Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])C.[Na+].Cl.Cl.[NH:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH2:8].[C:15](#[N:18])[CH:16]=[CH2:17].Cl>>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N:7]2[CH2:17][CH2:16][C:15]([NH2:18])=[N:8]2)[CH:10]=1
Reactant: NNc1cccnc1
Reactant: C=CC#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: NC1=NN(c2cccnc2)CC1
Temperature: 20 °C
Yield: 73.5 %

Procedure:
To a 4-neck, round bottomed flask (250 mL) was charged sodium ethanolate (21 wt % in ethanol, 32 mL). 3-Hydrazinopyridine.dihydrochloride (5.00 g, 27.5 mmol) was added, causing an exotherm from 20° C. to 58° C. The mixture was allowed to cool to 20° C. and acrylonitrile (2.91 g, 54.9 mmol) was added. The reaction was heated at 60° C. for 5 hours and cooled to 20° C. The excess sodium ethanolate was quenched with hydrochloric acid (4 M in 1,4-dioxane, 6.88 mL, 27.5 mmol) at <20° C. The mixture was absorbed on silica gel (10 g) and concentrated to dryness. The crude product was purified by flash column chromatography using 0-10% methanol/dichloromethane as eluent. The fractions containing pure product were concentrated to dryness to afford the title compound as a yellow solid (3.28 g, 74%): mp 156-160° C.; 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=2.8, 0.8 Hz, 1H), 8.01 (dd, J=4.6, 1.4 Hz, 1H), 7.22 (ddd, J=8.4, 2.8, 1.5 Hz, 1H), 7.12 (ddd, J=8.4, 4.6, 0.8 Hz, 1H), 4.20 (s, 2H), 3.70 (t, J=9.3 Hz, 2H), 2.92 (t, J=9.3 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 154.23, 144.78, 139.22, 135.08, 123.44, 119.44, 49.23, 32.74; ESIMS m/z 163 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:10][C@@H:9]2[CH2:11][C@H:6]1[CH2:7][N:8]2C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:10][C@@H:9]2[CH2:11][C@H:6]1[CH2:7][NH:8]2)=[O:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1C[C@@H]2C[C@H]1CN2)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
204 mg of the (t-butyl(1S,4S)-5-(trifluoroacetyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [151-1] was dissolved in 3 mL of chloroform, then 3 mL of trifluoroacetic acid was added thereto, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in methanol, and the trifluoroacetic acid was removed through a weak anion-exchange resin. The solvent was distilled off under reduced pressure, and 156 mg of (1S,4S)-2-(trifluoroacetyl)-2,5-diazabicyclo[2.2.1]heptane [151-2] was obtained as a brown oily product.
Reaction SMILES: ClC.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].C(=O)(O)[O-].[Na+]>>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]([CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[S:27]([CH2:25][CH3:26])(=[O:29])=[O:28]
Reactant: Fc1ccc(NCc2cccnc2)c(F)c1
Reactant: CCS(=O)(=O)Cl
Agent: CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(F)cc1F

Procedure:
A 4.4 g. portion of 3-(2,4-difluorophenylaminomethyl)pyridine chloromethane, and 4.1 g. of potassium carbonate and 3.9 g. of ethanesulfonyl chloride were added. The mixture was stirred under reflux for several days. It was then diluted with 20 ml. of aqueous sodium bicarbonate and 20 ml. of dichloromethane, and the organic phase was dried and evaporated to an oil. The oil was dissolved in dichloromethane and chromatographed over silica gel, eluting with dichloromethane, to obtain 1.2 g. of the desired product, after triturating with diethyl ether and petroleum ether. M.P. 91°-92°.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].B(OCC)(OCC)OCC.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OC(=O)C)C.C1CCCCC1>[CH2:20]([O:2][C:1]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cccc(O)c1O
Reactant: BrCc1ccccc1
Agent: CCOB(OCC)OCC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Oc1cccc(OCc2ccccc2)c1O

Procedure:
Using the procedure of Example 13, 25.22 g of pyrogallol, 35.1 ml of triethyl borate and 23.76 ml of benzyl bromide were reacted to obtain 33.8 g of the expected product in the form of a thick red oil after chromatography on silica eluting with a cyclohexane - ethyl acetate (6-4) mixture (Yield: 78%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]2[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[NH:13][C:12]([CH3:19])=[C:11]2[C:20]#[N:21])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[H-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:30](Cl)[CH3:31]>CN(C=O)C>[CH2:30]([N:13]1[C:14]([CH3:18])=[C:15]([C:16]#[N:17])[CH:10]([C:5]2[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[CH:4]=2)[C:11]([C:20]#[N:21])=[C:12]1[CH3:19])[CH3:31]
Reactant: CCCl
Reactant: CC1=C(C#N)C(c2ccc(F)c(C#N)c2)C(C#N)=C(C)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCN1C(C)=C(C#N)C(c2ccc(F)c(C#N)c2)C(C#N)=C1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-cyano-4-fluorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (1 eq), from Synthetic Example 1, in DMF was added either NaH or Cs2CO3 (1.2 eq) at 0° C. After 30 min, ethyl chloride was introduced. The reaction mixture was stirred at rt overnight, and quenched with brine. The reaction mixture was extracted with EtOAc, washed with brine, and dried. Concentration followed by flash chromatography gave 1-ethyl-4-(3-cyano-4-fluorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile. 1H-NMR (400 MHz, DMSO-D6): δ=7.86 (dd, 1H), 7.69 (m, 1H), 7.55 (t, 1H), 4.57 (s, 1H), 3.12 (q, 2H), 2.1 (s, 6H), 1.4 (t, 3H) ppm.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11]N1C(=O)CCC1=O.O>ClCCl>[Br:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([NH2:10])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: NC(=O)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzeneacetamide (3.0 g, 0.022 mol) was dissolved in dichloromethane (60 mL) and N-bromosuccinimide (4.0 g, 0.022 mol) was added. The reaction was stirred at room temperature under UV light for 24 hr. The mixture was poured into water and the layers were separated. The organic layer was washed with water (2×50 mL) then with brine (1×50 mL). The organic layer was dried (magnesium sulfate) then chromatographed on silica (40% ethyl acetate/hexanes) to give 2-Bromo-2-phenylacetamide, compound h Rf 0.37, 40% ethyl acetate/hexanes; MS m/z 216 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:13][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2occc2c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1ccc2occc2c1
Reaction time: 3 h
Yield: 90.8 %

Procedure:
Benzofuran-5-carbaldehyde (315 mg, 2.16 mmol) was dissolved in anhydrous methanol (10 mL). Methylamine (0.86 mL of 33% solution in ethanol, 6.91 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a brown oil and then dissolved in anhydrous methanol (10 mL). Sodium borohydride (83.2 mg, 2.20 mmol) was added and the mixture was stirred overnight at room temperature. Water (5 mL) was added and the solution was concentrated. Sodium hydroxide (10 mL, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 mL). Combined organic layers were dried over MgSO4, filtered and concentrated to afford benzofuran-5-yl-N-methylmethanamine (316 mg, 91%) as a light brown oil: 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.56 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 3.70 (s, 2H), 3.17 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23]([O-:25])[CH3:24].[Na+].C(O)C>O>[CH2:23]([O:25][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:24]
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cccc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 200 °C
Yield: 39 %

Procedure:
A solution of (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (63 mg, 0.2 mmol) and 21% sodium ethanolate solution in ethanol (112 uL, 0.3 mmol) was heated to 200° C. for 30 minutes in a microwave oven. The same amount of sodium ethanolate solution was added and the reaction was again heated to 200° C. for 30 minutes in a microwave oven. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound as a light brown solid (25 mg, 39%). MS ISP (m/e): 325.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.45 (t, 1H), 7.34 (s, 1H), 7.15 (d, 1H), 6.92 (d, 1H), 6.87 (s, 1H), 6.50 (s, 1H), 6.37 (d, 1H), 6.24 (d, 1H), 4.35 (q, 2H), 3.83 (s, 3H), 2.30 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:13]1[CH2:14][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[CH2:10][C:11](=[O:16])[CH:12]=1
Reactant: [NH4+]
Reactant: O=C1CC(=O)CC(c2cccc(Cl)c2Cl)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2cccc(Cl)c2Cl)C1
Yield: 89.2 %

Procedure:
A mixture of 5-(2,3-dichlorophenyl)cyclohexane-1,3-dione (1.8 g) and ammonium acetate (1.7 g) in ethanol (20 ml) was refluxed for 14 hours, and the reaction solution was concentrated under reduced pressure. To the residue was added water (20 ml), and the resulting crystals were filtered. The crystals were washed with water and toluene, and dried to give 1-amino-5-(2,3-dichlorophenyl)cyclohexen-3-one (1.6 g) as pale yellow crystals.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@H:22]1[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:25]([N:36]=[N+]=[N-])[C@@H:24]([CH3:39])[CH2:23]1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=1[C:48]1[N:53]=[C:52]([C:54](O)=[O:55])[CH:51]=[CH:50][C:49]=1[F:57].[N-]=[N+]=[N-]>CN(C=O)C.O.CC(O)C.[Pd]>[NH2:36][C@@H:25]1[C@@H:24]([CH3:39])[CH2:23][C@@H:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:15][C:54](=[O:55])[C:52]2[CH:51]=[CH:50][C:49]([F:57])=[C:48]([C:42]3[C:41]([F:40])=[CH:46][CH:45]=[CH:44][C:43]=3[F:47])[N:53]=2)[CH2:27][C@H:26]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1N=[N+]=[N-]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: [Pd]
Agent: On1nnc2cccnc21
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CC(C)O
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
EDC (2.0 equiv.) and HOAt (2.0 equiv.) was added to a solution of (+/−)-tert-butyl ((1R,2R,3S,5R)-5-(3-aminopyridin-4-yl)-2-azido-3-methyl cyclohexyl)carbamate (1.0 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.5 equiv.) in DMF (0.20 M). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, concentrated and purified by ISCO SiO2 chromatography. To a degassed a solution of the azide (1.0 equiv.) in 2-propanol (0.10 M) was added Pd/C (0.2 equiv.). The mixture was stirred under H2 for 48 hrs. Filter the mixture over cetlite and wash the cake with MeOH. Concentrate the filtrate to yield (+/−)-tert-butyl ((1R,2R,3S,5R)-2-amino-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexyl)carbamate in 35% yield). LC/MS (m/z)=556.3 (MH+), Rt=0.64 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1

Procedure:
A mixture of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (3 g, 9.76 mmol) and 10% palladium on carbon (300 mg) in 50 mL ethanol and 20 mL ethyl acetate was hydrogenated at room temperature under a 50 psi hydrogen atmosphere for 2 hrs. The reaction mixture was filtered through a plug of Celite and evaporated under reduced pressure to give 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester that was used in the in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:26]([O-])=O)=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][N:7]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:26][C:4]1[C:3]([O:2][CH3:1])=[CH:25][CH:24]=[CH:23][C:5]=1[CH2:6][N:7]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8](=[O:16])[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCOC(=O)CN(Cc1cccc(OC)c1[N+](=O)[O-])C(=O)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CN(Cc1cccc(OC)c1N)C(=O)c1ccc(Cl)cc1

Procedure:
1.8 g (4.4 mmol) of ethyl [(3-methoxy-2-nitrobenzyl)-(4-chlorobenzoyl)amino]acetate was dissolved in a mixture of 10 ml of ethyl acetate and 10 ml of ethanol. 180 mg of 10% palladium/carbon was added to the obtained solution, and they were stirred in the presence of hydrogen at room temperature for 4 hours. The reaction mixture was filtered through Celite and the solvent was evaporated. The obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[O-:10][CH2:11][CH3:12].[Na+].C(O)C>O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][CH3:12])=[N:4][CH:3]=1
Reactant: CC[O-]
Reactant: COc1cncc(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ncc(Br)cc1OC

Procedure:
As shown in step 5-i of Scheme 5,5-bromo-2-chloro-3-methoxypyridine (1.0 g, 4.5 mmol, prepared in the same manner as Compound 1003 in Example 2 starting with 3-bromo-5-methoxypyridine) was treated with a sodium ethoxide/ethanol solution (5.05 mL, 21% w/v, 13.5 mmol) and the reaction mixture microwave irradiated at 100° C. for 20 minutes. Water was added and the ethanol evaporated under reduced pressure. The resulting aqueous solution was extracted with DCM and ether, followed by drying the combined extracts over MgSO4. After filtration, removal of the volatiles under reduced pressure provided 5-bromo-2-ethoxy-3-methoxypyridine (Compound 1016), 0.72 g, 69% yield): ESMS (M+H) 232.32/234.23. As shown in step 5-ii of Scheme 5, Compound 1017 (ESMS (M+H) 218.32/220.23) was prepared in the same manner as Compound 1016, using sodium methoxide in methanol instead of sodium ethoxide in ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:18]1([O:24][CH2:25][CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[OH-].[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([C:21]1[CH:22]=[CH:23][C:18]([O:24][CH2:25][CH3:26])=[CH:19][CH:20]=1)=[O:9]
Reactant: CCOc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a stirred suspension of commercial 5-bromo-2-chlorobenzoic acid (250 g, 1.06 mol) in 450 mL of CH2Cl2 containing oxalyl chloride (1.1 mol) was added 1.5 mL of DMF. Once the vigorous evolution of gas ceased, the reaction was stirred overnight prior to removal of the volatiles under vacuum using a rotary evaporator. After dissolving the crude 5-bromo-2-chlorobenzoyl chloride in 200 ml of CH2Cl2, the yellow solution was transferred to a 2 L 3-neck flask equipped with an overhead stirrer and an internal thermometer. The stirred mixture was cooled to −3° prior to adding phenetole (130 g, 1.08 mol). AlCl3 (140 g, 1.07 mol) was added via a solid addition funnel over 30 min to insure that the temperature did not exceed 4°. The copious amounts of HCl gas which began to evolve after 60% of the AlCl3 had been added were trapped by passing the gas over a stirred conc. NaOH solution. HPLC revealed the reaction to be 95% complete 10 minutes after the addition was finished. After the mixture was stirred at 4° for 1 hr, the reaction was quenched by pouring over ice. Subsequently, the suspension was diluted with H2O (1 L ) and extracted 3× with CH2Cl2. The combined organic extracts were washed 2× with 1N HCl, 1× with H2O, 2× with 1M NaOH, and 2× with brine prior to drying over Na2SO4. After removal of the volatiles, HPLC revealed the residue to be a 1:7 mixture of ortho/para isomers. Recrystallization 2× from 400 mL of absolute EtOH yielded 230 g (64%) of 5-bromo-2-chloro-4′-ethoxybenzophenone.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:18][Mg]Cl.FC1C=C(F)C=CC=1/C=C1\CCC2NC(C(OC)=O)=CC\1=2>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Fc1ccc(C[Mg]Cl)cc1Cl
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1ccc(F)cc1F
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)c(Cl)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.8 mmol) was reacted with 3-chloro-4-fluorobenzylmagnesium chloride (0.25 M in diethyl ether, 28 mL, 7 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3-chloro-4-fluorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with Pt2O). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-50% EtOAc/heptane to afford the title compound. 0.034 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.00-2.16 (m, 1H) 2.50-2.64 (m, 1H) 2.64-2.71 (m, 2H) 2.75 (d, J=7.37 Hz, 2H) 3.16-3.38 (m, 1H) 3.82 (s, 3H) 6.37 (d, J=1.66 Hz, 1H) 6.97-7.11 (m, 2H) 7.23 (dd, J=7.13, 2.00 Hz, 1H) 8.85 (br. s, 1H)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([C:14](=[O:15])[NH:13][CH2:12][CH:11]2[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([C:14](=[O:15])[N:13]([CH3:26])[CH2:12][CH:11]2[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCC2c1cccnc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1CC(c2cccnc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a cooled (−60° C.) solution of 1-oxo-4-pyridin-3-yl-2,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester (diastereomer 1) (343 mg, 1.03 mmol) in THF (7 ml) was added dropwise 1M LHMDS in THF (1.34 ml, 1.34 mmol). After stirring for 1 h at −60° C., iodomethane (0.084 ml, 1.34 mmol) in THF (1 ml) was added. The cooling bath was removed and the reaction mixture was allowed to warm to RT and stirred for 3 h. A further portion of 1M LHMDS in THF (0.75 ml, 0.75 mmol) was added to the cooled (−60° C.) reaction mixture. After 30 minutes, iodomethane (0.042 ml, 0.67 mmol) in THF (0.5 ml) was added, the cooling bath was removed and the reaction mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with NH4Cl saturated solution (5 ml) and extracted with EtOAc (2×25 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-5% MeOH in DCM afforded the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][C:33]1[N:34]=[C:35]([CH3:38])[S:36][CH:37]=1.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:32][C:33]3[N:34]=[C:35]([CH3:38])[S:36][CH:37]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Reactant: Cc1nc(CCl)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(OCc4csc(C)n4)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (100 mg, 0.3 mmol), cesium carbonate (488 mg, 1.5 mmol), 4-(chloromethyl)-2-methylthiazole.HCl (110 mg, 0.6 mmol), tetrabutylammonium bromide (96 mg, 0.3 mmol), triethylamine (0.5 ml), and DMF (10 mL) were combined and stirred at ambient temperature overnight. The reaction was concentrated under reduced pressure and dichloromethane was added to the residue. Undissolved solids were removed by filtration. The filtrate was concentrated under reduced pressure and subsequently purified by flash column chromatography on silica gel, eluting with a gradient of 0-5% methanol in dichloromethane. The clean fractions were combined and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile to yield 77 mg of 1-[4-amino-2-ethoxymethyl-7-(2-methylthiazol-4-ylmethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white powder, mp 200.0-201.0° C.