Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[OH:11].[H-].[Na+].[CH3:18]I.CO>O1CCOCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[O:11][CH3:18]
Reactant: O[C@H]1CCC[C@H]1OCc1ccccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CO[C@H]1CCC[C@H]1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
6.3 g (0.03 mol) of cis-1-(2-fluorobenzyloxy)-cyclopentan-2-ol (Example 2) in 100 ml of absolute dioxan were added dropwise to a suspension of 0.72 g (0.03 mol) of sodium hydride (0.9 g of 80% pure sodium hydride in toluene) in 100 ml of absolute dioxan at 5° C. under nitrogen. After stirring the mixture at room temperature for 30 minutes, it was warmed to 70° C. for 45 minutes and cooled, 1.26 g (0.03 mol) of methyl iodide in dioxan were added dropwise and the mixture was then heated to the boil for 4 hours. After cooling the mixture to room temperature, 5 ml of methanol were added dropwise and the suspension was concentrated on a rotary evaporator. The residue was taken up in water and the mixture was extracted again with methylene chloride. The combined methylene chloride phases were dried over sodium sulphate and filtered and the solvent was stripped off from the filtrate on a rotary evaporator. The oily residue was distilled. 5 g (75% of theory) of cis-1-(2-fluorobenzyloxy)-2-methoxy-cyclopentane of boiling point 90° C./0.1 mm Hg were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=[O:13])[C:9]([NH:15][C:16]([C:18]([O:20]CC)=O)=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2>C(O)C>[Br:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:8]=2[C:9]2[NH:15][C:16](=[O:17])[C:18](=[O:20])[N:12]([OH:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2cccnc12
Solvent: CCO
Product: O=c1[nH]c2c3ncccc3c(Br)cc2n(O)c1=O
Yield: 69.6 %

Procedure:
0.5 g (1.4 mmol) 5-Bromo-8-ethoxalylamino-7-nitroquinoline in 30 ml ethanol was hydrogenated at atm. pressure by using 100 mg (5%) Pt/c as a catalyst. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was stirred with water and the precipitate was filtered off. The crude product was washed with ethanol to give 0.3 g (72%) of 6-Bromo-4-hydroxypyrido[2,3-f]quinoxaline-2,3(1H,4H)-dione. M.p. decomp. M+, 20%), 2gl (70%), 156 (100%), 128 (70%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[C@H:18]([C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:17][C@H:16]([S:27]C(=O)C)[CH2:15]1)(=[O:13])=[O:12].[Li+].[OH-]>C1COCC1>[SH:27][C@@H:16]1[CH2:15][N:14]([S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:12])=[O:13])[C@H:18]([C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:17]1
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCCCC2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([C@@H]1C[C@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1)N1CCCCC1
Yield: 74.2 %

Procedure:
148 mg (0.33 mmol) (3S,5S)-Thioacetic acid S-[1-(naphthalene-2-sulfonyl)-5-(piperidine-1-carbonyl)-pyrrolidin-3-yl] ester in 9 ml THF were treated with 9 ml 0.1M LiOH for 30 min at 0° C. and 1h at RT. The solution was extracted with ether, the inorganic phase was acidified with 1M KHSO4 and extracted with EtOAc. The EtOAc phase was washed with brine and dried over Na2SO4, trituration with hexane gave 99 mg (74%) (2S,4S)-[4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-piperidin-1-yl-methanone as white solid, MS: 405 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:25][S:26][C:27]2[NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][C:13]([O:15]CC)=[O:14].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:3]([CH2:25][S:26][C:27]2[NH:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CN(CCSc1ccnc(CSc2nc3ccccc3[nH]2)c1C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCCN(CC(=O)O)Cc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-((3-Methyl-4-(2-(N-benzyl-N-ethoxycarbonylmethylamino)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole (1.0 g) was dissolved in ethanol (10 ml) and thereto was added an aqueous solution (3 ml) of 1N sodium hydroxide. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and adjusted to pH 4 with an aqueous solution of dilute acetic acid. The resultant crystals were collected by filtration to give 2-((3-methyl-4(2-(N-benzyl-N-carboxymethylamino)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole as colorless crystals.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][C:31]=3[CH3:36])[N:28]=[CH:29][C:22]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C@@H:4]([O:3][C:21]2[C:22]3[CH:29]=[N:28][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[CH3:36])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:15][O:16][CH:17]([CH3:19])[CH3:18])=[N:9][CH:10]=1
Reactant: Cc1ccc(NC(=O)[C@@H](O)COC(C)C)nc1
Reactant: Cc1cnccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ccncc2C)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
60% Sodium hydride in mineral oil (48.8 mg, 1.22 mmol) was added in one portion to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (194 mg, 0.81 mmol) in anhydrous THF (5 mL) cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate M1) (200 mg, 0.81 mmol) as suspension in dry THF (4 mL) added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric acid (2 mL) was added and the mixture extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography with ethyl acetate to give the product (300 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 1.17 (3H, d), 1.19 (3H, d), 2.29 (3H, s), 2.34 (3H, s), 3.69-3.76 (1H, m), 4.09 (2H, d), 6.01 (1H, t), 7.51 (1H, d), 7.53 (1H, dd), 8.09-8.10 (1H, m), 8.13 (1H, d), 8.43 (1H, s), 8.60 (1H, s), 8.62 (1H, dd), 8.67 (1H, s), 8.68 (1H, s); m/z (ESI+) (M+H)+=448; HPLC tR=1.78 min.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:36][CH3:37])=[C:7]([CH:25]=[C:26]([N:28]2[CH:33]=[CH:32][C:31](=[O:34])[NH:30][C:29]2=[O:35])[CH:27]=1)/[CH:8]=[CH:9]/[C:10]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])([CH3:4])([CH3:3])[CH3:2]>CO.C1COCC1.[Pd]>[C:1]([C:5]1[C:6]([O:36][CH3:37])=[C:7]([CH:25]=[C:26]([N:28]2[CH:33]=[CH:32][C:31](=[O:34])[NH:30][C:29]2=[O:35])[CH:27]=1)[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-n2ccc(=O)[nH]c2=O)cc(C(C)(C)C)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(NS(C)(=O)=O)ccc1CCc1cc(-n2ccc(=O)[nH]c2=O)cc(C(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
To a solution of the product from Example 25 (40 mg, 0.076 mmol) in MeOH (2 ml) and THF (2 ml) was added 10% Pd/C (20 mg) and the resulting mixture was stirred at room temperature under 1 atm H2 for 16 h. The mixture was filtered through celite and concentrated in vacuo to give a solid (27.5 mg, 68%). 1H NMR (300 MHz, DMSO-d6) 11.39 (s, 1 H) 9.88 (s, 1 H) 7.61-7.71 (m, 2 H) 7.28-7.36 (m, 2 H) 7.20 (d, J=2.57 Hz, 1 H) 7.13 (d, J=2.94 Hz, 1 H) 5.64 (d, J=7.72 Hz, 1 H) 3.83 (s, 3 H) 3.75 (s, 3 H) 3.14 (dd, J=10.30, 5.88 Hz, 2 H) 2.96 (s, 3 H) 2.83-2.92 (m, 2 H) 1.34 (s, 9 H).
Reaction SMILES: BrC1S[C:4]2C=C(OC)C=C[C:5]=2N=1.BrC1C=CC(B2OC(C)(C)C(C)(C)O2)=CN=1.CO[C:31]1[CH:46]=[CH:45][C:34]2[N:35]=[C:36]([C:38]3[CH:39]=[N:40][C:41](N)=[N:42][CH:43]=3)[S:37][C:33]=2[CH:32]=1>>[S:37]1[C:33]2[CH:32]=[CH:31][CH:46]=[CH:45][C:34]=2[N:35]=[C:36]1[C:38]1[CH:4]=[CH:5][C:41]([NH:42][CH3:43])=[N:40][CH:39]=1
Reactant: COc1ccc2nc(-c3cnc(N)nc3)sc2c1
Reactant: COc1ccc2nc(Br)sc2c1
Agent: CC1(C)OB(c2ccc(Br)nc2)OC1(C)C
Product: CNc1ccc(-c2nc3ccccc3s2)cn1
Reaction time: 2 h

Procedure:
2-Bromo-6-methoxy-1,3-benzothiazole (49 mg, 0.20 mmol) and 2-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (68 mg, 0.24 mmol) were reacted according to the procedure used for the preparation of 5-(6-methoxy-1,3-benzothiazol-2-yl)pyrimidin-2-amine, with the following exceptions: The reaction was stirred for 2 h and was then allowed to reach rt on. The mixture was filtered through a plug of silica and Na2SO4, eluting with DCM. The volume of the filtrate was reduced in a centrifuge and the remainder was purified by HPLC to give the title compound (4.2 mg). 1H NMR (CHLOROFORM-d: CD3OD) δ 8.93 (d, 1 H) 8.21 (dd, 1 H) 7.92 (d, 1 H) 7.68 (d, 1 H) 7.43 (d, 1 H) 7.12 (dd, 1 H) 3.89 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N)c(CO)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
2-Amino-5-methoxy-benzoic acid (2.0 g, 12 mmol) in tetrahydrofuran (20 ml) was added dropwise to an ice cooled 1 molar solution of lithium aluminium hydride (14.4 ml) in tetrahydrofuran and stirred at 5° C. for 2 hours. Water (0.5 ml) was added dropwise, followed by 2 molar aqueous sodium hydroxide solution (0.5 ml). The resulting emulsion was dried over magnesium sulphate, then filtered and evaporated under reduced pressure to give the title compound as a yellow solid (766 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc([N+](=O)[O-])ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a mixture of 2-tert-butyl-5-nitrophenol (C-1-a) (100 mg, 0.52 mmol) and K2CO3 (86 mg, 0.62 mmol) in DMF (2 mL) was added CH3I (40 uL, 0.62 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After filtration, the filtrate was evaporated to dryness to give 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, 76%) that was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.77 (t, J=4.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 3.94 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[Br:11].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[Br:11]
Reactant: OC1CCNCC1
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(N2CCC(O)CC2)cc1Br
Temperature: 90 °C
Yield: 75.6 %

Procedure:
A mixture of 2-bromo-4-fluoro-benzoic acid methyl ester (2.06 g, 8.84 mmol), 4-hydroxy piperidine (1.86 g, 18.4 mmol), and potassium carbonate (1.33 g, 9.62 mmol) in acetonitrile (25 mL) is heated to 90° C. for 17 h. The mixture is concentrated and partitioned between ethyl acetate and water. The solvent layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4), filtered, and concentrated under reduced pressure. The residue is purified on silica (120 g) using a gradient of 0% to 90% ethyl acetate in heptane to provide the title compound (2.10 g, 76%) LC-ES/MS m/z 314.0 (M+1)
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:22]NC(=O)C)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[C:6]=1[Br:7].O(Cl)[Cl:28].O>C(Cl)Cl>[Br:1][C:2]1[N:3]([CH2:22][Cl:28])[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:12])[F:13])(=[O:10])=[O:9])[C:6]=1[Br:7]
Reactant: ClOCl
Reactant: CC(=O)NCn1c(Br)c(Br)c(S(=O)(=O)C(F)(F)F)c1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1c(Br)c(Br)n(CCl)c1-c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 8 h

Procedure:
N-{{2,3-Dibromo-5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrol-1-yl}methyl}acetamide (4.5 g, 0.00835 mol) is added to phosphoros oxychloride (15 mL). The reaction mixture is refluxed for 31/2 hours, poured into water, stirred overnight and filtered to obtain a solid. The solid is dissolved into methylene chloride and the solution is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a yellow solid (3.8 g, mp 153°-156° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH2:11])[CH3:10].C(O)(=O)[C@H](C1C=CC=CC=1)O.[OH-].[Na+]>C(OC)(C)(C)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([NH2:11])[CH3:10]
Reactant: CC(N)c1cccc(Cl)c1Cl
Agent: O=C(O)[C@@H](O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: C[C@@H](N)c1cccc(Cl)c1Cl
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution consisting of 10 g of (RS)-1-(2,3-dichlorophenyl)ethylamine and 30 g of methyl t-butyl ether was heated to 45° C. while stirring, and a mixture of 3.6 g of L-mandelic acid and 30 g of methyl t-butyl ether was added thereto over about 30 minutes, followed by stirring at the same temperature for 30 minutes. Then, after cooled to 20° C. over 6 hours, the precipitated crystals were filtered, washed twice with 20 g of methyl t-butyl ether and dried to obtain 7.2 g of diastereomer salt. 21 g of a 5% aqueous sodium hydroxide solution was added to the crystals, followed by extraction twice with 10 g of methyl t-butyl ether. The solvent was distilled off from the resulting organic layer to obtain 4 g of (R)-1-(2,3-dichlorophenyl)ethylamine. This had the optical purity of 90.4%ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[CH:14][C:15](=[O:17])[CH3:16])[CH:7]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.[Pd]>[CH3:16][C:15]([CH2:14][CH2:13][C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1)=[O:17]
Reactant: COc1ccc2cc(C=CC(C)=O)ccc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc2cc(CCC(C)=O)ccc2c1
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
4-(6-Methoxy-2-naphthyl)-but-3-en-2-one (100.0 g, 0.442 mol), (6.0 g), and potassium carbonate (13 g) were slurried in ethyl acetate (1100 mL), stirred 15 minutes, and 5% Pd/C (9.0 g) was added. The flask was purged with H2, a H2 balloon was added, and the reaction was followed by GC. After 12.5 hours, the reaction mass was filtered, washed with H2O (2×150 mL), dried (Na2SO4), filtered, and concentrated in vacuo, affording 95.3 g (95%) of nabumetone (93% purity, 98.5:1.5 ketone:alcohol ratio). The product was recrystallized from EtOH (275 mL) to give 81 g (80%) of 99% nabumetone (92% recovery of contained product). mp 79.5° C.; DSC 81.8° C.; 1H NMR (300 MHz, CDCl3) δ 7.61 (d,2H), 7.48 (s,1H), 7.22 (dd,1H), 7.12-7.04 (m,2H); 13C NMR (75 MHz, CDCl3) δ 208.2, 157.8, 136.6, 133.6, 129.6, 129.4, 128.0, 127.4, 126.7, 119.3, 106.2, 55.7, 45.5, 30.5, 30.2.
Reaction SMILES: COC(C1C=CC(C(O)=O)=NC=1)=O.C(N)(C)(C)C.[C:19]([NH:23][C:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][N:27]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([NH:23][C:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc(C(=O)NC(C)(C)C)nc1
Agent: COC(=O)c1ccc(C(=O)O)nc1
Solvent: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(C(=O)O)cn1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to tert-butylamine via Procedure G. Crude methyl 6-(tert-butylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 250 mg of 6-(tert-butylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(tert-butylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N2-tert-butyl-N5-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide. MS (Q1) 409 (M)+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:24]>O1CCOCC1.ClCCl>[NH2:24][C:2]1[C:11]([C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N
Reactant: COc1cccc(OC)c1C(=O)c1cc2ccccc2nc1Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cccc(OC)c1C(=O)c1cc2ccccc2nc1N
Temperature: 150 °C

Procedure:
(2-Chloroquinolin-3-yl)(2,6-dimethoxyphenyl)methanone (2.0 g, 6.1 mmol) was dissolved in dioxane (15 mL), mixed with 25% aqueous ammonia solution (10 mL) and heated to 150° C. under its own pressure for 24 hours in a pressurized reactor. The reaction mixture was diluted with dichloromethane and washed several times with water. The organic phase was dried (sodium sulfate) and concentrated. The crude product was purified by chromatography (silica gel, dichloromethane, methanol). Yield: 1.15 g (3.73 mmol, 61%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:23][CH:22]=[C:21]([C:24]([OH:26])=[O:25])[C:20]=1[CH2:27][CH2:28][OH:29])=O>>[OH:29][CH2:28][CH2:27][C:20]1[C:21]([C:24]([OH:26])=[O:25])=[CH:22][NH:23][C:19]=1[CH:17]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: O=Cc1[nH]cc(C(=O)O)c1CCO
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1[nH]cc(C(=O)O)c1CCO

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-4-(2-hydroxyethyl)-1H-pyrrole-3-carboxylic acid to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH:12]=O)=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1.[CH3:25][NH2:26].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][NH:26][CH3:25])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1
Reactant: CN
Reactant: O=Cc1cnc2ccc(Cl)nc2c1Nc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1cnc2ccc(Cl)nc2c1Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-chloro-4-((3-(trifluoromethyl)phenyl)amino)-1,5-naphthyridine-3-carbaldehyde (0.75 g, 2.13 mmol) was dissolved in ethanol (20 mL), added 1.2 mL of a solution of methylamine in ethanol (concentration 27%), stirred at room temperature for 4 h, and then added sodium borohydride (0.82 g, 21.7 mmol) to the system, continued stirring at room temperature for 18 h. The reaction was quenched with a saturated aqueous solution of sodium carbonate, concentrated under reduced pressure to remove ethanol, extracted with 80 mL of dichloromethane, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain 0.77 g of the titled compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[C:44]1([N:50]=[C:51]=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:51]([NH:50][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:52])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reactant: O=C=Nc1ccccc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)Nc2ccccc2)CC1

Procedure:
In a manner similar to the method described in example 160, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with phenyl isocyanate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H47Cl2N6O3 [(M+H)+] 741.3081, observed 741.3081.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=1.[CH3:12][N:13]([CH3:16])[CH:14]=O.C(N(CC)CC)C.C(Cl)(=O)C1C=CC=CC=1>O>[NH2:7][C:5]1[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=[C:2]([N:1]=[CH:12][N:13]([CH3:16])[CH3:14])[N:6]=1
Reactant: CNC(=S)n1nc(N)nc1N
Reactant: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=C(Cl)c1ccccc1
Product: CNC(=S)n1nc(N=CN(C)C)nc1N
Reaction time: 4.5 h
Yield: 27 %

Procedure:
A solution of the compound (1.00 g) obtained in Example 31, dimethylformamide (25 ml) and triethylamine (1.0 ml, 7.2 mmol) was cooled to 0° C. and benzoyl chloride (0.70 ml) was gradually added dropwise thereto. The mixture was stirred at 0° C.-room temperature for 4.5 hours and the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. After the concentration, silica gel column chromatography (chloroform-methanol) and recrystallization from chloroform-methanol gave 350 mg of pale-yellow crystals (yield 27%).