Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C:18](=O)[NH2:19])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[C:38](N)=[CH:39][CH:40]=1>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C:18]1[N:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[C:37]2[CH:36]=[C:35]([F:34])[CH:40]=[CH:39][C:38]=2[N:19]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)cc1Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of ((S)-2-benzyloxy-1-carbamoylethyl)carbamic acid tert-butyl ester (820 mg, 2.8 mmol) in anhydrous THF (10 mL) was added triethyloxonium tetrafluoroborate (550 mg, 2.9 mmol) in one portion under a nitrogen atmosphere. The resulting mixture was stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue redissolved in absolute EtOH (10 mL). To the mixture was added 4-fluoro-N2-pyridin-2-yl-benzene-1,2-diamine (355 mg, 1.7 mmol) and the mixture stirred at 75° C. for 16 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM and the combined organic fractions washed with water, dried (MgSO4) and concentrated in vacuo. The resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cHex) to afford the title compound as a yellow oil (420 mg, 53%). LCMS (Method B): RT 3.95 min [M+H]+ 463.1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:28])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2OS(C(F)(F)F)(=O)=O)[CH:10]([CH3:29])[CH2:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[CH3:37][OH:38].CN(C)[CH:41]=[O:42]>>[C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:28])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:37]([O:42][CH3:41])=[O:38])[CH:15]=2)[CH:10]([CH3:29])[CH2:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CN(C)C=O
Reactant: CO
Reactant: CCCCCC(=O)N1CCC(C)(c2ccccc2OS(=O)(=O)C(F)(F)F)C(C)C1
Solvent: CCN(CC)CC
Product: CCCCCC(=O)N1CCC(C)(c2cccc(C(=O)OC)c2)C(C)C1
Temperature: 60 °C

Procedure:
To a solution of 1-hexanoyl-3,4-dimethyl-4-(trifluoromethanesulfonyloxyphenyl)piperidine (Preparation 6, 267 mg, 0.48 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added triethylamine (0.18 mL) and methanol (0.4 mL). The mixture was de-oxygenated by evacuating and flushing with nitrogen five times. Palladium(II) acetate (4.4 mg) and 1,1′-bis(diphenylphosphino)ferrocene (8 mg) were added and the solution was purged with carbon monoxide. The reaction mixture was heated to 60° C. under an atmosphere of carbon monoxide for 7 hours then it was cooled to room temperature and diluted with saturated aqueous sodium chloride solution (10 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (4×15 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (50 g) eluted with hexane:ethyl acetate:0.880 ammonia (66:33:1). The title compound was obtained as a pale yellow oil (110 mg).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+]>CC(O)C.C(OCC)(=O)C>[CH2:1]([O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10])[CH2:2][CH2:3][CH3:4]
Reactant: OCc1ccccc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCCCOc1ccccc1CO

Procedure:
12.4 g (90.5 mmol) of butyl bromide, 11.2 g (90.5 mmol) of 2-hydroxybenzyl alcohol and 12.5 g (90.5 mmol) of potassium carbonate in 270 ml of 2-propanol are heated at reflux overnight. The suspension is cooled, taken up in ethyl acetate and washed with 1N aqueous sodium hydroxide solution and water, dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][OH:8])(=S)[NH2:2].[C:15]([O:18]CC(C1C=CC=CC=1)CO)(=[S:17])[NH2:16]>>[C:1](=[O:4])([OH:18])[NH2:2].[C:15]([CH:5]([OH:4])[C@@H:6]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][OH:8])(=[S:17])[NH2:16]
Reactant: NC(=S)OC[C@H](CO)c1ccccc1
Reactant: NC(=S)OCC(CO)c1ccccc1
Product: NC(=O)O
Product: NC(=S)C(O)[C@H](CO)c1ccccc1

Procedure:
Example V was repeated using as the starting material (S)-2-phenyl-1,3-propandiol monothiocarbamate prepared in Example IV, instead of 2-phenyl-1,3-propandiol monothiocarbamate racemate. The title compound thus obtained was tested for optical purity with a high pressure liquid chromatograph equipped with a column for separating optical isomers.
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH2:3][CH3:4].[CH3:6][C:7]12[CH2:12][CH:11]1[CH2:10][CH:9]([CH2:13][CH:14]=O)[C:8]2([CH3:17])[CH3:16].[OH-].[K+].CO>O>[CH3:4][C:3](=[CH:14][CH2:13][CH:9]1[CH2:10][CH:11]2[C:7]([CH3:6])([CH2:12]2)[C:8]1([CH3:16])[CH3:17])[C:2](=[O:5])[CH3:1]
Reactant: CC1(C)C(CC=O)CC2CC21C
Reactant: CCC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)C(C)=CCC1CC2CC2(C)C1(C)C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
560 g (8.5 mol) of butan-2-one and 234 g (1.4 mol) of (1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanal were added to 48 g (0.75 mol) of potassium hydroxide dissolved in 500 ml of water and 1.41 of methanol. The reaction mixture was stirred overnight with ice-bath cooling, poured into 3 1, of water and extracted with diethyl ether. The extract was washed with water, dried (MgSO4) and evaporated in vacuo. The residue was distilled at 108° C./0.1 Torr to give 140 g (45% yield) of 3-methyl-5-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)pent-3-en-2-one.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:15]([NH2:17])=[C:14]1[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]1)=[N:8]2.C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O.O>[OH2:2].[NH2:17][C:15]1[C:16]2[C:7]([N:8]=[C:9]3[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27]
Reactant: Nc1c2c(nc3cccc(O)c13)CCCC2
Reactant: COC(=O)C(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1cccc2nc3c(c(N)c12)CCCC3
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 8-hydroxy-1,2,3,4-tetrahydro-9-acridinamine hydrochloride (3.77 g) in dry dimethylformamide (100 ml) was added potassium carbonate (4.7 g), with stirring. After one hr, methyl 2-bromopropionate (2.51 ml) was added and stirring was continued overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the residue was flash chromatographed (ethyl acetate, then 5% triethylamine/ethyl acetate) to yield 4.05 g (86.7%) of methyl α-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]propionate hydrate.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:18]1C[CH2:21][CH2:20][CH2:19]1.C(Cl)(=O)C=C>CC(C)=O>[C:19]([O:10][CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])[CH:20]=[CH2:21]
Reactant: OCCSc1ccccc1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCSc1ccccc1
Temperature: -30 °C
Yield: 62 %

Procedure:
To a 500 mL three-neck round bottom flask equipped with mechanical stirrer were charged 2-hydroxyethyl phenyl sulfide (33.0 g, 0.21 mol), anhydrous triethylamine (45 mL, 0.32 mol), and anhydrous tetrahydrofuran (160 mL). The solution was cooled in a −30° C. acetone/dry ice bath under nitrogen blanket for 15 mins. Acryloyl chloride (22 mL, 0.27 mol) was added into the vigorously stirred cold solution through an addition funnel over 30 min. After the addition, the reaction mixture was stirred in the cold acetone bath for additional four hours followed by quenching with the addition of 2M HCl (200 mL). The mixture was extracted with diether ether (150 mL×3) and the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2), and dried over MgSO4. Filtration and removal of solvents under reduced pressure gave the crude product as a light brown oil which was purified on silica gel using Hexanes/Ethyl acetate (50/1, v/v) as eluent to give the final product as a colorless oil (27.4 g, 0.13 mol, yield: 62%), H1 NMR (CDCl3): δ 7.44 (2H), 7.33 (2H), 7.24 (1H), 6.41 (1H), 6.12 (1H), 5.85 (1H), 4.35 (2H), 3.21 (2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:11](=[O:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NN(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of N-methylhydrazinecarboxylic acid tert-butyl ester (0.62 g, 4.20 mmol) in methylene chloride (10 ml) was added acetic acid anhydride (0.79 ml, 8.40) and pyridine (1.36 ml, 16.80 mmol) and the mixture was stirred overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (3×10 ml), dried (MgSO4), filtered and concentrated in vacuo to give 0.32 g (41%) of N'-acetyl-N-methylhydrazinecarboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]([CH3:17])C(O)=O)=O)=[CH:9][C:8]=2[C:20]([F:23])([F:22])[F:21])[CH2:3][CH2:2]1.[N:24]1([C:30](N)=[O:31])CCOCC1.O.[NH2:34]N>C(O)(=O)C>[F:23][C:20]([F:21])([F:22])[C:8]1[CH:9]=[C:10]([C:11]2[CH2:13][CH2:17][C:30](=[O:31])[NH:24][N:34]=2)[CH:18]=[CH:19][C:7]=1[N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: NN
Reactant: CC(C(=O)O)C(=O)c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Reactant: NC(=O)N1CCOCC1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(c2ccc(N3CCOCC3)c(C(F)(F)F)c2)=NN1

Procedure:
5.8 g of 4-morpholino-3-trifluoromethylbenzoylpropionic acid-morpholineamide together with 2.2 ml of hydrazine hydrate and 90 ml of 50% acetic acid are refluxed for 1 hour. The reaction mixture is cooled, concentrated in a rotary evaporator, and a small amount of water is added; the pH-value is adjusted to 6 with a 2 N sodium carbonate solution, and the mixture is extracted with methylene chloride. The methylene chloride extracts are washed with water, dried over sodium sulfate and concentrated by evaporation. From the residue is obtained, by recrystallisation from ethanol/petroleum ether, 6-(3-trifluoromethyl-4-morpholino-phenyl)-4,5-dihydro-3(2H)-pyridazinone, m.p. 163°-166° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C[O:23][B:24](OC)[O:25]C.O>C(OCC)C>[Si:15]([O:14][CH2:13][CH2:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[B:24]([OH:25])[OH:23])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCCc1occc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1occc1B(O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
n-Butyllithium (2.5M in hexanes, 5.78 mL) was added to a solution of [2-(3-bromofuran-2-yl)-ethoxy]-tert-butyldimethylsilane (Intermediate 34, 4.01 g) in diethyl ether (130 mL) at −60° C. under nitrogen and the resultant mixture was stirred for 30 minutes. Trimethylborate (2.73 g) was then added to the mixture and it was stirred for a further 10 minutes. The reaction mixture was warmed to 0° C., water was added and the mixture was stirred for 15 minutes. The organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give 2-[2-(tert-butyldimethylsilanyloxy)-ethyl]-furan-3-yl-boronic acid (1.23 g) as a colourless oil.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[CH2:7]1)=[O:5].Br[Mg][CH2:25][CH3:26]>O1CCCC1>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:12]([N:8]2[CH2:7][C@H:6]([C:4](=[O:5])[CH2:25][CH3:26])[CH2:10][C:9]2=[O:11])[CH3:13])=[CH:19][CH:18]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(=O)N(C)OC)CC2=O)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: -10 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of N-methoxy-1-[(1R)-1-(4-methoxyphenyl)ethyl]-N-methyl-5-oxopyrrolidine-3-carboxamide 1.02 (20 g, 65.28 mmol, 1.00 equiv) in tetrahydrofuran (200 mL), followed by the addition of bromo(ethyl)magnesium in THF (1 M) (44 mL) dropwise with stirring at −10° C. The resulting solution was stirred at −10° C. for 2 h, quenched by the addition of 200 mL of water/ice and extracted with 3×500 mL of ethyl acetate. The organic layers were combined, washed with 2×500 mL of hydrogen chloride (1 M) and 3×500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate: petroleum ether (1:5-1:1) to afford (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-propionylpyrrolidin-2-one 1.22.
Reaction SMILES: FC(F)(F)C(O)=O.B1([O-])OO1.[OH2:12].[OH2:13].O.O.[Na+].[NH2:17][C:18]1[C:27]([F:28])=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([F:29])[C:19]=1[CH3:30]>C(O)(=O)C>[F:29][C:20]1[C:19]([CH3:30])=[C:18]([N+:17]([O-:13])=[O:12])[C:27]([F:28])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1cc(F)c(N)c(C)c1F
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)c([N+](=O)[O-])c(C)c1F
Temperature: 60 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
Trifluoroacetic acid (50 ml), acetic acid (50 ml) and sodium perborate tetrahydrate (26.6 g) were added to methyl 4-amino-2,5-difluoro-3-methylbenzoate (7.5 g), and the mixture was stirred at 60° C. for 24 hours. Impurities in the reaction mixture was removed by filtration, chloroform was added to the resultant filtrate, and the resultant mixture was washed with water. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (6.1 g) as a reddish brown oil.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])[C:10](O)=O)([CH3:6])[CH3:5].Cl.[O-:22][C:23]#[N:24].[Na+].[OH-].[Na+]>C(O)C.O>[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([C:10]2[NH:24][C:23](=[O:22])[NH:1][N:2]=2)[CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])([CH3:6])[CH3:5]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: N#C[O-]
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(-c2n[nH]c(=O)[nH]2)cc(C(C)(C)C)c1O
Temperature: 35 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid hydrazine (2.8 g, 10.6 mmol) in ethanol (140 ml) and water (50 ml) is added 1N HCl (16 ml) and sodium cyanate (1.03 g, 16 mmol). The reaction mixture is stirred at room temperature for 30 minutes and at 35° C. for five minutes. The reaction mixture is cooled, evaporated, and partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer is dried (MgSO4) and evaporated. The crude product is cyclized by refluxing a solution in 1N NaOH (2-3 equiv.) for two hours. It is neutralized with 1N HCl and extracted with ethyl acetate. Pure 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.32 g, 10%) is separated from 3,5-di-t-butyl-4-hydroxybenzoic acid by flash chromatography (silica, EtOAc), mp 276°-280° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:24])([O-:19])=[O:18]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc([N+](=O)[O-])c3)c2)CC1
Yield: 20.7 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 3-nitrobenzoyl chloride (128 mg, 0.687 mmol), 17.4 mg (21%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:24])[CH:8]=2)[N:3]=1.[CH3:25][O-:26].[Na+]>C1(C)C=CC=CC=1>[Cl:23][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:24])[CH:8]=2)[N:3]=[C:2]([O:26][CH3:25])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: FC(F)(F)c1cccc(Cc2c(Cl)nc3ccc(I)cc3c2Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1cccc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
A suspension of 2,4-dichloro-6-iodo-3-(3-(trifluoromethyl)benzyl)quinoline (1.551 g, 3.217 mmol, Intermediate 7: step b) and sodium methoxide (1.738 g, 32.174 mmol) in dry toluene (16 mL) was heated at 90° C. for 16 hours. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified (FCC, 80 g SiO2, 0-20% CH2Cl2/hexanes over 20 minutes) to afford the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[CH:11]1[N:16]([CH3:17])[CH2:15][CH2:14][C:13]([CH3:18])=[CH:12]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:17][N:16]1[CH2:15][CH2:14][C:13]([CH3:18])=[CH:12][CH:11]1[C:4]1[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccc(C2C=C(C)CCN2C)c(OC)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1=CC(c2ccc(O)cc2O)N(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a stirred solution of 6-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2,3,6-tetrahydro-pyridine (6) (300 mg, 1.27 mmol) in dichloromethane (20 ml) cooled at 0° C. under nitrogen was added boron tribromide (3.1 ml, 3.18 mmol of 1.0M solution in dichloromethane), the resultant dark solution was allowed to warm to room temperature and stirred for 1 hour. The solution was poured onto ice and basified with sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (20 ml), the combined organic layers were dried over anhydrous magnesium sulphate, filtered and evaporated to a gum (200 mg). The material was purified on a log silica cartridge eluting with methanol/dichloromethane/ammonia (7:92:1) to yield 4-(1,4-dimethyl-1,2,5,6-tetrahydropyridin-2-yl)-benzene-1,3-diol (8) (93 mg, 35%) as a gum, 1H NMR D6-acetone ?? 1.67 (s, 3H), 1.97 (m, 1H), 2.3 (s, 3H), 2.42 (m, 1H), 2.74 (m, 1H), 3.08 (m, 1H), 3.74 (s, 1H), 5.15 (s, 1H), 6.2 (d, 1H J=2), 6.27 (dd, 1H J=2.8), 6.82 (d, 1H J=8), 9.4 (bs, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC2C3N(CC(C)C)C(CCC)=NC=3C=[N:45]C=2C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[C:15]([NH2:45])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Reactant: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)C

Procedure:
The general methods described in Parts H and I of Example 1 were followed using 7-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (29.2 g, 78.2 mmol) in lieu of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline. The crude product was triturated with acetonitrile, isolated by filtration, and dried for 18 hours in a vacuum oven at 68° C. to provide 16.3 g of 7-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine an off-white solid, mp 201.0-203.0° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH2:9]([O:16][NH:17][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)CCCCCCCBr
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCCBr)NOCc1ccccc1
Reaction time: 18 h
Yield: 77.7 %

Procedure:
In an ice bath, 14 ml triethylamine was added to a suspension of 3.2 g (20 mmol) O-benzylhydroxylamine hydrochloride in 150 ml dichloromethane. Stirring was continued until the solution became clear. Then, 4.5 g (20 mmol) 8-bromo octanoic acid was added, followed by 5.6 g (22 mmol) bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. Stirring was continued at ambient temperature for 18 h. The solution was extracted twice with 150 ml each of 1M aqueous hydrochloric acid and twice with 150 ml each of 1M aqueous sodium bicarbonate. The organic solvent was removed i. vac. to give 5.1 g (78%) of 8-bromo-octanoic acid benzyloxyamide as a colorless oil. MS: 330 (M+H+)
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[O:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:24][CH2:25][C@@H:26]([OH:45])[C@@H:27]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1>CN(C)C=O.C(OCC)(=O)C>[F:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([F:36])[CH:32]=1)[CH2:28][C@H:27]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:26]([OH:45])[CH2:25][NH:24][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[O:4][CH2:3]1
Reactant: CC(C)Oc1ccc2c(c1)C(Br)COC2(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)C(NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)COC2(C)C
Yield: 46.8 %

Procedure:
A solution of 4-bromo-6-isopropoxy-1,1-dimethyl-3,4-dihydro-1H-isochromene (0.61 g, 2.04 mmol), cesium carbonate (1.33 g, 4.08 mmol), and tert-butyl (1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (0.64 g, 2.04 mmol) in N,N-dimethylformamide (10 mL) was stirred at 60° C., under nitrogen, for 24 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 5% lithium chloride (3×40 mL), water (2×30 mL), saturated sodium chloride (30 mL), dried (sodium sulfate), and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, 95:5 methylene chloride/methanol) to afford the desired product (0.51 g, 47%) as a pale-yellow foam: ESI MS m/z 535 [C29H40F2N2O5+H]+.