Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N2CN3CN(C2)CN1C3.F[C:12](F)(F)[C:13]([OH:15])=O.[Br:18][C:19]1[CH:24]=[C:23]([Br:25])[CH:22]=C[C:20]=1[OH:26]>>[Br:18][C:19]1[C:20]([OH:26])=[C:12]([CH:22]=[C:23]([Br:25])[CH:24]=1)[CH:13]=[O:15]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccc(Br)cc1Br
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(Br)cc(Br)c1O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Hexamine (3.35 g, 23.92 mmol) was added portionwise to trifluoroacetic acid (25 ml) keeping the temperature below 40° C. with a water bath. 2,4-Dibromophenol was then added slowly and the reaction mixture heated at 80° C. for 31/2 hours. The reaction mixture was cooled, partially evaporated and then poured into ice/water. This mixture was stirred at ambient temperature overnight and the precipitate that formed filtered, dried and purified by chromatography (CH2Cl2 /hexane) to give the title compound (2.1 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:20][C:19]2[C:10](=[C:11]3[C:16](=[C:17]([O:21][CH3:22])[CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[C:9](=[O:23])[CH:8]=1)=[O:6].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([O:23][CH2:24][CH3:25])[C:10]2[C:19]([N:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[C:16]1[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]1)=[O:6]
Reactant: COC(=O)c1cc(=O)c2c(cc(OC)c3ncccc32)[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)nc2cc(OC)c3ncccc3c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.2 g of sodium hydride (50% suspension in mineral oil) is added to a solution of 6.5 g of 6-methoxy-1-oxo-1,4-dihydro-4,7-phenanthroline-3-carboxylic acid methyl ester in 50 ml of absolute dimethylformamide, whilst stirring at 40° in an inert gas atmosphere. After 30 minutes the reaction mixture is allowed to cool to room temperature, 4.3 g of ethyl iodide are added in portions, the mixture is stirred for 6 hours, 200 ml of ice-water are added, the mixture is extracted by shaking with 50 ml of petroleum ether and then extracted three times with 200 ml of chloroform each time. The chloroform extracts are combined, washed with water, dried over sodium sulphate and concentrated by evaporation under reduced pressure. 1-ethoxy-6-methoxy-4,7-phenanthroline-3-carboxylic acid methyl ester is obtained which, after recrystallisation from ethanol, melts at 188°-190°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])/[C:4](/[CH2:10]Br)=[CH:5]/[C:6]([O:8][CH3:9])=[O:7].[CH3:13][Mg]Br.Cl.[Cl-].[NH4+]>C(OCC)C.CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:10])[C:5](=[CH2:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C(\CBr)C(=O)OC
Reactant: C[Mg]Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: C=C(C(=O)OC)C(C)C(=O)OC
Reaction time: 1 h

Procedure:
To a solution of (Z)-2-bromomethyl-2-butenedioic acid dimethyl ester (19.3 g) and hexamethylphosphoric acid triamide (70 ml) in diethyl ether (200 ml) was added dropwise methyl magnesium bromide (1.12 M solution in tetrahydrofuran, 100 ml) over 1 hour at −20° C. and stirred for additional 1 hour. To this reaction mixture were added a 6M aqueous solution of hydrochloric acid (18 ml) and a saturated aqueous solution of ammonium chloride (100 ml), and then the mixture was warmed to room temperature and extracted with diethyl ether (200 ml). The resulting organic layer was washed with water twice, followed by a saturated aqueous solution of sodium chloride once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/chloroform=1/1 to 0/1) to give the titled compound (9.92 g).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[CH2:4][NH2:5].[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[CH3:1][N:2]([CH3:17])[CH:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[CH2:4][NH:5][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([C:22]2[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=2)[CH:26]=1
Reactant: CN(C)C(CN)c1nc(-c2ccccc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CN(C)C(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccccc2)cs1
Yield: 17 %

Procedure:
This compound was synthesized from N,N-dimethyl-1-(4-phenylthiazol-2-yl)ethane-1,2-diamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (16 mg, yield 17%). 1H NMR (400 MHz, CDCl3) δ 8.57-8.56 (t, J=1.5 Hz, 1H), 8.26-8.23 (dt, J=7.8 Hz, 1.4 Hz, 1H), 8.07-8.05 (dt, J=7.8 Hz, 1.4 Hz, 1H), 7.91-7.87 (m, 3H), 7.63-7.59 (t, J=7.8 Hz, 1H), 7.51 (s, 1H), 7.42-7.38 (m, 2H), 7.36-7.31 (m, 1H), 4.35-4.29 (ddd, J=13.2 Hz, 6.6 Hz, 5.5 Hz, 1H), 4.15-4.12 (m, 1H), 3.85-3.78 (ddd, J=13.0 Hz, 8.3 Hz, 4.6 Hz, 1H), 2.51 (s, 6H). MS (ESI) m/z: Calculated for C23H20F3N5O2S: 487.13. found: 488.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9](OC)(=[O:12])[CH2:10][CH3:11].ClCCl>CO>[NH:1]1[C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:11]=[CH:10][C:9]1=[O:12]
Reactant: CCC(=O)OC
Reactant: NC1=CC(=O)CCC1
Solvent: ClCCl
Solvent: CO
Product: O=C1CCCc2[nH]c(=O)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
With stirring, 113.79 g (1.02 mol) of 3-aminocyclohex-2-en-1-one and 114.37 ml (1.19 mol) of methyl propionate were heated at 105° C. for 1 hour. The dark homogeneous solution formed was then slowly heated further to 170° C. After 20 min (temperature: 135° C.), a viscous material formed, and there was a marked evolution of gas. After a further 15 min (temperature: 160° C.), the reaction material became even more viscous while the evolution of gas subsided. After a total of 42 min, a temperature of 170° C. had been reached. After a further 13 min at this temperature, the reaction material was cooled to room temperature. 200 ml of dichloromethane were then added, the mixture was heated briefly and placed into an ultrasonic bath and the crystalline residue formed was filtered off. This procedure was repeated once more with a further 200 ml of dichloromethane. The crystalline residues obtained in this manner were combined, taken up in 1.6 liters of methanol and then heated with stirring until the solid had dissolved completely. This solution was then slowly cooled to room temperature and then stored in a fridge at about 4° C. for 2 days. The crystalline precipitate was filtered off and dried under reduced pressure. This gave 47.65 g (0.29 mol, 29% of theory) of the target product.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[OH:14][C:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)(C)C>[OH:14][C:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (210 mg, 1.0 mmol), tert-butyl [(3R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (255 mg, 1.04 mmol) and triethylamine (296 μL, 2.12 mmol) in isopropyl alcohol (1 mL) was stirred at 80° C. for 2 h. The solvent was evaporated under reduced pressure and the resulting residue was purified by chromatography on silica gel eluting with 25% EtOAc in hexanes to give the sub-title compound as a yellow oil (318 mg, 74%). LCMS calc. for C20H31N4O5 (M+H)+ m/z=407.2. found 407.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH3:31])[C:15]1=[O:32]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][CH:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]([CH3:31])[C:15]2=[O:32])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CN1C(=O)C(NC(=O)Cc2cc(F)cc(F)c2)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure A above using 3,5-difluorophenylacetic acid (Oakwood) and 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-X), the title compound was prepared as a solid having a melting point of 236-239° C. The reaction was monitored by tlc on silica gel (Rf=0.7 in 10% methanol/dichloromethane) and purification was by silica gel chromatography using 10% methanol/dichloromethane as the eluant.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[C:10]([CH:14]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[N:17]=[C:16]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>ClCCl>[CH:41]1([S:44]([N:5]2[CH2:4][CH2:3][N:2]([C:8]3[CH:9]=[C:10]([CH:14]4[N:18]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:17]=[C:16]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])[CH2:15]4)[CH:11]=[CH:12][CH:13]=3)[CH2:7][CH2:6]2)(=[O:46])=[O:45])[CH2:43][CH2:42]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(N3CCNCC3)c2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
5-[3-(Piperazin-1-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (100.0 mg, 0.2 mmol) prepared in Step 1 of Example 96, triethylamine (143.0 uL, 1.02 mmol) and cyclopropanesulfonyl chloride (43.0 mg, 0.30 mmol) were added to dichloromethane (2.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 80.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]([CH3:11])[NH:8][CH:7]([CH3:12])[CH2:6]1)(=[O:4])=[O:3].Br[CH2:14][C:15]1[S:23][C:22]2[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:20][C:19]([Cl:30])=[N:18][C:17]=2[C:16]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:30][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:22]2[S:23][C:15]([CH2:14][N:8]3[C@H:9]([CH3:11])[CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][C@@H:7]3[CH3:12])=[C:16]([CH3:31])[C:17]=2[N:18]=1
Reactant: Cc1c(CBr)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1CN(S(C)(=O)=O)CC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(CN2[C@H](C)CN(S(C)(=O)=O)C[C@@H]2C)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To a mixture of 1-methanesulfonyl-3,5-dimethylpiperazine and 6-bromomethyl-2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine in acetonitrile was added potassium carbonate and the mixture refluxed overnight. After cooling to room temperature, the acetonitrile was removed under reduced pressure. DCM/sat. aq. NaHCO3 extraction and purification on silica gave 2-chloro-6-((2S,6R)-4-methanesulfonyl-2,6-dimethyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1([CH3:16])[CH2:13][C:12](=[O:14])[O:11][C:10]1=[O:15].[Cl-].[Cl-].[Cl-].[Al+3]>ClC(Cl)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12](=[O:14])[CH2:13][C:9]([CH3:16])([CH3:8])[C:10]([OH:15])=[O:11])=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CC1(C)CC(=O)OC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(C)(CC(=O)c1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a chilled solution (ice/water bath) of bromobenzene (7.71 g, 49.1 mmol) and 3,3-dimethyldihydro-2,5-furandione (5.99 g, 46.7 mmol) in dichloroethane (150 mL) was added aluminum trichloride (13.28 g, 99.58 mmol). The ice bath was removed and the reaction mixture was stirred at rt overnight. The mixture was again chilled in an ice/water bath, and then quenched with 1 M aqueous hydrochloric acid. Water (70 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage apparatus, 17:83 ethyl acetate/hexane) to give 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid as a white solid (8.34 g, 63%). LC-MS: ret. time 2.79 min; m/z 284.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.36 (s, 6H), 3.27 (s, 2H), 7.60 (d, 2H), 7.81 (d, 2H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:33](Cl)([Cl:35])=[O:34]>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:33]([Cl:35])=[O:34]
Reactant: O=C(Cl)Cl
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)Cl)CCC5(C)C4CCC32CN1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Compound 7B (125 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0° C. Triethylamine (150 μL, 1.1 mmol) and phosgene (20% in toluene, 0.23 mL, 0.44 mmol) were added to it. The mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with water, extracted with dichloromethane. The combined extracts were dried over Na2SO4, filtered and concentrated to give crude desired product (144.6 mg, 97.8%), which was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.CCN(C(C)C)C(C)C.[NH2:20][C@@H:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1>C(O)CCC>[C@@H:21]1([NH:20][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)CC[C@@H]2Nc1ncnc2[nH]ccc12
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (2.10 g, 13.6 mmol), DIPEA (3.57 mL, 20.5 mmol) and (S)-(+)-1-aminoindan (1.93 mL, 15.0 mmol) in 1-butanol (60.0 mL) and was heated to reflux for 60 hours, cooled down to room temperature and concentrated. The residue was purified by flash chromatography (0 to 100% EtOAc/DCM) to afford the title compound (2.72 g, 80%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH:19]1([CH2:24][CH2:25][C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:26](=[O:27])[CH2:25][CH2:24][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCC1CCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of (S)-(−)-4-benzyl-2-oxazolidinone (25 g, 141 mmol) in THF (350 mL) at −78° C. was added dropwise n-BuLi (56.4 mL, 2.5M solution in hexane, 141 mmol). After stirring for 60 min at the same temperature, the reaction mixture was then treated with 3-cyclopentylpropionyl chloride (21.6 mL, 141 mmol) over 0.25 h. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl solution (320 mL). The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were dried (MgSO4) and evaporated to yield (4S)-benzyl-3-(3-cyclopentylpropanoyl)oxazolidin-2-one as a white solid (42.4 g, 100%). LCMS: (M+H)+: 302.3.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:12][C:7]=2[O:6][C:5](=[O:19])[C:4]=1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:22]=1[F:30].[F-:31].[K+].C1OCCOCCOCCOCCOCCOC1.Cl>C(#N)C>[F:31][CH2:2][C:3]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:12][C:7]=2[O:6][C:5](=[O:19])[C:4]=1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:22]=1[F:30]
Reactant: [F-]
Reactant: CN(C)C(=O)Oc1ccc2c(CBr)c(Cc3cccc([N+](=O)[O-])c3F)c(=O)oc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: CN(C)C(=O)Oc1ccc2c(CF)c(Cc3cccc([N+](=O)[O-])c3F)c(=O)oc2c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
Acetonitrile (1.0 mL) was added to dimethylcarbamic acid 4-bromomethyl-3-(2-fluoro-3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester (compound 6b-1-4) (24.0 mg), and potassium fluoride (3.1 mg) and 18-crown-6 (13.2 mg) were added to the resultant suspension while stirring at room temperature. The mixture was stirred at 60° C. for 4 hours, potassium fluoride (3.1 mg) and 18-crown-6 (13.2 mg) were then added to the reaction solution, and the mixture was further stirred at 60° C. for 1.5 hours. This reaction solution was poured into 1N hydrochloric acid (0.110 mL) diluted with ice water (20 mL), and then extracted with ethyl acetate. The resultant organic layer extraction liquid was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the resultant residue was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:1) to yield the title compound (14.7 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:35]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:28]=[C:27]([NH2:36])[C:26]=2[N:25]=[C:24]1[CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)(Cl)Cl>[NH2:36][C:27]1[C:26]2[N:25]=[C:24]([CH2:37][CH2:38][CH2:39][CH3:40])[N:23]([CH2:22][CH2:21][CH2:20][CH2:19][O:18][NH:17][C:15]([NH:14][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:16])[C:35]=2[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCON
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCONC(=O)Nc1ccccc1
Temperature: 50 °C
Yield: 12.2 %

Procedure:
Triethylamine (495 μL, 3.55 mmol) and phenyl isocyanate (316 mg, 1.65 mmol) were added to a mixture of 1-[4-(aminooxy)butyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (580 mg, 1.77 mmol) in chloroform (10 mL). The reaction was heated at 50° C. overnight and became homogeneous. The solution was diluted with 1 chloroform, washed with brine (2×), dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure to provide the crude product as an orange solid (700 mg). The crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in ratios ranging from 100:0 to 95:5) to provide 90 mg of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-N′-phenylurea as a white solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([OH:15])[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1>CN(C)C=O>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([O:15][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=4)[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: On1nnc2ccc(Cn3ccnc3)cc21
Reactant: Cc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(COn2nnc3ccc(Cn4ccnc4)cc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A mixture of 3.2 parts of 6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol, 1 part of potassium carbonate and 27 parts of N,N-dimethylformamide was stirred for 30 minutes at room temperature. 2.1 Parts of 1-(chloromethyl)-3-methylbenzene were added and stirring was continued for 3 hours at room temperature. The mixture was allowed to stand overnight at room temperature and was evaporated. The residue was diluted with water and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated. The concentrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The solid residue was crystallized from a mixture of ethyl acetate and 2,2'-oxybispropane (10:20 by volume). The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 3.4 parts (70.9%) of 6-(1H-imidazol-1-ylmethyl)-1-[(3-methylphenyl)methoxy]-1H-benzotriazole; mp. 120.1° C. (compound 160). In a similar manner there were also prepared:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:24][NH2:25].F[P-](F)(F)(F)(F)F.ClC(=[N+]1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)=[CH:7][C:3]=1[C:4]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=1)=[O:6]
Reactant: Cc1cc(C)cc(-c2cnc(Cl)c(C(=O)O)c2)c1
Reactant: COc1ccc(CN)cc1OC
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)cnc2Cl)cc1OC
Temperature: 23 °C
Reaction time: 20 h

Procedure:
To a solution of 2-chloro-5-(3,5-dimethylphenyl)nicotinic acid (1-2, 0.200 g, 0.764 mmol, 1 equiv) and 3,4-dimethoxybenzylamine (0.319g, 1.91 mmol, 2.50 equiv) in DMF (5 mL) was added 1-(chloro-1-pyrrolidinylmethylene)-pyrrolidinium hexafluorophosphate (PyClu, 0.383 mg, 1.15 mmol, 1.51 equiv), and diisopropylethylamine (0.667 mL, 3.82 mmol, 5.00 equiv). The resulting mixture was stirred at 23° C. for 20 hours. The reaction mixture was filtered and purified via reverse phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL). The combined organic layers were washed with brine then dried over sodium sulfate and concentrated to give 2-chloro-N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)nicotinamide (1-3) as a white powder. LRMS m/z (M+H) 262.3 found, 262.1 required.