Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[S:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].CC(C)(C)C(Cl)=O.[CH3:31][C@@H:32]([NH:41][CH3:42])[C@H:33]([OH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([N:41]([C@H:32]([CH3:31])[C@H:33]([OH:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:42])=[O:17])[CH:5]=[CH:6][C:7]=1[S:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)Cc1ccc(SC2CCCC2)c(Cl)c1
Reactant: CN[C@H](C)[C@H](O)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)Cc1ccc(SC2CCCC2)c(Cl)c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a three neck round bottom flask is added a stir bar, dropping funnel, argon inlet and thermometer. It is then charged (3-chloro-4-cyclopentylsulfanyl-phenyl)-acetic acid (5.00 mmol), acetone (15 mL) and potassium carbonate (3.0 equiv.) and cooled to −10° C. To this cooled solution is then added trimethylacetyl chloride (1.05 equiv.) dropwise slowly to keep the temperature below −10° C. throughout the addition. It is then stirred at −10° C. for 15 min, then warmed to 0° C. and stirred for an additional 10 min and then recooled to −10° C. To the reaction is then added (1R,2R)-(−)-pseudoephedrine (1.5 equiv.) in one portion. It is then stirred at −10° C. for 10 min and then warmed to 25° C. and stirred for 1 h. After such time, the reaction is quenched with water (10 mL) and poured into a separatory funnel and added ethyl acetate (25 mL). The layers are separated and the organic layer is washed with water (2×10 mL) and the organic layers are then back extracted with ethyl acetate (3×25 mL) dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (silica gel cartridge) will afford 2-(3-chloro-4-cyclopentylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[Cl:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17]Cl>>[Cl:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1
Reactant: ClCCOCCCl
Reactant: Clc1ccc2[nH]nc(I)c2c1
Product: ClCCOCCn1nc(I)c2cc(Cl)ccc21
Yield: 54 %

Procedure:
The title compound was prepared from 5-chloro-3-iodo-indazole and bis(2-chloroethyl)ether in 54% yield according to the general procedure for Preparation 11A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 3.47 (2H, t, J=5.2 Hz), 3.60 (2H, t, J=5.2 Hz), 3.92 (2H, t, J=5.2 Hz), 4.56 (2H, t, J=5.2 Hz), 7.37 (1H, dd, J=2.0, 9.2 Hz), 7.44-7.46 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:12][NH2:13].[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([O:33][CH3:34])[CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1>>[Br:8][C:6]1[CH:5]=[N:4][C:3]2[C:9](=[O:11])[N:13]([CH3:12])[C:29]([C:28]3[CH:31]=[CH:32][C:25]([O:24][CH:21]4[CH2:22][CH2:23][N:18]([CH:14]5[CH2:17][CH2:16][CH2:15]5)[CH2:19][CH2:20]4)=[CH:26][C:27]=3[O:33][CH3:34])=[N:1][C:2]=2[CH:7]=1
Reactant: COc1cc(OC2CCN(C3CCC3)CC2)ccc1C=O
Reactant: CN
Reactant: Nc1cc(Br)cnc1C(=O)O
Product: COc1cc(OC2CCN(C3CCC3)CC2)ccc1-c1nc2cc(Br)cnc2c(=O)n1C

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 3-amino-5-bromopyridine-2-carboxylic acid, methylamine and 4-[(1-cyclobutylpiperidin-4-yl)oxy]-2-methoxybenzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Si](C=[N+]=[N-])(C)(C)[CH3:16].C(O)(=O)C>CO.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 4-fluoro-3-(trifluoromethyl)benzoic acid (260 mg, 1.25 mmol, 1 eq) in MeOH (0.5 mL) and CH2Cl2 (2 mL) was treated with TMSCHN2 (2M in hexanes, 0.85 mL, 1.70 mmol, 1A eq) dropwise with stirring at room temperature. After the reaction was stirred for 10 min, acetic acid was added until the yellow color disappeared. The mixture was concentrated to afford methyl 4-fluoro-3-(trifluoromethyl)benzoate, which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:25]=[CH:24][C:23]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:33])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccc1Oc1ccc(C(F)(F)F)cc1)C1CCNCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-[2-(4-Trifluoromethyl-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (HVB01043, 0.2 g, 0.43 mmol) was dissolved in anhydrous DCM (5 ml), cooled to 0° C. and to this was added TFA (2.3 ml), and the reaction mixture was stirred under nitrogen for 1 h. The reaction mixture was poured onto solid potassium carbonate (6 g), and water (25 ml) added. Extracted with DCM and the organic layers dried over anhydrous magnesium sulphate, and evaporated in-vacuo, to afford an off white oil, 0.14 g, 89%. Rf: 0.47 (DCM), 1HNMR: (CDCl3, 270 MHz) δ 1.65 (2H, m, CHCH2), 1.79 (2H, m, CHCH2), 2.30 (1H, m, CH), 2.64 (2H, td, J=12.4, 2.7 Hz, NCH2), 3.10 (2H, m, NCH2), 6.97 (1H, dd, J=6.4, 30.5 Hz, Ar HD), 7.05 (2H, m, Ar HF), 7.06 (1H, m, Ar HB), 7.17 (1 h, t, J=7.2 Hz, Ar HC), 7.58, d, J=8.6 Hz, Ar HE), 8.39 (1H, d, J=7.9 Hz, Ar HA).
Reaction SMILES: C(OC([CH:6]1[CH2:13][CH:12]2[NH:14][CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7]1)=O)C.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17]([CH:9]1[CH:8]2[N:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]([CH2:13][CH2:6][CH2:7]2)[CH2:11][CH2:10]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C1CC2CCCC(C1)N2
Reactant: CCOC(=O)CBr
Solvent: CCO
Product: CCOC(=O)CN1C2CCCC1C(C(=O)OCC)CC2
Yield: 100 %

Procedure:
To a 250 mL round-bottomed flask equipped with a condenser and nitrogen inlet were added 5.59 g (28.36 mmol) ethyl-9-azabicyclo[3.3.1]nonane-3-carboxylate, 142 mL ethanol, and 9.47 g (56.72 mmol) ethyl bromoacetate. The reaction was refluxed 3 days, cooled, and evaporated. The residue was partitioned between methylene chloride and aqueous sodium hydroxide, and the organic layer was dried over sodium sulfate and evaporated. The residue was filtered through silica gel using ethyl acetate to afford an oil, 4.835 g (100% yield crude), as a mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][OH:11].Cl.[OH-].[Na+].CCOC(C)=O.CCCCCC>CCO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:10][OH:11])[NH2:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=NO)c1ccc(F)cc1
Yield: 62.9 %

Procedure:
To a stirred solution of 4-fluorobenzonitrile (10 g, 82.5 mmol) in EtOH (71 mL) was added NH2OH.HCl (6.42 g, 92.1 mmol), followed by NaOH pellets (3.69 g, 92.1 mmol). The resulting reaction mixture was then heated at reflux for 3 h. The reaction progress was monitored by TLC using solvent system EtOAc:Hexane (1:1). After completion of reaction the solvent was evaporated under reduced pressure and the minimum amount of water (ca. 30 mL) was added to the residue. The mixture was extracted with dichloromethane (3×300 mL), dried over Na2SO4, and concentrated under vacuum. The crude compound obtained was recrystallized from hot toluene to obtain 8.0 g (63%) of 4-fluoro-N′-hydroxybenzimidamide as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 9.6 (s, 1H), 7.07-7.67 (m, 2H), 7.18 (t, 2H, J=8.8 Hz), 5.80 (br s, 2H); LC-MS m/z calculated for [M+H]+ 155.05. found 155.1.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C([Li])(C)(C)C.S(C)C.C1C[O:22]CC1>CCCCC>[OH:22][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: C1CCOC1
Agent: [Li]C(C)(C)C
Solvent: CSC
Solvent: CCCCC
Product: Cc1cc(C#N)ccc1O
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (7.07 g, 36.1 mmol) in 225 mL of THF at -78° C. is added a 1.7 M solution of tert-butyl lithium (45.6 mL, 77.6 mmol) in pentane. After 5 minutes, CuBr.SMe2 (15.9 g, 77.6 mmol) is added. The resulting solution is stirred for 10 minutes, then O2 is slowly bubbled through the reaction mixture for 30 minutes. After this time, the solution is allowed to warm to ambient temperatures. The solution is stirred for 16 hours. The solution is then poured into 100 mL of H2O. The solution is diluted with EtOAc. The layers are separated. The organic layer is washed with saturated (NH4)2SO4 solution. The organic layer is then extracted with 10 N NaOH. The collected aqueous basic layers are acidified to pH=6 with 6N HCl. The solution is then extracted with EtOAc. The combined organic layers are dried over MgSO4, filtered and concentrated. The title compound is obtained as a solid.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16](O)[C:17]3[CH:18]=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[N:21][C:22]=3[CH:23]=2)=[CH:10][CH:9]=1>>[Cl:3][C:16]1[N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[N:21]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc3nc(C(F)(F)F)ccc3c(O)n2)cc1
Product: COc1ccc(-c2cc3nc(C(F)(F)F)ccc3c(Cl)n2)cc1
Temperature: 100 °C
Yield: 55 %

Procedure:
POCl3 (3 mL) was added to 7-(4-methoxyphenyl)-2-trifluoromethyl-[1,6]naphthyridin-5-ol (Example 19) (125 mg, 0.4 mmol). The mixture was heated at 100° C. for 3 hours. The excess POCl3 was concentrated under reduced pressure. The residue was diluted with CH2Cl2, washed with sat. NaHCO3, dried over Na2SO4, and concentrated giving the title compound (73 mg, 55%) as an orange solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][N:10]1[C:14]([C:15]2[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[S:18][CH:19]=2)=[CH:13][CH:12]=[N:11]1>O1CCCC1>[Br:8][C:13]1[CH:12]=[N:11][N:10]([CH3:9])[C:14]=1[C:15]1[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[S:18][CH:19]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(Br)cnn2C)cs1
Temperature: 70 °C
Yield: 82.7 %

Procedure:
NBS (747 mg, 4.20 mmol) was added in portions to a 50 mL sealed tube reactor containing methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (860 mg, 3.48 mmol) [prepared according to the procedure of Example 37] in Tetrahydrofuran (THF) (17 mL) at room temperature. The mixture was heated to 70° C. for 1.5 hours, cooled to room temperature and partitioned between CHCl3 and H2O. The organic layer was dried with Na2SO4, adsorbed onto silica and purified via column chromatography (20-40% EtOAc/hexanes) affording the title compound (867 mg, 83%): LC-MS (ES) m/z=303 (M+H)+.
Reaction SMILES: [CH:1]([S:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:8]=[N:7][N:6]=1)([CH3:3])[CH3:2].Br[CH:18]([OH:21])[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH:1]([S:4][C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][CH2:19][CH2:18][OH:21])=[CH:14][CH:15]=2)[N:8]=[N:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CCC(O)Br
Reactant: CC(C)Sc1nnnn1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Sc1nnnn1-c1ccc(OCCCO)cc1

Procedure:
400 mg of 4-(5-isopropylsulfanyl-tetrazol-1-yl)-phenol, 471 mg of bromopropanol, 473 mg of potassium carbonate and 10 mg of potassium iodide are stirred for 15 hours at reflux in 10 ml of acetone. The reaction mixture is filtered and concentrated. The residue is taken up in ethyl acetate, washed with water and concentrated. Purification over silica gel yields 3-[4-(5-isopropylsulfanyl-tetrazol-1-yl)-phenoxy]-propan-1-ol. 1H-NMR (CDCl3) 300 MHz: 1.50 (d, 6H), 2.09 (m, 2H), 3.90 (t, 2H), 4.12 (m, 1H), 4.19 (t, 2H), 7.03 (d, 2H), 7.43 (d, 2H)
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34]C(O)=O)=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39].N1C=CC=CC=1.C[C:50]1([CH3:58])[O:55][C:54](=[O:56])[CH2:53][C:52](=[O:57])O1>ClCCl>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:52](=[O:57])[CH2:53][C:54]([O:55][CH2:50][CH3:58])=[O:56])=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(=O)C1=C(COCC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.8 %

Procedure:
A solution of carbonyl diimidazole (5.20 g) and 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetic acid (14.00 g) in dichloromethane (200 ml) was stirred at room temperature under nitrogen for 2 hours and then added to a solution of pyridine (2.40 g) and 2,2-dimethyl-1,3-dioxane-4,6-dione (4.56 g) in dichloromethane (200 ml) over 8 minutes. The mixture was stirred at room temperature for 2.5 hours, washed successively with water, ice-cold 2.5M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in ethanol (200 ml) and the solution heated under reflux for 2.75 hours and evaporated. The residue was triturated with diethyl ether and the resulting solid collected washed with diethyl ether and dried to give the title compound (9.0 g), m.p. 99°-102° C.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCl.P.C[OH:24].C(Cl)CCl>>[C:14]1([P:7](=[O:24])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CO
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: ClBr
Agent: P
Solvent: ClCCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of triphenylphosphine (2.62 g, 10 mmol) in a methanol-EDC mixture (100 mL, 50:50, Vol.) was placed in a 250-mL round bottom flask and cooled in an ice bath. Stabilized BrCl (15 wt. % solution, 7.5 mL, 12 mmol) was added dropwise to the homogeneous phosphine solution. The reddish-brown color of the BrCl solution disappeared instantaneously as it was added. An orange color persisted during the addition of the last 0.5 mL, indicating total conversion. The reaction mixture was allowed to stand for 30 minutes at room temperature and then was quenched with a few drops of sodium sulfite solution which totally decolorized it. Dilution with EDC (100 mL) and washing with water (100 mL) was followed by phase separation. The organic layer was dried (Na2SO4) and concentrated to afford 2.64 g (95% yield) of triphenylphospine oxide as a white solid in 97% purity (3% starting material).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.[O:18]=[C:19]1[C:24](C(Cl)=O)=[CH:23][CH:22]=[C:21]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:20]1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:38][NH2:39]>>[Cl:14][CH:13]=[C:11]1[CH2:12][N:8]([C:6]([C:24]2[C:19](=[O:18])[O:20][C:21]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:22][CH:23]=2)=[O:7])[C@H:9]([C:15]([NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:42]([O:43][CH3:44])=[C:35]([O:34][CH3:33])[CH:36]=2)=[O:17])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: COc1ccc(CN)cc1OC
Product: CCCCCc1ccc(C(=O)N2CC(=CCl)C[C@H]2C(=O)NCc2ccc(OC)c(OC)c2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=503.4.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[CH:23]([C:25]1[CH:26]=[C:27]([C:35]#[N:36])[C:28]2[O:33][CH2:32][CH2:31][O:30][C:29]=2[CH:34]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(Cl)(Cl)[Cl:57]>CO>[ClH:57].[O:21]=[C:18]1[CH:17]=[N:16][C:15]2=[C:20]3[N:19]1[C@H:9]([CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:23][C:25]4[CH:26]=[C:27]([C:35]#[N:36])[C:28]5[O:33][CH2:32][CH2:31][O:30][C:29]=5[CH:34]=4)[CH2:3][CH2:4]1)[CH2:10][N:11]3[C:12](=[O:22])[CH:13]=[CH:14]2
Reactant: ClC(Cl)Cl
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: N#Cc1cc(C=O)cc2c1OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N#Cc1cc(CNC2CCN(C[C@@H]3Cn4c(=O)ccc5ncc(=O)n3c54)CC2)cc2c1OCCO2
Reaction time: 1.5 h
Yield: 42.3 %

Procedure:
A suspension of (2R)-2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(j)) (60 mg, 0.199 mmol) and 7-formyl-2,3-dihydro-1,4-benzodioxin-5-carbonitrile (for a synthesis see WO06014580 Preparation 13 or WO2007122258, Example 31(d)) (37.7 mg, 0.199 mmol) in chloroform (2 ml) and methanol (0.100 ml) at room temperature under nitrogen was treated with sodium triacetoxyborohydride (127 mg, 0.597 mmol) and stirred for 90 min. This was then treated with saturated aqueous NaHCO3(10 ml) and extracted with 20% methanol/DCM (3×25 ml). The combined organic extracts were dried (NaSO4), filtered, evaporated and purified using silica chromatography (0-20% methanol/DCM) to give the free base of the title compound as a yellow gum (40 mg, 42.3%).
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[F:12][C:13]([F:31])([F:30])[C:14]([O:17][C:18](=O)[O:19]C1C=CC([N+]([O-])=O)=CC=1)([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CC#N.O>[O:9]1[CH2:8][CH2:7][CH:6]([CH:2]([NH:1][C:18]([O:17][C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])=[O:19])[C:3]([OH:5])=[O:4])[CH2:11][CH2:10]1
Reactant: NC(C(=O)O)C1CCOCC1
Reactant: CC(C)(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(OC(=O)NC(C(=O)O)C1CCOCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
Amino-(tetrahydro-pyran-4-yl)-acetic acid (80 mg, 0.5 mmol) was dissolved in CH3CN (5 mL) and H2O (1 mL), carbonic acid 4-nitro-phenyl ester 2,2,2-trifluoro-1,1-dimethyl-ethyl ester (175 mg, 0.6 mmol) and DIEA (88 μL, 0.5 mmol) were added slowly. The reaction was allowed to stir at room temperature for 16 h. After concentrated, diluted with EtOAc, washed with brine and H2O, dried over Na2SO4, the crude product was purified on silica (12 g, 25-75% EtOAc/hexanes) to give intermediate (tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-1,1-dimethyl-ethoxycarbonylamino)-acetic acid as light yellow solid (110 mg, 70%).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][C:20]4[CH:21]=[C:22]([C:34](=[O:36])[CH3:35])[CH:23]=[CH:24][C:25]=4[O:26]CC4C=CC=CC=4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[ClH:39]>C(O)(=O)C>[ClH:39].[F:1][C:2]1[CH:38]=[CH:37][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][C:20]4[CH:21]=[C:22]([C:34](=[O:36])[CH3:35])[CH:23]=[CH:24][C:25]=4[OH:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(OC/C=C/CN2CCC(c3noc4cc(F)ccc34)CC2)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc(O)c(OC/C=C/CN2CCC(c3noc4cc(F)ccc34)CC2)c1
Temperature: 75 °C

Procedure:
The mixture of (E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanone (5.5 g, 10.7 mmol), acetic acid (50 ml), and hydrochloric acid (6 ml) was heated at 75° C. for 2 hours. At the end of reaction, the solvent was reduced to about 20 ml on a rotary evaporator. The solution was poured into ice water (350 ml) and extracted with dichloromethane (3×250 ml). The dichloromethane solute, on was washed with brine and dried over Na2SO4. A solid formed on concentration of the solvent. This was collected by filtration (3.4 g). Recrystallization from hot methanol (40 ml) gave 1.82 g of (E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-hydroxyphenyl]ethanone hydrochloride as white crystals, 37.5%, m.p.=208°-210° C.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([P:8](=[O:19])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.CCCCCC.CCOC(C)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:29][CH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([P:8](=[O:19])([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
A mixture of di(tert-butyl) (4-methylbenzoyl)phosphonate (10 g), NBS (8.3 g), NaHCO3 (10 g) and benzoyl peroxide (0.1 g) in 200 mL of CCl4 was heated to reflux for 20 min. The mixture was cooled to room temperature, diluted with 200 mL of 10:1 hexane/EtOAc and filtered through a pad of silca gel. The filtrate was concentrated and the residue was swished from hexane to give 2.8 g of the title compound as a beige solid.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH2:9][N:8](C(=O)C(F)(F)F)[CH2:7][CH2:6][N:5]1[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O>[O:3]=[C:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a stirring solution of sodium hydroxide (1.38 g, 34.5 mmol), and H2O (5.0 mL), at 0° C., was added. 4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (5.0 g, 11.5 mmol) portionwise over 10 minutes. The mixture was stirred at ambient temperature for 30 minutes. The solution was cooled to 0° C. followed by the addition of 1.0 N HCl aqueous solution (34.5 mL, 34.5 mmol). The light yellow solution was azeotroped with MeOH (4×100 mL) at <30° C. The obtained solid was suspended in 50% MeOH in CH2Cl2 (200 mL) and stirred for 5 minutes. The mixture was filtered and the filtrate was evaporated to give the desired amine as light yellow solid (2.5 g, 7.4 mmol, 64% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=339.3; tR=0.51 min.