Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCC2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (60%).
Reaction SMILES: C([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:5][CH:4]=1)=O.C(OO)(=[O:21])C>C1(C)C=CC=CC=1>[OH:21][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(=O)OO
Reactant: CCCCOC(=O)C(C)Oc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C(C)Oc1ccc(O)cc1
Yield: 79.8 %

Procedure:
While stirring a mixture of 25 g of (+)-butyl 2-(4-formylphenoxy)propionate ([α]D25 =+44.1°) and 75 g of toluene at room temperature, 22.8 g of 40% peracetic acid was dropwise added. After the reaction at 50° C. for 2 hours, the reaction mixture was subjected to liquid separation with an addition of water. The toluene layer was separated and washed with water. To the toluene layer, 25 g of sodium hydrogen carbonate and water was added, and the mixture was reacted at 50° C. for 5 hours. Then, the reaction mixture was subjected to liquid separation. The organic layer was washed twice with water. The organic layer was concentrated by distilling off toluene, and then subjected to distillation under reduced pressure, whereby 19.0 g of (+)-butyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was 160° C./1 mmHg.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])([O-:28])=[O:27]>O1CCCC1>[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:33])([O-:28])=[O:27]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1cccc([N+](=O)[O-])c1)c1ccc(OC)c(OC)c1
Yield: 95.3 %

Procedure:
To an ice bath cooled stirred suspension of methyl 3-amino-3-(3,4-dimethoxyphenvl)propionate hydrochloride (1.38 grams, 5.00 mmol) and triethylamine (1.5 milliliters, 10.8 mmol) in 10 milliliters of tetrahydrofuran was added 3-nitrobenzoyl chloride (0.928 grams, 5.00 mmol) in a single portion. A thick slurry resulted. The cooling bath was removed after 15 minutes, the mixture diluted with 10 milliliters of tetrahydrofuran and the mixture stirred for an additional hour. The reaction mixture was diluted with 50 milliliters of water and then partially concentrated in vacuo to remove the tetrahydrofuran. The reaction slurry was filtered, the solid washed with copious amounts of water, air-dried, and dried in vacuo (60° C., <1 mm) to afford 1.85 grams (95%) of the product as an off white powder: 1H NMR (CDCl3, 250 MHz) δ 8.63 (t, J=1.9 Hz, 1 H), 8.35 (m, 1 H, Ar), 8.20 (m, 1 H, Ar), 7.77 (d, J=8 Hz, 1 H, NH), 7.63 (t, J=8.0 Hz, 1 H), 6.95-6.75 (m, 3 H, Ar), 5.86 (m, 1 H, CHCO), 3.85 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.68, (s, 3 H, CO2CH3), 3.01 (m, 2 H, CH2); 13C NMR (CDCl3) δ 172.0, 164.1, 149.1, 148.6, 148.2, 135.8, 133.1, 132.7, 129.8, 126.1, 122.0, 118.2, 111.2, 109.9, 55.9, 55.8, 52.0, 50.2, 39.5.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][C:15]=2[N+:19]([O-:21])=[O:20])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)cc1
Reactant: O=[N+]([O-])O
Product: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3 g of N-acetyl-4-(4-acetyl-phenyl)-piperidine is added at -15°, with stirring, to 20 ml of fuming nitric acid, and the reaction mixture is subsequently stirred for 30 minutes at a temperature of between 0° and 15°. It is then poured onto 100 g of ice; the pH value is adjusted to 14 with concentrated sodium hydroxide solution, and extraction is performed three times with 50 ml of methylene chloride each time. The organic phases are combined, washed until neutral, dried over sodium sulphate and concentrated in vacuo. The residue is dissolved in ether/ethanol and treated with active charcoal. The crude oily N-acetyl-4-(2-nitro-4-acetyl-phenyl)-piperidine, obtained after filtration and concentration by evaporation, can be further reacted without additional purification.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[CH:13]=[N:14][N:15]([C:17]([CH3:25])([CH3:24])[CH2:18][C:19](OCC)=[O:20])[CH:16]=1>C1COCC1>[Br:11][C:12]1[CH:13]=[N:14][N:15]([C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][OH:20])[CH:16]=1
Reactant: CCOC(=O)CC(C)(C)n1cc(Br)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(CCO)n1cc(Br)cn1
Temperature: -10 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Diisobutylaluminium hydride (1 M in toluene, 10.43 mL) was added dropwise to a solution of ethyl 3-(4-bromo-1H-pyrazol-1-yl)-3-methylbutanoate (Compound 50E, 1.3 g, 4.74 mmol), in THF (30 mL) at −78° C. and allowed to stir for 3 hours eventually warming to −10° C. The reaction mixture was quenched with an aqueous solution of K/Na tartrate tetrahydrate (10 mL) and allowed to stir for 2 hours. The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic extracts were washed with water, followed by brine, dried over sodium sulfate, filtered and concentrated to afford 1.0 g of the desired product (91%). 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.46 (s, 1H), 3.54-3.58 (q, J=4.5 Hz, 2H), 2.28 (t, J=4.2 Hz, 1H), 2.09 (t, J=4.5 Hz, 2H), 1.58 (s, 6H).
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8])=[O:4].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>C(O)C.[OH-].[Na+]>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][S:8][CH2:7][C@@H:6]([C:9]([OH:11])=[O:10])[NH:5][C:3](=[O:4])[C:2]([S:1][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)([CH3:13])[CH3:12])=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CSC[C@H](NC(=O)C(C)(C)SCc2ccc(OC)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a stirred solution of N-(2-mercapto-2-methylpropionyl)-L-cysteine (2.0 g) in ethanol(10 ml), 4N sodium hydroxide solution(7.7 ml) and paramethoxybenzyl chloride(3.0 ml) were added dropwise under ice-cooling and under nitrogen atomosphere. After the addition, the reaction mixture was stirred for 2 hours under ice-cooling and 2 hours at room temperature. The reaction mixture was concentrated in vacuo, acidified with 2N hydrochloric acid and extracted with ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give crystals. The crystals were recrystallized with ether to give 2.8 g(67%) of the titled compound.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1.[C:15]([C:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:21][N:20]=1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:21]2[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][C:19]([C:15]([CH3:16])([CH3:18])[CH3:17])=[N:20]2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(-c2nnco2)cc1
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc(-c2nnco2)cc1
Yield: 80.8 %

Procedure:
A mixture of 4-(1,3,4-oxadiazol-2-yl)phenylboronic acid (303 mg, 1.60 mmol) and powdered 4A molecular sieves (300 mg) in CH2Cl2 (6 mL) was heated to reflux for 2 h. Ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (310 mg, 1.6 mmol), pyridine (0.13 mL, 1.6 mmol) and copper (II) acetate (290 mg, 1.6 mmol) were added and the reaction mixture was refluxed for 24 h. The reaction was filtered and the solid was washed with EtOAc (40 mL) and MeOH (40 mL). The combined filtrate and washings were concentrated in vacuo and partitioned between EtOAc (40 mL) and water (20 mL). The organics were washed with water (20 mL), satd aq NaHCO3 (20 mL), water (20 mL), and brine (20 mL), dried (Na2SO4) and concentrated in vacuo. The oily residue was chromatographed to provide ethyl 1-(4-(1,3,4-oxadiazol-2-yl)phenyl)-3-tert-butyl-1H-pyrazole-5-carboxylate (440 mg, > 100% yield) as a visocus oil contaminated with the starting ester. The mixture was used without further purification.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2.O>N1C=CC=CC=1>[C:1]12([C:11]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[O:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: Oc1ccc2ncccc2c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: O
Product: O=C(Oc1ccc2ncccc2c1)C12CC3CC(CC(C3)C1)C2
Reaction time: 16 h

Procedure:
1-Adamantanecarbonyl chloride (1.37 g, 6.90 mmol) in pyridine (5 mL) was added to a solution of 6-hydroxyquinoline (1.00 g, 6.89 mmol) in pyridine (15 mL). The reaction was stirred for 16 h. To the stirring reaction mixture was added water (200 mL) which caused the product to precipitate. This precipitate was filtered, washed with water (3×50 mL), and dried under high vacuum. This provided 1.56 g (73.7%) of (41) as a light-brown powder:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH3:2].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH2:17][CH2:18]2)=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: CCOCCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CCOCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-ethoxyethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (24.8% yield). 1H NMR (500 MHz, CDCl3) δ 8.18, 8.07, 7.76, 7.65, 7.58, 7.38, 7.00, 4.07, 3.90, 3.83-3.65, 3.60, 3.52, 3.36, 1.20. MS (ES+) m/z 452 (M+1).
Reaction SMILES: CO[C:3](=O)[C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[H-].C([Al+]CC(C)C)C(C)C.C1(P(=[CH:47][C:48]([O:50][CH3:51])=[O:49])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:13]([O:12][C:10]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[CH:3]=[CH:47][C:48]([O:50][CH3:51])=[O:49])=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COC(=O)C=C[C@@H]1CCCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A stirred solution of (S)-N-(t-butoxycarbonyl)-pipecolinic acid methyl ester (2.04 g, 8.39 mmol) in methylene chloride (75 mL) at −78° C. under nitrogen was treated with diisobutylaluminum hydride (1.0 M in toluene, 14.2mL, 14.2 mmol). After 1.25 h a second aliquot of diisobutylaluminum hydride (2.00 mL, 2.00 mmol) was added. The mixture was stirred for an additional 30 min. and then quenched by the addition of a 20% aqueous Rochelle's salt solution (100 mL) followed by vigorous stirring for 1 h. The aqueous layer was extracted with methylene chloride and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The crude aldehyde was dissolved in methylene chloride (100 mL) and treated with methyl (triphenylphosphoranylidene)acetate (4.00 g, 12.0 mmol). After 15 hours (h) the reaction mixture was concentrated and purified by flash chromatography to give the desired product (1.46 g, 65%).
Reaction SMILES: Br[C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(NC(C)C)(C)C>CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[O:7][C:6]3[C:2]([C:25]#[C:24][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:3][S:4][C:5]=3[C:10](=[O:11])[CH:9]=2)[CH2:13][CH2:14]1
Reactant: O=c1cc(N2CCOCC2)oc2c(Br)csc12
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CO
Solvent: CC(C)NC(C)C
Product: O=c1cc(N2CCOCC2)oc2c(C#Cc3ccccc3)csc12
Temperature: 100 °C
Yield: 45 %

Procedure:
A microwave vial was charged with a magnetic stirring bar, 3-bromo-5-morpholino-7H-thieno[3,2-b]pyran-7-one (103) (50 mg, 158.1 μmol), phenylacetylene (32.0 mg, 316.2 μmol), trans-dichlorobis(triphenylphosphine)palladium (II) (5.6 mg, 7.9 μmol), copper (I) iodide (1.6 mg, 7.9 μmol) and diisopropylamine (1.0 mL). The mixture was magnetically stirred and heated via microwave irradiation to 100° C. for 20 minutes. The mixture was cooled to room temperature, and then concentrated in vacuo resulting in a brown solid. The solid was dissolved in methanol (1.0 mL) and loaded onto Isolute functionalized silica column (PE-AX/SCX-2). The column was washed with methanol and 7N methanolic ammonia. The methanolic ammonia fractions were combined and concentrated in vacuo. The resulting solid was purified using preparative high-pressure liquid chromatography to give 5-morpholino-3-(phenylethynyl)-7H-thieno[3,2-b]pyran-7-one (31) (24.0 mg, 71.1 μmol) as an orange solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:25](=[O:26])[CH:24]=[C:23]3[C:18]([C:19]4[CH:29]=[CH:28][S:27][C:20]=4[CH2:21][CH2:22]3)=[N:17]2)=[CH:12][CH:11]=1>C(Cl)Cl>[C:5]([C:28]1[S:27][C:20]2[CH2:21][CH2:22][C:23]3[C:18]([C:19]=2[CH:29]=1)=[N:17][N:16]([C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][CH:14]=1)[C:25](=[O:26])[CH:24]=3)(=[O:7])[CH3:6]
Reactant: Cc1ccc(-n2nc3c(cc2=O)CCc2sccc2-3)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc2c(s1)CCc1cc(=O)n(-c3ccc(C)cc3)nc1-2
Reaction time: 0.17 h

Procedure:
To a suspension of 6.4 g of aluminum chloride in methylene chloride was added 2.3 ml of acetyl chloride under ice-cooling and the mixture was stirred for 10 minutes. A solution of 4.7 g of 5,6-dihydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one in methylene chloride was added thereto, the mixture was stirred at room temperature for 30 minutes and then refluxed for an hour. The mixture was poured into ice-cold water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel (SiO2 :100 g) column using chloroform as an eluent. The resulting solid was recrystallized from a mixed solvent of chloroform and methanol to give 3.7 g of 8-acetyl-5,6-dihydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one as a white powder, melting at 240°-242° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[C:18]1[CH:22]=[C:21]([S:23][CH3:24])[N:20]([CH3:25])[N:19]=1.O>C(Cl)(Cl)(Cl)Cl>[Cl:4][C:22]1[C:18]([C:8]2[C:7]([Cl:6])=[CH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:10][C:9]=2[Cl:17])=[N:19][N:20]([CH3:25])[C:21]=1[S:23][CH3:24]
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1c(Cl)c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 0.3 g quantity of sulfuryl chloride was added to 1.2 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-5-methylsulfenylpyrazole (compound 1) in 5 ml of anhydrous carbon tetrachloride at room temperature, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into cold water, and the resulting mixture was extracted with methylene chloride. The organic layer was washed with 10% aqueous sodium hydrogen carbonate solution and with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was then purified by column chromatography on silica gel (eluent: ether/hexane=1/5), giving 1.0 g of the desired compound in the form of white crystals (yield 83.3%).
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][C@H:6]([OH:8])[C@@H:5]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.O>C(#N)C>[F:14][C:2]1([F:1])[CH2:7][C@H:6]([OH:8])[C@@H:5]([C:9]2[CH:13]=[N:12][N:11]([CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH:10]=2)[CH2:4][CH2:3]1
Reactant: O[C@H]1CC(F)(F)CC[C@@H]1c1cn[nH]c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(Cn2cc([C@H]3CCC(F)(F)C[C@@H]3O)cn2)cc1
Yield: 24.6 %

Procedure:
A solution of the (1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexanol (0.24 g, 1.17 mmol) prepared in Example 143c, potassium carbonate (0.32 g, 2.34 mmol) and 4-methoxybenzyl chloride (0.16 mL, 1.17 mmol) in acetonitrile (5.9 mL) was stirred at 80° C. for 12 hours. After allowing to cool, water (20 mL) was added to the reaction solution, and an organic layer was extracted with ethyl acetate (20 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography to yield the title compound (92.9 mg, 25%) as a colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19](=[CH2:22])[CH2:20]Br>CN(C=O)C.O>[C:1]1([C:7]([CH2:20][C:19]([CH3:22])=[CH2:18])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(C)CBr
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CC(C(=O)OCC)(C(=O)OCC)c1ccccc1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
NaH (440 mg of a 60% dispersion in mineral oil, 11 mmole) was washed free of mineral oil, and suspended in 20 mL of DMF. This was treated with a solution of diethyl phenylmalonate (2.36 g, 10 mmole) in 10 mL of DMF, and the reaction was stirred for 15 minutes, at which time the solution was clear. 2-Methylallyl bromide (2.0 mL) was added, and stirring continued for 1 hour. The reaction was diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried and the solvent removed and gave the titled compound, 2.85 g (95% yield). MS (ESI) 291 (MH+)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([Cl:14])[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1ncnc(Cl)c1-c1ccncc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2ncnc(Cl)c2-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 77.2 %

Procedure:
To a mixture of 4,6-dichloro-5-(pyridin-4-yl)pyrimidine (1.07 g, 4.8 mmol), 4-chlorophenylboronic acid (740 mg, 4.8 mmol) and tetrakis(triphenylphosphine)palladium (550 mg, 0.48 mmol) in toluene (10 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 5 mL, 10 mmol). The resulting mixture was stirred at 100° C. under argon for 15 h. Analysis by HPLC/MS indicated that the reaction was complete. After the reaction mixture was cooled to room temperature, water (25 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain the title compound (1.12 g, HPLC purity about 92%) as a white solid. 1H NMR (CDCl3): δ7.18 (d, 2H), 7.2-7.3 (m, 4H), 8.66 (d, 2H), 9.07 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17](O)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1cc(C#N)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
240 mg (purity 85%, 0.62 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 93 mg (30% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]2)[CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:27][CH2:26]2)[CH:20]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(N)ccn2)CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)ccn2)CC1
Yield: 30.3 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (211 mg, 0.7 mmol) was reacted with tert-butyl 1-(4-aminopyridin-2-yl)piperidin-4-ylcarbamate (300 mg, 1 mmol) to afford the desired product (120 mg, 30%) as a yellow solid: ESI MS m/z 566 [C28H32BrN5O3+H]+.