Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)cc2)C(=O)C1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a heterogeneous solution of 33 (1.6 g, 8.1 mmol) in 16.2 mL of dry THF under a N2 atmosphere was added 0.211 g (8.80 mmol) of 95% NaH. Once the bubbling subsided, 4-fluorobenzylbromide (1.2 mL, 9.7 mmol) was added dropwise to the solution. After 1 hour, when the reaction was complete as judged by TLC, the reaction was quenched by addition of water and the organic layer was diluted with EtOAc. The organic layer was washed with water and the solvent removed in vacuo. The product was purified by column chromatography using 1:1 EtOAc-Hex solvent system to provide 2.3 g (93%) of the product 34 as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.47 (s, 9H), 3.24 (t, 2H, J=5 Hz), 3.60 (t, 2H, J=5 Hz), 4.16 (s, 2H), 4.59 (s, 2H), 7.03 (t, 2H, J=9 Hz), 7.26 (dd, 2H, J=5.8 Hz); 19F NMR (282.6 MHz, CDCl3) δ 62.2.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[N:16]=[C:15]([N:22]3[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCNCC1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC1CCN(c2nc(-c3ccccc3)nc3ccccc23)CC1
Yield: 41.9 %

Procedure:
A mixture containing 6 g (0.025 mole) of 2-phenyl-4-chloroquinazoline, 3.53 g (0.035 mole) of 4-hydroxypiperidine and 100 ml of 95% ethyl alcohol was refluxed for 3 hrs. One gram of sodium hydroxide (in one ml of water) was added and the mixture was refluxed for an additional 2 hr period. The mixture was filtered and the filtrate was added to 300 ml of water. The white crystalline precipitate was separated and recrystallized with methanol and water to give 3.2 g of the title compound, m.p. 165°-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:12].Br[C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](=[O:12])[C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)[O:8][C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C(CCc1ccc(O)cc1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1

Procedure:
Tert-butyl 2-(3-chloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(2-chloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:11][C:12]#[CH:13]>[Cu]I.N1CCCC1>[N:14]1([CH2:10][CH2:11][C:12]#[C:13][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C#CCCN1CCCCC1
Reactant: O=Cc1cccc(Br)c1
Agent: [Cu]I
Solvent: C1CCNC1
Product: O=Cc1cccc(C#CCCN2CCCCC2)c1
Temperature: 50 °C
Reaction time: 40 h
Yield: 85.3 %

Procedure:
To the mixture of Pd(PPh3)Cl2 (24 mg, 0.034 mmol, 0.02 equiv.), CuI (13 mg, 0.068 mmol, 0.04 equiv.) and 3-bromobenzaldehyde (0.316 g, 1.7 mmol, 1 equiv.), pyrrolidine (10 mL) were added under N2. The use of pyrrolidine is preferred in the context of this synthesis. A stream of N2 was bubbled into to the solution for 5 min, and then 1-but-3-ynyl-piperidine (0.46 g, 3.3 mmol, 2 equiv.) was added. The reaction mixture was stirred at 50° C. for 40 h. This temperature is preferred in the context of this synthesis. On TLC and HPLC, the reaction was complete. The white precipitate (Et3N.HBr) was filtered and washed with EtOAc. The solvent was evaporated and the residue was re-dissolved in EtOAc. The organic layer was washed with aqueous NaOH (1N) twice, and dried over MgSO4. After filtration, the EtOAc solution was poured directly onto a short pad of silica gel (neutralized with 5% Et3N in hexanes) and washed with EtOAc. The solvent was evaporated to afford the product as a brown oil (0.35 g, 1.45 mmol, 86%); purity >95% on HPLC; MS M+H+242. This product does not need further purification in its use for subsequent steps in the context of this invention. A yield of 86% is in marked contrast with conventional methodologies, which produce the title compound with typical yields that do not exceed 30%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[CH:21](Br)([CH3:23])[CH3:22]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH:21]([CH3:23])[CH3:22])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)Br
Reactant: OC1(c2ccc(F)c(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC(O)(c2ccc(F)c(F)c2)C1
Temperature: 120 °C
Yield: 39.6 %

Procedure:
In a sealed tube a mixture of 3-(3,4-difluorophenyl)pyrrolidin-3-ol (0.192 g, 0.963 mmol), acetonitrile (3 mL), potassium carbonate (0.133 g, 0.963 mmol) and isopropylbromide (0.118 g, 0.963 mmol) was heated under microwave irradiation at 120° C. for 25 minutes. The mixture was filtrated and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 4:1 to 1:1) and by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 55:45) gave the title compound (0.092 g). The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 143-147° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 11), 226 (bp), 182 (46), 85 (53), 84 (31).
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:6][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)([CH3:1])[C:3]([NH:29][CH:27]([CH3:28])[CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=1)=[O:5]
Reactant: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)O
Reactant: Cc1ccc(CC(c2ccccc2)C(C)N)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(CC(c2ccccc2)C(C)NC(=O)C(C)(C)Oc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoic acid (Reference example 55, 250 mg, 1.04 mmol) and 4-(4-methylphenyl)-3-phenylbutan-2-amine (Reference example 102, 260 mg, 1.04 mmol, mixture of 4 isomers) in CH2Cl2 (5.5 mL) at RT was added diisopropylethylamine (272 μl, 1.56 mmol) followed by PyBOP (649 mg, 1.25 mmol) and the reaction mixture stirred overnight. The reaction was purified by loading the reaction mixture directly onto a silica gel column and eluting from 0-30% EtOAc/hexane to give the title compound as a mixture of 4 isomers. The diastereomers were separated by HPLC on a ZORBAX RxSi column eluting 97% hexane: 3% ethanol at 20 mL/min with retention times of:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10](O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:16])[C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([Cl:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: Cc1c(C(O)CC(C)C)oc2ccc(Cl)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(C(Cl)CC(C)C)oc2ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution (10 mL) of 1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutan-1-ol (650 mg) synthesized above in toluene was added thionyl chloride (225 μL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (668 mg, 96%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].Cl.[CH:28]1([CH:32]([NH2:35])[CH2:33][CH3:34])[CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:35][CH:32]([CH:28]2[CH2:31][CH2:30][CH2:29]2)[CH2:33][CH3:34])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Reactant: CCC(N)C1CCC1
Agent: Cl
Product: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-])C1CCC1
Yield: 72.6 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.50 g, 1.21 mmol), prepared substantially as described in Example 19a, and 1-cyclobutyl-propylamine HCl (0.36 g, 2.42 mmol) were treated substantially as described in Part C of Example 19a to produce 0.33 g (72%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-propyl)-amine: MS (AP) m/z 375.9 [(M+H)+, 25].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH2:16][CH2:17][NH2:18])[CH3:2].[OH-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH2:16][CH2:17][NH:18][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)Cc1c(CCN)[nH]c2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)Cc1c(CCNC(=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
61.7 g (0.223 mol) of the 2-aminoethyl-5-fluoro-indole-3-acetic acid ethyl ester produced in (d) are dissolved in 600 ml of methylene chloride and the solution is covered with a layer of 150 ml of 2 N sodium hydroxide solution. A solution of 43 g (0.245 mol) of benzoyl chloride is added, at 0°-5°, in the course of 21/2 hours, while stirring vigorously, and extraction by stirring is then carried out for a further hour. The methylene chloride phase is then separated off, washed with water, dried over MgSO4 and concentrated to dryness by evaporation. The residue crystallises on being taken up in ether, to form colourless crystals of 2-[(benzoyl-amino)-ethyl]-5-fluoro-indole-3-acetic acid ethyl ester.
Reaction SMILES: ClCCl.[NH:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[C:23](=[O:47])[N:24]([C:33]4[N:38]=[CH:37][C:36]([O:39][CH:40]5[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]5)=[CH:35][N:34]=4)[C:25]([CH3:32])=[N:26][C:27]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][CH:16]=2)=[N:7][N:6]=[N:5]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O>[NH:7]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[C:23](=[O:47])[N:24]([C:33]4[N:38]=[CH:37][C:36]([O:39][CH:40]5[CH2:41][CH2:42][C:43](=[O:46])[CH2:44][CH2:45]5)=[CH:35][N:34]=4)[C:25]([CH3:32])=[N:26][C:27]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][CH:16]=2)=[N:4][N:5]=[N:6]1
Reactant: CCCCc1nc(C)n(-c2ncc(OC3CCC(O)CC3)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCCc1nc(C)n(-c2ncc(OC3CCC(=O)CC3)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the dichloromethane (0.5 mL) solution of 5-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-6-butyl-3-[5-(4-hydroxycyclohexyloxy)pyrimidin-2-yl]-2-methylpyrimidin-4 (3H)-one (10 mg, 0.017 mmol), Dess-Martin reagent (11 mg, 0.026 mmol) was added and stirred at room temperature for 1 hr. Dess-Martin reagent (11 mg, 0.026 mmol) was added, and further stirred at room temperature overnight. The reaction mixture was added water and extracted with chloroform. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (chloroform:methanol=5:1) to obtain the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CO.CCOC(C)=O.[Pd]>[NH2:1][C:2]1[C:3]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(N)c1C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C(C(=O)OCC)c1ccc(N)c(N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 99.5 %

Procedure:
A mixture of diethyl [3-amino-2-(methoxycarbonyl)-4-nitrophenyl]malonate (4.80 g, 13.6 mmol), 10% Pd/C (0.72 g) in MeOH (70 mL) and EtOAc (70 mL) was stirred under H2 atmosphere (balloon) at room temperature for 21 h. The catalyst was removed by filtration through diatomaceous earth. The cake was washed with EtOAc and the filtrate was concentrated to give the title compound (4.39 g, 100% yield) as a brown solid.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.C(Cl)Cl>[C:1]1([C:11]([Cl:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2ccccc12
Reaction time: 24 h
Yield: 100.2 %

Procedure:
a mixture of 17.2 g (0.1 mole) 1-naphthoic acid, 14 g (0.11 moles) oxalyl chloride, 150 ml methylene chloride and three drops DMF (dimethylformamide) were stirred for about 24 hours. The clear reaction mixture was stripped to give about 19.1 g of the 1-naphthoyl chloride as a brown liquid which was used in step (b) without further isolation.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32](O)[CH:33]=[CH:34][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:35]=[C:34]([CH:33]=[CH:32][CH:31]=1)[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Oc1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cccc(Cl)c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3-chlorophenol (6.40 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.9 mg, 40.0% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.35–7.10 (m, 7H), 7.02 (t, 1H, J=8.0 Hz), 6.90 (d, 1H, J=7.6 Hz), 6.84–6.75 (m, 2H), 6.65 (m, 1H), 5.09 (apparent dd, 1H, J=4.99, 8.1 Hz), 3.10 (m, 2H), 2.60 (m, 2H), 2.50 (m, 2H), 2.30–1.70 (m, 8H), 1.18 (d, 6H, J=6.8 Hz); ESMS m/e: 491.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[NH:9][C:10]([C:12]3[N:13]([CH3:20])[CH:14]=[C:15]([N+:17]([O-])=O)[N:16]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[CH3:23][C:24]([O:27][C:28]([NH:30][C:31]1[CH:35]=[C:34]([C:36](ON2N=NC3C2=CC=CC=3)=[O:37])[N:33]([CH3:48])[CH:32]=1)=[O:29])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[NH:9][C:10]([C:12]3[N:13]([CH3:20])[CH:14]=[C:15]([NH:17][C:36]([C:34]4[N:33]([CH3:48])[CH:32]=[C:31]([NH:30][C:28]([O:27][C:24]([CH3:25])([CH3:23])[CH3:26])=[O:29])[CH:35]=4)=[O:37])[N:16]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)On1nnc2ccccc21
Reactant: COC(=O)c1ccc2[nH]c(-c3nc([N+](=O)[O-])cn3C)nc2c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(-c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)nc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
Pd/C (10 wt. %, 150 mg) was added to a solution of nitro-ester 21a (1.00 g, 3.32 mmol) in DMF (100 mL) and the mixture was hydrogenated at 450 psi for 2 h at ambient temperature. The reaction mixture was filtered through Celite to remove the catalyst and the filtrate was treated immediately with Boc-Py-OBt (27a, 1.42 g, 3.98 mmol) and DIEA (20 mL) and stirred at 60° C. for 18 h. The resulting yellow solution was poured into ice water and extracted with EtOAc. The organic phase was washed with 10% citric acid, brine, and saturated aqueous sodium bicarbonate and dried with MgSO4. Evaporation of the solvent yielded the crude product as a yellow foam which was purified by column chromatography on silica gel (n-hexane/EtOAc 1:2) to give the title compound as a beige solid (409 mg, 25%). 1H NMR (300 MHz, [D6] DMSO): δ=1.45 (s, 9H), 3.82 (s, 3H), 3.87 (s, 3H), 4.16 (s, 3H), 6.88 (s, 1H), 6.99 (s, 1H), 7.60-8.20 (m, 4H), 9.11 (s, 1H), 10.23 (s, 1H), 13.03 (br s, 1H); MS (ESI): m/z: 494 [M+H]+; HR-MS (FAB): calcd for C24H28N7O5: 494.2151; found: 494.2143 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH:5]([CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[C:6]#[N:7])(=[O:3])[CH3:2].[CH2:20](N(CC)CC)C>>[C:1]([O:4][C:5](=[C:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:20])[C:6]#[N:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C#N)C(Cl)c1ccc(CC(C)C)cc1
Reactant: CCN(CC)CC
Product: CC(=O)OC(C#N)=C(C)c1ccc(CC(C)C)cc1

Procedure:
Following generally the procedure of Example 1, 3-methyl-3-pentyl-glycidonitrile (II) is treated with propionoyl bromide (III) in the presence of a catalytic amount of triethylamine hydrobromide to form 2-propionoyloxy-3-bromo-3-methyl-3-pentylpropionitrile (IV). The propionitrile (IV) is treated with triethylamine to form the 2-propionoyloxy-3-methyl-3-pentylacrylonitrile (V) enolacylate. The enol-acylate (V) is treated with aqueous potassium hydroxide to form the potssium 2-methylheptanoate salt (VI). The reaction mixture is treated with potassium hypochlorite to destroy cyanide ion in the mixture. The potassium salt (VI) is removed from the reaction mixture and diluted with a Skellysolve B-water mixture and then treated with 12N sulfuric acid to form the 2-methylheptanoic acid. Such acid is useful for modifying starches. (U.S.S.R Patent 348,576; C.A., 78 31775 w.).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12]>C(OCC)(=O)C>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[N:3]=[CH:4][C:5]([C:6]([NH2:8])=[O:7])=[CH:9][CH:10]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCN1CCNCC1
Solvent: CCOC(C)=O
Product: CCN1CCN(c2ccc(C(N)=O)cn2)CC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of 6-chloronicotinamide and 3 ml of 1-ethylpiperazine was stirred at 110° C. for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford 0.10 g of the title compound.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[Br:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([F:12])[CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:5][C:6]1[CH:7]=[C:8]([O:13][CH2:1][CH2:2][CH3:3])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CCCI
Reactant: Oc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add propyl iodide (5.74 g, 33.77 mmol) to 3-bromo-5-fluoro-phenol (4.30 g, 22.51 mmol) and cesium carbonate (11.00 g, 33.77 mmol) in N,N-dimethylformamide (75 mL) and stir at room temperature 1 hour, then heat at 50° C. for 1 hour. Cool to room temperature and dilute with hexanes. Wash (water, 1N lithium chloride, saturated aqueous sodium chloride), dry (magnesium sulfate), filter and concentrate to give the desired compound as a colorless oil, 4.40 g (83.8%).
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[C:13]([CH3:16])[C:12]([F:17])=[C:11](F)[N:10]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:14]([F:15])=[C:13]([CH3:16])[C:12]([F:17])=[C:11]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:10]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1c(F)c(N)nc(F)c1F
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(N)c(F)c(C)c2F)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
To 3 ml of N-methylpyrrolidone were added 1.35 g of 2-amino-3,5,6-trifluoro-4-methylpyridine together with 3.0 g of p-methoxybenzylamine, and the mixture was stirred under nitrogen atmosphere at 140° C. for 18 hours and allowed to cool. After adding 30 ml of chloroform, the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography (silica gel, 20 g; eluent: chloroform:n-hexane, 1:1, and then, chloroform) to obtain 0.90 g of the title compound as a pale yellow crude oil.
Reaction SMILES: [F:1][C:2](=[C:11]([F:13])[F:12])[CH2:3][CH2:4][S:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[Cl:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:14][C:8]1[S:7][C:6]([S:5][CH2:4][CH2:3][C:2]([F:1])=[C:11]([F:12])[F:13])=[N:10][CH:9]=1
Reactant: FC(F)=C(F)CCSc1nccs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)=C(F)CCSc1ncc(Cl)s1

Procedure:
2-(3,4,4-Trifluoro-3-butenylthio)thiazole (6.75 g, 30 mM) is dissolved in carbon tetrachloride (60 ml). N-chlorosuccinimide (4.8 g) is added to the solution and refluxed for 18 hours by heating. As soon as the reaction has reached room temperature, the mixture is filtered and the solvent is distilled off. The concentrate is purified by column chromatography (eluent: hexane/ethyl acetate=90/10) to obtain 5-chloro-2-(3,4,4-trifluoro-3-butenylthio)thiazole as pale yellow liquid (n20D 1.5326).