Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 99.9 %

Procedure:
Using general procedure A, 4-methoxyphenylamine (246 mg, 2.00 mmol) and 1-Boc-4-piperidone (418 mg, 2.10 mmol) gave 4-(4-methoxyphenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (612 mg, 100%).
Reaction SMILES: O[CH:2]1[CH2:9][CH2:8][CH:7]([OH:10])[CH:6]2[N:11]([CH3:12])[CH:3]1[CH2:4][CH2:5]2.[C:13]([C:17]1[CH:18]=[C:19]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:16])([CH3:15])[CH3:14]>C1(C)C(C)=CC=CC=1.CCOCC.[Ti]>[C:13]([C:17]1[CH:18]=[C:19]([CH2:28][CH2:29][C:30]([O:32][CH:3]2[CH2:4][CH2:5][CH:6]3[N:11]([CH3:12])[CH:2]2[CH2:9][CH2:8][CH:7]3[O:10][C:30](=[O:31])[CH2:29][CH2:28][C:19]2[CH:20]=[C:21]([C:24]([CH3:25])([CH3:27])[CH3:26])[C:22]([OH:23])=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:18]=2)=[O:31])[CH:20]=[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:22]=1[OH:23])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Reactant: CN1C2CCC1C(O)CCC2O
Agent: [Ti]
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: CN1C2CCC(OC(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C1CCC2OC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 56.6 %

Procedure:
In a nitrogen atmosphere a stirred mixture of the diol mixture 2,6-dihydroxy-9-methyl-9-azabicyclo[3.3.1]nonane and 2,5-dihydroxy-9-methyl-9-azabicyclo[4.2.1]nonane (4.28 g., 0.025 mole), 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid (15.3 g, 0.055 mole) and 0.7 ml of titanium tetraisopripylate in 100 ml of xylene was heated under reflux in a flask equipped with a Dean-Stark trap for 14 hours. The xylene was evaporated under reduced pressure and the residue thus obtained was dissolved in ether. The ether solution was washed with 5% aqueous sodium hydroxide and then water. The dried (Na2SO4) solution was evaporated under reduced pressure to give an oily residue which was crystallized from petroleum ether. Recrystallization from methanol gave 9.8 g (56.6%) of the title ester, m.p. 107°-109°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH3:11][S:12]([CH2:15][C:16](=O)[CH3:17])(=[O:14])=[O:13].[NH2:19][C:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:15]([S:12]([CH3:11])(=[O:14])=[O:13])=[C:16]([CH3:17])[NH:19][C:20]3[CH2:24][CH2:23][C:22](=[O:25])[C:21]2=3)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: NC1=CC(=O)CC1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: CC1=C(S(C)(=O)=O)C(c2ccc(Cl)c(Cl)c2)C2=C(CCC2=O)N1
Yield: 21.9 %

Procedure:
3,4-Dichlorobenzaldehyde (175 mg, 1.0 mmol), methanesulfonylacetone (137 mg, 1.01 mmol) and 3-aminocyclopentenone (95 mg, 0.98 mmol) were heated to 80° C. in ethanol (4 mL) in a sealed tube for 3 days, cooled and the solvent evaporated. The crude material was flash chromatographed on silica gel (5% methanol/chloroform) to provide 80 mg of the title compound as a tan solid.
Reaction SMILES: CC(O)=O.Cl[S:6]([C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:22])[CH:10]=1)(=O)=O.Cl[Si](Cl)(C)C.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH:42](O)[CH3:43])[CH:37]=2)=[CH:32][CH:31]=1>CCOC(C)=O.[Zn]>[CH3:22][C:11]1[CH:10]=[C:9]([S:6][CH:42]([C:38]2[CH:37]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:45])[F:46])=[CH:31][CH:32]=3)[CH:41]=[CH:40][CH:39]=2)[CH3:43])[CH:21]=[CH:20][C:12]=1[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Reactant: CC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(SC(C)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
Zinc (229 mg, 3.50 mmol) was added to EtOAc (10 mL) followed by AcOH (115 μM, 2.00 mmol) and ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (293 mg, 1.00 mmol). After 2 hours, dichlorodimethylsilane (258 mg, 2.00 mmol) was added followed by 1-[4′-(trifluoromethyl)-3-biphenylyl]ethanol (266 mg, 1.00 mmol) and the mixture stirred for a further 1 hour and then heated at 80° C. for 5 hours. The mixture was then cooled, diluted with EtOAc and washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, water and brine, and then reduced. Purification by Biotage™ chromatography (silica) eluting with petrol:EtOAc (9:1) afforded the title compound as a colourless oil (238 mg).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>O.C(OCC)(=O)C>[C:13]([O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:36][CH:37]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])=[CH:22][CH:23]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.97 g), sodium hydrogen carbonate (2.86 g) and dimethyl sulfoxide (14 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-tert-butoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.39 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (14 mL). N,N′-carbonyldiimidazole (0.55 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.21 g, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cccc([N+](=O)[O-])c2)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cccc(N)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To 10% palladium-carbon (100 mg), a solution of tert-butyl 3-((3-nitrophenyl)amino)piperidine-1-carboxylate (C21, 229 mg) in tetrahydrofuran (10 mL) and methanol (4 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain tert-butyl 3-((3-aminophenyl)amino)piperidine-1-carboxylate (C22, 211 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[N+:20]=[N-:21].C[O-].[Na+].[Na]>CO>[CH3:26][O:25][C:23](=[O:24])[C:22]([N:19]=[N+:20]=[N-:21])=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:17][CH3:18])[CH:11]=1
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=Cc1ccc(OCc2ccccc2)c(OC)c1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.5 %

Procedure:
A solution of the 4-Benzyloxy-3-methoxy-benzaldehyde (12.0 g, 49.6 mmol) and methyl azidoacetate (23 g, 0.200 mol) in methanol (50 mL) was added over 30 min to a cooled (ice-salt bath) solution of sodium methoxide which had been prepared from addition of methanol (80 mL) to sodium (3.4 g, 0.149 mol). The reaction mixture was stirred at 0° C. for 45 min, during this time a thick cream precipitate formed, and then stood in the freezer overnight. Ice-cold water was added and the precipitate was removed by filtration and dried to give methyl-2-azido-3-[4′-(benzyloxy)-3′-methoxyphenyl]prop-2-enoate (55) (12.2 g, 73%) which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:28][CH3:29])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:30]>CO.ClCCl.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>[CH2:28]([C:13]1[N:14]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:17]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:30])[C:11]=2[N:12]=1)[CH3:29]
Reactant: N
Reactant: CCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2-ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinoline (2.624 g, 6.451 mmol), 7 N ammonia in methanol (40 mL), and tetrakis(triphenylphosphine)palladium(0) were combined in a pressure vessel and heated at 120° C. for 16 hours. An analysis by HPLC indicated that the reaction was incomplete. The volatiles were removed under reduced pressure, and the residue was dissolved in chloroform. The solution was washed sequentially with aqueous potassium carbonate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The resulting dark yellow solid was added to a pressure vessel with 7 N ammonia in methanol (60 mL), and the reaction was sealed and heated at 150° C. for 18 hours. The volatiles were removed under reduced pressure, and the residue was stirred with 0.5 N potassium hydroxide in methanol for 30 minutes. The resulting solid was isolated by filtration, diluted with dichloromethane, purified by column chromatography on silica gel (eluting with 5% to 10% CMA in chloroform), triturated with diethyl ether and filtered, and recrystallized from acetonitrile after a hot filtration. The crystals were isolated by filtration, washed with diethyl ether, and dried to provide 0.139 g of 2-ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 232.0-233.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[C:9]#[N:10])=[O:5])[CH3:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>C(OCC)(=O)C>[NH2:10][C:9]1[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][C:11]=2[F:15])[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)Nc1cccc(F)c1C#N
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2c(F)cccc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 2-(ethoxycarbonylamino)-6-fluorobenzonitrile (step 1) and 2-bromoacetophenone. tlc: Rf=0.3 (33% ethyl acetate in hexanes)
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[C:12](=[O:23])[N:11]3[CH:24]=2)=[CH:4][CH:3]=1.[H][H]>CCO.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:9]=[C:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[C:12](=[O:23])[N:11]3[CH:24]=2)=[CH:25][CH:26]=1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(COc3ccc(F)cc3)cn12
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccc(F)cc3)cn21
Yield: 45.2 %

Procedure:
A solution of 2-(4-fluoro-phenoxymethyl)-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one (0.1 g, 0.28 mmol) in EtOH (25 mL) was hydrogenated in a H-cube reactor (1 mL/min, 30 mm Raney nickel cartridge, 35° C., full hydrogen mode, 3 cycles) and then (1 mL/min, 30 mm Raney nickel cartridge, 40° C., full hydrogen mode, 3 cycles). The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 50/50 to 75/25). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(4-fluoro-phenoxymethyl)-6-(4-fluoro-phenyl)-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (45 mg, 45% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.29 (t, J=6.6 Hz, 2H), 4.00 (t, J=6.6 Hz, 2H), 4.98 (s, 2H), 6.92-7.01 (m, 4H), 7.10-7.18 (m, 2H), 7.29-7.36 (m, 2H), 7.56 (s, 1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[H-].[Na+].CS(O[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>ClCCl.CO>[C:31]([O:30][C:28](=[O:29])[NH:27][CH:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][C:3]2=[O:11])[CH2:22][CH2:23]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C1COc2ccccc2N1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccccc32)CC1
Yield: 63 %

Procedure:
2H-1,4-Benzoxazin-3(4H)-one (298 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (2.0 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave the product in 63% yield as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4]
Reactant: OB(O)c1ccccc1
Reactant: Nc1c(F)cc(I)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1c(F)cc(-c2ccccc2)cc1Cl
Temperature: 100 °C

Procedure:
2-Fluoro-4-iodo-6-chloroaniline (8.0 g, 36.0 mmol) is dissolved in DMF (110 mL) and treated with 2.8 equivalents of phenylboronic acid (10.0 g, 82 mmol), and a catalytic amount of tetrakistriphenylphosphine palladium(0) (3.0 g, 2.6 mmol) as a solution in DMF (20 mL). Sodium carbonate (30 mL of 2 M aqueous solution) is added and the reaction mixture stirred and heated to 100° C. for 24 hours. After cooling to room temperature most of the DMF is removed by rotary evaporator under high vacuum. The residual brown oil is partitioned between Et2O (300 mL) and water (150 mL). The organic layer is washed with brine, dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2-fluoro-4-phenyl-6-chloroaniline (m.p. 105–107° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]([OH:27])([CH2:24][CH2:25]C)[CH2:21][CH2:22]C)#[CH:19].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CN(C=O)C.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>[CH2:18]([C:20]([OH:27])([CH2:24][CH3:25])[CH2:21][CH2:22][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)(CC)CCc1cccc(CCCNC(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a degassed solution of N-(3-(3-bromophenyl)propyl)-2,2,2-trifluoroacetamide (10) (2.29 g, 7.4 mmol) and 4-ethynylheptan-4-ol (2.4 g, 18.5 mmol) in triethylamine (2 mL) and DMF (18 mL) was added PdCl2(PPh3)2 (0.130 g, 0.185 mmol), P(o-Tol)3 (0.113 g, 0.37 mmol), and CuI (0.070 g, 0.37 mmol). The resulting mixture was degassed and stirred under argon at 90° C. overnight. The mixture was cooled to room temperature and the solids were removed by filtration through Celite. The filtrate was partitioned between diethyl ether and water and the combined organics were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (6 to 50% EtOAc-hexanes gradient) gave N-(3-(3-(3-ethyl-3-hydroxypentyl)phenyl)propyl)-2,2,2-trifluoroacetamide (12) as an amber oil. Yield (2.6 g, 95%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.18-7.29 (m, 4H), 3.16 (q, J=7.2 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.76 (quint, J=7.2 Hz, 2H), 1.53-1.67 (m, 8H), 0.97 (t, J=7.2 Hz, 6H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:11][C:12](=[O:30])[C:13]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2)=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].O>CS(C)=O>[N:25]1[C:26]2[C:21](=[C:20]([C:13]3([C:12]([O:11][CH2:9][CH3:10])=[O:30])[CH2:4][CH:14]3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=C(C(=O)OCC)c1cccc2ncccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1(C(=O)OCC)c1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Sodium hydride (0.93 g) was added in small portions to a stirred suspension of trimethylsulfoxonium iodide (5.12 g) in DMSO (50 mL) at room temperature. After 0.5 h, the clear reaction mixture was cooled to 0° C. and a solution of diethyl-2-(5-quinolinyl)-2-butenedioate (P24, 3.48 g) in DMSO (25 mL) was quickly added and the stirring continued for 0.5 h after which time water (30 mL) was added. The mixture was extracted twice with ether (30 mL), the organic phase was washed with saturated ammonium chloride, dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with cyclohexane-ethyl acetate from 100 to 70%) to give 3.02 g of the title compound as a slightly yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].[CH:11]([N-]C(C)C)(C)C.[Li+].CI.[C:21](C#N)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C.CN(C)P(N(C)C)(N(C)C)=O>[C:21]([CH:4]1[C:5](=[O:8])[CH:6]([CH3:11])[CH2:7][C:2]([CH3:10])([CH3:1])[C:3]1=[O:9])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: CC(C)[N-]C(C)C
Reactant: N#CC(=O)c1ccccc1
Agent: [Li+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Product: CC1CC(C)(C)C(=O)C(C(=O)c2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Compounds of formula (V) can be prepared according to a first representative procedure, as follows: 4,4-dimethylcyclohexane-1,3-dione 7 (1 mole eq) (commercially available) is dissolved in anhydrous diethylether and hexamethylphosphoramide (solvent ratio, 20:1 respectively) under an atmosphere of nitrogen. The mixture is cooled to 0° C. and lithium diisopropylamide (2.1 mole eq) is added dropwise over 40 mins. The mixture is then stirred for a further 10 mins before the addition of methyl iodide (1 mole eq). The mixture is stirred for 12 h and then benzoyl cyanide (2 mole eq) is added and the mixture stirred for a further 24 h. The reaction was quenched with water and the ether layer partitioned and dried (Na2SO4). The solvent was removed and the residue subjected to SiO2 column chromatography (hexane/ethyl acetate) affording 1-benzoyl-3,3,5-trimethylcyclohexan-2,6-dione 8 (Scheme 4).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)=[O:6]
Reactant: NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=441.1, tR (minutes, Method G)=2.63
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7](O)=[O:8].C1C=CC=CC=1.C(Cl)([Cl:24])=O.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7]([Cl:24])=[O:8]
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)Cl
Temperature: 35 °C

Procedure:
71.8 g. (0.288 moles) of α-(3,5-dichlorophenoxy) butyric acid and 75 ml. of benzene are placed in a 500 ml. flask to which a dropping funnel with dry-ice condenser is attached. The slurry is stirred and the 0.2 ml. dimethyl formamide is added. The mixture is heated to 35° C. and 10 g. of phosgene is condensed into the mixture to initiate reaction. The start of the reaction is evidenced by HCl evolution and foaming. 26.0 g. more phosgene is added in 5 gm. increments. At the conclusion of the reaction (HCl evolution ceasing), the reaction mixture is evaporated leaving a residual liquid α-(3,5-dichlorophenoxy) butyryl chloride 77.6 g., ND20 = 1.5345