Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([N:7]1[CH2:15][CH2:14][CH:10]([C:11](Cl)=[O:12])[CH2:9][CH2:8]1)=[O:6].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1>>[F:16][C:17]1[CH:18]=[C:19]([F:23])[CH:20]=[CH:21][C:22]=1[C:11]([CH:10]1[CH2:14][CH2:15][N:7]([CH:5]=[O:6])[CH2:8][CH2:9]1)=[O:12]
Reactant: Fc1cccc(F)c1
Reactant: O=CN1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Product: O=CN1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 0 °C
Yield: 32.3 %

Procedure:
To a slurry of 39 g of aluminum chloride and 120 ml of 1,3-difluorobenzene was added dropwise, with stirring, 30 g of N-formylisonipecotic acid chloride. The reaction mixture was stirred under reflux for two hrs and poured into 1 l of ice-water. The mixture was extracted with 4 350-ml portions of chloroform. The combined organic extracts were washed with 2 300-ml portions of water, dried, filtered and evaporated. Trituration with petroleum ether and washing with ether at 0°, yielded 14 g (32.3%) of product, mp, 75°.
Reaction SMILES: CO[C:3](OC)(OC)[CH2:4][CH2:5][CH3:6].Cl.N1C=CC=CC=1.[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[NH:29][CH2:30][C:31]1([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[CH:26][CH:25]=[CH:24][CH:23]=2>C1(C)C=CC=CC=1>[CH2:4]([C:3]1[N:29]([CH2:30][C:31]2([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:18]=1)[CH2:5][CH3:6]
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1

Procedure:
Trimethylorthobutyrate (1.9 mL, 12.0 mmol) and pyridine hydrochloride (58 mg, 0.5 mmol) were added to a suspension of 4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (10.0 mmol) in toluene (50 mL). The reaction mixture was heated at reflux for 4 hours and then concentrated under reduced pressure. The residue was triturated with acetonitrile and the filtered to provide 4-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a tan solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH2:16]([CH2:18][NH2:19])[OH:17].O>C1(C)C(C)=CC=CC=1>[OH:17][CH2:16][CH2:18][N:19]1[C:8](=[O:10])[C:7]2=[C:2]([Br:1])[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11]1=[O:12]
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: NCCO
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1c2c(Br)c(Br)c(Br)c(Br)c2C(=O)N1CCO

Procedure:
To a suspension of 464 gm (1 mole) of tetrabromophthalic anhydride in 1.2 liters of xylene was added 61 gm (1 mole) of ethanolamine. The solution was heated and refluxed with a Dean-Stark water separator until the theoretical amount of water separated. The mixture was cooled, diluted with hexane, and filtered. The resulting 413 gm of an off-white solid was washed with hexane and dried at 100° C. This material is used as is for subsequent reactions without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=2)=[CH:4][CH:3]=1.[N:25]1C2C(=CC=CC=2)C=C[CH:26]=1.Cl>ClCCl>[C:26]([C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[C:9]2[CH:10]=[C:11]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:12]([OH:19])=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:14]=2)=[CH:4][CH:3]=1)#[N:25]
Reactant: CC(C)(C)c1cc(C(=O)c2ccc(Br)cc2)cc(C(C)(C)C)c1O
Reactant: c1ccc2ncccc2c1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)c2ccc(C#N)cc2)cc(C(C)(C)C)c1O
Temperature: 180 °C

Procedure:
A stirred mixture of 52 g (0.13 mole) of 4'-bromo-3,5-di(tertiary-butyl)-4-hydroxybenzophenone, 20 g (0.22 mole) of cuprous cyanide and 150 ml of quinoline was heated at about 180° C. for one day, followed by heating at reflux (235° to 245° C.) for two hours. The cooled solution was mixed with about one liter of 10% aqueous hydrochloric acid, and 400 ml of dichloromethane was added. The solid was separated by filtration, and extracted with additional hydrochloric acid and dichloromethane. The filtrates and washings were combined and the organic layer was separated and evaporated. The residue was recrystallized from a benzene-hexane mixture with treatment with decolorizing charcoal to provide 4'-cyano-3,5-di(tertiary-butyl)-4-hydroxybenzophenone. A further recrystallization from a mixture of ethanol and isopropanol with treatment with decolorizing charcoal provided white needles, m.p. 166.5° to 168° C. Analysis: Calculated for C22H25NO2 : % C, 78.8; %H, 7.5; %N, 4.2; Found; %C, 78.8; %H, 7.5; %N, 4.1.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH:20]1([CH:23]2[NH:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH:20]1([CH:23]2[NH:28][CH2:27][CH2:26][N:25]([C:2]3[CH:11]=[C:10]4[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]4[CH:12]4[CH2:14][CH2:13]4)=[CH:4][C:3]=3[F:19])[CH2:24]2)[CH2:22][CH2:21]1
Reactant: C1CNC(C2CC2)CN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(C4CC4)C3)c(F)cc2c1=O
Temperature: 140 °C
Yield: 17.5 %

Procedure:
A mixture of 787 mg of 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.736 g of 3-cyclopropylpiperazine and 8 ml of pyridine was heated at 140° C. in a pressure bottle for 18 hours and then purified as described in Example 95, giving 182 mg of the desired product, mp 245° C. (dec.).
Reaction SMILES: [CH2:1]([C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[NH2:12][OH:13].C(N(CC)CC)C>CCO>[OH:13][NH:12][C:9](=[NH:10])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC#N
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=N)NO
Yield: 27 %

Procedure:
Octyl cyanide (2 g, 14 mmol) and hydroxylamine hydrochloride (2.495 g, 36 mmol) were dissolved in EtOH (10 mL) and treated with triethylamine (5 mL, 36 mmol) at reflux over night. Extraction: AcOEt/water. Silica gel chromatography: heptane/AcOEt 1:2 afforded a white solid (0.65 g, 26%). MS: m/z=173 (M +H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:32][CH2:28][CH2:29][CH2:30][CH3:31])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reactant: CCCCN
Agent: [H-]
Agent: [Na+]
Product: CCCCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.41 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.58 mmol), and n-butylamine (0.16 mL, 1.65 mmol) are treated according to method E yielding the title product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[S:10]([O-])(=[O:12])=[O:11].[Na+].P(Cl)(Cl)([Cl:19])=O>CCOCC>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[S:10]([Cl:19])(=[O:12])=[O:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(C(F)(F)F)c1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cccc(C(F)(F)F)c1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 290 g of sodium 2-trifluoromethyl-6-methylbenzenesulfonate and 500 mL of phosphorous oxychloride was heated to reflux for 5 hours. The mixture was then cooled to 0° C. and poured into a large flask containing 2000 g of ice and 2 L of ether. After stirring for 30 minutes, the phases were separated and the organic phase washed with cold water, cold saturated aqueous sodium carbonate, and then brine. The solvent was removed in vacuo to yield 2-trifluoromethyl-6-methylbenzenesulfonyl chloride as a brown oil.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 4-fluorobenzeneboronic acid: MS (ESI) m/z 306 [M+H]+, 1H-NMR (CDCl3) δ 7.44-7.02 (8H, m), 3.89 (2H, t, J=6.6 Hz), 2.93 (2H, t, J=6.6 Hz), 2.30(3H, s), 2.27 (3H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20](OC)=[O:21])[C:14]=2[CH:13]=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c1ccn2CCOCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: O=Cc1cccc2c1ccn2CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
3.6 g of Methyl 1-(2-benzyloxyethyl)-1H-indol-4-carboxylate was dissolved in 40 ml of diethyl ether, and 0.44 g of lithium aluminum hydride was added under ice-cooling. After stirring at room temperature for 10 minutes, the reaction solution was cooled with ice, and diethyl ether and water were added. When the insoluble substances adhered to and solidified on the wall of the flask, the reaction solution was dried over anhydrous magnesium sulfate, then the solvent was evaporated. The residue was dissolved in 40 ml of dichloromethane, 20 g of manganese dioxide was added, and the mixture was stirred at room temperature for 2 hours. After filtering off the manganese dioxide through Celite, and washing through with ethyl acetate, the solvent was evaporated, to give 1.5 g of the title compound.
Reaction SMILES: C[O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:4]=1[CH3:28].Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:12][C:9]1([CH3:13])[CH2:8][C:7]2[C:6]([CH3:14])=[C:5]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[CH2:19][CH2:20]3)[C:4]([CH3:28])=[C:3]([OH:2])[C:11]=2[O:10]1
Reactant: COc1c(C)c(N2CCN(c3ccc(C)cc3)CC2)c(C)c2c1OC(C)(C)C2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(N2CCN(c3c(C)c(O)c4c(c3C)CC(C)(C)O4)CC2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 16.4 %

Procedure:
To 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methylphenyl)piperazine (444 mg, 1.18 mmol) synthesized in Example 62, acetic acid (7 mL) and 48% aqueous solution of hydrobromic acid (7 ml) were added, followed by stirring at 100° C. for 12 hours. After cooling to room temperature, aqueous solution of saturated sodium hydrogen carbonate was added to the mixture solution, and then the mixture solution was extracted with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0-90:10) and the resulting solids were recrystallized from hexane-ethyl acetate to obtain the title compound 71.0 mg (yield 16%). Melting point was 185 to 189° C.
Reaction SMILES: [Br-].[CH:2]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=O)[CH:33]=1>O1CCCC1>[C:2]1(=[CH:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cccnc1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C(=C1CCCC1)c1cccnc1
Temperature: 5 °C
Reaction time: 1.33 h
Yield: 61.8 %

Procedure:
A suspension of cyclopentyltriphenylphosphonium bromide (226 g, 0.55 mol) in anhydrous tetrahydrofuran (1000 ml) at 2° C. was treated with vigorous stirring under an atmosphere of argon, with potassium t-butoxide (61.7 g, 0.55 mol). The dark red mixture was stirred at 5° C. for 80 minutes and then treated with pyridine-3-carbaldehyde (58.9 g, 0.55 mol) during a period of 20 minutes. The reaction mixture was stirred at 0° C. for 2 hours and then at 20° C. for 18 hours. The tetrahydrofuran was removed in vacuo (30° C.; 14 mmHg) and the residue extracted with pentane (2×500 ml). After treatment with decolourising charcoal (5 g), the mixture was filtered through a plug of flash silica gel (Merck 70-230 mesh; 13 cm×2 cm diameter). The filtrate was concentrated in vacuo (30° C., 14 mmHg; then 20° C., 0.01 mmHg) to afford 3-cyclopentylidenemethylpyridine (54 g, 0.34 mol) as an orange oil which was used without further purification;
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[C:8]([CH3:18])[CH:7]=1)([CH3:5])([CH3:4])C.[C:19](C1C=CC(CC#N)=C(C)C=1)(C)(C)C>>[ClH:1].[CH3:18][C:8]1[CH:7]=[C:6]([CH:2]([CH3:4])[CH3:5])[CH:11]=[C:10]([CH3:19])[C:9]=1[CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1
Reactant: Cc1cc(C(C)(C)C)ccc1CC#N
Reactant: Cc1cc(C(C)(C)C)ccc1CC1=NCCN1
Agent: Cl
Product: Cc1cc(C(C)C)cc(C)c1CC1=NCCN1

Procedure:
2-[(4-t-Butyl-2-methylphenyl)methyl]-4,5-dihydro-1H-imidazole hydrochloride, from 4-t-butyl-2-methylphenylacetonitrile (Example 4e); white solid, mp 255° C., Anal. C15H22N2.HCl.0.25H2O: C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:29]=[CH:28][C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[C:14]([CH2:22][C:23]([O:25]CC)=[O:24])=[N:13]2)=[CH:9][CH:8]=1)=[O:5].O.[OH-].[Li+].O.Cl>O1CCCC1>[F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:29]=[CH:28][C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[C:14]([CH2:22][C:23]([OH:25])=[O:24])=[N:13]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(F)cc3F)cc2)c2cc(F)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc(F)cc3F)cc2)c2cc(F)ccc12
Yield: 89.8 %

Procedure:
Ethyl 2-[1-[4-(2,4-difluorobenzamido)benzyl]-6-fluoro-1H-indazol-3-yl]acetate (213 mg, 0.456 mmol) was dissolved in tetrahydrofuran (15 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (58 mg, 1.38 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 180 mg, at a yield of 89.9%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH:12]=O.CN.CO.CC(O)=O.[C:22]([BH3-])#[N:23].[Na+]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][NH:23][CH3:22]
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1c(C)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To 1,3-dimethyl-1H-indole-2-carboxaldehyde (13.0 g, 75 mmole) was added a solution of 2.0 M methylamine in methanol (150 mL, 300 mmole) and HOAc (4.3 mL, 75 mmole). The solution was stirred at RT for 4 hr, then was cooled to 0° C., and sodium cyanoborohydride (5.0 g, 80 mmole) was added portionwise over 5 min. The reaction was then allowed to warm to RT. After 16 hr, the reaction was concentrated under vacuum and the residue was taken up in Et2O. The solution was washed with 1.0 N NaOH then with brine, dried (Na2SO4), and concentrated to dryness. Flash chromatography on silica gel (95:5 CHCl3/methanol containing 5% NH4OH) gave the title compound (7.34 g, 52%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=7.8 Hz, 1 H), 7.26 (d, J=7.8 Hz, 1 H), 7.20 (t, 1 H), 7.09 (t, 1 H), 3.88 (s, 2 H), 3.76 (s, 3 H), 2.46 (s, 3 H), 2.32 (s, 3 H), 1.36 (br s, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Br:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: O=C(O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Br)C[C@H]1N
Temperature: 25 °C
Yield: 29.5 %

Procedure:
A mixture of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.11 g), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.082 g), DBU (0.054 g) and anhydrous acetonitrile (5 ml) was refluxed for 1.5 hours and then concentrated. The resulting residue was dissolved in chloroform (50 ml) and washed with 10% aqueous citric acid solution and water successively. The organic layer was concentrated under reduced pressure and to the oily residue was added methanol to crystallize. The resulting precipitate was collected by filtration, washed with chilled methanol and this was added to concentrated hydrochloric acid-methanol (1:1, 2 ml) and stirred for an hour at room temperature. The reacting mixture was neutralized with concentrated aqueous ammonia, concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:concentrated aqueous ammonia=20:6:1) and then recrystallized from dichloromethanemethanol (1:1) to give the title compound (0.04 g) as pale yellow powder, mp 186°-190° C. (decompd.).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][C:13]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:15]1[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:26])=[O:2])[C:13](=[O:25])[CH:14]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a stirred solution of (S)-2-[4-(3-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (340 mg, 0.9 mmol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (118 mg, 2.7 mmol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-2-[4-(3-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (280 mg, 86%) as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11](I)[C:10]([CH3:14])=[C:9]([F:15])[CH:8]=1)[CH3:4].C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C1COCC1.O>[CH2:3]([NH:5][C:6]([C:7]1[CH:8]=[C:9]([F:15])[C:10]([CH3:14])=[C:11]([B:26]([OH:27])[OH:25])[CH:12]=1)=[O:16])[CH3:4]
Reactant: CCNC(=O)c1cc(F)c(C)c(I)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1cc(F)c(C)c(B(O)O)c1
Temperature: -75 °C
Reaction time: 6 h

Procedure:
Sodium hydride (60% in mineral oil, 1.23 g) was added in portions to a solution of N-ethyl-3-fluoro-5-iodo-4-methylbenzamide (Intermediate 4, 4.81 g) in anhydrous THF (75 ml). The resulting mixture was cooled to −75° C. and n-butyllithium (1.6M in hexanes, 20 ml) was added dropwise over 20 min. Triisopropylborate (8 ml) was added over 5 min and the reaction mixture was stirred at −75° C. for 6 h. Water (20 ml) was added and the mixture was warmed to 15° C. overnight and the mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic phase was washed with aqueous ammonium chloride and brine, dried (MgSO4) and concentrated under vacuum. The residue was dissolved in dichloromethane and applied to a silica column (10 g) eluting with an ethyl acetate/dichloromethane gradient (0-100% ethyl acetate) followed by methanol. The methanol fractions were concentrated under vacuum to give the title compound as an off-white foam (550 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C1(C)C=CC=CC=1.[Ni]>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:12][CH2:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: C1=COCCC1
Reactant: Cc1c(CO)cccc1[N+](=O)[O-]
Agent: [Ni]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1c(COC2CCCCO2)cccc1[N+](=O)[O-]
Yield: 98.4 %

Procedure:
A solution of 100 g (0.598 mol) of 2-methyl-3-nitrophenylmethanol, 75.5 g (0.897 mol) of dihydropyran, and 15.0 g (0.06 mol) of the pyridinium salt of 4-methylbenzenesulfonic acid in 1 L of methylene chloride was stirred at ambient temperature for 24 hours. The reaction mixture was washed with two portions of 200 mL each of a saturated aqueous solution of sodium chloride, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to column chromatography on silica gel, eluting with methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure to give a residual oil. The oil was dissolved in 1 L of toluene, and was stirred in a Morton flask for 19 hours in the presence of 5 g of powdered Raney nickel. The mixture was filtered, and the filtrate concentrated under reduced pressure to give 147.8 g of 3-nitro-2-methylbenzenemethanol tetrahydropyranyl ether.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([Cl:14])[CH:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1>>[CH2:1]([C:8]1[N:9]=[C:10]([NH:30][C:20]2[CH:21]=[CH:22][C:23]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:11]=[C:12]([Cl:14])[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(Cl)nc(Cc2ccccc2)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(Cl)nc(Cc3ccccc3)n2)ccc1-n1cnc(C)c1
Yield: 48 %

Procedure:
The title compound was prepared in analogous manner as described in example 62 from 2-benzyl-4,6-dichloro-pyrimidine and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine. Obtained as yellow solid in 48% yield after column chromatography of the crude product on silica gel using dichloromethane/methanol (98:2 and then 95:5 v/v) as eluent.