Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.[CH:88]1([NH2:93])[CH2:92][CH2:91][CH2:90][CH2:89]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:88]1([NH:93][C:2]2[C:3]3[N:4]([C:8]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[N:19]=4)=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:92][CH2:91][CH2:90][CH2:89]1
Reactant: NC1CCCC1
Reactant: Fc1ccc(-c2nc3c(Cl)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 100 °C
Yield: 55 %

Procedure:
To a solution of 4-[8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (200 mg, 0.49 mmol) in cyclopentylamine (10 mL) was added, successively, racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (91 mg, 0.15 mmol), cesium carbonate (0.24 g, 0.7 mmol) and palladium(II) acetate (22 mg, 0.1 mmol). The resulting mixture was heated in a sealed tube at 100° C. for 18 hours at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and ethyl acetate and water were added. The phases were separated and the organic layer was washed with water and brine. The combined organics were dried (magnesium sulfate), filtered and concentrated to a solid. This solid was purified by silica gel chromatography (1:1 hexanes:ethyl acetate) to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-8-amine (120 mg, 55%) as a solid. 1H NMR (CDCl3) δ 8.80 (d, 1H), 8.06 (d, 1H), 7.62 (q, 2H), 7.10 (t, 2H), 6.76 (t, 1H), 6.34 (d, 1H), 6.27 (d, 1H), 5.22 (d, 2H), 4.34 (m, 1H), 3.93 (m, 1H), 2.0–2.1 (m, 4H), 1.4–1.9 (m, 12H); 19F NMR (CDCl3) δ −113.9; MS m/z 457 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[O:4][N:3]=1.Cl.CC(OC)(C)C>C(O)C>[NH2:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc(N)no2)C1
Agent: Cl
Solvent: CCO
Solvent: COC(C)(C)C
Product: Nc1noc(C2CCCNC2)n1
Temperature: 40 °C
Yield: 61.4 %

Procedure:
tert-Butyl 3-(3-amino-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate 26 (0.33 g, 0.00123 mol) was dissolved in 2 mL ethanol. Hydrochloric acid in ethanol (2.5 M) (2.00 mL, 0.00493 mol) was added and the mixture was heated to 40° C. for 1 hour. 12 mL of MTBE was added and the product precipitated from solution. The solids were filtered and washed with 2×5 mL MTBE, and recrystallized 3 times from methanol:isopropanol to give 127 mg white solid. MS (ESI) m/z 168 [M+1]+. 1H NMR (DMSO-d6) δ 1.67-1.82 (m, 3H), 2.08-2.12 (d, 1H), 2.86-2.90 (t, 1H), 3.06-3.12 (t, 1H), 3.21-3.24 (d, 1H), 3.33 (s, 2H), 3.49-3.52 (d, 1H), 6.32 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[C:20]([O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][C:20]=3[O:33][CH2:34][CH2:35][O:36][CH3:37])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: COCCOc1cc(OC)ccc1B1OC(C)(C)C(C)(C)O1
Product: CCOC(=O)c1c[nH]c2c(-c3ccc(OC)cc3OCCOC)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A43) the title compound is obtained as colorless solid.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])O.[Na+].[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:26][C:27]3[N:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][CH:28]=3)=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17]2)=[CH:13][CH:12]=1>CS(C)=O.O>[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:26][C:27]3[N:32]=[C:31]([C:33](=[N:3][OH:2])[NH2:34])[CH:30]=[CH:29][CH:28]=3)=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17]2)=[CH:13][CH:12]=1
Reactant: [NH3+]O
Reactant: COc1ccc2c(Cc3cccc(C#N)n3)c(-c3ccccc3)[nH]c2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 105.6 %

Procedure:
To a solution of hydroxylammonium chloride (891 mg) in dimethylsulfoxide (5 mL) was added sodium hydrogen carbonate (1.29 g), and this mixture was stirred at 50° C. for 75 minutes. Then, a solution of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carbonitrile (435 mg) in dimethylsulfoxide (1.4 mL) was added dropwise thereto, followed by stirring at 50° C. for 24 hours. The reaction mixture was left to be cooled and diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (504 mg). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 4.40 (2H, s), 5.63 (2H, br s), 6.43-6.69 (1H, br), 6.77 (1H, dd, J=2.2, 8.8 Hz), 6.91 (1H, d, J=2.2 Hz), 7.09-7.15 (1H, m), 7.31-7.40 (2H, m), 7.40-7.49 (2H, m), 7.49-7.60 (3H, m), 7.66-7.74 (1H, m), 8.06 (1H, br s).
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][N:39]=1)[C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([NH:29][C:27](=[O:28])[C:26]1[CH:37]=[CH:38][N:39]=[C:24]([NH:23][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=2)[CH:25]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: O=C(Cl)c1ccccc1
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2ccc(C(F)(F)F)cc2)c1
Yield: 60 %

Procedure:
Following the procedure as describe in preparation of Example 5, variations as required to replace benzoyl chloride with 4-(trifluoromethy)benzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(4-trifluoromethylbenzoylamino)-isonicotinamide was obtained in 60% yield: mp 181-183° C.; 1H NMR (300 MHz, CDCl3) δ 8.92 (br s, 1H), 8.61 (s, 1H), 8.32 (d, J=4.3 Hz, 1H), 7.97 (d, J=7.8 Hz, 2H), 7.73 (d, J=7.8 Hz, 2H), 7.53 (d, J=4.3 Hz, 1H), 7.38-7.15 (m, 5H), 6.98 (br s, 1H), 4.63 (d, J=5.7 Hz, 2H); MS (ES+) m/z 400.4 (M+1).
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:16][N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:19][C:18]2([CH3:30])[CH3:29])=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C1(C)C=CC=CC=1>[CH:10]1([N:9]([C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:8]([O:16][N:17]2[C:18]([CH3:30])([CH3:29])[CH2:19][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:21][C:22]2([CH3:24])[CH3:23])=[N:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)NC2CCCCC2)C(C)(C)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)N(C(=NC1CCCCC1)ON1C(C)(C)CC(OC(C)=O)CC1(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution of compound 1 (4.21 g, 10 mmol) [prepared according to Example 1] in toluene (25 ml) is added triethylamine (1.46 ml, 10.5 mmol) and stearoyl chloride (3.2 g, 10.5 mmol). The mixture is stirred at room temperature for 30 minutes and then additional triethylamine (1.46 ml, 10.5 mmol) and stearoyl chloride (3.2 g, 10.5 mmol) is added. The suspension is stirred at room temperature for 18 hours, then evaporated and chromatographed over silica gel with hexane-ethyl acetate (9:1) to afford 4.03 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=O)[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=1
Reactant: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(Cl)n1

Procedure:
The title compound was prepared from the above described 6-ethyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (4.6 g, 17.2 mmol) and phosphoryl chloride (7.85 mL, 86.1 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as a light yellow solid (2.2 g, 44%). MS (ISP) 286.1 [(M+H)+] and 288.0 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].[OH-].[K+]>C(#N)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccccc1O
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ccccc1Oc1ccc2ccc(N)nc2n1
Temperature: 4 °C
Yield: 62.1 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-naphthyridine (17.95 g), 2-methylphenol (43.2 g) and potassium hydroxide pellets (13.2 g; 85% purity). After treatment with caustic soda and washing, the product obtained (21.2 g; m.p. 188° C.) is dissolved in boiling acetonitrile (100 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). 2-Amino-7-(2-methylphenoxy)-1,8-naphthyridine (15.6 g) is produced, m.p. 192° C.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:32])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[CH:17][CH:16]=2)[CH:9]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:8]1=[O:37])[CH3:6]>[OH-].[Na+].C(O)(C)(C)C>[CH2:33]([CH:9]1[N:10]([C:13](=[O:32])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[CH:19][CH:20]=2)[CH2:11][CH2:12][N:7]([CH:5]([CH3:6])[CH2:4][C:3]([OH:38])=[O:2])[C:8]1=[O:37])[CH:34]([CH3:36])[CH3:35]
Reactant: COC(=O)CC(C)N1CCN(C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)C(CC(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCN(C(C)CC(=O)O)C(=O)C2CC(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A solution of 3-(3-isobutyl-2-oxo-4-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-piperazin-1-yl)-butyric acid methyl ester (20 mg, 0.038 mmol) in a mixture of 1 ml of 0.1 N NaOH and 1 ml of tert-butanol was stirred for 16 hrs at room temperature. The reaction mixture was then concentrated under reduced pressure, dissolved in water (5 ml) and extracted with ether (5 ml×2). The aqueous portion was then acidified to pH<3 with 1N HCl and extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 16 mg of the title compound as a yellow sticky oil. MS [M+1]+509.3; 1H nmr (400 MHz, CD3OD) δ0.88-1.70 (m, 12H), 2.25 (s, 3H), 2.34-4.96 (m, 10H), 6.98 (t, J=7.4 Hz, 1H), 7.11-7.40 (m, 6H), 7.59 (d, J=7.5 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][C:38]=1[O:45][CH3:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]3[C:16]4[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)=[CH:39][C:38]=1[O:45][CH3:46])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)ccc1OCc1ccccc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-benzyloxy-3-methoxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 605.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>CO>[F:14][C:15]([F:22])([F:21])[C:16]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:17]
Reactant: C[C@@H](N)C(=O)O
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C

Procedure:
To the mixture of D-alanine (20.00 g; 0.224 mol) and triethylamine (31.3 ml; 0.224 mol) in absolute methanol (100 ml), ethyl trifluoroacetate (33.4 ml; 0.280 mol) is added and stirred at room temperature to homogenise the mixture (approx. 1 day). The solution is concentrated on a rotavapor (35° C.; 16 mmHg) and then dissolved in the mixture THF/water (1:1; 140 ml). Acidic ion exchanger Dowex 50W-X8 (100 g) is added, stirred for 10 minutes, filtered and concentrated again on a rotavapor (35° C.; 16 mmHg). The residue is sublimed (80° C.; 0.05 mmHg). The pure product in the form of colourless crystals is obtained (33.50 g; 80.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@@H:5]([C:17]([O:19]C)=O)[CH2:4][O:3]1.[Cl-].[NH4+].[CH2:24](OCC)[CH3:25]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[OH:19][C:17]1([C@H:5]2[CH2:4][O:3][C:2]([CH3:1])([CH3:21])[N:6]2[C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:25][CH2:24]1
Reactant: CCOCC
Reactant: COC(=O)[C@H]1COC(C)(C)N1C(=O)OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Product: CC1(C)OC[C@H](C2(O)CC2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-benzyl 4-methyl(4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (6.66 g) and titanium tetraisopropoxide (3.33 mL) in diethyl ether (200 mL) was added dropwise 3M ethyl magnesium bromide diethyl ether solution (18.9 mL) over 20 min under ice-cooling. The reaction mixture was stirred at room temperature overnight, and to the reaction mixture was added saturated aqueous ammonium chloride solution. The precipitated solid was removed by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.52 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=O.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:14]
Reactant: C1CCNCC1
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (430 mg, 1.0165 mmol) and piperidine (173 mg, 2.0352 mmol) were dissolved in methylene chloride (30 ml), then 4-dimethylaminopyridine (62 mg, 0.5081 mmol) and WSC-HCl (487 mg, 2.5404 mmol) were added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (334 mg, 0.6816 mmol, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH:38]([NH2:40])[CH3:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:40][CH:38]([CH3:39])[CH2:37][O:36][CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Reactant: COCC(C)N
Product: COCC(C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-1-(methyloxy)-2-propanamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white rigid foam: 1H NMR (CDCl3) δ 10.07 (1H, d, J=8 Hz), 8.55 (1H, s), 7.16 (2H, dd, J=9, 6 Hz), 7.03 (2H, t, J=9 Hz), 6.93 (1H, s), 4.97 (1H, d, J=17 Hz), 4.90 (1H, d, J=17 Hz), 4.34 (1H, m), 4.11 (2H, s), 3.50 (2H, m), 3.44 (4H, m), 3.38 (3H, s), 1.69 (2H, m), 1.57 (2H, m), 1.52 (2H, m), 1.28 (3H, d, J=7 Hz); HRMS calcd for C27H31FN4O5+H+: 511.2357. Found: 511.2162.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:17][CH2:16][C:11]2[N:12]=[C:13]([NH2:15])[S:14][C:10]=2[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([CH2:30][O:31][C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35](O)=[O:36])=[O:29])=[CH:23][CH:22]=1)#[N:20]>CN(C)C(=O)C.O>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:17][CH2:16][C:11]2[N:12]=[C:13]([NH:15][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:32]([O:31][CH2:30][C:28](=[O:29])[NH:27][C:24]4[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=4)[CH:33]=3)[S:14][C:10]=2[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(N)sc2C1
Reactant: N#Cc1ccc(NC(=O)COc2cccc(C(=O)O)c2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)c3cccc(OCC(=O)Nc4ccc(C#N)cc4)c3)sc2C1
Temperature: 50 °C
Yield: 75.2 %

Procedure:
Add ((S)-2-amino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.10 g, 0.37 mmol) followed by O-(7-aza-benzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (0.13 g, 0.34 mmol) and N,N-diisopropylethyl (0.13 mL, 0.70 mmol) amine to a solution of 3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoic acid (0.10 g, 0.34 mmol) in N,N-dimethylacetamide (3 mL). Heat the mixture to 50° C. for 2 h then cool to room temperature and dilute with water causing a solid to precipitate from solution. Collect the light yellow solid by filtration, wash with water, and dry on the filter pad to provide 0.14 g of ((S)-2-{3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoylamino}-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([Br:19])[C:3]=1[S:20][CH3:21].S(OOS([O-])(=O)=O)(O)(=O)=[O:23].[K+].O.S(=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([Br:19])[C:3]=1[S:20]([CH3:21])=[O:23]
Reactant: O=S(=O)([O-])OOS(=O)(=O)O
Reactant: CSc1c(Br)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1c(Br)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
A solution of 5-amino-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylthiopyrazole (2.0 g) [preparation described in Example 15] in methanol (45 ml) at -25° C. was treated with a rapidly added solution of potassium hydrogen persulphate (1.66 g), followed immediately by the addition of water (22 ml). The mixture was stirred for 30 minutes at 0° C., and potassium hydrogen persulphate (0.4 g) added. After 21/2 hours stirring at room temperature, the mixture was poured onto water (300 ml) and saturated sodium bisulphite solution (35 ml) added. This was extracted with dichloromethane (2×150 ml) and the extract washed with water (2×50 ml), dried over anhydrous magnesium sulphate, and evaporated in vacuo. The crude product was purified by chromatography eluting with dichloromethane/ethyl acetate (4:1) to give 5-amino-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulphinylpyrazole (0.9 g) as a white solid, m.p. 135°-136° C.
Reaction SMILES: [NH4+].[C:2]([CH:4]([CH2:9][CH3:10])[CH2:5][C:6]([O-:8])=[O:7])#[N:3]>Cl>[C:2]([CH:4]([CH2:9][CH3:10])[CH2:5][C:6]([OH:8])=[O:7])#[N:3]
Reactant: CCC(C#N)CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Product: CCC(C#N)CC(=O)O
Temperature: -20 °C
Yield: 96 %

Procedure:
A 300-mL portion of the filtrate described above, containing 1.26M 3-cyanopentanoic acid ammonium salt, was adjusted to pH 2.5 with ca. 60 mL of 6N HCl, then saturated with sodium chloride and extracted with 4×200 mL of ethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, and the solvent removed by rotary evaporation at reduced pressure at 28° C. The resulting slightly-yellow viscous oil was stirred under high vacuum (50 millitorr) to remove residual solvent at 28° C., then cooled to -20° C. for 2-3 h to produce 3-cyanopentanoic acid as a crystalline white solid (45.9 g, 96% yield); m.p. 33.0-34.0° C.
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[C:16]([O:21][CH2:22]Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].C(N(CC)CC)C.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[C:16]([O:21][CH2:22][O:3][C:2](=[O:1])[CH:4]([CH3:5])[C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)OCCl
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC(=O)OCOC(=O)C(C)c1ccc(CC(C)C)cc1
Temperature: 70 °C
Yield: 57.9 %

Procedure:
To a stirred solution of ibuprofen (10.16 g, 49 mmol) and chloromethyl butyrate (6.80 g, 1 eq.) in dry dimethylformamide (20 mL), under nitrogen, was dropwise added triethylamine (8.5 mL, 6 g, 1.2 eq). The mixture was heated at 70° C. for four hours, during which time a large amount of precipitate formed; thin layer chromatography (TLC: ethyl acetate:hexane 1:1) showed that all of the acid had reacted. The precipitate was filtered and washed with ethyl acetate. The filtrate was partitioned between water and ethyl acetate. The aqueous phase was washed with a small amount of ethyl acetate and the combined organic phase was washed with water (3 x), 5% solution of sodium bicarbonate (2 x), and brine (2 x), dried with magnesium sulfate and evaporated to give the crude product as a colorless oil (11.6 g). The crude product was distilled at 170° C./1 mm Hg. The pure product was obtained as a colorless oil (8.7 g, 58% yield).