Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.Cl[CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([NH:23][S:34]([CH:33]=[CH2:32])(=[O:36])=[O:35])[CH:20]=[CH:21][CH:22]=3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1cccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)c1
Reactant: O=S(=O)(Cl)CCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Nc1cccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)c1
Reaction time: 1 h
Yield: 9.3 %

Procedure:
A solution of 3-[6-(3-chloro-4-fluorophenylamino)-pyrimidin-4-ylamino]phenylamine (IR-4) (300 mg, 0.9 mmol) and triethylamine (500 mg, 5 mmol) in 10 mL of THF was stirred at RT. 2-Chloroethanesulfonyl chloride (360 mg, 2.25 mmol) was added into the reaction mixture and stirring was continued at RT for 1 hr. The crude product was purified by flash chromatography on silica gel with EtOAc/heptane solvent system to afford 35 mg (9%) of the title compound, a brown colored solid. MS (m/z): MH+=420, 422. 1H NMR (DMSO): 9.92 (s, 1H), 9.29 (s, 1H), 9.21 (s, 1H), 8.26 (s, 1H), 7.92 (m, 1H), 7.40-7.22 (m, 4H), 7.14 (m, 1H), 6.20 (m, 2H), 6.05 (m, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].CN(C)C(N(C)C)=N.[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([N+:43]([O-:45])=[O:44])[C:39]=1[N+:40]([O-:42])=[O:41])[CH:35]=O>O1CCCC1>[CH3:1][O:2][C:3](/[C:5](/[NH:6][C:7](=[O:8])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[CH:35]/[C:34]1[CH:37]=[C:38]([N+:43]([O-:45])=[O:44])[C:39]([N+:40]([O-:42])=[O:41])=[C:32]([CH3:31])[CH:33]=1)=[O:4]
Reactant: Cc1cc(C=O)cc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cc(C)c([N+](=O)[O-])c([N+](=O)[O-])c1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of N-(benzyloxycarbonyl)-α-phophonoglycine trimethyl ester (2.4 g, 7.3 mmol) in tetrahydrofuran (40 mL) at −78° C. was added 1,1,3,3-tetramethylguanidine (729 mg, 6.33 mmol) and the mixture was stirred for 1 h at −78° C. To this mixture was added a solution of 3-methyl-4,5-dinitrobenzaldehyde (1.4 g, 6.7 mmol) in tetrahydrofuran (15 mL). The reaction mixture was allowed to slowly warm to room temperature and was then stirred for 16 h at room temperature. The solvent was evaporated and the residue subjected to flash column chromatography (gradient, 1:2 to 1:1 ethyl acetate/hexanes). The product was then recrystallized from ethyl acetate/hexanes (1:1) to give the title compound (1.7 g, 62% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.01 (s, 1H), 7.55 (s, 1H), 7.33-7.22 (m, 6H), 6.94 (bs, 1H), 5.06 (s, 2H), 3.89 (s, 3H), 2.29 (s, 3H). 13C-NMR (CDCl3, 75 MHz) δ 164.7, 152.5, 143.1, 140.6, 137.7, 137.0, 135.3, 132.5, 128.8, 128.7, 128.6, 127.1, 123.5, 123.2, 68.3, 53.5, 17.4. Mass spec.: 414.20 (MH)−.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[H-].[Na+].[CH3:28]I>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[N:4]=[C:5]([N:13]([CH3:28])[C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccccc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1nc(C#N)cc2ccccc12)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (S)-tert-butyl 3-((3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (235 mg, 0.694 mmol) in DMF (6 mL) was added NaH (27.8 mg, 0.694 mmol) and methyl iodide (0.052 mL, 0.833 mmol) at 0° C. The reaction mixture was allowed to warm to RT with stirring over a 2 hour period and was subsequently diluted with EtOAc and washed with aqueous NH4Cl, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Toluene (2×5 mL) was added and removed in vacuo to give the title compound as a crude residue.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:26])[C@:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])([OH:17])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)(C(C)(C)C)(C)C.Cl.C1(C)C=CC=CC=1>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@:10]([OH:17])([C@H:9]([OH:8])[CH3:26])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@@H](O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 4 h

Procedure:
The (2R, 3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (12.2 g) synthesized in Example 12 was dissolved in methanol (41 mL). Hydrochloric acid (3 N, 21 g) was added to the solution and the mixture was stirred at 50° C. for four hours. Toluene (120 g) was added to the reaction mixture and was then stirred. Subsequently, an aqueous layer was separated. An aqueous solution (2 N, 41 g) of sodium hydroxide was added to the aqueous layer so that the pH of the mixture was controlled to be 9. The target compound was extracted with ethyl acetate (120 mL). The extracted organic layer was dried with anhydrous magnesium sulfate. The drying agent was filtered, and the filtrate was concentrated under reduced pressure. The resultant light yellow syrup was crystallized with toluene to recover-white crystals of the target compound (7.9 g, 92%). The values of the physical properties corresponded with those in Example 15. Diastereomeric excess: 99.5% de
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:17])([F:16])[F:15])[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:43]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:15])([F:16])[F:17])[C:3]=1[C:18]([N:46]1[CH2:45][CH2:44][N:43]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[CH2:48][CH2:47]1)=[O:20]
Reactant: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 66.8 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (551 mg, 1.23 mmol, 67%) was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:11](N(OC)C)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11](=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
(R)-tert-butyl 3-(tert-butyldimethylsilyloxy)-1 (methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (22) (2.2 g, 6.0 mmol, 1.0 equiv.) was added to a 250 mL RBF followed by THF (60 mL). The mixture was cooled to 0° C. via an ice bath and a 1.0 M solution of PhMgBr in THF (18.0 mL, 18.0 mmol, 3.0 equiv.) was added over 8 min. The reaction stirred for 1.0 h at 0° C. and the ice bath was removed. The reaction stirred for an additional 1.0 h at rt. and was again cooled to 0° C. via an ice bath. Next, the reaction was quenched by addition of 1.0 M HCl (55 mL). The solution was transferred to a separatory funnel with additional 1.0 M HCl (40 mL) and extracted with EtOAc (3×100 mL). The organic layers were washed with sat. NaCl (1×50 mL) and dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 2.5 g of crude material. The residue was purified by flash column chromatography (10% EtOAc/Hexanes) to give 2.0 g (89%) of 23 as a colorless oil. Rf=0.29 (10% EtOAc/Hexanes); [α]D23.5=−12.3 (c 1.26, MeOH); IR (film) 3433, 3360, 3062, 2952, 2929, 2883, 2856, 1715, 1688, 1498, 1253, 1167, 1114 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J=7.0 Hz, 2H, Ph-H), 7.61 (t, J=7.0 Hz, 1H, Ph-H), 7.50 (t, J=7.0 Hz, 2H, Ph-H), 5.73 (d, J=7.5 Hz, 1H, carbamate-NH), 5.35 (m, 1H, Boc-NH—CH), 3.97 (dq, J=9.5, 2.5 Hz, 2H, CH—CH2), 1.50 (s, 9H, Boc-t-butyl-CH3), 0.79 (s, 9H, Si-t-butyl-CH3), −0.07 (s, 3H, Si—CH3), −0.12 (s, 3H, Si—CH3); 13C (125 MHz, CDCl3) δ 197.9, 155.5, 135.6, 133.5, 128.8, 128.7, 79.9, 64.5, 57.4, 28.5, 25.8, 18.2, −5.6, −5.7; LRMS (ESI-MS m/z): Mass calcd for C20H33NO4Si [M]+, 379.57. Found 380.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[C:32]3[S:37](Cl)(=[O:39])=[O:38])(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>O1CCCC1>[CH2:8]([NH:15][S:37]([C:32]1[C:33]2[C:28](=[C:27]([O:26][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:30][CH:31]=1)(=[O:38])=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc3c(S(=O)(=O)Cl)cccc23)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2cccc3c(S(=O)(=O)NCc4ccccc4)cccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Triethylamine (0.17 ml, 1.2 mmol) was added to benzylamine (117.9 mg, 1.1 mmol) dissolved in tetrahydrofuran (5 ml). After the solution was cooled in the ice bath, 5-{[(4-methylphenyl)sulfonyl]oxy}naphthalene-1-sulfonyl chloride (396.9 mg, 1.2 mmol) was added, and the mixture was stirred at room temparature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (eluent; n-hexane : ethyl acetate=2:1) and crystallized (ethyl acetate/hexane) to give the title compound as a white crystal (398.8 mg, 85.3%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.OS(O)(=O)=O>O>[O:14]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:12][CH2:13]1
Reactant: Nc1ccc(C(CCO)CCO)cn1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(C2CCOCC2)cn1
Temperature: 25 °C

Procedure:
To 3-(6-aminopyridin-3-yl)pentane-1,5-diol/toluene mixture (1.96 g, 10 mmol in 40 mL) were added 1 mL water to help dissolving, and then conc. H2SO4 (98%, 1.6 mL, 30 mmol). The resulting mixture was heated to reflux with Dean-Stark to remove water from reaction mixture for 1 h 20 min. The reaction mixture was cooled down to room temperature, and concentrated. The residue was diluted with ice cold water (15 mL), neutralized by solid Na2CO3 (4 g), and extracted with EtOAc (3×30 mL). The EtOAc extracts were combined, washed with brine (30 mL), dried over Na2SO4, and concentrated. A light yellow solid was obtained as crude 5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine. LCMS (m/z) 179.2 (MH+) 0.33 min; 1H NMR (CDCl3) δ ppm 7.95 (d, J=2.0 Hz, 1H), 7.32 (dd, J=8.2, 2.3 Hz, 1H), 6.49 (d, J=8.2 Hz, 1H), 4.34 (br. s., 2H), 4.11-3.99 (m, 2H), 3.51 (td, J=11.2, 3.3 Hz, 2H), 2.73-2.56 (m, 1H), 1.75-1.69 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:23]3[N:18]4[C:19](=[N:24][C:25]([CH3:26])=[C:17]4[C:16]2=[O:27])[CH:20]=[CH:21][CH:22]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:23]3[N:18]4[C:19](=[N:24][C:25]([CH3:26])=[C:17]4[C:16]2=[O:27])[CH:20]=[CH:21][CH:22]=3)[CH2:10][CH2:9]1
Reactant: Cc1nc2cccc3n(CC4CCN(C(=O)OC(C)(C)C)CC4)c(=O)c1n23
Agent: Cl
Solvent: CO
Product: Cc1nc2cccc3n(CC4CCNCC4)c(=O)c1n23
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
To a solution of 3.65 g (9.85 mmol) of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 30 ml of methanol was added 15 ml of conc. HCl. The mixture was stirred for 1.5 hours at room temperature. The solvent was distilled off. To the residue was added chloroform and 2N agueous solution of sodium hydroxide to make alkaline. The mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 2.316 g of the desired compound (86.9%, pale yellow solid). This product was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](OC)=[O:16])[C@@H:11]([O:19][CH3:20])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[AlH4-].[Li+]>CCOCC>[OH:16][CH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][C@@H:11]1[O:19][CH3:20]
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C[C@@H]1OC
Agent: [AlH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CO[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CC[C@@H]1CO
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl (1S,2S,4S)-4-[(tert-butoxycarbonyl)amino]-2-methoxycyclohexanecarboxylate (racemic) (1.02 g, 3.55 mmol) were dissolved in ether (32 mL) and cooled to 0° C. Lithium tetrahydroaluminate (162 mg, 4.26 mmol) was added and the resulting mixture was stirred for 4 h. The reaction was quenched with 5 mL water at 0° C., then diluted with 5 mL 15% NaOH and 15 mL water after stirring for 30 min. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified with flash chromatography (eluting with a gradient of 0-80% ethyl acetate in hexanes) to give the desired product as white foam. LCMS calculated for C8H18NO2 (M+H-Boc)+: m/z=160.1. Found: 160.2. 1H NMR (300 MHz, CDCl3) δ 4.46 (1H, brs), 3.71-3.40 (3H, m), 3.37 (3H, s), 3.12 (2H, m), 2.48 (1H, m), 1.94 (1H, m), 1.71-1.50 (3H, m), 1.41 (9H, s), 1.05 (2H, m) ppm.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][N:9]=1.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:12]([C:11]4[CH:10]=[N:9][C:8]([CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:14])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)nc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3CCCS3(=O)=O)nc2)CC1
Yield: 85.7 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)nicotinate (108 mg) described in Preparation Example 45 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (87 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (156 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26]>O1CCCC1>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]([C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[OH:26]
Reactant: COc1ccccc1C=O
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccc2OC)cn1
Temperature: 25 °C
Yield: 63 %

Procedure:
5-Bromo-2-methoxypyridine (41.36 g) (prepared by the method of I. Kompis et al, European Journal of Medicinal Chemistry 1977, 12, 531) in dry tetrahydrofuran (50 ml) was cooled to -85° with stirring under a nitrogen atmosphere. n-Butyl lithium (137 ml of a 1.6M hexane solution) in dry tetrahydrofuran (50 ml) was added dropwise, keeping the temperature below -80°. After stirring for 5 minutes, 2-methoxybenzaldehyde (25.0 g) in dry tetrahydrofuran (150 ml) was added dropwise with stirring, keeping the temperature below -70°. The mixture was stirred whilst allowing to warm to room temperature, then quenched with saturated ammonium chloride solution (150 ml). The organic layer was separated and the aqueous was further extracted with ethyl acetate. The organic layers were combined, dried with anhydrous magnesium sulphate and evaporated to dryness to give an orange gum which was crystallised from dichloromethane/petroleum spirit (60°-80°) to give 1-(2-methoxyphenyl)-1-(6-methoxy-3-pyridyl)-methanol as a pale yellow solid (28.39 g, 63%) m.p 83°-84°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: OCCCc1ccc(O)cc1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1ccc(CCCO)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
4-(3-Hydroxypropyl)phenol (1.0 g, 6.57 mmol) and methyl 2-(bromomethyl)benzoate (1.66 g, 7.23 mmol) was dissolved in acetonitrile (10 ml). Potassium carbonate (1.82 g, 13.14 mmol) was added and the mixture was stirred at 60° C. for three hours. Polymer supported trisamine (0.3 eqv) was added and the solution was stirred at room temperature overnight. The PS-trisamine was filtered off and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic layer was washed with 3 portions of water (3×10 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 1.66 gram of methyl 2-{[4-(3-hydroxypropyl)phenoxy]-methyl}benzoate (yield 84.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C@H:19]([O:21][Si](C(C)(C)C)(C)C)[CH3:20])=[C:12]([C:29]3[CH:34]=[CH:33][C:32](SC)=[CH:31][CH:30]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:37](OO)(=O)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[S:69]([O-:73])([O-])(=[O:71])=S.[Na+].[Na+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])=[C:12]([C:29]3[CH:34]=[CH:33][C:32]([S:69]([CH3:37])(=[O:73])=[O:71])=[CH:31][CH:30]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S([O-])([O-])=S
Reactant: CSc1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCC[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(=O)OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C[C@@H](O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A stirred solution of the product from step Example 545D(˜2 mmol) in acetone (10 mL) was chilled to 0° C. To this was added 32% peracetic acid in acetic acid solution (1.42 mL, 6 mmol). The reaction mixture was stirred for 1 hour while warming to room temperature. At this point the oxidation was complete, but some of the product's hydroxy group was still silylated so 1M tetrabutylammonium fluoride in THF (4 mL, 4 mmol) was added and stirring was continued for 0.5 hours. The reaction mixture was then treated with 5% aqueous sodium thiosulfate solution (30 mL) for 2 hours. The precipitated product was collected by filtration, washed with water (10 mL) and hexane (10 mL). The solid was stirred in isopropanol (5 mL) for 6 hours then collected by filtration and dried to provide the title compound (0.78 g, 87%). mp 126-129° C.; 1H NMR (300 MHz, CDCl3) δ 1.22 (d, J=6 Hz, 3H), 1.62-1.74 (m, 1H), 1.84-1.94 (m, 1H), 3.16 (s, 3H), 3.30 (s, br, 1H), 4.00-4.10 (m, 1H), 4.20-4.30 (m, 1H), 4.63 (td, J=9.6 Hz, J=4 Hz, 1H), 7.25-7.34 (m, 1H), 7.46-7.52 (m, 1H), 7.56-7.64 (m, 1H), 7.78-7.84 (m, 2H), 7.97 (s, 1H), 8.06-8.12 (m, 2H); MS (DCI/NH3) m/z 468 (M+NH4)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([CH:11]([NH:13][C:14]3[N:19]=[C:18]([N:20]4[C@@H:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:22][C:21]4=[O:28])[CH:17]=[CH:16][N:15]=3)[CH3:12])[CH:9]=[CH:10][C:2]1=2.CC(O)C>C(=O)=O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@H:11]([NH:13][C:14]3[N:19]=[C:18]([N:20]4[C@@H:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:22][C:21]4=[O:28])[CH:17]=[CH:16][N:15]=3)[CH3:12])[CH:9]=[CH:10][C:2]1=2.[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([NH:13][C:14]3[N:19]=[C:18]([N:20]4[C@@H:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:22][C:21]4=[O:28])[CH:17]=[CH:16][N:15]=3)[CH3:12])[CH:9]=[CH:10][C:2]1=2
Reactant: CC(Nc1nccc(N2C(=O)OC[C@@H]2C(C)C)n1)c1ccc2c(c1)OCCO2
Agent: O=C=O
Solvent: CC(C)O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc3c(c2)OCCO3)n1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@H](C)c2ccc3c(c2)OCCO3)n1

Procedure:
(4S)-3-(2-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (example 130, 52 mg) was resolved on a column (IA 4.6×100 mm) using 40% iPrOH in CO2 to give (S)-3-(2-((R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-((S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1.[I:13]C1C=CC(CC#N)=CC=1>>[OH:1][NH:2][C:3](=[NH:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([I:13])=[CH:7][CH:6]=1
Reactant: N=C(Cc1cccc(I)c1)NO
Reactant: N#CCc1ccc(I)cc1
Product: N=C(Cc1ccc(I)cc1)NO

Procedure:
The title compound is prepared essentially as described for N-hydroxy-2-(3-iodo-phenyl)-acetamidine, employing (4-iodo-phenyl)-acetonitrile. LC-MS (m/e): 277 (M+1).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15](\[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])/[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1/[C:15](/[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[CH:14]\[CH:13]=[CH:12]\[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)=[O:10]
Reactant: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2OC)cc1
Reactant: NCCCCc1cccnc1
Product: COc1ccc(/C(=C/C=C/C(=O)NCCCCc2cccnc2)c2ccccc2OC)cc1
Yield: 96.3 %

Procedure:
As before in Example 134, a solution of (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (0.82 g) and 3-pyridinebutanamine (0.33 g) in tetrahydrofruan (7 mL) was stirred overnight at room temperature. After the usual work up. the crude product was purified by HPLC (ethyl acetate) and lyophilized from benzene to give 0.81 g of (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide as an amorphous solid.