Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[NH:5][S:6]([C:9]1[CH:24]=[CH:23][C:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][C:11]=2[CH:10]=1)(=[O:8])=[O:7])C.[CH3:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>>[CH3:20][N:19]([CH3:21])[C:18]([N:15]1[CH2:14][CH2:13][C:12]2[CH:23]=[CH:24][C:9]([S:6]([NH:5][C:4]([NH:33][C@H:30]3[CH2:31][CH2:32][C@H:27]([CH3:26])[CH2:28][CH2:29]3)=[O:3])(=[O:8])=[O:7])=[CH:10][C:11]=2[CH2:17][CH2:16]1)=[O:22]
Reactant: CCOC(=O)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N(C)C)CC2
Reactant: C[C@H]1CC[C@H](N)CC1
Product: CN(C)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)N[C@H]3CC[C@H](C)CC3)cc2CC1

Procedure:
By the reaction of [(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]carbamic acid ethyl ester with trans-4-methylcyclohexylamine in a manner analogous to that described in Example 12, there is obtained 1-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]-3-(trans-4-methylcyclohexyl)urea.
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13](O)(=O)C>>[CH3:13][C:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)O
Reactant: CC(=O)O
Product: CCCCCCCCCC(C)=O

Procedure:
The cross ketonization reaction with the triacylglycerol from Cuphea sp. and acetic acid is demonstrated. The seed oil from Cuphea sp. contains up to 71% decanoic acid and the reaction of this with acetic acid yields the fragrance compound 2-undecanone. Several ketonization catalysts from the literature including CeO2, CeO/Al2O3, CeO/ZrO2, MnOx/Al2O3 were screened and compared with a coprecipitated mixed metal oxide of empirical formula Fe0.5Ce0.2Al0.3Ox (also represented as 50Fe20Ce30AlOx). Each of these catalysts effected the conversion but the highest yield was found with Fe0.5Ce0.2Al0.3Ox. In a flow reactor, Fe0.5Ce0.2Al0.3Ox gave 2-undecanone at 91% theoretical yield with reaction conditions of 400° C., weight hourly space velocity of 2, molar ratio of acetic acid to Cuphea oil of 23, and N2 carrier gas flow of 125 ml/min at 2.4 bar. In the absence of acetic acid, coupling of the decanoic acid residues gives 10-ketononadecane.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.NC1C=C([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)C=CC=1CN.C1N=CN(C(N2C=NC=C2)=O)C=1>>[O:12]=[C:8]1[NH:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:3][CH:4]=2)[NH:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CN)c(N)c2)CC1
Reactant: O=C1NCc2ccc(Br)cc2N1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)NC(=O)NC3)CC1
Yield: 75 %

Procedure:
Following the same procedure adopted for the synthesis of compound 13, reaction of compound 20 with CDI afforded 0.73 g (75%) of compound 16 as an off-white solid, m.p. 218-219° C.; IR (KBr) νmax. cm−1: 3211, 3166 (NH), 3037 (Ar—H), 1693 (C═O), 1610, 1519, 1417 (C═C). 1H NMR (500 MHz, CDCl3) δ=1.48 (s, 9H, (CH3)3C); 3.00 (m, 4H, 2CH2); 3.56 (m, 4H, 2CH2); 4.48 (s, 2H, CH2); 6.62 (d, 1H, J=2.5 Hz, H-8); 6.64 (d, 1H, J=8.5 Hz, H-5); 6.74 (dd, 1H, J=2.5, 8.4 Hz, H-6); 7.80 (br.s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) δ=28.65 (CH3)3C), 43.31 (CH2), 43.98 (CH2), 50.63 (CH2), 80.18 (CH3)3C), 115.13 (C-8/C-6), 115.21 (C-8/C-6), 117.59 (C-5), 118.35 (C-5), 130.66 (C-5), 147.20 (C-5), 154.91 (C═O), 155.95 (C═O). Calculated (%) for C17H24N4O3 (332.18); C, 61.43; H, 7.28; N, 16.86. found (%) C, 61.37; H, 7.32; N, 16.80.
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>>[C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
100 g of crude methyl cinnamate and 926.8 g of 2.8% caustic soda were placed in a 2-liter flask equipped with a thermometer and a stirrer, and the solution was then stirred at 80° C. for 30 minutes to carry out hydrolysis. Furthermore, 1 g of powdery active carbon (trade name PMSX, made by Toyo Calgon Inc.) was added, and the solution was stirred for 30 minutes and then filtered at 80° C. by the use of Nutsche. Next, 100 g of toluene was added to the resultant filtrate, and the solution was then stirred at 80° C. for 30 minutes, and after the stop of the stirring, the solution was allowed to stand and separate and the resultant toluene layer was then removed. The resultant aqueous solution was placed in a 2-liter flask equipped with a thermometer and a stirrer and then maintained at 40° C., and 137.1 g of 25% sulfuric acid was added dropwise to precipitate the crystals of cinnamic acid. After the addition of sulfuric acid had been over, the temperature of the solution was lowered to 20° C., followed by filtering through Nutsche. The resultant filter cake was washed with 1000 g of water, and then vacuum-dried at 50° C. to obtain 85.4 g of cinnamic acid. The purity of cinnamic acid was 99.9%, and the content of each of palladium, copper and manganese was 5 ppm or less. The recovered active carbon was dried, and metallic components were then measured. As a result, the contents of palladium, copper and manganese were 880 ppm, 8.6 ppm and 5.8%, respectively. In the filtrate and the washing solution with which cinnamic acid had been washed, metallic components of palladium, copper and manganese were each contained in an amount of 5 ppm or less.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].Br[CH2:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1([C:6]#[N:7])[CH2:11][CH2:10]1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C#N)CC1
Temperature: 80 °C
Yield: 72 %

Procedure:
A suspension of cyano-acetic acid ethyl ester (11.3 g, 0.1 mol), 1,2-Dibromo-ethane, Na4(n-Bu)4Br and K2CO3 in DMF (100 mL) was heated to 80° C. overnight. The mixture was poured into water (600 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether: EtOAc=10:1˜5:1) to give 1-cyano-cyclopropanecarboxylic acid ethyl ester (10 g, yield: 72%). 1H NMR (CDCl3 400 MHz): δ4.21 (q, J=7.2 Hz, 2H), 1.65-1.61 (m, 2H), 1.58-1.55 (m, 2H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:6][C:7]1[CH:16]=[C:15]([O:17][C@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)[C:14]2[C:9](=[CH:10][C:11]([O:42][CH3:43])=[C:12](/[CH:34]=[CH:35]/[CH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])[CH:13]=2)[N:8]=1)[CH3:5]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:4]([O:6][C:7]1[CH:16]=[C:15]([O:17][C@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)[C:14]2[C:9](=[CH:10][C:11]([O:42][CH3:43])=[C:12]([CH:34]3[CH2:3][CH:35]3[CH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])[CH:13]=2)[N:8]=1)[CH3:5]
Reactant: C=[N+]=[N-]
Reactant: CCOc1cc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)c2cc(/C=C/CC(C)(C)CO)c(OC)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOc1cc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)c2cc(C3CC3CC(C)(C)CO)c(OC)cc2n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Palladium acetate (0.67 g, 2.97 mol) and freshly prepared diazomethane (300 mL, 0.5 M solution in Et2O, 150 mmol) were added to a solution of the product from Step 3 (16.6 g, 29.7 mmol) in Et2O (300 mL) cooled to 0° C. After 15 minutes, N2 was bubbled through the mixture for 15 minutes, and the black mixture was filtered through CELITE with Et2O as the eluent. The solvent was removed in vacuo, and the residue was taken up in Et2O (300 mL) and cooled to 0° C. Palladium acetate (0.67 g, 2.97 mol) and freshly prepared diazomethane (100 mL, 0.5 M solution in Et2O, 50 mmol) were then added. After 15 minutes, N2 was bubbled through the mixture for 15 minutes, and the black mixture was filtered through CELITE with Et2O as the eluent. The solvent was removed in vacuo, and the residue was taken up in Et2O (300 mL) and cooled to 0° C. Palladium acetate (0.67 g, 2.97 mol) and freshly prepared diazomethane (100 mL, 0.5 M solution in Et2O, 50 mmol) were then added. After 15 minutes, N2 was bubbled through the mixture for 15 minutes, and the black mixture was filtered through CELITE with Et2O as the eluent. The solvent was removed in vacuo, and the crude product was purified on silica (gradient elution, 0-60% EtOAc/hexanes) to yield the title compound. LRMS ESI+ (M+H)+ 573.2, calcd for C31H45N2O8: 573.3.
Reaction SMILES: [CH2:1]([N:7]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:8]([CH:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].CI.[C:37](OCC)(=O)C>CN(C)C=O>[CH2:27]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([CH:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:37])[C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1)=[O:9])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCN(CCCCCC)C(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)C(=O)C1Sc2ccccc2-c2c1c1ccccc1n2C
Temperature: 25 °C

Procedure:
To a solution of 200 mg of N,N-dihexyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-6-carboxamide in 10 ml of N,N-dimethylformamide was added 21 mg of 60% sodium hydride/oil, followed by stirring at room temperature for an hour. To the solution was added 33 μl of methyl iodide, followed by stirring at room temperature for 5 hours. The reaction solution, after addition of ethyl acetate, was washed with water, 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane to give 155 mg of N,N-dihexyl-6,11-dihydro-11-methyl-5-thia-11-aza-benzo[a]fluoren-6-carboxamide.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:29])[CH2:5][C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH:8]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:20])[N:7]=1.[I-].[Na+].Cl[CH2:33][C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][N:35]=1>CN(C)C=O>[CH3:3][CH:4]([CH3:29])[CH2:5][C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:33][C:34]2[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][N:35]=2)[C:9](=[O:17])[CH:8]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:20])[N:7]=1
Reactant: Cc1cccnc1CCl
Reactant: Cc1cccc(NC(=O)NC2N=C(CC(C)C)c3ccccc3NC2=O)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)NC2N=C(CC(C)C)c3ccccc3N(Cc3ncccc3C)C2=O)c1
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a suspension of sodium hydride (0.027 g of a 64% dispersion in mineral oil) in N,N-dimethylformamide (3 ml) was added gradually N-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (0.200 g) at ambient temperature and the mixture was stirred for 1 hour under the same conditions. To the mixture was added sodium iodide (0.107 g) and followed dropwise a solution of 2-chloromethyl-3-methylpridine (0.093 g,) in N,N-dimethylformamide (2 ml) at the same temperature. The resultant mixture was concentrated in vacuo and the residue was taken up with ethyl acetate and water. The aqueous layer was extracted with another ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a crude compound. The crude compound was recrystallized with isopropyl ether and chloroform to give N-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-1-(3-methylpyridin-2-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (0.23 g) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 136.3 %

Procedure:
To a suspension of 3-hydroxy-2-nitrobenzoic acid (500 mg) and potassium carbonate (1.13 g) in dimethylformamide (5 ml) was added benzyl bromide (1.12 g) at ambient temperature, and the mixture was stirred overnight. To the reaction mixture-was added water, and extracted with ethyl acetate twice. The organic layers were combined, wished with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel flash chromatography (hexane—ethyl acetate) and crystallized with diisopropyl ether to give benzyl 3-benzyloxy-2-nitrobenzoate (676 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[F:14][C:15]1[C:20](B(O)O)=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:14][C:15]1[C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: OB(O)c1cccnc1F
Reactant: C[Si](C)(C)C#Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[Si](C)(C)C#Cc1cccc(-c2cccnc2F)c1
Yield: 92.8 %

Procedure:
To a solution of [(3-bromophenyl)ethynyl](trimethyl)silane (2.28 g, 9.0 mmol) in DME (150 mL) is added (2-fluoropyridin-3-yl)boronic acid (1.41 g, 10.0 mmol), tetrakis(triphenylphosphine)palladium (0.52 g, 0.5 mmol) and a solution of sodium carbonate (3.8 g, 36.0 mmol) in H2O (15 mL) at room temperature. After refluxing for 3 h, the reaction mixture is cooled, quenched with saturated sodium carbonate, diluted with EtOAc. The two layers are separated and the aqueous layer is extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated. The crude mixture is purified by chromatography (silica gel, EtOAc/hexane: 5/95) to give the 2-fluoro-3-{3-[(trimethylsilyl)ethynyl]phenyl}pyridine (2.25 g, 91%) as an oil. MS(+) APPI: 270 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-hexane (150 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-hexyl-1H-pyrazole (118 mg, 56%) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][CH:11]([C:14]1[CH:31]=[CH:30][C:17]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:20](O)=[O:21])=[CH:16][CH:15]=1)[CH2:12][CH3:13]>>[CH3:1][O:2][C:3]1[C:4]([NH:9][C:20](=[O:21])[CH:19]([O:18][C:17]2[CH:30]=[CH:31][C:14]([CH:11]([CH3:10])[CH2:12][CH3:13])=[CH:15][CH:16]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1N
Reactant: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)O
Product: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)Nc1ncccc1OC

Procedure:
3-Methoxy-2-aminopyridine, prepared by reduction of the corresponding nitro compound according to Example 31, was coupled with 2-(4-(1-methylpropyl)phenoxynonanoic acid according to Example 25 to give the title compound.
Reaction SMILES: [C:1]([C:4]1([CH2:11][CH:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6]C1=O)(=[O:3])C.[OH:26]O>C(O)(C)(C)C.S(=O)(=O)(O)O>[C:22]([O:21][C:19]([CH:12]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][C:4]1([C:1]([OH:26])=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COCCOCC(CC1(C(C)=O)CCCCC1=O)C(=O)OC(C)(C)C
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: COCCOCC(CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.9 %

Procedure:
To a solution of 2-acetyl-2-[2-(tert-butoxycarbonyl)-3-(2-methoxyethoxy)propyl]cyclohexanone (see Preparations 5 and 11) (50 m9, 0.14 mmol) in tert-butanol (0.5 ml) was added a 30% aqueous hydrogen peroxide solution (0.02 ml, 0.168 mmol) and concentrated sulphuric acid (one drop) at room temperature. The mixture was stirred at room temperature for 4 hours, partitioned between dichloromethane (10 ml) and water (10 ml), and the layers separated. The aqueous layer was extracted with dichloromethane (2×10 ml), the combined organic extracts dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound, (49 mg). Rf. 0.36 (silica, ethyl acetate). 1H-NMR (300 MHz, CDCl3) =1.43 (s, 9H), 1.43-1.60 (m, 2H), 1.61-1.65 (m, 4H), 1.78 (dd, 1H), 2.0 (dd, 1H), 2.08-2.20 (m, 2H), 2.59-2.70 (m, 1H), 3.38 (s, 3H), 3.48-3.65 (m, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1
Reactant: Cc1cnc(-c2ccccc2)o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Prepare a solution of 5-methyl-2-phenyloxazole (790 mg, 4.97 mmol) in CCl4 (70 mL) under nitrogen. Add N-bromosuccinimide (884 mg, 4.97 mmol) and a catalytic amount of benzoyl peroxide. Reflux the mixture for 2 hours, cool to room temperature, and stir overnight. Wash the reaction mixture with a saturated solution of Na2SO3 (75 mL) followed by saturated sodium hydrogencarbonate (100 mL). Dry the organic phase (magnesium sulfate), filter, and concentrate to afford 1.17 g of 5-bromomethyl-2-phenyloxazole as a white solid. MS: m/e=238 (MH+)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[F:31])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43]>C(Cl)Cl>[F:31][C:22]1[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][NH:18][C:12]1[N:13]=[C:14]([O:16][CH3:17])[N:15]=[C:10]([C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:42](=[O:43])[CH2:41][O:40][CH3:39])[CH:9]=[CH:8][CH:7]=2)[CH:11]=1
Reactant: COCC(=O)Cl
Reactant: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CCN)c2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)NCCc1cccc(-c2cc(NCCc3ccc(C(F)(F)F)cc3F)nc(OC)n2)c1
Reaction time: 0.17 h

Procedure:
A solution of {6-[3-(2-amino-ethyl)-phenyl]-2-methoxy-pyrimidin-4-yl}-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine (150 mg, 0.35 mmol) and triethylamine (0.24 mL, 1.73 mmol) in DCM (5 mL) is treated with methoxyacetyl chloride (75 mg, 0.69 mmol) at 10° C. After 10 minutes at 10° C., the mixture is quenched with aqueous NaHCO3 solution (8 mL), and filtered through Chem-Elut with CH2Cl2 washing (10 mL). The filtrate is concentrated, and subjected to chromatography on silica gel eluting with 80% EtOAc in heptane to 5% MeOH in CH2Cl2 to give N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-2-methoxy-acetamide, which is treated with saturated solution of hydrogen chloride in EtOAc followed by lyophilization to afford N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-2-methoxy-acetamide hydrochloride [76 mg, Example 64]. LCMS: RT=2.24 minutes, MS: 507 (M+H). 1H NMR (300 MHz, CDCl3), □9.35 (1H, s), 7.9 (1H, brs), 7.6-7.4 (7H, m), 6.65 (1H, s), 4 (3H, s), 3.76 (3H, s), 3.8-3.7 (2H, m), 3.4 (2H, q, J=6.9 Hz), 3.25 (2H, s), 3.06 (2H, t, J=6.6 Hz), 2.82 (2H, t, J=7.5 Hz). IC50=56 nM
Reaction SMILES: Cl.[O:2]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:23]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[C:26]([CH3:31])[C:25]=2[Cl:32])[C:22]2[C:21](=[O:33])[CH2:20][N:19](CC3C=CC=CC=3)[CH2:18][C:17]=2[NH:16][C:15]=1[CH3:41])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O.[H][H]>[Pd].CO>[O:2]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:23]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[C:26]([CH3:31])[C:25]=2[Cl:32])[C:22]2[C:21](=[O:33])[CH2:20][NH:19][CH2:18][C:17]=2[NH:16][C:15]=1[CH3:41])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CC1=C(C(=O)OCCOc2ccccc2)C(c2c(F)ccc(C)c2Cl)C2=C(CN(Cc3ccccc3)CC2=O)N1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1=C(C(=O)OCCOc2ccccc2)C(c2c(F)ccc(C)c2Cl)C2=C(CNCC2=O)N1
Yield: 55 %

Procedure:
Twelve grams of the above hydrochloride, 125 ml of methanol, 2 ml of concentrated hydrochloric acid, 10 ml of water, and 1 g of 10% palladium on carbon were shaken with hydrogen (50 psig initial pressure) for 24 hours. The mixture was diluted with 500 ml of methanol, heated to reflux and filtered. The filtrate was evaporated to dryness and the residue was slurried with ethanol and filtered. The solid was recrystallized from methanol to obtain 5.2 g of the title compound as the hydrochloride, m.p. 252°-5° C. dec.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:26][CH3:27])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH3:27]
Reactant: CCN(C1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C1CCNCC1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[ethyl-(4-methoxy-benzenesulfonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (11.1 g, 28 mmol) in CH2Cl2 (50 mL) is cooled at 0° C. and TFA (40 mL) is added. The mixture is stirred at 0° C. for 0.5 h and then evaporated. The residue is dissolved in CH2Cl2 (50 mL) and 1 M aq. NaOH (50 mL) is added. The mixture is stirred for 15 h at r.t., then the phases are separated and the aq. phase is extracted with CH2Cl2 (4×30 mL). The combined org. phases are washed with 1 M aq. NaOH (2×30 mL), dried (Na2SO4), filtered and evaporated to provide the title compound.