Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12]>CC(O)(C)C>[CH3:14][O:13][C:11]([CH:10]([C:9]([O:16][CH3:17])=[O:15])[CH:3]1[C:2]([CH3:8])([CH3:1])[CH2:6][C:5](=[O:7])[CH2:4]1)=[O:12]
Reactant: CC1(C)C=CC(=O)C1
Reactant: COC(=O)CC(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=O)OC)C1CC(=O)CC1(C)C
Temperature: 30 °C
Reaction time: 72 h
Yield: 83.4 %

Procedure:
Under an atmosphere of argon, 11.0 mg (0.02 mmol, S/C=50) of Ru[(S,S)-Msdpen] (hexamethylbenzene), 122 μL (1.0 mmol) of 4,4-dimethyl-2-cyclopentenone, 114 μL (1.0 mmol) of dimethyl malonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 30° C. for 72 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 202 mg (83% yield) of the title compound. The optical rotation [α]D25 was +101.6 (c 1.04, CHCl3). After this was converted into an ethylene ketal derivative by the same procedure as in Example 3, the optical purity was measured by HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane: 2-propanol=97:3, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 99% ee.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([NH:16][CH2:17][CH2:18][NH2:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)CC)C>C(O)C>[C:12]([O:11][C:9](=[O:10])[NH:16][CH2:17][CH2:18][NH:19][C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Clc1ncc(Br)cn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1ncc(Br)cn1
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (500 mg), N-Boc-ethylenediamine (496 mg), and triethylamine (1 mL) in ethanol (10 mL) was heated at 80° C. for 4 hours. The reaction was then concentrated in vacuo and the residue purified by preparative HPLC (hexanes:EtOAc; 60:40) to afford compound 10 (700 mg) as a white solid.
Reaction SMILES: Cl.[CH2:2]1[C@H:6]2[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][C@H:5]2[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30].O>CN(C=O)C>[F:26][C:25]([F:27])([F:28])[C:22]1[CH:21]=[C:20]([C:29]([F:30])([F:31])[F:32])[CH:19]=[CH:24][C:23]=1[N:3]1[CH2:4][C@@H:5]2[CH2:9][CH:8]([CH:10]=[O:11])[CH2:7][C@@H:6]2[CH2:2]1
Reactant: OCC1C[C@H]2CNC[C@H]2C1
Reactant: Fc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC1C[C@@H]2CN(c3ccc(C(F)(F)F)cc3C(F)(F)F)C[C@@H]2C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
To a solution of (3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethanol hydrochloride (862 mg) and potassium carbonate (1.68 g) in DMF (10 mL) was added 1-fluoro-2,4-bis(trifluoromethyl)benzene (1.24 g). The reaction mixture was stirred at 80° C. for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). To a solution of the obtained oil (1.71 g) and triethylamine (2.03 mL) in DMSO (10 mL) and ethyl acetate (10 mL) was added sulfur trioxide pyridine complex (2.32 g) under cooling to 0° C. The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (215 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([OH:23])=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:14][C:15]=1[Cl:16].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15]([Cl:16])=[N:14][C:13]([CH:17]2[CH2:18][CH2:19][N:20]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:21][CH2:22]2)=[N:12][C:11]=1[OH:23]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1nc(C2CCNCC2)nc(Cl)c1-c1nc2ccccc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
Into a mixture of 5-(1,3-benzothiazol-2-yl)-6-chloro-2-(piperidin-4-yl)pyrimidin-4-ol (50 g, 144.16 mmol, 1.00 equiv) and triethylamine (36.5 g, 361.39 mmol, 2.51 equiv) in dichloromethane (300 ml) was added benzyl chloroformate (29.5 g, 172.93 mmol, 1.20 equiv) dropwise. The resulting solution was stirred overnight at room temperature. Upon concentrated under vacuum, the residue was purified by flash chromatography on a silica gel column eluting with petroleum ether/ethyl acetate (2:1) to give 3 g of benzyl 4-[5-(1,3-benzothiazol-2-yl)-4-chloro-6-hydroxypyrimidin-2-yl]piperidine-1-carboxylate as yellow solid. MS m/z [M+H]+ (ESI): 481.
Reaction SMILES: CN(C)C=O.N1C=CN=C1.[OH:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]([CH:20]=[CH:21][C:22](=[O:24])[CH3:23])=[C:14]([CH3:25])[CH2:13]1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>C(OCC)C>[Si:30]([O:11][CH:12]1[CH2:17][C:16]([CH3:18])([CH3:19])[C:15]([CH:20]=[CH:21][C:22](=[O:24])[CH3:23])=[C:14]([CH3:25])[CH2:13]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32]
Reactant: CC(=O)C=CC1=C(C)CC(O)CC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
To 30 ml of an anhydrous dimethylformamide (hereinafter "DMF") solution containing 588 mg of imidazole and 1.2 g of 4-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)but-3-en-2-one was added dropwise 15 ml of an anhydrous DMF solution containing 1.3 g of t-butyldimethylchlorosilane at room temperature in a nitrogen atmosphere. After the dropwise addition, the mixture was stirred under the same conditions for 15 hours. Diethyl ether was added to the reaction mixture, and the mixture was washed several times with water cooled with ice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent, etc. were removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.5 g (yield: 78%) of 4-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1-enyl]-but-3-en-2-one.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH2:20][C:21](N)=[O:22])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[Na].[OH-:32].[Na+].Cl>O.C(O)C>[CH:8]1[C:7]([CH:10]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][O:19][CH2:20][C:21]([OH:32])=[O:22])[CH2:15][CH2:16]2)[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[CH:6][CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: [OH-]
Reactant: NC(=O)COCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)COCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
In a round-bottomed flask fitted with a mechanical stirrer, a Nitrogen inlet and a condenser, 30 g (0.065 mole) of 2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide dihydrochloride are added to a mixture of 325 ml of ethanol, 130 ml of a 1 N aqueous sodium hydroxyde solution and 62 ml of a 6.3 N aqueous sodium hydroxide solution. The mixture is heated under reflux and under a Nitrogen atmosphere for 1.5 hours. The reaction mixture is then cooled down to room temperature and its pH is adjusted to 5 with 78 ml of a 5 N aqueous hydrochloric acid solution. Water is added, and ethanol is evaporated off under vacuum using a rotary evaporator. The resulting aqueous phase is extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness to give 25 g of crude efletirizine as an amorphous solid, 5 g of which are recrystallized in acetonitrile.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[C:31]([CH:40]=[O:41])=[CH:32][C:33]3[NH:37][CH:36]=[N:35][C:34]=3[C:38]=2[F:39])=[C:25]([Cl:42])[CH:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[C:31]([CH:40]([OH:41])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:32][C:33]3[NH:37][CH:36]=[N:35][C:34]=3[C:38]=2[F:39])=[C:25]([Cl:42])[CH:24]=1
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: CS(C)(=O)=O
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
To a solution of methyl sulfone (65 mg, 0.68 mmol) in THF (1.5 mL) is added a solution of n-BuLi (0.27 mL, 0.68 mmol, 2.5 M solution in hexane) at −78° C. After stirring for 5 minutes, HMPA (0.1 mL) is added. After stirring for additional 10 minutes, a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f (26 mg, 0.069 mmol) in THF (1 mL) is added. The resulting solution is stirred for 1.5 hours at −78° C. The reaction is quenched with saturated aqueous NH4Cl, warmed to room temperature, and diluted with EtOAc. The organic layer is washed with water, dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (3% MeOH in CH2Cl2) to give the crude desired product (31 mg, 96%) which is used directly without further purification: MS APCI (+) m/z 462, 464 (M+, Br pattern) detected.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[CH3:13])#[CH:2].[Cl:14][C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19](Cl)[CH:20]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[Cl:14][C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=2[CH3:13])[CH:20]=1
Reactant: C#Cc1ccc(OCOC)cc1C
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 1-ethynyl-4-(methoxymethoxy)-2-methylbenzene (8) (1.0 equiv.), 3,5-dichloropicolinonitrile (9) (0.90 equiv.), CuI (0.10 equiv.), and Pd(PPh3)2Cl2 (0.10 equiv.), and triethylamine (5.0 equiv.) in DMF (0.25M) was degassed and flushed with nitrogen. The reaction mixture was then heated to 60° C. and stirred overnight. After cooling to room temperature, water was added. The mixture was extracted with EA (2×). The combined organic layers were washed with 10% aq NH4OH (2×), brine, and concentrated. The crude material was filtered through a pad of silica (wetted with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated. The resulting solids were washed in hot ether and filtered to give a yellow solid, which was used in the next step without further purification. The filtrate was concentrated and purified by Combiflash using 0-10% EtOAc in Hexanes to give 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (10) as a yellow solid.
Reaction SMILES: C(C=C=O)CCC.[CH2:8]([C@H:12]1[C:13](=[O:21])[O:14]/[C:15]/1=[CH:16]\[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][CH3:11]>ClCCl>[CH2:8]([C@@H:12]1[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:14][C:13]1=[O:21])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC/C=C1\OC(=O)[C@@H]1CCCC
Agent: CCCCC=C=O
Solvent: ClCCl
Product: CCCCC[C@@H]1OC(=O)[C@@H]1CCCC
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
The purified n-butyl ketene dimer 2a, (5.1 mmol, 1.0 g) was dissolved in 40 mL dichloromethane (0.1 M) and transferred to a Parr bomb apparatus under a N.sub.2 atmosphere using an additional 10 mL dichloromethane as wash solvent. Pd/C (107 mg, 1 mol %, 5 wt %) was then added at one time under N.sub.2 atmosphere. The Parr bomb was then subjected to three consecutive evacuation-saturation cycles of hydrogen gas and then pressurized to 30 psi hydrogen gas pressure. Hydrogenation with shaking (Parr shaker) was continued for 30 min at this pressure and then the heterogeneous slurry was vacuum filtered through a plug of Celite, and concentrated yielding a colorless oil. Flash chromatography with gradient elution (5→15% diethyl ether/hexanes; 2.5×35.0×5 cm pad) gave 3-butyl-4-pentyl-oxetan-2-one (3a, 897 mg, 90%) as a colorless oil (>96% ee, chiral GC): Rf 0.47 (15% Et2O:hexanes ); IR (thin film) 1824 cm−1; 1H NMR (300 MHz, CDCl.sub.3) δ 4.54 (ddd, J=2.1, 3.6, 5.7 Hz, 1H), 3.59 (ddd, J=4.5, 5.4, 8.4 Hz, 1H), 1.46-1.84(m,6H), 1.31-1.44 (m, 8H), 0.88-0.94 (m, 6H); 13C NMR (500 MHz, CDCl3) δ 173.1, 76.5, 53.3, 32.2, 30.9, 30.5, 26.0, 24.4, 23.2, 23.2, 14.7, 14.5; ESI LRMS Calcd. for C12H22O2 [M+Li]: 205: Found:205.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=1[CH2:23][OH:24].[B:25](OC)(OC)[O:26]C>C1COCC1>[F:20][C:19]([F:22])([F:21])[C:15]1[C:14]2[CH2:23][O:24][B:25]([OH:26])[C:13]=2[CH:18]=[CH:17][CH:16]=1
Reactant: OCc1c(Br)cccc1C(F)(F)F
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB1OCc2c1cccc2C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a 2.5 M solution of n-BuLi in hexane (27.81 mL, 69.53 mmol) in dry THF (30 mL), cooled to −78° C. and under an Argon atmosphere was added a solution of (2-bromo-6-(trifluoromethyl)phenyl)methanol (CXXIX) (5.49 g, 23.16 mmol) in dry THF (30 mL) dropwise very slowly. The reaction mixture was stirred at −78° C. for 2 h before adding trimethyl borate (3.88 mL, 34.76 mmol). The reaction mixture was stirred at −78° C. for an additional 30 min, and then allowed to warm up slowly to room temperature and stirred overnight. The reaction was then cooled to 0° C. and slowly quenched with 2 M HCl and stirred for 2.5 h at room temperature. The reaction mixture was extracted with EtOAc and the organic layer was dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography using (100:1 DCM/MeOH) to give 4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXX) as an orange oil (1.17 g, 5.79 mmol, 25% yield). ESIMS found for C8H6BF3O2 m/z 201.4 (M−H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCN1CCCc2ccccc21

Procedure:
Under the atmosphere of nitrogen, 4 parts of 1,2,3,4-tetrahydroquinoline, 6.4 parts of 1-bromooctane, 5 parts of dimethylformamide (DMF), and 5 parts of potassium carbonate were stirred at 130° C. for 4 hours. After the reaction, the resultant was extracted with water/ethyl acetate, and the ethyl acetate phase was dried over magnesium sulfate. Ethyl acetate was distilled off, and the residue was separated and purified by column chromatography to yield 3 parts of a precursor of the compound (301), 1,2,3,4-tetrahydro-1-octylquinoline as a colorless liquid. Next, 1.7 parts of phosphorus oxychloride were dropwise added to 10 parts of chloroform and 1 part of N,N-dimethylacrolein, the temperature of which was adjusted to 5° C., while the temperature of the reaction solution was kept at 10° C. or lower. The reaction solution was then stirred at 5° C. for 1 hour. Thereafter, 2.5 parts of 1,2,3,4-tetrahydro-1-octylquinoline described above were added thereto, and then the reactive components were caused to react at 25° C. for 1 hour. The reaction solution was then stirred at 70° C. for 1 hour. Thereafter, a 20% solution of sodium hydroxide in water was added to the reaction solution until the pH turned to 12. The precipitated crystal was filtrated, and the resultant crystal was washed with water. The crystal was then separated by column chromatography (hexane/ethyl acetate), and recrystallized from ethanol to yield 2.7 parts of the compound (301) as a yellow crystal.
Reaction SMILES: CN(C)CCN.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][O:13][N:14]1C(=O)C2=CC=CC=C2C1=O.C(O)(=O)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])=[C:32]([C:44](=O)[CH2:45][CH3:46])[CH:31]=1>CCO>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])=[C:32]([C:44](=[N:14][O:13][CH2:12][C:8]2[S:7][CH:11]=[CH:10][CH:9]=2)[CH2:45][CH3:46])[CH:31]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1cccs1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(=NOCc1cccs1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.3 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(thiophen-2-ylmethoxy)phthalimide (365 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (1 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (316 mg, 1.0 mmol) in EtOH (2 mL), and the mixture stirred for 15 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-{4-chloro-2-[1-(thiophen-2-ylmethoxyimino)propyl]phenyl}trifluoromethanesulfonamide 207 (364 mg, 85%), as a white solid. M.p. 53-54° C. 1H n.m.r. (400 MHz, CDCl3) δ 11.49, br s, 1H, 7.64, d, J=8.8 Hz, 1H, 7.47, d, J=2.4 Hz, 1H, 7.33) m, 2H, 7.16, m, 1H, 7.01, m, 1H, 2.82, q, J=7.6 Hz, 2H, 1.17, t, J=7.6 Hz, 3H. HRMS (M+) 426.0065.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: COC(=O)c1ccc(N)cc1F
Product: COC(=O)c1ccc(NC(=O)C(C)n2ccc(-c3cc(Cl)ccc3C#N)cc2=O)cc1F

Procedure:
120 mg (0.39 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of methyl 4-amino-2-fluorobenzoate were reacted according to General Method 5A. Yield: 64 mg (36% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Reactant: [H][H]
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Yield: 97.8 %

Procedure:
To a solution of 10% Pd--C (5 g) in ethanol (500 ml) is added 1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline (53.4 g) and the mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. After the reduction, 10% Pd--C is removed by filtration, and the filtrate is concentrated under reduced pressure to give 1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (46.7 g) as yellow powder, m.p. 185°-188° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C.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:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:25])([F:24])[F:13])[N:3]=[C:4]([CH3:12])[N:5]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
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: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(-c2ccccc2C(F)(F)F)n1
Yield: 39.9 %

Procedure:
Part A: To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (3.12 g, 15 mmol, J. Chem. Soc 3832 (1954); ibid 677 (1944)) and 2-(trifluoromethyl)phenylboronic acid (3.42 g, 18 mmol) in benzene (50 ml) was added 1M aqueous sodium carbonate (20 ml) and 500 mg of tetrakis(triphenylphosphine)palladium. This mixture was refluxed for 4.5 hours, then was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (10% then 20% ethylacetate in hexanes) afforded 4-Chloro-2-methyl-5-nitro-6-(2-(trifluoromethyl)phenyl)-pyrimidine (1.90 g) as a pale yellow solid. CI Mass Spec. (M+H)+ =318.0.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:54][CH2:55][C:56]1[CH:67]=[CH:66][C:59]2[B:60]([OH:65])[O:61][C:62]([CH3:64])([CH3:63])[C:58]=2[CH:57]=1.Cl>CC#N>[OH:65][B:60]1[C:59]2[CH:66]=[CH:67][C:56]([CH2:55][NH:54][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([C:11]4[CH2:15][C:14]([C:20]5[CH:21]=[C:22]([Cl:28])[C:23]([Cl:27])=[C:24]([Cl:26])[CH:25]=5)([C:16]([F:18])([F:17])[F:19])[O:13][N:12]=4)=[CH:10][C:2]=3[CH3:1])=[CH:57][C:58]=2[C:62]([CH3:64])([CH3:63])[O:61]1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CC1(C)OB(O)c2ccc(CN)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)C(C)(C)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
The solution of 2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)benzoic acid (300 mg, 0.665 mmol) and HATU (505.4 mg, 1.33 mmol) in CH3CN (15 mL) at rt was stirred for 5 min. The mixture was added to a solution of 5-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (181.1 mg, 0.798 mmol) and TEA (268.7 mg, 2.66 mmol) in CH3CN (15 mL). Then the mixture was stirred at rt for 2 h. The solution was acidified with HCl (1 N) and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=2:1) to give the final title compound (105 mg, yield 25%): 1H NMR (300 MHz, DMSO-d6): δ 9.0 (s, 1H), 8.95 (t, 1H), 7.83 (s, 2H), 7.64-7.59 (m, 3 H), 7.47 (d, 1H), 7.34-7.29 (m, 2H), 4.52-4.50 (d, 2H), 4.37-4.34 (m, 2 H), 2.38 (s, 3H), 1.44 (s, 6 H); HPLC purity: 98.1% at 220 nm and 98.8% at 254 nm; MS: m/z=625 and 627 [M+H]+.