Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C@@H:29]3[CH2:33][NH:32][CH2:31][C@H:30]3[CH2:34][OH:35])[N:20]=[N:21][C:22]=2[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C=O.O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].Cl>ClCCl.C(O)(=O)C.O.C(OCC)(=O)C.CCOCC>[ClH:1].[ClH:1].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C@@H:29]3[CH2:33][N:32]([CH3:39])[CH2:31][C@H:30]3[CH2:34][OH:35])[N:20]=[N:21][C:22]=2[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCc1nnc(OC[C@@H]2CNC[C@H]2CO)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCc1nnc(OC[C@@H]2CN(C)C[C@H]2CO)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 164.6 %

Procedure:
To a solution of (±)-trans-{4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-pyrrolidin-3-yl}-methanol dihydrochloride (0.2 mmol, 104 mg) in dichloromethane (2.0 mL) was added formaldehyde solution in water (37%, 2.0 mmol, 0.2 mL), and 1 drop of acetic acid. Then sodium triacetoxyborohydride (2.0 mmol, 424 mg) was added. The mixture was stirred at room temperature for 0.5 hour then condensed, diluted with water/ethyl acetate, and neutralized with NaHCO3 powder. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N ammonia in MeOH) to give a solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to yield the title compound (88 mg). LCMS: m/z 464 [M+2]. 1H NMR (400 MHz, CD3OD) δ 7.83 and 7.93 (1H, s), 7.45-7.55 (4H, m), 7.36-7.40 (2H, m), 7.31-7.35 (1H, m), 7.20-7.24 (2H, m), 5.20 (2H, s), 4.59-4.63 (2H, m), 3.63-3.95 (4H, m), 2.58-3.3 (9H, m), 1.44-1.53 (2H, m), 1.25-1.33 (2H, m), 0.81 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:16][CH3:17])=[O:15])=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=2)=[C:4](F)[C:3]=1[F:20].[H-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=3)[C:14](=[O:15])[N:16]([CH3:17])[C:4]=2[C:3]=1[F:20]
Reactant: CNC(=O)c1c(-c2ccc(Br)c(F)c2F)ccnc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccc2c1c(=O)n(C)c1c(F)c(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.5 %

Procedure:
To a solution of 4-(4-bromo-2,3-difluorophenyl)-N,2-dimethylnicotinamide (600 mg, 1.76 mmol) in tetrahydrofuran (20 mL) at 0° C. was added NaH (176 mg, 4.40 mmol) and the reaction mixture was brought to room temperature gradually. The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford 8-bromo-7-fluoro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (400 mg, 1.24 mmol, 71% yield) as yellow solid. LC/MS (ESI) m/e 322.8 [(M+2H)+, calcd for C14H12BrFN2O 322.9]; LC/MS retention time (method G): tR=2.21 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH:4](Br)[CH3:5].[CH:8]([S:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:7])[CH:4]([O:18][C:17]1[C:12]([S:11][CH:8]([CH3:10])[CH3:9])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:5]
Reactant: CC(C)Sc1ncccc1O
Reactant: COC(=O)C(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)Oc1cccnc1SC(C)C
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
12.3 ml of 2-bromopropionic acid methyl ester are added dropwise at room temperature to a mixture of 16.9 g of 2-isopropylthio-3-hydroxypyridine and 15.2 g of potassium carbonate in 250 ml of dimethylformamide and the batch is stirred for 75 minutes. The suspension is introduced into a mixture of ice-water (300 ml), 50 ml of 2N hydrochloric acid and 300 ml of ethyl acetate, washed four times with 120 ml of water and 120 ml of ethyl acetate each time, and the organic phase is dried over sodium sulfate and concentrated by evaporation. 25.4 g of the desired intermediate are obtained in the form of a viscous oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=[O:6].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(CCCCl)Nc1cccc2cccnc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCN1c1cccc2cccnc12
Reaction time: 16 h
Yield: 90 %

Procedure:
A solution of 4-chloro-N-(8-quinolyl)butyramide (2.5 g, 0.01 mole) and benzyltriethyl ammonium chloride (0.115 g, 5 mole%) in methylene chloride (30 ml) was stirred at room temperature. A solution of 30% aqueous sodium hydroxide (10 ml) was added and the mixture was stirred for 16 hours. The reaction mixture was then diluted with methylene chloride, the organic layer was drawn off and washed with a saturated salt solution, dried over sodium sulphate and evaporated to a solid residue. The residue was recrystallized from methylene chloride/petroleum ether to afford 1-(8-quinolyl)-2-pyrrolidinone which was identical by tlc and NMR in comparison with the product of Example 1, yield 90%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.[Li][CH3:34]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)([OH:13])[CH3:34])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1
Reactant: COc1nc2ccc(C(=O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: COc1nc2ccc(C(C)(O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -78 °C

Procedure:
To flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (250 mg, 0.54 mmol, Intermediate 9: step b) was added THF (15 mL). The solution was cooled to −78° C. and MeLi (1.6 M in Et2O, 0.4 mL, 0.64 mmol) was introduced. The reaction mixture was quenched after 25 minutes with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (4×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness to afford an off white solid. Chromatography on silica gel (10% CH3CN-DCM increasing to 30% CH3CN) provided the title compound as a white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=2.1 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.74 (d, J=2.9 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.45-7.35 (m, 3H), 4.35 (s, 2H), 4.07 (s, 3H), 3.71 (s, 3H), 2.82 (br. s, 1H), 2.06 (s, 3H); MS (ESI): mass calcd. for C23H20ClF3N4O2, 476.1, m/z found 477.1 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-1,2,3-triazol-5-yl)ethanol was purified by chiral SFC (Stationary phase: Lux 5 m cellulose-3, 4.6 mm×250 mm, Mobile phase: 12% EtOH, 0.2% Et3N, 88% CO2) to give 2 enantiomers. The first eluting enantiomer was Example 11b and the second eluting enantiomer was Example 11c.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:34]([O:27][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[CH:9]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(Cl)ccc3O)ccn2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(Cl)ccc3OCc3ccccc3)ccn2)CC1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
tert-Butyl 4-(4-(5-chloro-2-hydroxyphenyl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 117, 1.85 g, 4.755 mmol) was dissolved in dimethylformamide (10 mL) at room temperature under a nitrogen atmosphere. Potassium carbonate (1.31 g, 9.51 mmol) was added and the mixture was stirred for 10 minutes. Benzyl bromide (0.622 mL, 5.23 mmol) was added dropwise and the reaction mixture was heated at 60° C. for 18 hours and then partitioned between ethyl acetate (40 mL) and water (20 mL). The organic layer was separated and washed with brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the title compound (2.20 g, 96%) as a light yellow solid.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:11][NH2:12]>C(O)C>[CH3:8][C:7]([CH3:10])([CH3:9])[C:6]#[C:5][CH:4]=[CH:3][CH2:2][NH:12][CH3:11]
Reactant: CC(C)(C)C#CC=CCBr
Reactant: CN
Solvent: CCO
Product: CNCC=CC#CC(C)(C)C
Reaction time: 3 h

Procedure:
24.3 g of 1-bromo-6,6-dimethylhept-2-en-4-yne in 750 ml of ethanol are added at -50° to 245 ml of a 33% ethanolic solution of methylamine and the mixture stirred in a closed vessel at 55° for 3 hours. The resulting mixture is concentrated in a rotary evaporator and the residue taken up with chloroform and washed with 1 N NaOH and saturated NaCl. After drying over MgSO4 the crude product is purified by chromatography on kieselgel (eluant toluene/ethylacetate; 4/1). A colourless oil is obtained (trans- and cis compound in ratio 3:1).
Reaction SMILES: [OH:1][N:2]([CH3:27])[C:3]([N:5]1[CH2:9][CH2:8][C:7](=[CH:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)[C:6]1=[O:26])=[O:4].[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:1][N:2]([CH3:27])[C:3]([N:5]1[CH2:9][CH2:8][C:7](=[CH:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)[C:6]1=[O:26])=[O:4])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CN(O)C(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Solvent: c1ccncc1
Product: CC(=O)ON(C)C(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a solution of 1-(N-hydroxy-N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (Ia-6) (222 mg, 0.6 mmole) dissolved into pyridine (3 ml), 1.8 ml of acetic anhydride was added and the mixture was stirred at room temperature for 5 hours, then the resulting mixture was evaporated. Hydrochloric acid (0.5N) was added thereto, and the mixture was subjected to extraction with dichloromethane. The organic layer was washed with water, sodium bicarbonate, and water in order, dried over magnesium sulfate, and evaporated. The obtained residue was recrystallized from dichloromethane/ether, whereby 211 mg of the objective compound (Ia-16) was obtained in 84% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](C)([CH3:12])[C:10]#N)[CH:5]=[CH:6][C:7]=1[Cl:8].C[Mg]I.CC[O:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:12])([CH3:10])[C:20](=[O:19])[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C#N)c1ccc(Cl)c(Cl)c1
Reactant: CCOCC
Agent: C[Mg]I
Product: CC(=O)C(C)(C)c1ccc(Cl)c(Cl)c1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A solution of 2-(3,4-dichlorophenyl)-2-methylpropionitrile (12.8 g) in ether (100 ml) was added dropwise at −10° C. under nitrogen over 20 minutes to stirred ethereal methylmagnesium iodide solution (3M; 30 ml), then the mixture was stirred at reflux temperature for 2 hour and at ambient temperature for 18 hours. The resulting solid was collected by filtration, washed well with ether, and added in portions to a mixture of ice-cold water (100 ml) and concentrated hydrochloric acid (50 ml). The resulting mixture was heated at 95° C. with occasional stirring for 1 hour, then cooled to ambient temperature. The product was extracted into dichloromethane (3×100 ml), then the combined extracts were dried (CaCl2), and the solvents were removed in vacuo to give 3-(3,4-dichlorophenyl)-3-methylbutan-2-one as a pale brown oil (9.07 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:26])[N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([F:16])[CH:6]=2.S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:3](=[O:26])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([F:16])[CH:6]=2
Reactant: COC(=O)c1cc2nc(Cl)c(=O)n(Cc3ccc(OC)cc3)c2cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2nc(Cl)c(=O)[nH]c2cc1F
Temperature: 25 °C

Procedure:
Methyl 3-chloro-7-fluoro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (4.0 g, 10.62 mmol) was added to sulfuric acid (conc, 15 ml) in several batches with stirring at room temperature, and then stirred for 10 minutes. The resulting solution was diluted with ice-water (100 ml) and extracted with ethyl acetate (3×200 ml). The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-chloro-7-fluoro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (2.0 g, crude), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O.I[CH2:23][C:24]1([CH3:36])[CH2:28][C:27]2[C:29]([CH3:35])=[CH:30][C:31]([CH3:34])=[C:32]([CH3:33])[C:26]=2[O:25]1>C(OCC)(=O)C.O>[CH3:1][N:2]([CH2:23][C:24]1([CH3:36])[CH2:28][C:27]2[C:29]([CH3:35])=[CH:30][C:31]([CH3:34])=[C:32]([CH3:33])[C:26]=2[O:25]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CI)C2
Reactant: CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c2c(c1C)OC(C)(CN(C)Cc1ccccc1)C2
Temperature: 25 °C
Yield: 74.7 %

Procedure:
N-methylbenzylamine (766 mg, 3.16 mmol) and potassium carbonate (1.09 g, 7.90 mmol) were added to a solution of DMA (5 mL) containing 2-(iodomethyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (1.00 g, 3.16 mmol) synthesized in Reference Example 126, and the mixture was stirred under heated reflux for 4 hours. The reaction solution was cooled to room temperature, and water and ethyl acetate were added thereto to separate an organic layer. The organic layer was washed with water and saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 99:1-93:7) to give 730 mg of the title compound (yield: 75%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[N:17]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=[C:12]2[CH:11]=1.C(O)(=O)C.C(O[C:33]1(O[Si](C)(C)C)[CH2:35][CH2:34]1)C.[Na]>CO>[CH:33]1([N:23]2[CH2:24][CH2:25][CH:20]([C:18]3[N:19]=[C:12]4[N:13]([C:14](=[O:16])[NH:15][C:10]([C:4]5[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=5[Cl:2])=[CH:11]4)[N:17]=3)[CH2:21][CH2:22]2)[CH2:35][CH2:34]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCNCC3)nn12
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCN(C4CC4)CC3)nn12
Temperature: 25 °C

Procedure:
1.00 g (2.50 mmol) of 7-(2,4-dichlorophenyl)-2-(piperidin-4-yl)[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one hydrochloride and 3 Å molecular sieve (1 g) were initially charged in 15 ml of dry methanol and acetic acid (1.43 ml, 25 mmol) of 3.01 ml (2.61 g, 15 mmol) of [(1-ethoxy-1-cyclopropyl)oxy]-trimethylsilane and 690 mg (11 mmol) of sodium cyanoborhydride were then added. The mixture was stirred at reflux overnight. The mixture was cooled to RT and the reaction mixture was filtered. 50 ml of dichloromethane and 50 ml of water were added to the filtrate, and the mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. This gave 540 mg (53% of theory) of the product.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][NH3+:23])=[O:8])([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:2]([O:6][C:7](=[O:8])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][NH:23][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c(SCCC[NH3+])nc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Cn1c(SCCCNC(=O)c2ccccc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-(1-tert-butoxycarbonylmethyl-1H-benzoimidazol-2-ylsulfanyl)-propyl-ammonium chloride (Precursor U-08b, 6 mg, 0.02 mmol) in dichloromethane (0.4 ml) are added subsequently DIPEA (10 mg, 15 μl, 0.085 mmol) and benzoyl chloride (3.9 mg, 3.241l, 0.03 mmol) and the resulting solution is allowed to stir for 1 h at rt. Tris-(2-aminoethyl)amine polystyrene (3.4 mmol/g, 33 mg, 0.11 mmol) is added and the mixture is allowed to stir for another 3 h at rt. The solvent is evaporated and the residue dried under high vacuum, yielding the title compound as a colourless oil: tR=2.62 min (LC-2), ESI-MS (pos.): m/z 510.49 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([OH:12])[CH2:10][OH:11].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([O:11][CH2:10][CH2:9][OH:12])[CH:7]=1
Reactant: OCCO
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1cc(Cl)ncn1
Reaction time: 2 h

Procedure:
To a mixture of 4,6-dichloropyrimidine (5.0 g), ethylene glycol (100 ml) and tetrahydrofuran (100 ml) is added sodium hydride (60% dispersion, 1.34 g) under ice-cooling, and the mixture is stirred at the same temperature for two hours, and evaporated under reduced pressure to remove the solvent. The residue is extracted with ethyl acetate, and the extract is dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=5:1~2:1) to give 2-(6-chloropyrimidin-4-yloxy)ethanol (5.67 g) as an oily product.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCOCC2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCOCC2)cc1
Temperature: 120 °C
Yield: 19.6 %

Procedure:
100 mg of 4-(4-Bromo-benzyl)-morpholine was combined with 111 mg of 2-(Trifluoromethyl)phenyl boronic acid, 23 mg of tetrakis(triphenylphosphine)palladium(0), 1.3 mL of 2M sodium carbonate solution, 3.6 mL toluene and 1.7 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography using flash chromatography followed by reverse phase HPLC. 24.6 mg of product is obtained. ES MS (+) m/z 322
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][CH2:13][C:14](=[O:16])[CH3:15])[CH3:11])=[CH:6][CH:5]=1>C(O)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([NH:12][CH2:13][CH:14]([OH:16])[CH3:15])[CH3:11])=[CH:8][CH:9]=1
Reactant: CC(=O)CN[C@@H](C)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(O)CN[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Sodium borohydride (2.39 g) was added to a solution of 1-[(S)-1-(4-fluorophenyl)ethylamino]propan-2-one (2.5 g) in ethanol (25 mL) under ice-cooling, and then the reaction solution was stirred at room temperature for one hour. The reaction solution was diluted with ice water and ethyl acetate, and then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (chloroform:2-propanol=100:1 to 0:100) to obtain 1.18 g of the title compound as a diastereomer mixture.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C([Li])CCC.CCCCCC.[CH2:22]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][OH:10])([OH:35])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: OCCc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCc1ccccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.9 %

Procedure:
To a solution of 2-bromophenyl ethyl alcohol (1.9 g, 9.6 mmol) in tetrahydrofuran (25 ml) was added 1.6 M n-butyl lithium solution in n-hexane (14 ml, 23 mmol) at −60° C. After stirring for 30 min a solution of 1-benzyl-4-piperidone (2.6 g, 14 mmol) in tetrahydrofuran (10 ml) was added over a period of 15 min at −40° C. The cooling bath was removed and the reaction mixture was stirred for 72 h at room temperature. The mixture was quenched with saturated aqueous ammonium chloride solution (30 ml). Basification to pH 11 with 2 M aqueous sodium carbonate solution (50 ml) was followed by extraction with three 100-ml portions of tert-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Volatile impurities were removed by kugelrohrdistillation at 170° C. and 1-2 mbar. Flash chromatography of the residual crude product with dichloromethane/methanol as eluent gave the title compound (2.3 g, 53%) as dark brown oil. MS m/e: 312 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7])=O.C(Cl)Cl.Cl.[O:20]([NH2:22])[CH3:21].C([O-])(=O)C.[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C.O>[CH3:21][O:20][N:22]=[CH:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C=O)c1
Reactant: CON
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CON=Cc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Yield: 98.8 %

Procedure:
To a well stirred mixture of 195 g of methyl 3-formyl-4-nitrobenzoate, 1 l methylene chloride and 370 mL of water was added sequentially 77.6 g of methoxylamine hydrochloride, 76.2 g of sodium acetate and 6.8 g of tetra-n-butylammonium hydrogen sulfate. The resulting mixture was stirred overnight at room temperature, then diluted with 2 l of ethyl ether. The organic phase was separated and washed sequentially with water (1×500 mL), 2% aqueous hydrochloric acid (2×500 mL), water (2×250 mL), and brine (1×250 mL); then dried over anhydrous magnesium sulfate. The solvent was removed using a rotary evaporator yielding 218.6 g of the expected methyl 3-methoxyiminomethyl-4-nitrobenzoate as a reddish oil that solidified upon standing, and which was used as such in the next step.