Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]>[C].[Pd].CO>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)/C=C/c1cccc(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cccc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 46.8 %

Procedure:
Methyl (2E)-3-[3-(methylsulfonyl)phenyl]acrylate (600 mg), MeOH (6.ml) and then 10% palladium carbon (99.9 mg) were combined under N2 atmosphere. The reaction mixture was stirred at r.t. for 7 hours under H2 atmosphere (1 atm), and filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with n-hexane/AcOEt (1:1→1:2) as an eluent to give methyl 3-[3-(methylsulfonyl)phenyl]propanoate (283.3 mg) as colorless oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:42][CH3:43])[C:34]=2[C:38]([F:41])([F:40])[F:39])[C:29]=1[CH3:44]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:44][C:29]1[C:30]2[C:35](=[C:34]([C:38]([F:40])([F:41])[F:39])[C:33]([O:42][CH3:43])=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[F:27]
Reactant: COc1ccc2c(C)c(F)ccc2c1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(CBr)c(F)ccc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of N-bromosuccinimide (6.93 g, 1.1 eq), benzoyl peroxide (38 mg) and 2-fluoro-6-methoxy-1-methyl-5-(trifluoromethyl)naphthalene (9.14 g, 35.39 mmol) in carbontetrachloride (160 mL) was heated to reflux with stirring under a dry nitrogen atmosphere for 1.5 hours. The reaction mixture was cooled to room temperature and filtered. The solid was washed with carbon tetrachloride (3×30 mL). The solvent was removed from the combined CCl4 phases to provide the product as a white solid in quantitative yield. A small portion of this solid was recrystallized from hexane:ethylacetate, m.p. 97°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([S:8]([NH:11][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])(=[O:9])=[O:10])[CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1S(N)(=O)=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1S(=O)(=O)NC(=O)C(C)(C)C
Temperature: 50 °C
Yield: 49.2 %

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzenesulfonamide (0.050 g, 0.11 mmol) in acetonitrile (1.0 mL) was added 2,2-dimethyl-propionyl chloride (0.050 g, 0.47 mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene (0.25 mL, 1.64 mmol). The resulting reaction mixture was heated to 50° C. for 2 hours, concentrated in vacuo and purified by silica gel chromatography to give the title compound (0.030 g, LRMS: 554.4).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:25]#[N:26]>C1(C)C=CC=CC=1>[CH2:3]1[O:4][C:5]2([CH2:10][CH2:9][N:8]([C:22]3[CH:23]=[C:24]([C:25]#[N:26])[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:7][CH2:6]2)[O:1][CH2:2]1
Reactant: COc1ccc(C#N)cc1Br
Reactant: C1CC2(CCN1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C#N)cc1N1CCC2(CC1)OCCO2
Temperature: 100 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (1.47 g, 10.28 mmol), sodium bis(trimethylsilyl)amide (1 N in THF, 12 ml), and PdCl2(p(o-tolyl)3)2 [2 mol % catalyst prepared from bis(acetonitrile) Pd(II) chloride(53 mg, 0.206 mmol) and tri(o-tolyl)phosphine (125 mg, 0.52 mmol)] were added to a solution of 3-bromo-4-methoxybenzonitrile (1.82 g, 8.58 mmol) in toluene (40 ml). The reaction was stirred for 5 hours at 100° C. The reaction was concentrated in vacuo, diluted with water, and extracted with methylene chloride. The organic extract was concentrated in vacuo, and the residue purified by chromatography on silica gel using hexane/ethyl acetate (80/20) as the eluent to give 1-(5-cyano-2-methoxyphenyl)-4-piperidone ethylene ketal (900 mg, 38%). This ketal was dissolved in dioxane (15 ml) and HCl (6 N, 2.2 ml) and stirred at 100° C. for 2 h. The solution was cooled, quenched with saturated aqueous NaHCO3. The mixture was extracted with methylene chloride, concentrated in vacuo, and purified by chromatography on silica gel using hexane/ethyl acetate (80/20) as the eluent to give 1-(5-cyano-2-methoxyphenyl)-4-piperidone (125 mg, 19%).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([C:21]#[CH:22])[CH2:10][C:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]=1[Cl:20])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[I:23]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([Si:5]([O:8][CH:9](/[CH:21]=[CH:22]/[I:23])[CH2:10][C:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]=1[Cl:20])([CH3:6])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: C#CC(Cc1sc2ccccc2c1Cl)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(/C=C/I)Cc1sc2ccccc2c1Cl
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Cp2ZrHCl (628 mg, 2.5 mmol) was added to a solution of tert-butyl((1-(3-chlorobenzo[b]thiophen-2-yl)but-3-yn-2-yl)oxy)dimethylsilane (565 mg, 1.61 mmol) in CH2Cl2 (11 mL). The reaction was stirred for 1 h and then N-iodosuccinimide (585 mg, 2.6 mmol) was added. After 30 minutes, 30 mL saturated NaHCO3 solution was added and the resulting mixture was extracted with CH2Cl2 (3×30 mL). The combined organic solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (669 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:6]([OH:7])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:19][C:2]1([CH3:1])[CH:6]([O:7][C:27]([NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: O=C=Nc1ccccc1
Reactant: CCC1(COCc2ccccc2)CC(O)C(C)(C)O1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC1(COCc2ccccc2)CC(OC(=O)Nc2ccccc2)C(C)(C)O1
Yield: 100 %

Procedure:
The alcohol of Example 3 (1 g) was dissolved in benzene (15 ml) and phenylisocyanate (600 mg) and a few drops of triethylamine were added. The mixture was refluxed for 20 hours. The solvent was then evaporated and the residue was taken up in ethyl acetate, washed with dilute hydrochloric acid and then with brine, dried over magnesium sulphate and evaporated down. The residue was purified on a silica column using 5% acetone in petrol as eluant. 1.4 g, corresponding to a 100% yield, of the desired product, as a viscous oil, were obtained. NMR showed the presence of both geometric isomers.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:36]=[CH:35][C:18]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:23]([F:34])[CH:22]=3)=[CH:17][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:36]=[CH:35][C:18]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([F:34])[CH:22]=3)=[CH:17][CH:16]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(C(C)(C)C)cc3C(C)(C)C)cc2)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C(C)(C)C)n(Cc2ccc(CNc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of ethyl 3-[4-({4-[(3,5-di-tert-butyl-1H-pyrazol-1-yl)methyl]benzyl}amino)-2-fluorophenyl]propanoate (0.96 g, 1.9 mmol) in a mixture of methanol (8 mL) and tetrahydrofuran (8 mL) was added 1 M aqueous sodium hydroxide solution (4.0 mL), and the mixture was stirred at 60° C. for 2 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60% ethyl acetate/hexane), and recrystallized from ethyl acetate-hexane to give the title compound (0.77 g, yield 89%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[O:10]=[P:11](Cl)([Cl:13])[Cl:12]>CCOCC>[P:11]([Cl:13])([Cl:12])([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:10]
Reactant: COc1ccc(O)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(OP(=O)(Cl)Cl)cc1

Procedure:
p-methoxyphenyl dichlorophosphate (11d) was prepared as described in Example 2 from p-methoxyphenol (4.00 g, 0.032 mol), POCl3 (3.00 mL, 0.032 mol) and TEA (4.49 mL, 0.032 mol) and dry Et2O (25 mL). The dichlorophosphate 11d was obtained as a yellow clear oil (5.1 g, 0.021 mol, 67%) and used without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.C(#N)C.[F:27][C:28]([F:33])([F:32])[C@@H:29]1[CH2:31][O:30]1>O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][N:11]([CH2:31][C@H:29]([OH:30])[C:28]([F:33])([F:32])[F:27])[CH2:12][CH2:13][O:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1cccc(C2CNCCO2)c1
Reactant: FC(F)(F)[C@@H]1CO1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O[C@@H](CN1CCOC(c2cccc(Cl)c2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.4 %

Procedure:
In a 50 mL round-bottomed flask, 2-(3-chlorophenyl)morpholine hydrochloride (OChem., Lot #100301A1, 200 mg, 854 μmol) and DIEA (265 mg, 358 μl, 2.05 mmol) were combined with acetonitrile (2.5 ml) to give an off-white suspension. (S)-2-(trifluoromethyl)oxirane (287 mg, 2.56 mmol) was added. The reaction mixture was stirred at room temperature for 48 h. The reaction was complete by LCMS (MH+=310). The reaction mixture was poured into 50 mL H2O and extracted with diethyl ether/dichloromethane 10:1 (3×50 mL). The organic layers were combined, washed with saturated NaCl (1×50 mL), dried over MgSO4 and concentrated in vacuo to afford 218 mg (82% yield) of (2S)-3-(2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol as an amber oil. (MH+=310).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:14])[CH2:9][CH2:8]3.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:22]=1[C:23]([NH:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:14])[CH2:9][CH2:8]3)=[O:24]
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CC1CCC2O1
Product: O=C(Nc1sc2c(c1C(=O)c1ccco1)CC1CCC2O1)c1c(F)cccc1C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 15A and commercially available 2-fluoro-6-trifluoromethyl-benzoyl chloride according to the procedure described for Example 1C. 1H NMR (CDCl3, 300 MHz) δ 1.63-1.71 (m, 1H), 2.13-2.17 m, 4H), 3.26 (dd, J=16.3, 5.1 Hz, 1H), 4.71 (dd, J=4.9, 4.9 Hz, 1H), 5.14-5.15 (m, 1H), 6.58-6.60 (m, 1H), 7.16-7.17 (m, 1H), 7.35-7.41 (m, 1H), 7.55-7.64 (m, 3H), 11.13 (br s, 1H); MS (ESI+) m/z 466 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][N:30]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][C:32]([NH2:39])=[N:31]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:28])[F:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:32]2[CH:33]=[C:34]([C:35]([F:36])([F:37])[F:38])[N:30]([CH3:29])[N:31]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1nc(N)cc1C(F)(F)F
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(F)(F)F)cc1=O
Product: Cn1nc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(F)(F)F)cc2=O)cc1C(F)(F)F
Yield: 10 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 21) and 1-methyl-5-trifluoromethyl-1H-pyrazol-3-ylamine (Intermediate 9) afforded 3-cyclopentyl-N-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a yellow solid (35.3 mg, 10%); ES+-HRMS m/e calcd for C24H23N5O3F6 [M+Na+] 566.1597 found 566.1596. 1H-NMR (400 MHz, CDCl3) δ ppm 1.08-1.24 (m, 2H), 1.44-1.84 (m, 7H), 2.24 (t, J=7.5 Hz, 2H), 3.85 (s, 3H), 5.56 (t, J=7.5 Hz, 1H), 5.98 (d, J=3.0 Hz, 1H), 7.06 (s, 1H), 7.21 (d, J=7.9 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.94 (d, J=3.0 Hz, 1H), 8.79 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:9])=[CH:6][CH:5]=1)([O-])=O>[Pt].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:9])=[CH:29][CH:30]=1
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc(N)cc1
Yield: 84 %

Procedure:
Under a nitrogen purge, 10% platinum on carbon (2.0 grams) was added to a mixture of octadecyl 4-nitrobenzoate (23 grams, 55 mmol) and ethyl acetate (230 milliliters) in a Parr vessel. The vessel was placed under hydrogen pressure (49 psi, 3.3×105 Pa) for sixteen hours. Added chloroform and filtered the reaction mixture through a layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to light tan solid. The solid was recrystallized from ethanol to obtain 18 grams of octadecyl 4-aminobenzoate as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>>[C:31]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)(=[O:34])[CH2:32][CH3:33]
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Reactant: CCC(=O)Cl
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A178) and propionyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][N:6]1[C:5]2[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11]
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A solution of Compound 11 (5 g, 28 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.24 g, 31 mmol) in DMF and further stirred at room temperature for 1 h. Then, methyl iodide (1.92 mL, 31 mmol) was added and further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 4.9 g (74%) of white solids. M.P. 153° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 3.52 (s, 3H), 7.38 (d, J=8.6 Hz, 1H), 7.54 (dd, J=1.7, 8.2 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH3:19])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][CH2:15][CH2:16]C)=[CH:8][C:7]=1[CH3:18])=[O:4].Cl>>[NH2:1][CH:2]([CH3:19])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][CH2:15][CH3:16])=[CH:8][C:7]=1[CH3:18])=[O:4]
Reactant: CCCCOc1cc(C)c(NC(=O)C(C)N)c(C)c1
Agent: Cl
Product: CCCOc1cc(C)c(NC(=O)C(C)N)c(C)c1

Procedure:
This compound was prepared in the same manner as 2-amino-4'-butoxy-2',6'-dimethylpropionanilide of Example 9D. The yield of crude base was 94% which was converted to the hydrochloride and recrystallized from absolute alcohol-ether; m.p. 226°-227° C. Calcd. for C14H23ClN2O2 : C 58.6, H 8.08, O 11.2. Found: C 58.8, H 8.08, O 11.2.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:30]=[CH:29][C:11]2[C:12]([CH2:15][O:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[C:20]([C:26]([OH:28])=O)[NH:21]4)=[CH:13][O:14][C:10]=2[CH:9]=1)([CH3:3])[CH3:2].[NH2:31][CH:32]1[CH2:37][CH2:36][C:35]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][C@H:44]([OH:47])[C@@H:43]([CH3:48])[CH2:42]2)([OH:38])[CH2:34][CH2:33]1>>[OH:38][C:35]1([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][C@H:44]([OH:47])[C@@H:43]([CH3:48])[CH2:42]2)[CH2:36][CH2:37][CH:32]([NH:31][C:26]([C:20]2[NH:21][C:22]3[C:18]([CH:19]=2)=[C:17]([O:16][CH2:15][C:12]2[C:11]4[CH:29]=[CH:30][C:8]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:2])[CH3:3])=[CH:9][C:10]=4[O:14][CH:13]=2)[CH:25]=[CH:24][CH:23]=3)=[O:28])[CH2:33][CH2:34]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: CC(C)OCCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Product: CC(C)OCCOc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[6-(2-Isopropoxy-ethoxy)-benzofuran-3-ylmethoxy]-1H-indole-2-carboxylic acid 30e and amine 14.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.CN(C)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:14]([O:9][C:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(=O)c(O)co1
Agent: CN(C)C
Solvent: C1CCOC1
Product: Cc1cc(=O)c(OC(=O)c2ccccc2)co1
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
Allomaltol (600 mg; 4.76 mmol) was weighed out into a round bottom flask (100 ml) containing a stir-bar. The contents were diluted with anhydrous THF (˜20 ml) and stirred (˜5 min) to afford a solution. Next, trimethyl amine (833 μl; 6.33 mmol; 1.33 equiv.) was added drop-wise and the contents stirred (˜5 min). Benzoyl chloride (517 μl; 627 mg; 4.46 mmol) was then added drop-wise, capped and stirred at room temperature. The reaction was monitored via silica gel TLC. Once complete, the reaction mixture was concentrated under reduced pressure and the contents purified by silica gel chromatography to afford 930 mg of light yellow crystalline product (4.04 mmol; 91% yield). This compound was found to have an EC50 of >1 mM. 1H NMR (DMSO-d6) δ 8.58 (s, 1H; 2-H); 8.09-8.07 (dd, 2H); 7.78-7.76 (t, 1H); 7.63-7.59 (t, 2H); 6.43 (s, 1H; 5-H); 2.34 (s, −3H; 6-CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[C:5]2[C:14]([F:17])([F:16])[F:15].N1C=CC=CC=1.[CH3:24][C:25]1[CH:35]=[CH:34][C:28]([CH2:29][CH2:30][N:31]=[C:32]=[S:33])=[CH:27][CH:26]=1>CN1C(=O)CCC1>[CH3:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:32]([NH:31][CH2:30][CH2:29][C:28]3[CH:27]=[CH:26][C:25]([CH3:24])=[CH:35][CH:34]=3)=[S:33])=[CH:11][CH:10]=2)[C:5]([C:14]([F:17])([F:15])[F:16])=[CH:6][C:7]1=[O:13]
Reactant: Cn1c(=O)cc(C(F)(F)F)c2cc(N)ccc21
Reactant: Cc1ccc(CCN=C=S)cc1
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(CCNC(=S)Nc2ccc3c(c2)c(C(F)(F)F)cc(=O)n3C)cc1
Reaction time: 168 h
Yield: 20 %

Procedure:
6-Amino-1-methyl-4-trifluoromethyl-1H-quinolin-2-one (Preparation 1, 200 μL of a 0.2 M solution in NMP, 40 μmol) was treated with pyridine (20 μL of a 0.2 M solution in NMP, 4 μmol) & 4-methylphenethyl isothiocyanate (240 μL of a 0.2 M solution in NMP, 48 μmol). After 7 d, the mixture was concentrated, then the residue was washed with MeCN (2×150 μL) to give the title compound (3.3 mg, 20%): RT=1.87 min; m/z (ES+)=420.2 [M+H]+.
Reaction SMILES: CN(C)C(=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].[CH2:32]([CH:35]1[CH2:40][CH2:39][CH:38]([CH:41]=[CH2:42])[CH2:37][CH2:36]1)[CH2:33][CH3:34]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([CH:42]=[CH:41][CH:38]3[CH2:39][CH2:40][CH:35]([CH2:32][CH2:33][CH3:34])[CH2:36][CH2:37]3)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18]
Reactant: C=CC1CCC(CCC)CC1
Reactant: COC(=O)C1CCC(c2ccc(Br)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCC1CCC(C=Cc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Yield: 59.7 %

Procedure:
180 mL of N,N-dimethylacetamide (DMA) solution including 12.8 g (60.1 mmol) of potassium phosphate, 14.3 g (48 mmol) of 4-(4-bromophenyl)cyclohexanecarboxylic acid methyl ester produced in Example 1-1, and 6.09 g (40 mmol) of 1-propyl-4-vinylcyclohexane was poured to flask filled with Argon gas. Then, 0.17 g (catalytic amount) of palladium acetate was added to the flask and reacted in oil bath at 120° C. for 32 hours. After reaction, 100 mL of distilled water was added to the reaction mixture, extracted by ethyl acetate, and then the aqueous layer was extracted by chloroform. The organic layer was dried by Na2SO4, concentrated under reduced pressure, and then recrystallized from ethanol to obtain 8.8 g (60%) of 4-{4-[2-(4-propyl-cyclohexyl)-ethenyl]-phenyl}cyclohexane carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH:7]=[C:8]1[C:20](=[O:21])[N:12]2[C:13]3[C:18]([CH:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[CH:15][CH:14]=3.C([O-])=O.[NH4+].C(O)C.O1CCCC1>[Pd].O>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH:8]1[C:20](=[O:21])[N:12]2[C:13]3[C:18]([CH:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: Cc1[nH]cnc1C=C1CCc2cc3ccccc3n2C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1[nH]cnc1CC1CCc2cc3ccccc3n2C1=O
Temperature: 60 °C
Yield: 89.7 %

Procedure:
To a mixture of 8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (10.9 g), ammonium formate (17.2 g), ethanol (130 ml), and tetrahydrofuran (110 ml) was added a suspension of 10% palladium on carbon (3.3 g) in water (30 ml). The mixture was heated at 60° C. for 2 hours and then cooled. After filtration of the catalyst, the filtrate was evaporated in vacuo. The residue was dissolved in 10% methanol-chloroform. The organic layer was washed successively with aqueous sodium bicarbonate solution, water, and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The crystalline residue was recrystallized from chloroform-hexane to give 8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (9.85 g).