Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2>O1CCCC1.[O-2].[Mn+4].[O-2]>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:15]=[CH:14]2
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: Brc1ccc2ncccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccc3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 66.7 %

Procedure:
4-Fluorophenylmagnesium bromide (1.0M in tetrahydrofuran, 30 mL, 30 mmol) was added dropwise to a solution of 6-bromoquinoline (5.0 g, 24 mmol) in tetrahydrofuran (50 mL) at −5° C. The reaction was stirred, maintaining the temperature below 0° C. for 1.5 hours, then allowed to warm to room temperature for 70 hours. Further 4-fluorophenylmagnesium bromide was added and the reaction heated to reflux for 20 hours. The cooled reaction mixture was quenched with saturated ammonium chloride solution then poured into water and extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was dissolved in dichloromethane (100 mL). Manganese (IV) oxide (2.22 g, 25.5 mmol) was added and the reaction stirred at room temperature for 1 hour. Further manganese(IV) oxide (4.51 g) was added and stirring continued for 3.5 hours. The reaction mixture was filtered through a plug of silica, washing with dichloromethane. The filtrate was concentrated in vacuo. The residue was stirred in methanol (100 mL) for 5 minutes then removed by filtration to give 6-bromo-2-(4-fluorophenyl)quinoline (4.84 g, 67%). 1H NMR (500 MHz, CDCl3) δ 8.17-8.11 (3H, m), 8.02-7.98 (2H, m), 7.85 (1H, d, J=8.6 Hz), 7.79 (1H, dd, J=2.1, 8.9 Hz), 7.21 (2H, t, J=8.6 Hz); m/z (ES+) 302, 304 [MH+].
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.Cl[C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]([NH:25][C:26]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=2)[N:14]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[OH:10])[CH2:3][NH:2][C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])[N:16]=[C:15]([NH:25][C:26]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:28][CH:27]=2)[N:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: NCc1ccc(O)c(Cl)c1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.3 %

Procedure:
To a 100 mL round-bottom flask equipped with a stir bar was added 4-(aminomethyl)-2-chlorophenol hydrobromide (1.34 g, 5.63 mmol), tert-butyl 4-((4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (3.00 g, 5.63 mmol) and THF (28 mL). To the solution was added N,N-diisopropylethylamine (2.95 ml, 16.9 mmol). The mixture was stirred at room temperature for 3 days. The mixture was concentrated in vacuo and the resulting residue was subjected to C18 chromatography (water:methanol 1:1 to methanol) to afford tert-butyl 4-((4-((3-chloro-4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate as a colorless solid (2.88 g, 90%). MS m/z=526.3 (M+H)+.
Reaction SMILES: Cl.[C:2](Cl)(=[O:4])[CH3:3].Cl.[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC.C([O-])(=O)C.[Na+]>C(O)(C(F)(F)F)=O.C(OC(=O)C)(=O)C.C(O)CCCCCCC>[CH3:3][CH:2]([OH:4])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCO
Reactant: CC(=O)Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCC(C)O

Procedure:
Assignment of the absolute configuration of the TSL-1 and ES 3,6-dideoxyhexose was achieved by GC/MS analysis of the acetylated glycosides formed from chiral 2-octanol. 3M HCl in both (-)-2 and (+)-2 octanol (available from Sigma) were prepared by the dropwise addition of about 256 μl acetyl chloride (available from Mallinkrodt, Inc., Paris, Ky.) to about 1.2 ml octanol. Derivatizations of TSL-1 and ES antigens were achieved by: (a) hydrolysis in 2M TFA at about 121° C. for about 1 hour (hr); (b) octanolysis in either (-)-2 or (+)-2 3M octanol HCl at about 80° C. for about 3 hr; (c) addition of sodium acetate; and (d) acetylation in acetic anhydride at about 100° C. for about 1 hr. The acetylated octyl glycosides were partitioned into the organic phase between about 1 ml chloroform and about 1 ml water, dried, and extracted into acetone (see, for example, Leontein et al., pp. 359-362, 1978, Carbohyd. Res., Vol. 62). Samples were analyzed by GC/MS as above for alditol acetates (total ion chromatogram) or in the selected ion monitoring mode (selecting m/z's of about 83, 85, 112, 145, and 215). Methyl tyvelose (3,6-dideoxy-D-arabinohexose) and Ascaris suum eggs (containing 3,6-dideoxy-L-arabinohexose) were also subjected to hydrolysis, (-)-2 and (+)-2 octanolysis, and acetylation. GC/MS data from the resulting acetylated 3,6-dideoxyarabinohexose octyl glycoside derivatives were compared to those obtained from the TSL-1 and ES antigen samples. Verification of absolute configuration was achieved by co-injection.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:76][C:77]([S-:80])([CH3:79])[CH3:78].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([S:80][C:77]([CH3:79])([CH3:78])[CH3:76])[C:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2OS(=O)(=O)C(F)(F)F)cc1
Reactant: CC(C)(C)[S-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cnc(COC(C)=O)cc2SC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (5-({[4-(methoxy)phenyl]methyl}oxy)-4-{[(trifluoromethyl)sulfonyl]oxy}-2-pyridinyl)methyl acetate (10 g, 23 mmol) in anhydrous toluene, (R)-(+)-2,2 bis(diphenylphosphino)-1,1-binaphthyl (312 mg, 0.4 mmol) was added. The reaction mixture was degassed before adding palladium acetate (103 mg, 0.4 mmol). Sodium 2-methyl-2-propanethiolate was added, the system degassed again and the reaction mixture was stirred at 60° C. for 3 hours, under argon atmosphere then at 70 oC for a further 18 hours. The reaction mixture was filtered and the filtrate was evaporated under vacuum. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted several times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with 20-35% ethyl acetate in hexane to afford the product as an oil (9.1 g, 100%); MS (+ve ion electrospray) m/z 376 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:2][CH2:3][O:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])=[CH:16][CH:17]=1
Reactant: N#Cc1cccc(COCCBr)c1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(COCCOc2ccc(CCO)cc2)c1
Temperature: 60 °C
Yield: 81.6 %

Procedure:
A mixture of 3-[(2-bromoethoxy)methyl]benzonitrile (5.00 g), 2-(4-hydroxyphenyl)ethanol (3.45 g), and potassium carbonate (5.76 g) in N,N-dimethylformamide (30 ml) was heated at 60° C. for 66 h. The mixture was allowed to cool and partitioned between ethyl acetate and 2N HCl. The aqueous phase was extracted with ethyl acetate and the combined organic phase washed with 2N NaOH, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (SPE, eluted with gradient between cyclohexane and 80% EtOAc in cyclohexane) to give the title compound (5.05 g). LCMS RT=2.96 min.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[C:33]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[C:33]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:12][CH:13]2[O:14][C:15]3[C:16](=[CH:17][CH:18]=[C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]4=3)[O:25][CH2:26]2)[CH2:41][CH:42]=1
Reactant: Fc1cccc2c(C3=CCNCC3)c[nH]c12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4c(F)cccc24)CC1)CO3
Temperature: 80 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmole) and 7-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.0 g, 4.6 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated at 80° C. under nitrogen for six hours. After completion, the reaction was cooled to room temperature and diluted to 400 mL with ethyl acetate. The organic phase was washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 1% methanol/chloroform to give 0.50 g of the (S)-enantiomer of the title compound, which was a yellow solid (m.p. 208-210° C.) after evaporation of the solvent.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3][C:2]1=[O:12].[H-].C([Al+]CC(C)C)C(C)C.O.[OH-].[Na+]>C(OCC)C>[CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3][CH:2]1[OH:12]
Reactant: O=C1CC2(CCCCC2)CCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: OC1CC2(CCCCC2)CCO1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 3-oxaspiro[5.5]undecan-2-one (1.68 g) in diethyl ether (50 mL) was added a 1M solution of diisobutylaluminum hydride in diethyl ether (15.0 mL) under ice cooling. The solution was stirred under ice cooling for 15 minutes. Diethyl ether (100 mL) was then added to the solution, followed by successive addition of water (0.6 mL) and a 15% aqueous sodium hydroxide solution (0.6 mL). The solution was stirred at room temperature for 30 minutes. Water (1.8 mL) was then added to the solution, and it was stirred for additional 15 minutes. The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:1) to give the title compound (1.36 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Cl[C:16]1[N:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:22][C:19]1[CH:18]=[N:17][C:16]([N:4]2[CH2:5][CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:2]([CH3:1])[C:3]2=[O:14])=[N:21][CH:20]=1
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Reactant: Fc1cnc(Cl)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (300 mg, 1.498 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-chloro-5-fluoropyrimidine (0.194 ml, 1.573 mmol) in 1,4-dioxane (10 ml) was treated with cesium carbonate (732 mg, 2.247 mmol), Xantphos™ (65.0 mg, 0.112 mmol), and tris(dibenzylideneacetone)dipalladium(0) (34.3 mg, 0.037 mmol) and then heated at reflux for ˜3 hrs. The mixture was cooled to room temperature, diluted with water (˜25 ml) and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with water and then with brine and evaporated to give a yellow/brown residue. This was purified by automated silica-gel column chromatography (Biotage SP-4), eluting with a 0-100% gradient of ethyl acetate in isohexane (8 column volumes), to give 1,1-dimethylethyl 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (232 mg, 52.3% yield) as a white solid. (ii) 1,1-Dimethylethyl 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (232 mg, 0.783 mmol) was dissolved in a mixture of trifluoroacetic acid (2 ml, 26.0 mmol) and dichloromethane (4 ml) at 0° C. and then left to warm to room temperature and stirred overnight. The mixture was evaporated (azeotroping with toluene and then with dichloromethane to remove all TFA traces) to give 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (211 mg) as a white solid which was used without further purification in subsequent chemistry. LC/MS MH+=240.85.
Reaction SMILES: Cl.[S:2]1[C:6]([NH2:7])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1.C(Cl)Cl>[S:2]1[C:6]([NH:7][S:19]([C:16]2[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1cc2ccccc2s1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc2ccccc2s1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a stirred solution of compound 1-C (9.28 g, 49.9 mmol) in pyridine (100 mL) and methylene chloride (50 mL), cooled on an ice bath, was added 4-bromobenzene-1-sulfonyl chloride (12.8 g, 49.9 mmol), portion-wise over a period of 4 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was concentrated under reduced pressure, the crude residue partitioned between EtOAc (500 mL) and 1N HCl (250 mL), the layers separated, the organic phase washed with 1N HCl (125 mL), brine, dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2) eluting with an EtOAc-Heptane gradient to afford 13.5 g of compound 361-A as a tan powder. 1H-NMR (DMSO-d6) δ: 6.89 (s, 1H), 7.33-7.20 (m, 2H), 7.75-7.64 (m, 3H), 7.84-7.76 (m, 3H), 11.30 (s, 1H); MS: m/z 366.1 (M-H)−.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[CH3:12][C:13]([CH:15]=[CH2:16])=[O:14].C1C=CC=CC=1.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[CH3:1][CH:2]1[CH2:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6](=[O:7])[CH:8]1[CH2:16][CH2:15][C:13](=[O:14])[CH3:12]
Reactant: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Reactant: C=CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)CCC1C(=O)C(C(C)C)CCC1C

Procedure:
A mixture of 19.6 g of the pyrrolidine-enamine of p-menthone, 10 ml of methylvinyl ketone and 150 ml of anhydrous benzene is refluxed under nitrogen for 20 hours. The mixture is then cooled and treated with 6 g of sodium acetate in 12 ml of water as well as with 12 ml of acetic acid. The mixture is again refluxed for 4 hours. Then, the product is extracted with benzene and the solvent evaporated. The residue is fractionated in vacuo and there is obtained 1-methyl-4-isopropyl-2-(3'-oxobutyl)-cyclohexan-3-one with a boiling point of 88°-90°C.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[N:5]([CH3:25])[C:4]1=[O:24])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC[C@@H]1C(=O)Nc2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (0.21 g, 0.64 mmol) in acetone (5 mL) was added potassium carbonate (0.12 g, 0.87 mmol) followed by iodomethane (0.20 mL, 0.46 g, 3.2 mmol). The reaction vessel was flushed with nitrogen and sealed. The mixture was stirred at room temperature for 16 h, after which time additional iodomethane (0.20 mL, 0.46 g, 3.2 mmol) and potassium carbonate (0.11 g, 0.80 mmol) were added. Stirring was continued at 40° C. for an additional 20 h. The solvent was then evaporated, and the resulting residue was partitioned between water and ethyl acetate, separated, washed with water and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (quantitative) as an oil that was used without further purification. MS (ESI) m/z 343 ([M+H]+); HRMS: calcd for C19H19FN2O3, 342.13804; found (ESI+), 343.14463.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([NH2:20])=O)[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH2:23][CH3:24])([C:10]2=[O:21])[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]#[N:20])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH2:23][CH3:24])([C:10]2=[O:21])[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC(N)=O)c(Cl)c1Cl)C2=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC#N)c(Cl)c1Cl)C2=O

Procedure:
[(5,6-Dichloro-3,9-dioxo-9a-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetamide (3.65 g, 10 mMole) is dissolved in pyridine (25 ml) and N,N'-dicyclohexylcarbodiimide (2.17 g, 10.5 mMole) in pyridine (15 ml) is added portionwise over 30 minutes with stirring at 15°-20° C. The mixture is then stirred at ambient temperature for 3 hours. The precipitated dicyclohexylurea is removed by filtration and the pyridine removed from the filtrate by evaporation in vacuo. Addition of water to the residue gives the product which is dissolved in methylene chloride, dried over MgSO4 and the solvent removed to provide the [(5,6-dichloro-3,9-dioxo-9a-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetonitrile.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][N:35]([CH3:54])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:47]=[C:48]([CH2:52]O)[CH:49]=[CH:50][CH:51]=2)=[N:44][CH:45]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:54][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[N:44][C:43]([C:46]2[CH:47]=[C:48]([CH:49]=[CH:50][CH:51]=2)[CH2:52][N:6]2[C:5]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=3[O:3][C:2]2=[O:1])=[N:42][CH:41]=1
Reactant: COC(=O)c1ccc2oc(=O)[nH]c2c1
Reactant: CN(C)CCCOc1cnc(-c2cccc(CO)c2)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2oc(=O)n(Cc3cccc(-c4ncc(OCCCN(C)C)cn4)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.84 g (9.5 mmol) of methyl 2-oxo-2,3-dihydrobenzoxazole-5-carboxylate and 4.75 g (14.25 mmol) of polymer-bound triphenylphosphine (3 mmol/g) are added to a solution of 3.03 g (10.45 mmol) of {3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}methanol in 40 ml of THF. The suspension is shaken at room temperature for 30 min. The suspension is cooled in an ice bath, and 3.35 g (14.25 mmol) of di-tert-butyl azodicarboxylate are added in portions. After the mixture has been stirred at room temperature for 24 h, a further 4.75 g (14.25 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 3.35 g (14.25 mmol) of di-tert-butyl azodicarboxylate are added, and the mixture is shaken at room temperature for a further 24 h. The reaction mixture is filtered, the filtrate is evaporated to dryness, and the residue is purified by column chromatography on silica gel, giving 947 mg of “A64”; m.p. 125° C., ESI: 463 (M+H); Rt=3.07 min (method C);
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][N:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:9]3[N:8]=[C:7]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])[C:6]4[N:2]([CH3:1])[CH:3]=[N:4][C:5]=4[CH:10]=3)=[N:12][CH:13]=2)[CH2:18][CH2:19]1)(=[O:34])[CH3:33]
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cn2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(-c3cc4ncn(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
Into a solution of (R)-4-((R)-1-((3-methyl-6-(5-(piperazin-1-yl)pyridin-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.39 (50 mg, 0.119 mmol) and TEA (0.12 g) in DCM (2 mL) was added acetic anhydride (0.02 g, 0.18 mmol) at 0° C. The reaction mixture was warmed to rt and stirred for 2 h. Then the reaction mixture was extracted with ethyl acetate and washed with brine. After drying, the solvent was removed, the residue was purified by silica chromatographgy to provide 36 mg of (R)-4-((R)-1-((6-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.40.
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO>[CH3:17][C:16]([CH3:19])([CH3:18])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25]1)[CH2:10][C:9]([OH:35])=[O:8])[C:20](=[O:23])[NH:21][CH3:22]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccccc2)c1)C(C)(C)C
Yield: 100 %

Procedure:
According to the procedure described in Example 1(a), N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester (371 mg, 0.781 mmol) in MeOH (15 mL) was hydrogenolyzed to provide 301 mg(100%) of N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid as a yellow foam. 1H NMR (CDCl3): δ 7.50-7.20 (m, 4H), 7.15 (tt, 1H, J=1.2, 7.3 Hz), 7.06 (dd, 1H, J=2.0, 2.0 Hz), 6.78 (dd, 1H, J=2.5, 2.5 Hz), 6.48 (dd, 1H, J=1.6, 2.8 Hz), 5.20 (t, 1H, J=6.9 Hz), 4.20 (d, 1H, J=9.3 Hz), 3.34 (dd, 1H, J=6.9, 17.4 Hz), 3.06 (dd, 1H, J=7.2, 17.4 Hz), 2.69 (d, 3H, J=4.7 Hz), 0.93 (s, 9H); IR (KBr): 3318, 2966, 1718, 1654, 1559, 1542, 1202, 745 cm−1. HRFABMS: Calcd for C21H27N3O4Cs (M+Cs+): 518.1056. Found: 518.1037. Anal. Calculated for C21H27N3O4.0.3 CHCl3: C, 60.73; H, 6.53; N, 9.97. Found: C, 60.70; H, 6.58; N, 9.84.