Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:16][CH2:15][C@H:14]([CH2:17][NH2:18])[O:13][C:9]3=2)[N:4]=1.[F:19][C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]1[CH2:27][CH:26]([C:33](O)=[O:34])[CH2:25][CH2:24][C:23]2=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(N(CC)CC)C>[F:19][C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]1[CH2:27][CH:26]([C:33]([NH:18][CH2:17][C@@H:14]3[O:13][C:9]4=[C:10]5[C:5](=[CH:6][CH:7]=[C:8]4[O:16][CH2:15]3)[N:4]=[C:3]([CH3:2])[CH:12]=[CH:11]5)=[O:34])[CH2:25][CH2:24][C:23]2=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CN)O3
Reactant: O=C(O)C1CCc2c([nH]c3ccc(F)cc23)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CNC(=O)C1CCc2c([nH]c4ccc(F)cc24)C1)O3
Reaction time: 0.25 h

Procedure:
[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methylamine hydrochloride (360 mg, 1.35 mmol) and compound I were suspended in anhydrous tetrahydrofuran (THF) containing triethylamine (1.8 mL) and HOBT (54 mg) with stirring for 15 min. The coupling reagent, DCC (300 mg) was added and stirring was continued overnight. The reaction mixture was filtered and the filtrate was diluted with water and extracted with ether. The ether layers were combined, dried (MgSO4), and evaporated under reduced pressure to give a residue which was purified by flash chromatography on silica gel eluting with 1-2% methanol in methylene chloride to give the intermediate II (240 mg) as a white solid. mp 262-267° C.; MS (ES) m/z 444.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32]C)=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].CO.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.4 %

Procedure:
To a mixture of 6-chloro-2-(4-methoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (2.50 g), methanol (10 ml) and tetrahydrofuran (20 ml) was added 8N aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure and water was added. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from methanol to give the title compound (1.27 g, 52%).
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][C:10]([C:11]([C:13]3[NH:17][CH:16]=[C:15]([C:18]([O:20]CC)=[O:19])[CH:14]=3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([C:13]3[NH:17][CH:16]=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=3)=[O:12])=[CH:23][CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2ccc(-c3ccccc3)cc2)c1
Solvent: CO
Product: O=C(O)c1c[nH]c(C(=O)c2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C

Procedure:
Ethyl 5-(4-phenylbenzoyl)pyrrole-3-carboxylate (3.1 g.) was boiled in an open flask with 100 ml. of methanol and 70 ml. of 1 N sodium hydroxide for 1 hour by which time most of the methanol was removed by evaporation. The solution was cooled to room temperature, and product which had precipitated as the sodium salt recovered by filtration. The salt was stirred with 75 ml. of 1 N hydrochloric acid and 5-(4-phenylbenzoyl)pyrrole-3-carboxylic acid (1 g., m.p. >280° C.) recovered by filtration.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]([N:24]3[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][CH2:25]3)=[O:23])=[N:12]2)=[CH:7][CH:6]=1.[CH3:32]I>CN(C)C=O>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]([N:24]3[CH2:30][CH2:29][C:28](=[O:31])[N:27]([CH3:32])[CH2:26][CH2:25]3)=[O:23])=[N:12]2)=[CH:7][CH:6]=1
Reactant: CI
Reactant: COc1ccc(-n2nc(C(=O)N3CCNC(=O)CC3)cc2-c2ccccn2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(=O)N3CCC(=O)N(C)CC3)cc2-c2ccccn2)cn1
Reaction time: 0.25 h

Procedure:
At 0° C., the sodium hydride (washed with pentan and dried, 20.4 mg) was added to a solution of 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-5-oxo-1,4-diazepane (0.253 g) obtained in Example 108 in N,N-dimethylformamide (5.0 mL), and the mixture was stirred for 15 minutes. To the reaction mixture, methyl iodide (0.0602 mL) was added, and the mixture was stirred at room temperature for 14 hours. The resultant mixture was partitioned between water and chloroform-methanol (5%). The aqueous layer was further extracted with chloroform-methanol (5%), and the organic layers were combined, followed by washing with saturated brine and drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an amorphous product (0.231 g, 88%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1C=CN=C1.S(Cl)(C)(=O)=O.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[N:53]=1>C1(C[C@H](CN(C=O)OCC2C=CC=CC=2)C(N2[C@H](C(O)=O)CCN2C(OCC2C=CC=CC=2)=O)=O)CCCC1.ClCCl>[Cl:58][C:54]1[N:53]=[C:52]([NH:51][C:15]([C@@H:14]2[CH2:13][CH2:12][N:11]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[N:10]2[C:8](=[O:9])[C@@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:17])[CH:57]=[CH:56][CH:55]=1
Reactant: Nc1cccc(Cl)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1C(C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Agent: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: ClCCl
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2cccc(Cl)n2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (as a mixture of diastereomers enriched in (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid) (300 mg, 0.558 mmol) in dichloromethane (5 ml) was added 1-methylimidazole (133 μl, 1.674 mmol) and cooled to 0° C. Mesyl chloride (56 μL, 0.725 mmol) was added dropwise at 0° C. and stirred for 1 hr at rt. The mixture was then treated with 2-amino-6-chloropyridine (86 mg, 0.67 mmol). The solvent mixture was removed. The residue was diluted with MeOH and purified by reverse-phase HPLC to afford 268 mg (0.413 mmol, 74%) of the title compound. LC/MS: (M+H)+: 648.3.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].CCCCC.[CH3:17][C:18]([CH:21]=O)([CH3:20])[CH3:19].C([O-])(O)=O.[Na+]>FC(F)(F)S(O)(=O)=O>[C:18]([C@H:21]1[O:10][C:1](=[O:11])[C@@H:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[O:3]1)([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)C=O
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCCCC
Product: CC(C)(C)[C@H]1OC(=O)[C@@H](c2ccccc2)O1
Temperature: 36 °C
Reaction time: 5.5 h
Yield: 83.1 %

Procedure:
(R)-Mandelic acid (20 g, 130 mmol) was dissolved in anhydrous pentane (200 mL, 1.7 mol). Pivaldehyde (13.6 g, 153 mmol) was added followed by trifluoromethanesulfonic acid (488 μL, 5.4 mmol). The reaction was allowed to reflux at 36° C. under nitrogen. After 5.5 hours, the mixture was allowed to cool to room temperature before stirring with 200 mL of an 8 wt % NaHCO3 solution for 10 minutes. Excess pentane was removed by rotary evaporation. The solids were collected by filtration and rinsed (100 mL water) while under vacuum filtration. The solids were dried overnight under high vacuum to yield intermediate (1a) as a white solid (23.8 g, 88% purity).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[C:12]([CH3:25])[CH:11]=1)(=[O:7])[CH3:6].[CH3:26]O>>[C:5]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[C:12]([CH3:25])[CH:11]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)NCc1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(CNC(C)=O)cc2C)cc1

Procedure:
Thionyl chloride (0.119 ml, 1.63 mmol) was added dropwise to MeOH (5 ml) at 0° C., followed by a solution of 4'-acetamidomethyl-2'-methylbiphenyl-4-carboxylic acid (D1, 0.345 g, 1.22 mmol) in MeOH (10 ml). The mixture was heated under reflux for 1.5 hr and the solvent removed in vacuo. The residue was dissolved in CH2 Cl2 (30 ml) and washed with aq. Na2CO3 followed by water. The organic extract was dried (Na2SO4) and concentrated in vacuo to give a colourless oil which purified by column chromatography on silica gel eluting with EtOAc to give a colourless oil that crystallised on standing (0.242 g, 68%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:10]Br)[CH2:9][CH2:8]1.CN(C)C=O.[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][NH:24]2)=[C:20]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:19]=1>C(OCC)(=O)C>[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[CH2:10][CH:7]2[CH2:9][CH2:8]2)=[C:20]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:19]=1
Reactant: BrCC1CC1
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1nc(N2CCOCC2)c2ncn(CC3CC3)c2n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
Potassium carbonate (36.0 g, 260.5 mmol) and cyclopropylmethyl bromide (20.2 g, 143.3 mmol) were added to an N,N-dimethylformamide suspension (400 ml) of 2-chloro-6-morpholin-4-yl-9H-purine (32.4 g; purity, approx. 96%; 130.2 mmol) at room temperature and the resulting mixture was stirred at 80° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was left standing to cool, then poured into ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting solid was washed with diethyl ether and collected by filtration to give the title compound (26.9 g, 70%) as a colorless acicular crystal. The mother liquor was further concentrated by the same procedure to give the secondary crystal of the title compound (7.68 g, 20%) as a white solid.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:31])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:29](=[CH:30][C:4]1=2)[C:28]1[N:27]=[C:17]2[CH:18]=[CH:19][C:20](O)=[C:21](CN(C)C)[C:16]2=[CH:15][C:14]=1[CH2:13]3)=[O:11].CCC1C2CN3C(=O)C4COC([C@](O)(CC)C=4C=C3C=2N=C2C=1C=C(OC(N1CCC(N3CCCCC3)CC1)=O)C=C2)=O>>[CH3:1][CH2:2][C@@:3]1([OH:31])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:29](=[CH:30][C:4]1=2)[C:28]1[N:27]=[C:17]2[C:16]([CH:21]=[CH:20][CH:19]=[CH:18]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CN(C)C)c(O)ccc3nc2-1
Agent: CCc1c2c(nc3ccc(OC(=O)N4CCC(N5CCCCC5)CC4)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1

Procedure:
R1a=R1b=R2=H; Topotecan: R1a=—CH2NMe2, R1b=OH, and R2=H; Irinotecan: R1a=H, R1b=
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8]1([C:14]2[O:18][N:17]=[CH:16][C:15]=2[CH2:19][CH2:20][C:21](O)=[O:22])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:21](=[O:22])[CH2:20][CH2:19][C:15]1[CH:16]=[N:17][O:18][C:14]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1cnccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A mixture of 2-aminopyrazine (0.26 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.58 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.46 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(2-pyrazinyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.46 g, yield 58%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 163–164° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:19]=[CH:18][C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH:25]1[C:20]2[CH:19]=[CH:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[C:15](=[C:12]3[CH2:11][CH2:10][N:9]([CH2:8][CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=4)[CH2:14][CH2:13]3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 56.7 %

Procedure:
This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and ethyl chloroformate. Yield 56.7%
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][C:25]#[CH:26])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.[OH:31][N:32]=[C:33](Cl)[CH3:34].C(=NO)C.ClN1C(=O)CCC1=O>C1COCC1>[Cl:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][C:25]3[O:31][N:32]=[C:33]([CH3:34])[CH:26]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(Cl)=NO
Reactant: C#CCCCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Agent: O=C1CCC(=O)N1Cl
Solvent: CC=NO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCCc1cc(C)no1

Procedure:
In the presence of triethylamine (5.2 mL, 10.7 mmol) in a solution of THF (50 mL), 4-chloro-2-(ethoxymethyl)-1-pent-4-ynyl-1H-imidazo[4,5-c]quinoline (prepared as described in Part F of Example 6, 3.50 g, 10.7 mmol) was reacted with N-hydroxyethanimidoyl chloride that was generated from acetaldehyde oxime (1.90 g, 32.1 mmol) and N-chlorosuccinimide (4.30 g, 32.1 mmol) using the method described in Part B of Example 5. The crude product was purified by flash chromatography (silica gel, gradient elution with 4:1 to 2:3 hexanes/ethyl acetate). The appropriate fractions were combined and concentrated to provide a solid that was triturated with diethylether. The solid was isolated by filtration and dried to yield 4-chloro-2-(ethoxymethyl)-1-[3-(3-methylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline (1.87 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30]>>[Cl:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)=[CH:3][CH:4]=1)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccc(F)cc2Cl)=N/O)ccc1=O
Product: Cn1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(F)cc2Cl)=N/O)ccc1=O

Procedure:
The title compound was prepared in analogy to example 166, from (E)-5-{3-(4-bromo-phenyl)-3-(2-chloro-4-fluoro-phenyl)-1-(hydroxyimino)-propyl}-1-methyl-1H-pyridin-2-one (example 410) and 4-carboxyphenylboronic acid (CAS RN 14047-29-1). The compound was purified by silica gel chromatography using a MPLC system eluting with a gradient of dichlormethane:methanol (100:0 to 90:10). The resulting yellow solid was purified by preparative HPLC (phenomenex gemini column) with a gradient of acetonitrile:water (10:90 to 95:5) followed by another preparative HPLC purification (Reprosil Chiral-NR column) using 80% n-heptane:20% EtOH (containing 0.5% formic acid) as eluant to give the desired compound as a colourless solid, MS (ESI+): m/z=505.1 ([M+H]+).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C.CO.O>C1COCC1.CCOC(C)=O>[CH:14]1([N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][CH2:6][OH:5])[CH2:13][CH2:12]2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)CC1CCN(C2CC2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: OCCC1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
Lithium tetrahydroborate (730 mg) was added to a solution of ethyl(1-cyclopropylpiperidin-4-yl)acetate (2.1 g) in THF (53 mL) under ice-cooling. MeOH (2.4 mL) was added thereto, and the mixture was stirred at room temperature overnight. After water and EtOAc were added to the reaction mixture, the mixture was stirred for 30 minutes, and extraction was performed using EtOAc. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (Hex:EtOAc=80:20 to 60:40), whereby 2-(1-cyclopropylpiperidin-4-yl)ethanol (1.3 g) was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([C:64](OC)=[O:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CC(C[AlH]CC(C)C)C.Cl>C1COCC1>[CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)OC)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
Methyl 3,4,5-tris(octadecyloxy)cyclohexylcarboxylate (70.0 g, 73.9 mmol) was dissolved in THF (1050 ml), and DIBAL (1.0 mol/L toluene solution, 200 ml, 200 mmol) was added dropwise at 0° C. over 40 min under a nitrogen atmosphere. After stirring at room temperature for 2 hr, 0.2N hydrochloric acid (50 ml) was added dropwise at 0° C. to quench the reaction. The solvent was evaporated to about half, and the residue was dissolved in chloroform (700 ml). The mixture was washed three times with 1N hydrochloric acid (300 ml), once with 5% aqueous sodium hydrogen carbonate solution (300 ml), and once with 20% brine (300 ml). The solvent was evaporated, and the residue was precipitated with methanol (700 ml), and washed with acetonitrile to give 3,4,5-tris(octadecyloxy)cyclohexylmethyl alcohol (68.2 g, 74.2 mmol, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[C:9](=[O:12])[N:8]([C@@H:13]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[C:5]2=[N:6][CH:7]=1.[ClH:25].O1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[C:9](=[O:12])[N:8]([C@@H:13]3[CH2:17][CH2:16][NH:15][CH2:14]3)[C:5]2=[N:6][CH:7]=1.[ClH:25]
Reactant: Cn1c(=O)n([C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncc(Cl)cc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1c(=O)n([C@@H]2CCNC2)c2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)-tert-butyl 3-(6-chloro-1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (109 mg) was dissolved in CH2Cl2 (3 mL) and 4 M HCl in dioxane (1 mL, 4 mmol) was added. The mixture was stirred at rt for 3 h and concentrated to give (R)-6-chloro-1-methyl-3-(pyrrolidin-3-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one as its HCl salt (78 mg, 87%). Method 1 tR=0.77 min, m/z=253.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[NH:8][C:7](=[O:9])[O:6][N:5]1[CH2:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1.CO.Cl>C1COCC1>[O:3]=[C:4]1[NH:8][C:7](=[O:9])[O:6][N:5]1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(-c2cccc(COc3ccc(Cn4oc(=O)[nH]c4=O)cc3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cccc(COc3ccc(Cn4oc(=O)[nH]c4=O)cc3)c2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A 1 M sodium hydroxide aqueous solution (5 ml) was added to a mixture of methyl 3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-4-biphenylcarboxylate (196 mg), methanol (5 ml) and THF (5 ml), followed by stirring for 1 hour with heating at 60° C. A 1 M hydrochloric acid (7 ml) was added to the reaction mixture, followed by stirring at room temperature. The solid precipitated was collected by filtration and dried by heating under a reduced pressure to obtain 3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-4-biphenylcarboxylic acid (176 mg) as a white solid.