Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1.NCC[NH:25][C:26](=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>CN1CCCC1>[CH3:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[C:10]1[C:9]([CH3:20])=[N:8][N:7]2[C:2]([NH:25][C:26](=[O:36])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[CH:3][C:4]([CH3:21])=[N:5][C:6]=12
Reactant: COc1ccc(CC(=O)NCCN)cc1
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)cc(C)nc23)c(C)c1
Agent: CN1CCCC1
Product: COc1ccc(CC(=O)Nc2cc(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn23)cc1
Temperature: 80 °C
Yield: 80.6 %

Procedure:
Dissolve 7-chloro-2,5-dimethyl-3-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidine (0.26 g, 8.69×10−4 mol) in 2 mL N-methylpyrrolidine, and add N-(2-aminoethyl)-2-(4-methoxyphenyl)acetamide (0.75 g, 3.6 mmol). Heat to 80° C. overnight under N2. Partition between EtOAc (50 mL) and H2O (50 mL), then separate layers and wash EtOAC layer successively with 0.1 N NaOH (25 mL), H2O (25 mL), and brine. Pool aqueous layers and extract with EtOAc (25 mL). Pool EtOAc layers, dry over Na2SO4, filter and concentrate to yellow oil. Chromatograph on silica gel eluting with EtOAc and evaporate to obtain 0.30 g of N-(3-(2,4,6-trimethylphenyl)-2,5-dirnethyl-pyrazolo[1,5-a]pyrimidin-7yl)-2-(4-methoxyphenyl)acetamide as a clear pale yellow oil. LCMS=472.3 (MH+); 470.2 (M−). 1H-NMR (CDCl3): 7.10 (d, 2H, J=10.2 Hz); 6.39 (s, 2H); 6.81 (d, 2H, J=10.2 Hz); 6.46 (t, 1H, J=6.0 Hz); 6.16 (t, 1H, J=6.0 Hz); 5.79 (s, 1H); 3.76 (s, 3H); 3.45-3.50 (m, 6H); 2.38 (s, 3H); 2.30 (s, 3H); 2.20 (s, 3H); 2.02 (s, 6H).
Reaction SMILES: C[O:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>C(Cl)Cl>[OH:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2ccoc12
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Oc1cccc2ccoc12
Temperature: 220 °C
Yield: 50 %

Procedure:
A mixture of 7methoxybenzofuran (1.8 g.) and pyridine hydrochloride (4.6 g.) was heated at 220° C. for 21/2 hours. The reaction was cooled and diluted with methylene chloride. The solution was washed with 5% aqueous hydrochloric acid (six times); dried (MgSO4) and concentrated to an oil, 0.8 g. (50% yield).
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH2:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl.C(OCC)(=O)C>[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[O:13])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(NC(=N)N)sc1C(=O)O
Reactant: CC(C)(C)OC(=O)COc1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc(NC(=N)N)sc1C(=O)Nc1cccc(OCC(=O)OC(C)(C)C)c1

Procedure:
2-Guanidino-4-methyl-thiazole-5-carboxylic acid is reacted with tert-butyl (3-amino-phenoxy)-acetate in the same manner as in Example 3. Chromatography on silica gel with methylene chloride-ethyl acetate and methylene chloride-alcohol gives 176 mg of tert-butyl {3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy}-acetate, m.p. 204° C., MS: 406 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([OH:14])=[N:12][S:11][N:10]=1.N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].O>CCOCC>[C:21]([O:14][C:13]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:10][S:11][N:12]=1)(=[O:23])[CH3:22]
Reactant: Oc1nsnc1-c1c(Cl)cccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)Oc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
In ether, 0.5 g of 3-(2,6-dichlorophenyl)-4-hydroxy-1,2,5-thiadiazole and 0.18 g of pyridine were dissolved and 0.23 g of acetic anhydride was added thereto. The mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with ether. The ether layer was washed twice with aqueous dilute sodium hydroxide solution, twice with water and twice with aqueous saturated sodium chloride solution. The resultant was dried over anhydrous sodium sulfate and concentrated, followed by silica gel column chromatography to obtain 0.41 g of 4-(2,6-dichlorophenyl)-1,2,5-thiadiazol-3-yl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[C:9]([CH3:17])[C:8]=2[CH3:18])=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1.[CH3:24][C:25]([CH3:27])=O.CC(C)([O-])C.[K+]>CS(C)=O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:17][C:9]1[C:8]([CH3:18])=[C:7]([O:6][C:5]2[C:4]([N+:21]([O-:23])=[O:22])=[C:3]3[C:2](=[CH:20][CH:19]=2)[NH:1][C:25]([CH3:27])=[CH:24]3)[CH:12]=[CH:11][C:10]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: Cc1c(CC(=O)O)ccc(Oc2ccc(N)cc2[N+](=O)[O-])c1C
Reactant: CC(C)=O
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c([N+](=O)[O-])c(Oc3ccc(CC(=O)O)c(C)c3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under an N2 atmosphere, 2-(4-(4-amino-2-nitrophenoxy)-2,3-dimethylphenyl)acetic acid (0.723 g, 2.29 mmol) was dissolved in DMSO (18 mL) and acetone (0.503 mL, 6.86 mmol) was added. The reaction was treated with potassium tert-butoxide (0.770 g, 6.86 mmol) and allowed to stir at room temperature for 1.5 h. The reaction was diluted with water and citric acid was added to pH 4. The mixture was extracted with ethyl acetate. The aqueous layer was washed with additional ethyl acetate. The organics were combined, dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the residue, eluting with 0% to 9% methanol in dichloromethane, afforded the title compound. LC-MS ESI (neg.) m/z: 353.2 (M−H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][N:8]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[CH:6]=1>CO>[NH:11]1[C:10]2=[CH:9][N:8]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:5]2[CH:4]=[CH:3]1
Reactant: COC(=O)c1cc(/C=C/N(C)C)c([N+](=O)[O-])cn1
Solvent: CO
Product: COC(=O)c1cc2cc[nH]c2cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
To a 500 mL Parr bottle was added methyl 4-[(E)-2-(dimethylamino)vinyl]-5-nitropyridine-2-carboxylate (18.9 g, 75.2 mmol) and anhydrous methanol (200 mL). The mixture was purged with nitrogen gas for 10 min. To this suspension was added Pd(10%)/C (1.90 g, 10 w/w %), and the suspension was degassed for 5 more minutes. The hydrogenation began with 43 psi H2 without heating. The reaction became exothermic as indicated by the rising temperature (about 2-3° C. per min) inside the Parr bottle (monitored by a thermal coupling thermometer). As the temperature inside of the reaction reached 45° C., the hydrogen gas flow into the Parr bottle was stopped, and the mixture was allowed to cool down to 25° C. for 30 min. The color of the liquid of the suspension changed from purple red to light green and then colorless in the first hour of the reduction, and about 30 psi H2 was consumed. The hydrogen pressure was brought to 50 psi, and the hydrogenation was continued at 50° C. for 20 h. There was no more hydrogen gas consumed in the last 20 h. After cooling the reaction mixture to 20° C., the solid mixture, which contained Pd(10%)/C and product, was filtered. The solid mixture was suspended in DMSO (200 mL), and the suspension was heated on a hot plate to 80° C. internal temperature with stirring for 10 min. The hot suspension was filtered and the Pd(10%)/C solid was washed with a small portion of DMSO (50 mL). The DMSO filtrate and washing were combined and poured into water (600 mL). Off white solid product precipitated out, and the suspension was stirred for 1 h before filtering, and lyophilizing. The title compound was obtained as an off-white solid product was obtained (11.3 g, >95% pure, 86% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.84 (s, 3H) 6.68 (d, J=2.8 Hz, 1H) 7.73 (d, J=3.0 Hz, 1H) 8.36 (s, 1H) 8.80 (s, 1H) 11.99 (s, 1H). LCMS: (APCI, M-H—)=175
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[OH-].[Na+].O.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>CO>[CH3:8][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[N:1][C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:19][CH:18]=1)=[O:22]
Reactant: CN1CCCCC1=N
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCCCC1=NC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.60 g.; 0.068 mole) is converted to free base by adding 7 ml. of NaOH (50%) to an aqueous slurry (using a minimal amount of water) of the salt and then extracting with benzene. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth. A benzene solution of 12.73 g. (0.068 mole) of p-trifluoromethylphenylisocyanate [prepared according to Inukai and Maki, Kogyo Kagaku Zasshi, 67 (5) 807-9 (1964] is added to the above solution slowly. After 4 hours of stirring at room temperature, the benzene is evaporated in vacuo to give a solid residue. Repeated recrystallizatons of the solid from methanol yields the pure product, 1-(1-methyl-2-piperidylidene)-3-(4-trifluoromethylphenyl)urea, m.p. = 154°-155° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[CH3:14][N:15]1CCCC1=O.O>[C-]#N.[Zn+2].[C-]#N.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>[CH2:11]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[N:15])=[CH:3][CH:4]=1)[CH2:12][CH3:13]
Reactant: CCCOCCc1ccc(Br)cc1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOCCc1ccc(C#N)cc1
Temperature: 125 °C
Reaction time: 4 h
Yield: 19 %

Procedure:
1-Bromo-4-(2-propoxy-ethyl)-benzene described in Preparation Example 195 (790 mg, 3.2 mmol), zinc cyanide (380 mg, 3.2 mmol) and tetrakis(triphenylphosphine)palladium (190 mg, 0.16 mmol) were added to N-methylpyrrolidinone (10 mL), and this mixture was stirred at 125° C. for 4 hours. This reaction mixture was allowed to cool, and water (50 mL) and ethyl acetate (50 mL) were added thereto. This mixture solution was filtered through Celite pad. The organic layer was separated, then, washed with water (3 times) and brine, and then, concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=8:1), and the title compound (120 mg, 0.62 mmol, 19%) was obtained as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)=[O:2].[CH2:21](O)[CH2:22][OH:23]>C1(C)C=CC=CC=1>[O:2]1[CH2:21][CH2:22][O:23][CH:1]1[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=Cc1cccc(C=O)c1)C(=O)OCC
Reactant: OCCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1cccc(C2OCCO2)c1)C(=O)OCC
Temperature: 25 °C

Procedure:
The solution of product 32 in toluene, from the previous reaction, is filtered, transferred to a round bottom flask, and ethylene glycol (2.4 eq) is added, followed by p-toulenesulfonic acid (0.5 eq). The reaction mixture is refluxed overnight with a Dean-Stark trap, then cooled down to room temperature, washed with sat. aq NaHCO3, brine, and dried (Na2SO4). Product 33 is not purified further but used as is in the following step.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].B(F)(F)F.C(OCC)C.C([SiH](CC)CC)C>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)OCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 85 °C
Yield: 65 %

Procedure:
A mixture of 4-(5-bromo-2-chlorobenzoyl)phenethyl acetate (intermediate BF) (1 g, 2.62 mmol), borontrifluoride diethylether (0.65 mL, 10.4 mmol) and triethylsilane (0.84 mL, 10.4 mmol) was heated at 85° C. for 2 h in a sealed tube. The reaction vessel was cooled to room temperature and ice-water (50 mL) was added. The product was extracted with ethyl acetate (2×25 mL), washed with brine (25 mL), dried (Na2SO4), filtered and evaporated. Purification on silica gel using an ISCO column with 5% ethyl acetate in hexane gave intermediate BG (620 mg, yield 65%). 1H NMR (300 MHz, CDCl3): δ 7.27-7.10 (m, 7H), 4.27 (t, J=6.9, 7.2 Hz, 2H), 4.03 (s, 2H), 2.92 (t, J=6.9, 7.2 Hz, 2H), 2.05 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO>[CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nccn1-c1ccc(CO)cc1
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a stirred solution of the crude 4-(2-methylimidazol-1-yl)benzaldehyde (1.0 g) in methanol(15 ml) cooled to 0° C. was added NaBH4 (0.2 g, 5.2 mmol) in portions over 15 min and the whole stirred for 1 h. A saturated aqueous NH4Cl solution (50 ml) was added to the reaction mixture and the whole extracted with ethyl acetate (100 ml×2). The organic layer was washed with water (100 ml), brine (50 ml), dried over MgSO4, and solvent removed under reduced pressure. The crude product was washed with an Et2O/ethyl acetate mixture (3:1, 15 ml) to give the title compound (0.51 g, 50 %) as a white powder. 1H NMR (CDCl3) δ: 7.5 (d, 2H, J=8 Hz), 7.28 (d, 2H, J=8 Hz), 7.01 (d, 1H, J=1 Hz), 6.99 (d, 1H, J=1 Hz), 4.78 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:31].CCOCC>O1CCOCC1>[ClH:31].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2nc3ccccc3[nH]2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1ccc2[nH]c(Oc3ccc(OC[C@H]4CCCN4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 3 (21 mg, 0.05 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stirred at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. The resulting solid was filtered out and dried in vacuo to yield the title product (15 mg, 90%); LCMS); 87%, ESI+, Calcd. 309.4. Found m/z 310.5 (M+1). 1H NMR (400 MHz, DMSO-d6); δ 1.66-1.79 (m, 1H), 1.84-2.05 (m, 2H), 2.05-2.18 (m, 1H), 3.17-3.28 (m, 2H), 3.97-4.07 (m, 1H), 4.11-4.18 (m, 1H), 4.29 (dd, J1=10.4 Hz, J2=3.2 Hz, 1H), 6.69-6.73 (m, 1H), 6.80-6.83 (m, 1H), 7.06-7.11 (m, 3H), 7.33-7.38 (m, 3H):
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:33])[O:23][CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=1.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:22]([O:23][CH2:24][C:25]2[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=2)=[O:33])[CH2:14][CH2:15]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A mixture comprising of tert-butyl(2-(piperidin-4-yl)ethyl)carbamate (1.85 g, 8.10 mmol) in DCM (80 ml), sat. aqueous sodium bicarbonate solution (20 ml, 8.10 mmol) and 3,5-dichlorobenzyl carbonochloridate (prepared according to Bioorganic & Medicinal Chemistry Letters, 21(21), 6608-6612; 2011, Intermediate 33) (1.940 g, 8.10 mmol) was stirred at room temperature for 3 hours. The resulting mixture was treated with 2M NaOH soln. (50 ml). The organics were separated, dried (MgSO4) and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH3:31])[C:21]=1[N:22]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[N:23]1)[O:5][C@H:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].Cl.[NH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH3:31])[C:21]=1[N:22]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[N:23]1)[O:5][C@H:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:16])=[CH:17][CH:18]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCOC(=O)CCN
Reactant: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 1 h
Yield: 94.3 %

Procedure:
N,N-dimethylformamide (17.6 mL) was added to a vial containing (S)-4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoic acid (6.1 g, 14.1 mmol), ethyl 3-aminopropanoate hydrochloride (4.33 g, 28.2 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (10.7 g, 28.2 mmol). Diisopropylethylamine (12.3 mL, 70.5 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) afforded (S)-ethyl 3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoate (7.07 g, 94% yield) as a colorless gum. 1H NMR (400 MHz, CDCl3, δ): 7.87 (s, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J=8.2 Hz, 2H), 6.84 (d, J=5.9 Hz, 1H), 6.57 (s, 2H), 5.15 (dd, J=7.8, 5.1 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.71 (q, J=6.0 Hz, 2H), 2.63 (t, J=5.7 Hz, 2H), 2.04-1.91 (m, 1H), 1.88 (s, 6H), 1.86-1.71 (m, 1H), 1.58-1.33 (m, 2H), 1.26 (t, J=7.0 Hz, 3H), 0.96 (t, J=7.4 Hz, 3H). MS (M+1): 532.
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH3:6][C:7](=[CH2:15])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].ICI.[Cl-].[NH4+]>CCCCCC>[CH3:15][C:7]1([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][CH2:6]1
Reactant: C=C(C)CCC(=O)OCC
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: CCCCCC
Product: CCOC(=O)CCC1(C)CC1
Temperature: 25 °C

Procedure:
Diethylzinc (40 ml. 1.1M solution in toluene) was added dropwise to a solution of ethyl 4-methylpent-4-enoate (1.25 g.) in dry hexane (100 ml.) at -20° under nitrogen After stirring for 10 minutes diiodomethane (23.6 g.) was added dropwise and the mixture maintained at -20° for 6 hours. The mixture was allowed to warm to room temperature, aqueous ammonium chloride solution (60 ml.) added and the two layers separated. The aqueous layer was extracted with diethyl ether (3×50 ml.) and the combined organic extracts washed with sodium thiosulphate solution (50 ml.) and water (50 ml.). The extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. Chromatography on silica, eluting with diethyl ether/hexane mixtures, gave ethyl 3-(1-methylcyclopropyl)propanoate as a colourless oil (1.21 g.).
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:14][C:4]=1[O:5][CH2:6][CH:7]1[CH2:11][O:10]C(C)(C)[O:8]1)[CH3:2].Cl>O1CCCC1>[CH2:1]([C:3]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:14][C:4]=1[O:5][CH2:6][CH:7]([OH:8])[CH2:11][OH:10])[CH3:2]
Reactant: CCCCCCCCCCCCCCc1ccc(CC)c(OCC2COC(C)(C)O2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc(CC)c(OCC(O)CO)c1

Procedure:
A mixture of 14.2 g of 4-[(2-ethyl-5-tetradecylphenoxy)methyl]-2,2-dimethyl-1,3-dioxolane, 50 ml of 5% hydrochloric acid and 100 ml of tetrahydrofuran was heated at reflux for 8 hours, then allowed to cool and the tetrahydrofuran removed under reduced pressure. Ethyl acetate was added, the mixture washed with water, dried and the solvents removed. The residue was chromatographed on silica gel, eluting impurites with hexane:ethyl acetate (16:1) and then (4:1) to elute the desired compound, giving 11 g, 55.5°-56.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]=[N+]=[N-])[CH:7]=1)[CH3:2]>CCO>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][NH2:24])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN=[N+]=[N-])c1
Solvent: CCO
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[3-(2-Azidomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.187 g, 0.49 mmol) was dissolved in EtOH (6 mL), and the solution was purged with H2 under an H2 balloon. Palladium on carbon (10%; 0.038 mg) was added, and the mixture was purged again with H2. The reaction was sealed and stirred at room temperature overnight. Analytical LCMS indicated that starting material was still present, so additional palladium on carbon (10%; 0.038 g) was added, and the mixture was stirred under 65 psi of H2 using a Parr apparatus. After 6 hours, no starting material was seen by analytical LCMS, so the mixture was filtered through a pad of Celite, and the filter cake was washed with EtOH. The filtrate was concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7]CC)=O.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:27])=[C:18]([C:20]2[S:21][C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=2)[CH:19]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:27][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:5](=[O:7])[CH2:4][C:3](=[O:10])[C:2]([F:1])([F:11])[F:12])=[CH:19][C:18]=1[C:20]1[S:21][C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=1
Reactant: Cc1nc(-c2cc(N)ccc2Cl)sc1C
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cc(NC(=O)CC(=O)C(F)(F)F)ccc2Cl)sc1C
Temperature: 110 °C
Yield: 109.4 %

Procedure:
Ethyl trifluoroacetoacetate (2.54 g) is added to a solution of 2-(5-amino-2-chlorophenyl)-4,5-dimethyl-1,3-thiazole (2.20 g) in 110 ml of toluene; a catalytic amount of 4-dimethylaminopyridine is added, then the mixture is heated to 110° C. while distilling off the solvent. When reaction is complete, the residue is concentrated under vacuum; 3.80 g of product are obtained.