (2) as a solid (132 mg). HRMS (EI+) calcd C15H1435ClN5O (M+) 315.0887, found 315.0882; calcd C15H1437ClN5O (M+) 317.0857, found 317.0862.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A mixture of 0.56 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.22 g of 4-trifluoromethylphenol, 0.21 g of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at room temperature. After stirring for 7 hours, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.48 g of 3,5-dichloro-4-(3-(4-trifluoromethylphenoxy)propyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (71% yield), nD24.4 1.5390.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.CN(C)C=O.S(C1C=CC(C)=CC=1)(O[CH2:17][C@@H:18]1[CH2:32][C@H:31]2[C@@H:21]([CH2:22][C:23]3[C:33]4[C:26](=[CH:27][CH:28]=[CH:29][C:30]2=4)[NH:25][CH:24]=3)[N:20]([CH3:34])[CH2:19]1)(=O)=O>C(O)C>[CH3:34][N:20]1[C@H:21]2[C@@H:31]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:33]=3[C:23]([CH2:22]2)=[CH:24][NH:25]4)[CH2:32][C@@H:18]([CH2:17][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CN1C[C@H](Cn2ccnc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
1.0 g of 50% sodium hydride in an oil was added in small portions to a mixture of 2.0 g of imidazole and 20 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 3.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 3 hours. After allowing the mixture to cool, ice-water was added to the reaction mixture, and the precipitated crystals were filtered and washed with water. The crystals thus obtained were dissolved in ethanol, and the solution was concentrated to a volume of about 1/3, followed by allowing to cool to obtain 1.3 g of the titled compound as colorless prisms having a melting point of higher than 260° C. (with decomposition).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[CH2:15]([Li])CCC.CI>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:15])=[C:3]([CH:10]2[O:14][CH2:13][CH2:12][O:11]2)[CH:4]=1
Reactant: COc1ccc(Br)c(C2OCCO2)c1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(C)c(C2OCCO2)c1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
A stirred solution of 2-(2-bromo-5-methoxyphenyl)-[1,3]dioxolane (25.92 g) in tetrahydrofuran (400 mL) at −70° C. is treated dropwise with a solution of n-butyl lithium in hexanes (48.0 mL, 2.5 M). After stirring for 10 minutes methyl iodide (21.29 g) is added dropwise whilst maintaining the temperature at −65° C. The reaction mixture is stirred at −65° C. for 1 hour, allowed to warm to room temperature and stirring is continued for a further hour. The reaction mixture is evaporated and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase is washed with brine (500 mL),dried over magnesium sulphate and evaporated to give 2-(5-methoxy-2-methyl-phenyl)-[1,3]dioxolane (18.25 g) as a yellow oil.
Reaction SMILES: [CH3:1]/[C:2](/O[Si](C)(C)C)=[N:3]\[Si:4]([CH3:7])([CH3:6])[CH3:5].[CH2:13](NCC)[CH3:14]>>[CH2:2]([N:3]([Si:4]([CH3:7])([CH3:6])[CH3:5])[CH2:13][CH3:14])[CH3:1]
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Reactant: CCNCC
Product: CCN(CC)[Si](C)(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
In a 500 ml four-neck flask equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer, 290.3 g (1.43 mol) of N,O-bis(trimethylsilyl)acetamide was placed, and thereto was added dropwise 94.9 g (1.3 mol) of diethylamine from the dropping funnel over a 1-hour period. During the addition, the temperature of the reaction system was kept within the range of 20° C. to 60° C. to make the reaction be proceeding. At the conclusion of the addition, the temperature was raised to 50-60° C. and kept there for 2 hours, whereby the reaction was matured. Then, the reaction product was subjected to vacuum distillation. As the result of this procedure, 152 g of diethylaminotrimethylsilane was obtained as a fraction having a boiling point of 60° C. under the pressure of 80 mmHg. The yield was 90%.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pt]>[CH:10]1[C:9]2[C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=3[O:7][C:8]=2[CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Pt]
Product: c1ccc2c(c1)oc1ccccc12

Procedure:
Commercial use of these materials has been hampered however, by reason of high costs, presence of impurities, and general unavailability. Commercially available dibenzofuran for example is presently obtained from coal tar and frequently contains impurities such as acenaphthene and fluorene which cannot conveniently be separated by commercially suitable methods such as washing, recrystallization, or distillation. In some cases dibenzofuran having greater purity as compared to that obtained from coal tar may be synthesized, but the prior art methods are costly because of expensive starting materials, complicated procedures, low yields or the like. For example, dibenzofuran has been obtained in a 30% yield by Graebe and Ullmann [Ber. 29, 1877 (1896)] by diazotization and subsequent hydrolysis of 2'-aminodiphenyl oxide, while Tauber and Halberstadt [Ber., 25, 2745 (1892)] obtained a yield of 75% by similar treatment of 2,2-diaminodiphenyl. These two methods however are not adapted to commercial operation due to the high cost and difficulty of obtaining the starting materials required. Hale and Stoesser (U.S. Pat. No. 1,808,349) obtained dibenzofuran by intramolecular dehydrogenation of orthophenylphenol over a refractory oxide catalyst, but again the high cost of the starting material limits the commercial utility of this route. Cullinane [J. Chem. Soc., 2267 (1930)] obtained dibenzofuran in 20% yield in eight hours by pyrolysis of phenol over litharge at 150° C. The low yield limits commercial utility of this route. Walsh and Preston (U.S. Pat. No. 3,108,121) reacted diphenyl oxide over a relatively expensive and sensitive 5% platinum on charcoal catalyst to obtain dibenzofuran. Shiotani and Itatani [Angew.Chem. 86 478 (1974)] used as palladium acetate catalysts to produce dibenzofuran from diphenyl oxide but obtained much dimerized product as well. In particular, in these latter two methods two synthetic steps are required to obtain dibenzofuran from phenol inasmuch as diphenyl oxide is frequently obtained from a reaction involving a condensation of phenol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>CN(C)C=O>[C:24]1(=[O:33])[N:23]([CH2:22][CH2:21][CH2:20][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc2[nH]c(=O)ccc2c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A suspension of 6-hydroxycarbostyril (300 g) and potassium carbonate (308 g) in dimethylformamide (2 liters) is heated with stirring at 70-80° C. for one hour. To the suspension is added N-(3-bromopropyl)phthalimide (498 g), and the mixture is further stirred at the same temperature for 9 hours. The reaction solution is poured into ice-water, and the precipitated crystals are collected by filtration, washed successively with water, ethanol and diethyl ether, and dried to give 6-(3-phthalimidopropoxy)carbostyril (410 g) as a white powder.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([O:35]CC)=[O:34])[C:28]2[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=2[S:26][CH2:25]1)[C:18]([O:20]CC)=[O:19])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>C(O)C.[OH-].[Na+]>[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([OH:35])=[O:34])[C:28]2[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=2[S:26][CH2:25]1)[C:18]([OH:20])=[O:19])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(CCCCNC(=O)OCc2ccccc2)C(=O)OCC)CSc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1C(=O)[C@@H](NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)CSc2ccccc21
Reaction time: 1 h
Yield: 85.8 %

Procedure:
In a mixture of 3 ml of ethanol and 2 ml of 1N aqueous sodium hydroxide solution is dissolved 55 mg of ethyl 3(R)-(5-benzyloxycarbonylamino-1-ethoxycarbonylpentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate.hydrochloride as obtained in Example 50, and the solution is allowed to stand at room temperature for 1 hour. Water(50 ml) is added to the reaction solution, and after the mixture is extracted with 20 ml of ethyl ether, the aqueous layer is adjusted to pH 4 with 1N hydrochloric acid. Ammonium chloride is added to the solution until it becomes saturated, and the aqueous layer is extracted ten times with 20 ml of ethyl acetate. The extract is washed with a small amount of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 40 mg of 3(R)-(5-benzyloxycarbonylamino-1-carboxypentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=5)(=[O:27])=[O:26])=[CH:19][CH:20]=4)[C:15](=[CH:36][C:37]([O:39]CC)=[O:38])[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1>C1COCC1.[OH-].[Na+]>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=5)(=[O:26])=[O:27])=[CH:19][CH:20]=4)[C:15](=[CH:36][C:37]([OH:39])=[O:38])[C:14]=3[CH:13]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=C1c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc2-c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C=C1c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc2-c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc21
Temperature: 25 °C
Yield: 21.6 %

Procedure:
The product from Example 5A (460 mg, 0.78 mmol) in THF (5 mL) and 15% aqueous NaOH (5 mL) was heated at reflux for 6 hours. The mixture was allowed to cool to ambient temperature, acidified, and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound as a yellow solid (95 mg, 22% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 10.16 (s, 1H), 9.43 (s, 1H), 9.18 (d, 1H), 8.37 (d, 1H), 8.1 (m, 2H), 7.86 (m, 2H), 7.2 (s, 1H), 7.0 (t, 2H), 6.53-6.63(m, 4H), 6.42 (m, 2H). MS (ESI) 563 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[CH:9]([OH:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[OH:16][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[OH:8]
Reactant: OC1OC(c2ccccc2)c2ccncc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCc1cnccc1C(O)c1ccccc1
Reaction time: 1 h

Procedure:
1-Phenyl-1,3-dihydro-furo[3,4-c]pyridin-3-ol (50 mg) was dissolved in ethanol (2 mL) and treated with sodium borohydride (13 mg). The reaction mixture was stirred for 1 hour and then diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield (3-hydroxymethyl-pyridin-4-yl)-phenyl-methanol as a colorless foam.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([Cl:11])[C:5]=1[NH2:12].O.[OH-].[K+].Cl>C(O)C>[NH2:12][C:5]1[C:6]([Cl:11])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1c(C(=O)O)cc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
3-Amino-2,6-dichloroisonicotinic acid methyl ester (460 mg) was dissolved in ethanol (8 mL), water (2 mL) and potassium hydroxide (234 mg) was added. The solution was stirred for 20 minutes at room temperature and for 1.5 hours under reflux. After cooling to room temperature, 2N hydrochloric acid was added to adjust the pH-value to −3 and the so-formed yellow precipitate was extracted 3× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum to afford 420 mg of the title compound of the formula
Reaction SMILES: [F:1][C:2]1([CH3:16])[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:8][CH:3]1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1([CH3:16])[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:8][CH:3]1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C1C=CC(S(C)(=O)=O)=CC1(C)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(F)C=C(S(C)(=O)=O)C=CC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
53.8 g of crude methyl 2-fluoro-2-methyl-4-(methylsulfonyl)benzoate were initially charged in 500 ml of THF, and 10.5 g NaOH dissolved in 500 ml of H2O were added. The mixture was stirred at RT for 3 h, and most of the THF was then removed under reduced pressure. The residue was washed with diethyl ether and the aqueous phase was then acidified with 10% strength H2SO4. The precipitated crystals were filtered off with suction, washed with cold water and dried. This gave colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[C:23]#[CH:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CCC(N)CC
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C
Solvent: CS(C)=O
Product: C#CC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester and 1-ethyl-propyl-amine in DMSO was heated at 130° C. overnight. The mixture was quenched with water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound. 1H NMR(CDCl3) d 8.26(d, 1H), 6.87(s, 2H), 6.26(s, 1H), 4.11(m, 1H), 3.87(s, 3H), 2.324(m, 1H), 2.30(s, 3H), 2.17s, 3H), 2.08(s, 6H), 1.92(q, 2H), 1.16(t, 3H) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH3:18]>>[CH2:16]([O:15][C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:18])=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)=[O:14])[CH3:17]
Reactant: N
Reactant: CCOC(=O)c1cnc2cc(F)ccc2c1Cl
Product: CCOC(=O)c1cnc2cc(F)ccc2c1N

Procedure:
Prepared as in Example 1a from ethyl 4-chloro-7-fluoroquinoline-3-carboxylate (Example 9b) and ammonia as an off white solid (99%). MS 235 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nn(-c2ccccc2[N+](=O)[O-])c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccccc2N)c1C

Procedure:
To a solution of 3,5-dimethyl-1-(2-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.4 g) in a solution of equal proportions of ethanol and ethyl acetate was added 5% Pd/C (37 mg). The solution was treated with hydrogen gas at 45 psi. Upon completion of the reaction, the mixture was filtered through Celite, then the filtrate concentrated under vacuum. The named product was collected as an oil, which then was purified by flash chromatography to provide a solid product having a melting point of 59° C.-61° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:20][O:21]CC2C=CC(OC)=CC=2)[CH:9]([CH3:10])[C:8](=[O:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])[CH2:6]1)=[O:4].C(Cl)Cl.O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:20][OH:21])[CH:9]([CH3:10])[C:8](=[O:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(COCc2ccc(OC)cc2)CN(c2c(C)cccc2C)C(=O)C1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1(CO)CN(c2c(C)cccc2C)C(=O)C1C
Yield: 71.5 %

Procedure:
To a vigorously stirring mixture of 1-(2,6-dimethylphenyl)-3-(4-methoxy-benzyloxymethyl)-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step b, 736 mg, 1.79 mmol) in 5:1 CH2Cl2/H2O (12 mL) was added 2,3-dichloro-5,6-dicyanobenzoquinone (609.5 mg, 2.68 mmol) at room temperature and stirred for 2 h at the same temperature. The reaction mixture was diluted with CH2Cl2 (25 mL) and filtered through celite, washed with CH2Cl2 (3×25 mL). The filtrate was then washed with saturated NaHCO3 solution (3×30 mL), water (30 mL), brine (30 mL), dried and evaporated. The obtained residue was purified by flash chromatography (SiO2, 20→70% EtOAc/hexanes) to give 1-(2,6-dimethylphenyl)-3-hydroxymethyl-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (373 mg, 72% yield). LC-MS: R, (retention time): 1.2 min, MS: (ES) m/z 292.2 (M+H+).