Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:24])[C:3]([NH:5][C@H:6]([CH2:22][F:23])[C@H:7]([OH:21])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][C:33]#[N:34]>CN(C)C=O.O>[Cl:24][CH:2]([Cl:1])[C:3]([NH:5][C@H:6]([CH2:22][F:23])[C@@H:7]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][N:17]([CH2:32][C:33]#[N:34])[C:16](=[O:20])[CH:15]=2)=[CH:12][CH:13]=1)[OH:21])=[O:4]
Reactant: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2cc[nH]c(=O)c2)cc1)C(Cl)Cl
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCn1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1=O
Temperature: 65 °C
Yield: 58.7 %

Procedure:
A microwave tube is charged with the product of step 2, Example 20 (185 mg, 0.496 mmol) in dimethylformamide (4.9 mL), cesium carbonate (194 mg, 0.595 mmol) and chloroacetonitrile (313.7 uL, 4.957 mmol) were added under nitrogen, and the tube is capped. The reaction mixture is heated at 65° C. for 2.5 hours using the microwave (max power—100 W). The mixture is diluted with water (20 mL), extracted with ethylacetate (2×20 mL), and the combined organic phase is washed with water (3×15 mL), brine (15 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel chromatography (40 g, 50-90% ethyl acetate/hexanes) gave the title compound (120 mg): 1H NMR (300 MHz, DMSO) δ 4.25 (m, 1.5H), 4.44 (m, 0.5H), 4.53 (m, 0.5H), 4.72 (m, 0.5H), 4.91 (m, 1H), 5.02 (s, 2H), 6.01 (d, 1H), 6.51 (s, 1H), 6.72 (dd, 1H), 6.77 (m, 1H), 7.47 (d, 2H), 7.70 (d, 2H), 7.83 (d, 1H), 8.60 (bd, 1H). MS (ESI+) m/z 412 [M+H].
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:29][C:2]2[CH:14]=[CH:13][C:5]3[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=3[CH:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Reactant: COc1cccc(S)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)c1
Reaction time: 48 h
Yield: 89.8 %

Procedure:
6-Bromo-2,2,3-trimethyl-2H-benzo[b]pyran (6.5 g) (see Preparation 4) was dissolved in absolute ethanol (135 ml), then sodium tert-butoxide (7.5 g), 3-methoxybenzenethiol (3.6 g) and tetrakis(triphenylphosphine)palladium(O) (0.35 g) were added and the mixture was heated under reflux under a nitrogen atmosphere for 48 hours. Further tetrakis(triphenylphosphine)palladium(O) (0.3 g) was added and heating was continued for a further 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the crude product chromatographed on silica using 1:1 hexane: dichloromethane as the eluent to yield 6-(3-methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (7.2 g) as an oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:33])[C@H:10]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C@H:9]([CH3:33])[C@H:10]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][O:12][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](OCc1ccccc1)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](OCc1ccccc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A solution of (2R,3R)-3-(benzyloxy)-2-(tritylamino)butan-1-ol (4.33 g, 9.91 mmol) dissolved in 150 mL of CH2Cl2 was treated with triethylamine (1.52 mL, 10.9 mmol), tert-butyldimethylsilyl chloride (1.65 g, 10.9 mmol) and DMAP (122 mg, 1.00 mmol) and the reaction mixture was stirred under N2 overnight. The reaction mixture was then concentrated and the resulting material was dissolved in 50 mL of CH2Cl2 and washed successively with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5-10% ethyl acetate/hexanes) gave 3.26 g of (2R,3R)-3-(benzyloxy)-1-{[tert-butyl(dimethyl)silyl]oxy}-N-tritylbutan-2-amine as a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([F:35])[CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([F:35])[CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cc(F)cc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
Sodium hydroxide (40 mg) was added to a solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D137) (287 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by MDAP to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoic acid (E97) (147 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.61 (2H, t), 2.96 (2H, t), 4.87-4.93 (1H, m), 7.35 (1H, s), 7.46 (1H, d), 7.65-7.70 (2H, m), 8.21 (1H, d), 8.39 (1H, d), 10.96 (1H, s), 12.12 (1H, br s); δF (DMSO-d6, 376 MHz): −124.9; MS (ES): C22H19ClFN3O4 requires 443; found 444.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19]>C1COCC1>[CH3:15][O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:19][CH2:18][C:17]([F:21])([F:20])[F:16])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: NCC(F)(F)F
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Solvent: C1CCOC1
Product: COc1ccc2nc(NCC(F)(F)F)c(C=O)cc2c1
Temperature: 160 °C
Reaction time: 10 h
Yield: 115.4 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.50 g, 6.77 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 2,2,2-trifluoroethanamine (10.06 mL, 102.0 mmol) and the reaction mixture was stirred for 10 h at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with saturated NaHCO3 aqueous solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered and concentrated under vacuum to give 6-methoxy-2-(2,2,2-trifluoroethylamino)quinoline-3-carbaldehyde SLA 41066 as an orange solid (2.22 g, >100% yield).
Reaction SMILES: [C-]#N.[Na+].C1(C)C=CC=CC=1.C[NH:12][CH2:13][CH2:14]NC.BrC1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1>N>[CH3:25][C:20]1[CH:19]=[C:14]([CH:23]=[C:22]([CH3:24])[CH:21]=1)[C:13]#[N:12]
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CNCCNC
Agent: N
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(C#N)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
An oven dried 100 mL three necked round bottom flask was charged, under positive pressure of argon, with NaCN (2.04 g, 41.6 mmol) CuI (660 mg, 3.47 mmol, 10 mol %), KI (1.14 g, 6.87 mmol, 20 mol %), and anhydrous toluene (25 mL). N,N′-Dimethylethylenediamine (3.7 mL, 35 mmol) and 5-bromo-m-xylene (4.7 mL, 35 mmol) were added dropwise under mechanical stiring. The reaction mixture was stirred at 110° C. for 24 h. The resulting suspension was allowed to reach room temperature, diluted with 30% aq ammonia (20 mL) and extracted with toluene (2×10 mL). The combined organic phases were dried over MgSO4, concentrated, and the residue was purified by distillation under reduced pressure (bp 100° C. @10 Torr) to provide the desired product as a white crystalline solid (4.08 g, 90% yield). Mp 42-43° C. (lit. 42.9° C., See Birch, S. F.; Dean, R. A.; Fidler, F. A.; Lowry, R. A. J. Am. Chem. Soc. 1949, 71, 1362). 1H NMR (400 MHz, CDCl3; lit. See Nomura, Y.; Takeuchi, Y. Tetrahedron 1969, 25, 3825): δ 7.27 (s, 2H), 7.23 (s, 1H), 2.36 (s, 6H); 13C NMR (100 MHz, CDCl3): 139.4, 135.0, 130.1, 119.7, 112.4, 21.5; IR (neat, cm−1): 2230, 1605, 1378, 907, 854, 682. Anal. Calcd. for C9H9N: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.11; H, 6.88, N, 10.52.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2]>[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC=CC1CC(=O)N1
Agent: [Pd]
Product: CC(=O)OCCC1CC(=O)N1
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
A mixture of 4-(2-acetoxyvinyl)-azetidin-2-one (3.00 g), 10% Pd/C (0.15 g) and ethylacetate(EtOAc) (120 ml) is hydrogenated in a 500 ml glass bomb on a Parr shaker at an initial pressure of 39 psi. After shaking 10 mins (final pressure of 20 psi), the mixture is filtered through a pad of MgSO4 to remove the catalyst. The filtrate is concentrated in vacuo and the residue stripped with anhydrous benzene to provide 4-(2-acetoxyethyl)-azetidin-2-one (3.098 g) as a clear oil: ir(neat) 3.01, 5.66, 5.75, 7.28, 8.05, and 9.61 cm-1 ; nmr(CDCl3) δ1.95 (m, 2), 2.07 (s, 3), 2.60 (m, 1), 3.12 (m, 1), 3.70 (m, 1), 4.15 (m, 2), and 6.77 (br s, 1).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[Na].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17](=O)[C:16](=[CH:21]N(C)C)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(O)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:4]=[C:3]([NH2:5])[N:2]=[CH:21][C:16]=2[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: N=C(N)N
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Reaction time: 2 h
Yield: 43 %

Procedure:
Guanidine hydrochloride 7.07 g (74 mmol) was added at 0° C. to a solution of sodium 1.65 g (74 mmol) in absolute ethanol and stirring was performed for 2 h at RT under nitrogen as inert gas. 60 ml (60 mmol) of this reaction mixture were added to the solution of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester in 100 ml of absolute ethanol and refluxing was performed for 5 h. After removal of the solvent and purification by means of column chromatography, 2-amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 5.72 g (43% of theoretical) was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].CI.C(OCC)C>CN(C)C=O>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOCC
Product: COC(=O)c1ccc(C)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of 5-methylthiophene-2-carboxylic acid (40.3 g, 282 mmol) in N,N-dimethylformamide (500 ml) were added potassium carbonate (43 g, 310 mmol) and methyl iodide (19.3 ml, 310 mmol). After stirring at room temperature for 4 hr, diethyl ether (1.0 L) was added, and the organic layer was washed successively with water (500 ml×3) and saturated brine (200 ml) and dried over magnesium sulfate. After filtration and concentration, methyl 5-methylthiophene-2-carboxylate (40.8 g, yield 93%) was obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.O1CCOCC1.B([C:38]1[CH:39]=[CH:40][C:41]([Cl:47])=[C:42]([CH:46]=1)[C:43]([OH:45])=[O:44])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>Cl.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.O>[Cl:47][C:41]1[CH:40]=[CH:39][C:38]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=3[CH:26]=2)=[CH:46][C:42]=1[C:43]([OH:45])=[O:44]
Reactant: O=C(O)c1cc(B(O)O)ccc1Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(Cl)c(C(=O)O)c3)cc12
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a 250 mL sealed tube was added 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (3.55 g, 8.5 mmol), dioxane (50 mL), water (10 mL), Tetrakis(triphenylphosphine)palladium(0) (0.196 g, 0.170 mmol), 5-borono-2-chlorobenzoic acid (2.55 g, 12.75 mmol), and cesium carbonate (4.15 g, 12.75 mmol). The tube was sealed and heated in an oil bath overnight at 85° C. The reaction mixture was then cooled, diluted with 300 mL of cold 0.5M HCl and stirred for 30 minutes. The resulting solid was washed with 0.5 N HCl then with water and allowed to dry under vacuum giving a quantitative yield of 2-Chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid which was used without further purification. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5 μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. LCMS m/z 424.77 (M+H), Rt 2.150 min., 90% purity.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[OH:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>CCOCC>[C:18]([O:17][C:16]([NH:15][O:14][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])(=[O:11])=[O:10])=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)NO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C

Procedure:
Mesitylenesulfonyl chloride (7.75 g, 35.4 mmol) and t-butyl N-hydroxycarbamate (4.72 g, 35.4 mmol) were dissolved in ether (150 mL). Triethylamine (4.88 mL, 35.4 mmol) was added dropwise with stirring at 0° C. The mixture was stirred at 0° C. for 1 h following the addition and the precipitate of triethylamine hydrochloride removed by filtration. The precipitate was washed twice with ether and the washings added to the filtrate. The ether was removed in vacuo and the residue was re-dissolved in the minimum volume of toluene. Petroleum ether 40-60 was added to precipitate N-t-Butoxycarbonyl-β-(mesitylsulfonyl)hydroxylamine as a white solid.
Reaction SMILES: Cl.[CH2:2]([C:5]1([C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH:3]=[CH2:4].[CH3:21]O>>[CH2:2]([C:5]1([C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH:3]=[CH2:4]
Reactant: CO
Reactant: C=CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: C=CCC1(C(=O)OC)CCNCC1

Procedure:
HCl (g) was bubbled through a solution of 4-allyl-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid [Jiang et al. (2004) Bioorg. Med. Chem. Lett. 14, 3675-3678] (6.50 g, 24.1 mmol) in MeOH (200 mL). The solution was heated at reflux for 16 h and then concentrated in vacuo to give the title compound as the hydrochloride salt. MS: m/z=184(M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>>[Cl:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]([CH2:33][CH2:34][OH:35])[CH3:31])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: CNCCO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN(C)CCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 2-(methylamino)ethanol following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 8.83 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.76 (s, 1H), 4.32 (br, 1H), 3.95 (t, 2H), 3.89 (s, 3H), 3.43 (m, 2H), 2.36 (t, 2H), 2.29 (t, 2H), 2.13 (s, 3H), 1.74 (m, 2H), 1.39 (m, 4H), 1.29 (m, 2H); MS (ESI): 509.3.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O-:11][C:12]#[N:13].[K+].C([O-])(O)=O.[Na+]>O>[C:1]1([C@H:7]([NH:9][C:12]([NH2:13])=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: C[C@@H](NC(N)=O)c1ccccc1
Temperature: 80 °C
Yield: 97.5 %

Procedure:
A mixture of (R)-1-phenylethylamine (1.00 g, 8.25 mmol) in water (4 mL) was treated with a 1 M solution of HCl in water (8.5 mL, 8.5 mmol) followed by potassium cyanate (3.35 g, 41.2 mmol). The reaction mixture was warmed to 80° C. for 1 hour and cooled. The mixture was neutralized with saturated NaHCO3 and extracted with ethyl acetate and 2-methyltetrahydrofuran. The combined organic phase was dried (Na2SO4), filtered and concentrated. Chromatography on SiO2 (0-10% MeOH/DCM) gave the desired urea product (1.32 g, 8.04 mmol; 97%) as a white solid. MS ESI calc'd for C9H12N2O [M+H]+ 165, found 165. 1H NMR (600 MHz, DMSO-d6) δ 7.23-7.28 (m, 4 H), 7.17 (t, J=6.7 Hz, 1 H), 6.38 (d, J=7.9 Hz, 1 H), 5.38 (br s, 2 H), 4.65 (m, 1 H), 1.26 (d, J=7.1 Hz, 3 H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25])[CH2:9][C@@H:8]1[CH2:43][CH3:44])=[O:6])([CH3:3])[CH3:2].Cl.[NH2:46]O.C([O-])(=O)C.[Na+]>CO>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:22]2[O:27][N:46]=[C:24]([CH3:25])[CH:23]=2)[CH2:9][C@@H:8]1[CH2:43][CH3:44])=[O:6])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)CC(C)=O)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C)no2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Yield: 5.4 %

Procedure:
To a solution of (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (225 mg, 0.35 mmol) in MeOH (1.7 mL) at 0° C., add hydroxylamine hydrochloride (37 mg, 0.53 mmol) and sodium acetate (1.4 mg, 0.017 mmol). Stir the reaction mixture under reflux overnight. Cool the mixture and remove the solvents under reduced pressure. Dilute the residue with ethyl acetate and brine. Separate the layers, and dry the organic phase over magnesium sulfate, filter, and concentrate in vacuo. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (12 mg, 5%). MS (ES+): 639 (M+H).
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].[NH2:7][CH2:8][C@@H:9]1[C@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]2[C@H:11]([N:19]2[C:23]3[N:24]=[CH:25][N:26]=[C:27]([NH:28][CH:29]4[CH2:31][CH2:30]4)[C:22]=3[CH:21]=[CH:20]2)[CH2:10]1.[Cl:32][C:33]1[C:34]([C:55]([F:58])([F:57])[F:56])=[CH:35][C:36]2[N:40]=[C:39]([CH2:41][CH2:42][CH2:43][CH:44]=O)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:37]=2[CH:54]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:32][C:33]1[C:34]([C:55]([F:58])([F:56])[F:57])=[CH:35][C:36]2[N:40]=[C:39]([CH2:41][CH2:42][CH2:43][CH2:44][NH:7][CH2:8][C@@H:9]3[C@H:13]4[O:14][C:15]([CH3:17])([CH3:18])[O:16][C@H:12]4[C@H:11]([N:19]4[C:23]5[N:24]=[CH:25][N:26]=[C:27]([NH:28][CH:29]6[CH2:31][CH2:30]6)[C:22]=5[CH:21]=[CH:20]4)[CH2:10]3)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:52])([CH3:51])[CH3:53])[C:37]=2[CH:54]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CN)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Reactant: C[Si](C)(C)CCOCn1c(CCCC=O)nc2cc(C(F)(F)F)c(Cl)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Product: CC1(C)O[C@@H]2[C@@H](CNCCCCc3nc4cc(C(F)(F)F)c(Cl)cc4n3COCC[Si](C)(C)C)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
MgSO4 (1.08 g, 9.0 mmol) was added to a solution of 7-[(3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (330 mg, 0.96 mmol) and 4-[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butanal (526 mg, 0.90 mmol) in DCE (10 ml) and stirred at RT for 15 mins. NaBH(OAc)3 (267 mg, 1.26 mmol) was then added to the reaction mixture and stirred for 1 hr. LC MS indicated complete consumption of the amine. Sat. NaHCO3 (20 ml) was added to the reaction mixture. The product was extracted with DCM (2×30 ml), dried over Na2SO4, filtered, and evaporated. Purification by silica gel column chromatography, eluting with 7N NH3 in MeOH:DCM (1:199-3:97) afforded the desired product as an off white/pink foamy solid (278 mg, 41%); MS (ESI+) for C36HClF3N7O3Si m/z 748.05 [M+H]+; HPLC purity 84% (ret. Time, 1.73 min). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.30 (1H, s), 7.39-8.21 (2H, m), 6.84-7.17 (1H, m), 6.63 (1H, br. s.), 5.43-5.55 (2H, m), 5.33-5.41 (1H, m), 4.82-5.14 (2H, m), 4.54 (1H, t, J=6.23 Hz), 3.53 (4H, dd, J=16.16, 8.12 Hz), 2.89-3.13 (3H, m), 2.82 (1H, d, J=7.41 Hz), 2.66-2.80 (2H, m), 2.45 (1H, s), 2.24-2.39 (1H, m), 2.18 (1H, s), 1.83-2.06 (2H, m), 1.63-1.73 (2H, m), 1.55-1.61 (3H, m), 1.30 (3H, s), 0.81-1.03 (4H, m), 0.56-0.78 (2H, m), −0.22-0.12 (9H, m).