Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])[CH:8]=2)[N:3]=1.[OH:29][C:30]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:31]=1[CH:32]=[O:33].CCN(CC)CC>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:32]([C:31]1[CH:34]=[C:35]([C:2]2[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)=[O:18])[CH:8]=3)[N:3]=2)[CH:36]=[CH:37][C:30]=1[OH:29])=[O:33]
Reactant: COc1ccc(COC(=O)c2ccc3nc(Br)c(N(C)C(C)C)nc3c2)cc1
Reactant: CC1(C)OB(c2ccc(O)c(C=O)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)c2ccc3nc(-c4ccc(O)c(C=O)c4)c(N(C)C(C)C)nc3c2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of (4-methoxyphenyl)methyl 2-bromo-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (400 mg, 0.90 mmol) in 1,2-dimethoxyethane (10 mL) was added 2-hydroxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (444 mg, 2.26 mmol), Et3N (273 mg, 2.7 mmol), Pd(dppf)Cl2 (58 mg, 0.08 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. and maintained under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated in vacuo to give the residue, which was purified by silica gel column chromatography eluting with 1% to 5% ethyl acetate in petroleum to afford (4-methoxyphenyl)methyl 2-(3-formyl-4-hydroxyphenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a yellow solid (190 mg, 43%).
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1.[Cl:24][C:25]1[C:30](Cl)=[N:29][CH:28]=[CH:27][N:26]=1>CN(C=O)C.O>[Cl:24][C:25]1[C:30]([NH:23][CH:21]2[CH2:20][N:19]([C:10]3[CH:11]=[CH:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:9]=3)[CH2:22]2)=[N:29][CH:28]=[CH:27][N:26]=1
Reactant: NC1CN(c2ccc3ccccc3n2)C1
Reactant: Clc1nccnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nccnc1NC1CN(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Yield: 53.6 %

Procedure:
Triethylamine (560 mg, 5.6 mmol), 1-(quinolin-2-yl)azetidin-3-amine hydrochloride (557 mg, 2.8 mmol) and 2,3-dichloro-pyrazine (414 mg, 2.8 mmol) were dissolved in DMF (20 mL). The resulting mixture was heated to 90° C. overnight. The mixture was then diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were combined and washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in petroleum ether) to give 3-chloro-N-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-amine (479 mg, 1.5 mmol, 55% yield) as white solid. ESI-MS (M+1): 312 calc. for C16H14ClN5 311.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[S:20]([O:1][CH2:2][C@H:3]1[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Commercially available (R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (1.8 g, 9.61 mmol) in pyridine was treated with p-toluenesulfonyl chloride (1.83 g, 9.61 mmol). The reaction mixture was stirred at room temperature for 20 h then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water (3×75 mL) and then dried (MgSO4), filtered, and concentrated in vacuo to afford the titled compound. MS (DCI) m/z 342 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([Sn](C)(C)C)[N:16]=3)=[C:9]([F:26])[CH:8]=1.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:31]([CH:27]2[CH2:30][CH2:29][CH2:28]2)=[O:32])[N:16]=3)=[C:9]([F:26])[CH:8]=1
Reactant: O=C(Cl)C1CCC1
Reactant: C[Sn](C)(C)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Solvent: Cc1ccccc1
Product: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCC1

Procedure:
A solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(trimethylstannyl)-thiazolo[5,4-b]pyridine (515.5 mg, 1.076 mmol) and cyclobutanecarbonyl chloride (0.147 mL, 1.291 mmol) in toluene (10.0 mL) was stirred under argon at 80° C. for 22 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (0-50% EtOAc/hexanes) to provide (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-thiazolo[5,4-b]pyridin-5-yl)(cyclobutyl)methanone as an off-white solid. MS (ESI) m/z: Calculated: 398.1; Observed: 398.9 (M++1).
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[C:22]([O:24][CH3:25])=[O:23])=[N:14][CH:15]=1)#[N:9].[F:26][C:27]([F:43])([F:42])[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=2)[C:36](O)=[O:37])[N:29]=1>>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[C:33]([C:30]4[N:29]=[C:28]([C:27]([F:43])([F:42])[F:26])[O:32][N:31]=4)[CH:34]=3)[CH2:18][CH:17]2[C:22]([O:24][CH3:25])=[O:23])=[N:14][CH:15]=1)#[N:9]
Reactant: COC(=O)C1CNCCN1c1ccc(C#N)cn1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(C(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)CCN1c1ccc(C#N)cn1
Yield: 82 %

Procedure:
This compound was synthesized from methyl 1-(5-cyanopyridin-2-yl)piperazine-2-carboxylate TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (80 mg, yield 82%). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=1.0 Hz, 1H), 8.26-8.23 (m, 1H), 8.18 (s, 1H), 7.76-7.73 (dd, J=8.9 Hz, 2.1 Hz, 1H), 7.65-7.64 (m, 2H), 6.73-6.71 (m, 1H), 5.43 (m, 1H), 4.68 (m, 1H), 3.94-3.90 (m, 2H), 3.73-3.68 (m, 3H), 3.59 (m, 2H), 3.28 (m, 1H). MS (ESI) m/z: Calculated for C22H17F3N6O4: 486.13. found: 487.2 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]([OH:13])[CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]1[O:13][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 33 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
(2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (3.57 g) and potassium carbonate (3.29 g) were added to an ethanol:water (97:3) mixed solution (35.7 ml). The mixture was stirred at 27° C. for 22 hours and further at 33° C. for 4 hours. A 11.3% citric acid aqueous solution (40.3 g) was added thereto, and the cooling was then conducted to −10° C. Crystals were collected by filtration, washed with water (35.7 ml), and dried under reduced pressure to obtain desired (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2.88 g) in a yield of 95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH2:12][CH2:13][OH:14])=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[CH:4]=1.C[C:16]([CH3:19])([O-:18])C.[K+].[OH2:21].Cl>C(O)(C)(C)C.CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH2:12][CH2:13][O:14][CH2:19][C:16]([OH:21])=[O:18])=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc2occc2cc1CCO
Reactant: CC(C)(C)[O-]
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2occc2cc1CCOCC(=O)O
Reaction time: 0.5 h

Procedure:
In a mixture of 7.0 mL of tert-butanol and 1.75 mL of N,N-dimethylformamide was dissolved 1.75 g of 2-(6-methoxy-1-benzofuran-5-yl)-1-ethanol, and 2.2 g of 1-chloroacetylpiperidine and 1.54 g of potassium tert-butoxide were added to the solution under ice-cooling, after which the resulting mixture was stirred at the same temperature for 30 minutes and then at the room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was dissolved in 10.5 mL of a 90% aqueous ethanol solution, followed by adding thereto 0.91 g of sodium hydroxide, and the resulting mixture was heated under reflux for 3 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Diisopropyl ether was added to the residue, and the crystals precipitated were collected by filtration, washed with diisopropyl ether and then dried to obtain 1.42 g of 2-[2-(6-methoxy-1-benzofuran-5-yl)ethoxy]acetic acid as yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:6][C:5]=1[F:42].O.[OH-].[Li+]>C1COCC1.O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C@@:17]2([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:40])([CH3:41])[CH3:39])[NH:15][C@@H:14]([C:12]([NH:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([F:42])[CH:6]=3)=[O:13])[C@@H:18]2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[F:26])=[C:30]([F:36])[CH:31]=1
Reactant: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCc2ccc(C(=O)O)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 97.4 %

Procedure:
In a manner similar to the method described in Example 380, rac-4-({[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid methyl ester (80.3 mg, 0.127 mmol) in THF (9 ml) was reacted with lithium hydroxide hydrate (37.6 mg, 0.896 mmol) in water (4.5 mL) to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid as a white lyophilized solid (76.5 mg, 97%). HRMS (ES+) m/z Calcd C31H28Cl2F3N3O3+H [(M+H): 618.1533. Found: 618.1533.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH2:21][O:22][CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:24][CH2:25][CH2:26][CH3:27])[CH:9]=2)[CH:4]1[C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([O:1][CH2:2][CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH2:21][O:22][CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:24][CH2:25][CH2:26][CH3:27])[CH:9]=2)[CH:4]1[C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)(=[O:40])=[O:39]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(CO)C2c1ccc2c(c1)OCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(COS(C)(=O)=O)C2c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of (1RS,2RS,3RS)-2-hydroxymethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (1.388 g, 2.82 mmol) in methylene chloride (10 ml) with TEA (1.2 ml) stirred under argon at 0° C. was added methanesulfonyl chloride (0.41 g, 3.5 mmol). The cooling bath was removed and stirring continued for 1 h. The mixture was partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo to afford the title compound as an oil (1.52 g, 95%).
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([CH:9]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[S:3][CH2:2]1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[Br:24][C:6]1[CH:7]=[C:8]2[C:12]3=[C:4]([S:3][CH2:2][CH2:1][N:11]3[CH:10]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH:9]23)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C(C1)c1cccc3c1N2CCS3
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2C(C1)c1cc(Br)cc3c1N2CCS3
Temperature: -10 °C
Reaction time: 0.67 h

Procedure:
The tert-butyl 1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (2.00 g, 6.02 mmol) was dissolved in anhydrous DMF (50 mL) and then cooled in an ice/acetone bath at −10° C. for 20 min. Next, N-bromosuccinimide (1.18 g, 6.62 mmol) was added in one portion. The reaction mixture was stirred for 40 min at −10° C., then poured over an ice/water mixture (300 mL). The resulting suspension was stirred at room temperature for 30 min, and extracted with diethyl ether (4×100 mL). The organic extracts were pooled together, washed with brine and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, tert-butyl 5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate was obtained as a yellow foam (2.24 g, 91%). 1H NMR (300 MHz, CDCl3) δ1.47 (s, 9H), 1.77 (m, 2H), 3.46-3.48 (m, 4 H), 2.87-3.48 (m, 6 H), 6.93 (s, 1H), 6.97 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1.[OH:14][CH:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][OH:26])[CH:19]=1)[CH2:16][NH2:17]>C(O)C.[Pt]=O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:17][CH2:16][CH:15]([OH:14])[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][OH:26])[CH:19]=2)[CH3:12])=[CH:6][CH:5]=1
Reactant: NCC(O)c1ccc(O)c(CO)c1
Reactant: COCc1ccc(CC(C)=O)cc1
Agent: O=[Pt]
Solvent: CCO
Product: COCc1ccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-methoxymethylphenyl)propan-2-one (0.46 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethanamine (0.45 g) in ethanol (50 ml) was refluxed 0.5 hours, cooled to ambient temperature and hydrogenated at atmospheric pressure using platinum oxide as catalyst. The solution was filtered, evaporated, the residue taken up in ethyl acetate and filtered again. Removal of the solvent gave an oil which was crystallised and recrystallised from benzene to give the title compound, mp 81°-92°, as a 53:47 mixture of diastereoisomers.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7][O:8][CH:9](OC)[C:10]1[N:11]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:13][CH:14]=1.B(F)(F)F.CCOCC>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[O:13][CH:14]=[C:10]([CH:9]([O:8][CH3:7])[C:5]#[N:6])[N:11]=2)=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)C#N
Reactant: COC(OC)c1coc(-c2ccc(F)cc2)n1
Agent: FB(F)F
Solvent: CCOCC
Product: COC(C#N)c1coc(-c2ccc(F)cc2)n1
Reaction time: 0.33 h
Yield: 25.5 %

Procedure:
Trimethylsilyl cyanide (4.13 g, 41.76 mmol) was added to a solution of 4-(dimethoxymethyl)-2-(4-fluorophenyl)oxazole (400 mg, 1.69 mmol) at room temperature, followed by boron trifluoride diethyl etherate (37 mg, 0.26 mmol). The reaction mixture was stirred for 20 min, quenched with saturated aqueous NaHCO3 solution, and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 8-10% EtOAc in petroleum ether) to afford 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methoxyacetonitrile (100 mg, yield 16%) as a light yellow liquid. 1H NMR (400 MHz, CDCl3) δ 8.08-8.06 (m, 2H), 7.90 (d, J=0.9 Hz, 1H), 7.19-7.15 (m, 2H), 5.29 (d, J=0.9 Hz, 1H), 3.62 (s, 3H). MS (ESI) m/z: Calculated for C12H9FN2O2: 232.21. found: 232.9 (M+H)+.
Reaction SMILES: COC([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=O.[CH:19](N(C(C)C)CC)(C)C.[O:28](C(OC(C)(C)C)=O)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=O>C(Cl)Cl>[C:29]([N:11]([CH2:8][C:7]1[CH:6]=[CH:5][CH:10]=[CH:9][CH:19]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28]
Reactant: COC(=O)c1ccc(NCc2ccccc2)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
To a mixture of N-(4-methoxycarbonylphenyl)benylamine (25 g, 0.098 mol) in CH2Cl2 (500 ml), was added diisopropyl ethylamine (38 g, 0.294 mol) and (BOC)2O (32 g, 0.147 mol). After stirring at r.t. for 5 h, the solvent was removed under reduce pressure. The crude product was then purified by chromatography using chloroform/methanol (9/1) to afford 4-methoxy carbonyl-[N-(BOC]-N-[benzyl]benzylamine (27 g, 78%) as a liquid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([Cl:35])=[CH:12][C:13]([CH3:34])=[C:14]([NH:16][C:17]([C:19]2[C@H:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[NH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[O:18])[CH:15]=1)(C)(C)C>C1COCC1.O.CC(O)=O>[Cl:35][C:11]1[C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:15][C:14]([NH:16][C:17]([C:19]2[C@H:20]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[NH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[O:18])=[C:13]([CH3:34])[CH:12]=1
Reactant: Cc1cc(Cl)c(OCCO[Si](C)(C)C(C)(C)C)cc1NC(=O)C1=CN(C)C(=O)N[C@H]1c1ccc(F)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCO)cc1NC(=O)C1=CN(C)C(=O)N[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The (S)-4-(4-Fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid{5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-amide from step 1 was dissolved in a mixture of 1 ml THF, 1 mL water, and 3 ml HOAc. This solution was stirred at room temperature for 18 hours, then diluted with water and extracted with ethyl acetate. The combined ethyl acetate layers were dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was chromatographed in 3% MeOH/CH2Cl2 to give 50 mg of (S)-4-(4-Fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid[4-chloro-5-(2-hydroxy-ethoxy)-2-methyl-phenyl]-amide, MS (M+H)=434.
Reaction SMILES: CC1NC(C)=CC=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:8]=1.C(O)C.Cl.[NH2:30]O.Cl>O>[NH:22]1[CH2:23][CH2:24][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([C:9]3[N:8]=[C:7]([NH2:30])[CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: NO
Reactant: Cc1cc(-c2cccc(-c3ccc(C4CCNCC4)cc3)n2)c(C)[nH]1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2ccc(C3CCNCC3)cc2)n1

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 100 mg (0.302 mmol) 4-(4-(2-(2,5-dimethylpyrrolyl)pyrid-6-yl)phenyl)piperidine, 10 mL ethanol, 1 mL water, and 417 mg (6.04 mmol) hydroxylamine hydrochloride. The reaction was refluxed 20 hours cooled, and poured into dilute aqueous hydrochloric acid, then washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 6 N sodium hydroxide solution and extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil (77 mg, 100%) was converted to the hydrochloride salt using HCl in, ether to afford a tan solid, 32 mg (32%), mp dec. above 150° C.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]([CH3:8])([OH:7])[CH3:6].[CH3:11][C:12]([S:15]([NH2:17])=[O:16])([CH3:14])[CH3:13].S([O-])([O-])(=O)=O.[Mg+2].CC1C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)Cl>[OH:7][C:5]([CH3:8])([CH3:6])[CH2:4]/[CH:3]=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: COC(CC(C)(C)O)OC
Reactant: CC(C)(C)S(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C/C=N/S(=O)C(C)(C)C
Reaction time: 8 h

Procedure:
To a stirred solution of 4,4-dimethoxy-2-methylbutan-2-ol (2.49 g, 16.8 mmol) in DCM (35 mL) were added 2-methyl-2-propanesulfinamide (1.7 g, 14 mmol), magnesium sulfate (8.44 g, 70.1 mmol), and pTsOH.H2O (0.13 g, 0.70 mmol). The reaction mixture was left to stir overnight, filtered through a fritted glass, concentrated, and purified by flash chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:36][CH2:35][CH2:34][CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: NCCCO
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCCO)[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (250 mg, 0.561 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and 3-amino-1-propanol (90.04, 1.18 mmol), WSCI•HCl (165 mg, 0.861 mmol) and 4-dimethylaminopyridine (140 mg, 1.15 mmol) were added, followed by stirring at room temperature for 16 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired product (216 mg, yield 77%) as a white solid.