Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[O:9][CH:8]=1)(=O)=O.[C:24](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.O>O1CCOCC1.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(OCC)(=O)C>[CH3:24][C:7]1[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[O:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(COC2CCCCO2)occ1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1coc(COC2CCCCO2)cc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 1.0 g of 4-oxo-6-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-3-yl trifluoromethanesulfonate in 10 mL of dioxane, 1.2 g of potassium carbonate, 0.4 mL of trimethylboroxin and 0.33 g of tetrakis(triphenylphosphine)palladium(0) were added, and the mixture was stirred at 70 to 80° C. for 2 hours under an argon atmosphere. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 0.62 g of 5-methyl-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one as a brown oily substance.
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([S:6](=[O:16])(=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)[CH2:4][CH2:3][NH:2]1.[C:17](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:17][N:2]1[CH2:3][CH2:4][N:5]2[S:6](=[O:15])(=[O:16])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH:10]2[CH2:1]1
Reactant: O=S1(=O)c2ccccc2CC2CNCCN21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN2C(Cc3ccccc3S2(=O)=O)C1
Reaction time: 4.5 h
Yield: 78 %

Procedure:
To a solution of the title compound of Example 215 (23.0 mg, 0.0965 mmol) in dimethylformamide (0.75 mL) were added cesium carbonate (94 mg, 0.29 mmol) and methyl iodide (0.0072 mL, 0.12 mmol). After 4.5 h, the reaction was partitioned between dichloromethane (2 mL) and water (2 mL). The aqueous layer was extracted with dichloromethane (2 mL). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The residue was taken up in a minimum amount of 50% aqueous methanol and loaded onto a methanol-activated water-equilibrated 1-g SCX-type cation exchange column. The column was washed with water (6 mL) and 50% aqueous methanol (6 mL). The column was eluted with 2N methanolic ammonia (8 mL). This fraction was concentrated in vacuo to provide (−)-1,2,3,4,11,11a-hexahydro-2-methyl-pyrazino[1,2-b][1,2]benzothiazine 6,6-dioxide as a white solid (19 mg, 79%): LCMS (pos. ion spectrum) m/z 253.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:29])[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:29])[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3[nH]c2=O)cc2cc(CO)ccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3[nH]c2=O)cc2cc(C=O)ccc21
Temperature: 45 °C
Reaction time: 1 h

Procedure:
The pre-activated MnO (34.5 g, 15 equiv) and the alcohol (5-7, 10.32 g, 1.0 equiv) were weighed into a 1 liter flask and suspended in dry dichloromethane (500 mL). The reaction mixture was heated to 45° C. and was complete by thin layer chromatography after 1 h. The mixture was allowed to cool to ambient temperature and the manganese oxide(s) were removed by vacuum filtration. The resulting pad of oxides on the filter were triturated with hot THF and the solvent filtered through under vacuum to remove any product from the oxides. The resulting filtrate was concentrated in vacuo to afford the crude aldehyde as a yellow solid. The solid was triturated with methanol (10 mL) and ethyl acetate (15 mL) followed by vacuum filtration to isolate the pure product. The light-yellow aldehyde was dried under vacuum (5-8); 1H NMR (500 MHz, DMSO-6) δ12.15 (s, 1H), 10.08 (s, 1H), 8.26 (d, 1H, J=1.5 Hz), 8.24 (d, 1H, J=8.5 Hz), 8.15 (s, 1H), 7.90 (dd, 1H, J=8.5, 1.5 Hz), 7.77 (d, 1H, J=7.5 Hz), 7.55 (m, 1H), 7.37 (d, 1H, J=8.5 Hz), 7.24 (m, 1H), 7.01 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][N:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[NH:22][CH2:23][C:24]([O:26]CC)=[O:25])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:31]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][N:12]=[CH:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:29])[NH:22][CH2:23][C:24]([O-:26])=[O:25])=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:31]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C=NNC(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CNC(=O)Nc1ccc(C=NNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.74 g (1.86 mmol) of ethyl (3-(4-(benzyloxycarbonylaminoiminomethyl)phenyl)ureido)acetate in 100 ml of ethanol is treated with 1.86 ml of 1N NaOH and the mixture is stirred at room temperature for 6 h. The solvent is removed in vacuo and the residue is freeze-dried.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][C:9]1[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=1.[CH:23]([O:25][CH3:26])=O.Cl>CN(C=O)C.O>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][C:9]1[C:14](/[C:15](=[CH:23]\[O:25][CH3:26])/[C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COC(=O)Cc1cccnc1Oc1cccc(CO)c1
Reactant: COC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a stirred suspension of sodium hydride (1.056 g, 50% dispersion in oil, pre-washed with petroleum ether) in dry DMF (15 ml) at 0°-5° C. was added dropwise over 5 minutes a solution containing methyl 2-(3-hydroxymethylphenoxy)pyridin-3-ylacetate (2.0 g) and methyl formate (9 ml) in DMF (effervescence). After the addition was complete, the reaction mixture was allowed to warm to room temperature. After stirring for a further 3 hours, the reaction mixture was carefully poured into water, neutralised with 2N hydrochloric acid and then extracted thoroughly with ether (× 6). The combined ether layers were dried, filtered and evaporated to afford a crude residue which was used without further purification. The residue was dissolved in DMF (10 ml) and then treated with potassium carbonate (0.60 g) and dimethyl sulphate (0.64 g). Standard work-up and chromatography on silica gel (eluent petroleum ether-ether, 1:1) afforded (E)-methyl 2-[2-(3hydroxymethylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.35 g, 15%); mass spectrum m/e 315 (M+).
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:6][C:7](=[O:33])[C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=3)=O)=[CH:10][CH:9]=2)[CH2:5][CH2:4]1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:36]/[N:35]=[C:16](/[C:18]1[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=1)\[CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][C:3]2([CH2:2][OH:1])[CH2:5][CH2:4]2)=[O:33])=[CH:9][CH:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC2(CO)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC2(CO)CC2)cc1

Procedure:
In analogy to example 151, step 3, N-(1-(hydroxymethyl)cyclopropyl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=460.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21][CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].CN(C)C=[O:34].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Cl:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:34])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]1=[O:14]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCSC4)cc1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Temperature: -7 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A mixture of 1-{[3-chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione (239.6 g) and dimethylformamide (1.8 L) was cooled to −7° C. and vanadium (IV) oxyacetylacetone (691 mg) was added thereto. 30% Hydrogen peroxide (59.2 g) was added dropwise and the mixture was stirred at 2° C. or lower for 8 hours. 0.5N Sodium thiosulfate (100 ml) and water (3 L) were added dropwise at 5 to 7° C. and the mixture was stirred at 15 to 20° C. for 1 hour. Crystals deposited were filtered off to obtain the titled compound (242 g, 97.5%). 1H-NMR (CDCl3) δ: 2.13-2.20 (1H, m), 2.54-2.73 (2H, m), 3.02-3.09 (1H, m), 3.90 (3H, s), 4.00 (1H, d, J=16.9 Hz), 4.10 (1H, d, J=16.9 Hz), 5.00 (1H, d, J=17.2 Hz), 5.06 (1H, d, J=17.2 Hz), 7.01 (2H, d, J=8.1 Hz), 7.16 (2H, d, J=8.1 Hz).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>ClCCl.[OH-].[Na+].S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1
Reactant: CN(C[C@H]1CC[C@H](CO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: BrCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 19.1, trans-N-(4-hydroxymethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide (example 5.1) was reacted with 1,4-dibromo-butane in dichloromethane and aqueous sodium hydroxide solution in the presence of tetrabutylammonium hydrogensulfate to yield trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 500 (MH+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16].[I-].[CH3:25][N:26]1[C:34]2[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:36][N+](C)(C)C)=[CH:27]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:36][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[N:26]([CH3:25])[CH:27]=2)[C:6]1=[O:16]
Reactant: COC(=O)[C@@H](C1CCCCC1)n1c(=O)[nH]c2ccccc2c1=O
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C1CCCCC1)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
To a mixture of (R)-cyclohexyl-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid methyl ester (100 mg, 0.32 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (160 mg, 0.47 mmol) in DMF (2.5 mL) is added potassium carbonate (K2CO3) (100 mg, 0.72 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, dilute with EtOAc (50 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and concentrated. The resulting residue is triturated with EtOAc and hexanes to afford (R)-cyclohexyl-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetic acid methyl ester (124 mg, 94%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C@@H:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[O:9][C:8]([CH3:14])([CH3:13])[C@H:7]2[OH:15])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(Cl)cc2)[C@@H]1O

Procedure:
A solution of 3 g of 6-cyano-2,2-dimethyl-3,4-epoxychroman and 2.1 g of parachloroaniline in 50 ml of ethanol is refluxed for 72 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[N+:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)([O-:36])=[O:35].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:40]2[CH:41]=[CH:42][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=2)=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
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: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 0.05 g (0.1 mmol) of above resin-bound 3-(4-bromo-phenyl)-2-(S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester in 2.0 mL of DME was added 50.1 mg (0.3 mmol) of 4-nitrophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated at 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% DCM) to give 28.2 mg of the title compound. LC/MS (m/z): 565 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10]C)=[O:9])=[C:4]([NH:14][C:15](OCC)=O)[CH:3]=1.BrC[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=1)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH2:7][C:8]([OH:10])=[O:9])=[C:15]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=3)=[O:23])[NH:14]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(C(=O)CBr)nc1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)OC
Product: Cc1ccc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)nc1

Procedure:
Two diastreomers of the title compound were prepared according the procedure described in step 2 of Example 31 from methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (Example 31, step 1) and 2-bromoacetyl-5-methylpyridine.*
Reaction SMILES: [CH2:1]([NH:4][C:5](=O)[CH2:6][O:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[CH:2]=[CH2:3].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[Cl:14][C:13]1[CH:12]=[C:11]([Cl:15])[CH:10]=[C:9]([Cl:16])[C:8]=1[O:7][CH2:6][CH2:5][NH:4][CH2:1][CH:2]=[CH2:3]
Reactant: C=CCNC(=O)COc1c(Cl)cc(Cl)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCNCCOc1c(Cl)cc(Cl)cc1Cl
Temperature: 10 °C

Procedure:
N-allyl-2,4,6-trichlorophenoxyacetamide, 14.6 gm, was added to 100 ml of anhydrous tetrahydrofuran. The solution was cooled to about 10° C. with an ice bath. Then lithium aluminum hydride, 1.86 gm, was added slowly. The resulting mixture was stirred in the cold and allowed to warm to room temperature overnight. The mixture was heated at reflux for 6 hours, then again stirred at room temperature overnight. Then 2 ml water, 2 ml of 15% NaOH solution and 6 ml of water were added sequentially. The mixture was filtered through a pad of Celite and the filtrate stripped to yield 10.6 gm of N-allyl ethanolamine 2,4,6-trichlorophenylether as an oil.
Reaction SMILES: [NH2:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:13]2[CH2:18][CH2:17][C@:16]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]2=[O:30])[CH3:12])=[CH:7][CH:6]=1.Cl[C:34]([O:36][CH3:37])=[O:35]>>[OH:29][C:26]([CH3:27])([CH3:28])[CH2:25][C@@:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:15][C:14](=[O:30])[N:13]([C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH:1][C:34](=[O:35])[O:36][CH3:37])([CH3:31])[CH3:32])=[CH:6][CH:7]=2)[CH3:12])[CH2:18][CH2:17]1
Reactant: C[C@@H](c1ccc(C#CC(C)(C)N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COC(=O)Cl
Product: COC(=O)NC(C)(C)C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 15 using (S)-3-((S)-1-(4-(3-amino-3-methylbut-1-ynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and methyl chloroformate. LC-MS Method 1 tR=1.65 min, m/z=493, 435; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.49 (d, 3H), 1.67 (s, 6H), 2.14 (m, 1H), 2.21 (s, 2H), 2.25-2.40 (2H), 2.78 (m, 1H), 5.65 (q, 1H), 6.88 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:36]1[O:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1>>[O:37]1[C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=[C:36]1[N:24]1[CH2:25][CH2:26][N:21]([C@H:18]2[CH2:19][CH2:20][N:15]([C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:4]=3)=[O:14])[CH2:16][C@H:17]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23]1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: Clc1nc2ccccc2o1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(c3nc4ccccc4o3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=603.0 (M+H+), was prepared in accordance with the general method of example 59 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and 2-chlorobenzoxazole.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1.CO.[OH-].[Na+].C(Cl)Cl>C1COCC1>[CH2:14]([O:13][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11])[C:3]([OH:21])=[O:2])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 60 °C
Yield: 85.9 %

Procedure:
Cmpd 2 (1.53 g, 1.0 eq) was dissolved in THF (52.8 mL) and MeOH (26.4 mL) in a round bottom flask, followed by addition of 2N NaOH (13.2 mL, 5.0 eq). The reaction was heated at 60° C. for 3 hours, occasionally opening the flask to release pressure. The reaction was monitored by TLC (5% MeOH:95% DCM). The resulting mixture was concentrated, and the residue was dissolved in water and acidified to pH=2-3 with 1N HCl. The acidic solution was extracted with AcOEt 3×, dried over Na2SO4, filtered and concentrated to afford Cmpd 3 as a light yellowish solid (1.25 g, 96% yield). Analytic: 1H NMR (DMSO d6, 500 mHz): δ 7.99 (d, 1H), 7.87 (s, 1H), 7.66 (dd, 1H), 7.46-7.40 (m, 4H), 7.33 (m, 1H), 5.39 (s, 2H). LCMS (C18, 2-98% CH3CN in 0.1% TFA/H2O over 6 min); Calculated mass for C14H11NO5 (M+H)+274.06. found by LC-MS 274.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example 18 using rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 460.0 (M+H).