Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][C:12]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[O:14]3)[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH3:30]O>>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]([O:14][CH3:30])=[O:22])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1OC2(CC(c3cccc(C(F)(F)F)c3)=NO2)c2ccccc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1-c1cc(-c2cccc(C(F)(F)F)c2)no1

Procedure:
A mixture of 2 g. (0.006 mole) of 3'-(m-trifluoromethylphenyl)-spiro[isobenzofuran-1(3H), 5'(4'H)-isoxazol]-3-one, 2 ml. of concentrated sulfuric acid and 50 ml. of methanol was heated at reflux for 17 hours. The solution was then poured into 100 g. of ice and extracted twice with 300 ml. of ether. The ether solutions were combined, washed twice with water saturated sodium chloride, and dried over CaSO4. Removal of the solvent gave 2 g. of colorless viscous liquid, which was crystallized from hexane at 0° C. to give colorless crystals; m.p. 46°-48° C.
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][O:4][C:5]1[C:10]2C(=O)C=C(C)O[C:9]=2[C:8](CCC)=[CH:7][CH:6]=1.[Se](=O)=[O:22].[O:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[OH:1][CH:2]([CH3:20])[CH2:3][O:4][C:5]1[CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:25][C:26]=2[O:27][C:28]=1[C:29]([OH:24])=[O:22]
Reactant: CCCc1ccc(OCC(C)O)c2c(=O)cc(C)oc12
Reactant: C1COCCO1
Reactant: O=[Se]=O
Product: CC(O)COC1=C(C(=O)O)Oc2ccccc2C1

Procedure:
5 -(2-Hydroxypropoxy)-2-methyl-4-oxo-8-propyl-4H-1-benzopyran (2.6 g) and selenium dioxide (1.1 g) were dissolved in 20% aqueous dioxan (150 ml) and heated at reflux for 24 hours. The suspension was filtered and the dioxan removed in vacuo. The residue was dissolved in chloroform (100 ml) and the chloroform solution extracted with saturated aqueous sodium bicarbonate. The bicarbonate extract was acidified with dilute hydrochloric acid and the resulting precipitate filtered off, washed with water and dried. Crystallisation from acetone gave 5-(2-hydroxypropoxy-4H-1-benzopyran-2-carboxylic acid. mp 135°-137° C.
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=4[CH:30]=3)=[O:19])[CH:9]([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1.CCOC(C)=O.Cl>O.C1COCC1>[Br:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=4[CH:30]=3)=[O:19])[CH:9]([CH2:12][C:13]([OH:15])=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: CCOC(=O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108 %

Procedure:
LiOH (55.3 mg, 2.31 mmol) dissolved in water (3 mL) was added to a solution of ethyl {7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 28, 366 mg, 0.77 mmol) in THF (6.0 mL). The mixture was stirred at rt for 1.5 h. EtOAc (40 mL) was added followed by 1 M HCl (3.1 mL, 3.1 mmol) and water (20 mL). The phases were separated and the organic layer was washed with brine (30 mL), dried over Na2SO4 and evaporated to give crude title compound (372 mg, 108%) as a solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3([CH2:21][CH2:20][N:19](C(OCC4C=CC=CC=4)=O)[CH2:18][CH2:17]3)[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2c1-c1ccccc1OC21CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)n1ncc2c1-c1ccccc1OC21CCNCC1
Yield: 101.8 %

Procedure:
Benzyl 1-isopropylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.1 g, 2.6 mmol) was stirred in methanol (14.4 mL) with Pd/C (140.3 mg, 0.1318 mmol) under a balloon of hydrogen for 16 h. The reaction was filtered through a syringe filter and the solvent evaporated to give 1-isopropylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (750 mg, 100%). ESI-MS m/z calc. 283.2, found 284.3 (M+1)+; Retention time: 1.01 minutes (3 min run).
Reaction SMILES: [I-].[CH2:2]([N+:9]1([CH3:22])[CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:20]C)=[C:14]([O:18]C)[CH:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:23]>>[Br-:23].[CH2:2]([N+:9]1([CH3:22])[CH2:10][C:11]2[C:16](=[CH:15][C:14]([OH:18])=[C:13]([OH:20])[CH:12]=2)[CH2:17]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc2c(cc1OC)C[N+](C)(Cc1ccccc1)C2
Reactant: Br
Agent: [I-]
Product: C[N+]1(Cc2ccccc2)Cc2cc(O)c(O)cc2C1
Product: [Br-]
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 10 g (24.3 mmol) of N-benzyl-5,6-dimethoxy-N-methylisoindolinium iodide, 50 ml of 48% hydrobromic acid was added, and the mixture was heated at reflux for 3 hours at an external temperature of 120° C. The reaction solution was evaporated to dryness under reduced pressure, and the crystal residue was washed with 20 ml of acetone to obtain 6.90 g of the above identified compound. The filtrate was left to stand overnight, to obtain 190 mg of the secondary crystals. The total yield was 7.09 g. The melting point, the infrared absorption spectrum and the 1H-NMR spectrum of this product agreed to those of Example 2.
Reaction SMILES: [C:1]([N@@:4]1[CH2:6][CH:5]1[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])(=[O:3])[CH3:2].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.[Cl-].[Cl-].[Zn+2]>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][N:14]=[N+:15]=[N-:16])[CH3:10]
Reactant: CCOC(OCC)C1CN1C(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CCOC(OCC)[C@@H](CN=[N+]=[N-])NC(C)=O
Temperature: 75 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
A mixture containing 3.26 g of 124 and 15 g of sodium azide in 140 ml of DMF was added 140 ml of ZnCl2 (1.0M solution in Et2O). The mixture was stirred at 75° C. for 3 days and then extracted with EtOAc. The organic layer was washed with water, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (hexane/EtOAc=3:2) to yield 2.52 g of 125 (62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7]([OH:9])=O.[CH3:14][NH:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[ClH:1].[CH3:14][N:15]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCOCC1
Reactant: O=C(O)COc1ccc(Cl)c(Cl)c1
Product: CN(C(=O)COc1ccc(Cl)c(Cl)c1)[C@@H]1CCCC[C@H]1N1CCOCC1
Product: Cl

Procedure:
The title compound was prepared according to the method described in Example 2, using 3,4-dichlorophenoxyacetic acid (2.51 g, 11 mmol), and (±)-trans-N-methyl-N-[2-(4-morpholinyl)cyclohexyl]amine prepared in Example 12 (2 g, 10 mmol). The crude product, which precipitated without the addition of any diethyl ether, was recrystallised from hot methanol. Yield 3.42 g (78%). Proton and carbon-13 NMR data in accord.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][CH:5]=1.[Br:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([OH:21])=[C:16]([Cl:22])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CC1C=CC=CC=1C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([O:21][C:17]2[CH:18]=[C:19]([Cl:20])[C:14]([Br:13])=[CH:15][C:16]=2[Cl:22])=[CH:8][C:7]([CH3:11])=[N:6][CH:5]=1
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Reactant: COC(=O)c1cnc(C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(C)cc1Oc1cc(Cl)c(Br)cc1Cl
Temperature: 120 °C
Reaction time: 20 h
Yield: 7.6 %

Procedure:
To a solution of 1.25 g (6.734 mmol) 4-chloro-6-methyl-nicotinic acid methyl ester (commercially available, CAS RN 886372-05-0) in 30 mL o-xylene was added 1.792 g (7.408 mmol) 4-bromo-2,5-dichlorophenol (commercially available, CAS RN 1940-42-7), 0.502 g (1.347 mmol) tetrakis(acetonitrile)copper (I) hexafluorophosphate (commercially available, CAS RN 64443-05-6) and 5.536 g (16.836 mmol) cesium carbonate. The reaction mixture was stirred at 120° C. for 20 hours and was then allowed to cool to room temperature. Ethyl acetate (50 mL) and water (50 mL) was added and stirring was continued for another 10 minutes. The reaction mixture was filtered over Dicalite® speed plus (Acros) and the layers were separated. The aqueous layer was extracted with 200 mL ethyl acetate and the combined organic layers were washed with 200 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (50 g silica gel column, CombiFlash Companion, Isco Inc.) and a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give 200 mg (8%) of the title compound as a light yellow solid. MS (Turbo Spray): m/z=391.9 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([OH:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Br.[K+].[Br-]>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([OH:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3ccc(C(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Agent: Br
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2nc(-c3ccc(O)cc3)c(-c3ccc(O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Into a 1000 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, a nitrogen inlet, and a condenser, 2,3-bis(4-methoxyphenyl)quinoxaline-6-carboxylic acid (34.7 g, 89.8 mmol) was dissolved in acetic acid (260 mL). Hydrobromic acid (48%, 500 mL) was then added to yellow clear mixture at room temperature. The reaction mixture was heated under reflux with vigorous stirring until the solution become homogeneous. It took about 6 h. After having been allowed to cool down to room temperature, the red-brown mixture was poured into distilled water. The resulting light brown precipitate was collected by suction filtration and dried under the reduced pressure to give 31.9 g (99% crude yield) of yellow solid, m.p. 315-317° C. (dec.). Anal. Calcd. for C21H14N2O4: C, 70.39%; H, 3.94%; N, 7.82%. Found: C, 66.70%; H, 3.98%; N, 7.20%. FT-IR (KBr, cm−1): 1698 (carbonyl), 3396 (hydroxy). Mass spectrum (m/e): 358 (M+, 100% relative abundance). 1H-NMR (DMSO-d6, δ in ppm): 6.76-6.79 (d, 4H, Ar), 7.35-7.39 (d, 4H, Ar), 8.09-8.12 (d, 1H, Ar), 8.20-8.24 (d, 1H, Ar), 9.87-9.89 (d, 1H), OH), 13.50 (s, 1H, COOH). 13C-NMR (DMSO-d6, δ in ppm): 114.93, 128.78, 129.21, 129.27, 130.39, 131.11, 131.23, 139.29, 142.06, 153.78, 154.38, 158.30, 158.44, 166.62.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[N:21]=[C:20]([CH3:34])[CH:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.[Cl:44]CCl>>[ClH:44].[CH3:35][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:22]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:27][CH:28]=3)[N:21]=[C:20]([CH3:34])[CH:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:36])=[O:5]
Reactant: Cc1cc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)n(-c2ccc(OC(F)(F)F)cc2)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NCCc2csc(SC(C)(C)C(=O)O)n2)n(-c2ccc(OC(F)(F)F)cc2)n1
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Methyl-2-({4-[2-({3-methyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (690 mg) synthesized in Example 253-1 was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1). The obtained compound was dissolved in diethyl ether (4 mL), 4 mol/L hydrochloric acid-ethyl acetate (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration to give the title compound (461 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=2[F:23])[N:3]=1.[C:24](Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[CH3:24][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([F:11])[C:2]([Cl:1])=[N:3][C:4]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:20])([CH3:22])[CH3:21])=[CH:15][C:14]=1[F:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[Si](C)(C)c1ccc(Nc2nc(Cl)c(F)cc2C(=O)O)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a suspension of 6-chloro-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid (7.6 g, 21.3 mmol) in dichloromethane (100 mL) and DMF (1 mL) was added oxalyl chloride (9.1 mL, 106.4 mmol) dropwise over 20 minutes. The reaction mixture was stirred at reflux for 18 hours and then concentrated in vacuo and the residue azeotroped with toluene. The resultant residue was taken up in cold (0° C.) methanol (100 mL). The resultant solution was heated at reflux for 1 hour, then cooled to room temperature and filtered. The precipitate was washed with cold methanol and dried under vacuum at 45° C. to give the title compound as a yellow solid (7.3 g, 92%). LCMS (method B): RT=5.38 min, [M+H]+=371.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([NH:36][C:37]([C:39]2[C:40](=[O:52])[N:41]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[CH:42]=[CH:43][CH:44]=2)=[O:38])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C=O>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([NH:36][C:37]([C:39]2[C:40](=[O:52])[N:41]([C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[CH:42]=[CH:43][CH:44]=2)=[O:38])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([CH3:2])[CH2:32][CH2:31]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2cc1OCC1CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of N-(3-fluoro-4-(6-methoxy-7-(piperidin-4-ylmethoxy)quinolin-4-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide TFA salt (22 mg, 0.030 mmol) and NaBH(OAc)3 (40 mg) in CH2Cl2 was added HCHO (0.1 mL of 33% solution) and the reaction mixture was stirred at rt for 6 h. Direct purification by preparative HPLC afforded the desired product as a white TFA salt solid (11 mg, 50%). 1H NMR (CDCl3) δ 12.16 (s, 1H), 8.77 (dd, 1H, J=7.7, 2.2 Hz), 8.55 (d, 1H, J=6.1 Hz), 8.08 (d, 1H, J=1.6 Hz), 8.06 (dd, 1H, J= 12.1, 1.6 Hz), 7.64-7.27 (m, 8H), 6.71 (d, 1H, J=6.6 Hz), 6.66 (t, 1H, J=6.6 Hz), 4.27 (d, 2H, J=5.5 Hz), 4.07 (s, 3H), 3.66 (d, 2H, J=12.1 Hz), 2.81 (s, 3H), 2.87-1.97 (m, 7H); MS(ESI+) m/z 627.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][C@H:20]([O:23]C(=O)C(C)(C)C)[C@@H:19]([CH3:30])[CH2:18]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][C@H:20]([OH:23])[C@@H:19]([CH3:30])[CH2:18]2)[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CN(CCN2CCC(NC(=O)OC(C)(C)C)CC2)CC[C@@H]1OC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Product: C[C@H]1CN(CCN2CCC(NC(=O)OC(C)(C)C)CC2)CC[C@@H]1O

Procedure:
Crude 15 (8.2 g, 19.27 mmol) is treated with NaOMe (0.5M in methanol, 77 ml, 38.5 mmol) and heated under reflux for 24 hours. The solvent is then evaporated, the residue taken up in DCM and extracted with 1N—NaOH and brine. Drying and evaporation gave a brown oil which is purified by chromatography on silicagel using DCM (saturated with ammonia) and MeOH (from 1% to 5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[N:10]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+].C(OCC)C>C(Cl)Cl.O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[N:10]1
Reactant: OCc1cnnn1-c1c(Cl)cccc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: O=Cc1cnnn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of [3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (1.87 g, 1 equiv) in methylene chloride (110 mL) is added Dess-Martin oxidant (4.20 g, 1.3 equiv). The reaction mixture is allowed to stir at room temperature for 3 h. The reaction is incomplete as evidenced by TLC. The reaction mixture is treated with Dess-Martin oxidant (1.20 g). The reaction mixture is allowed to stir at room temperature for an additional 2 h. The reaction mixture is treated with 80 mL 1.5 N sodium hydroxide and 40 mL diethyl ether. The resulting solution is allowed to stir at room temperature for ten minutes. The reaction mixture is diluted with 120 mL water and extracted three times with chloroform. The combined organic layers are dried over magnesium sulfate and filtered though a plug of silica gel eluting with chloroform/ethyl acetate (3:1, 200 mL). The filtrate is concentrated under reduced pressure to give the title compound (1.76 g, 94%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C@@H:28]([NH2:37])[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C@@H:28]([NH:37][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[O:15])[CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CC(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 6.4 g of 4-((S)-2-Amino-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester in 37 ml of DMF, 3.0 g of HOBT and 3.7 g of EDC was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by crystallization from ethyl acetate/heptane. Yield: 5.4 g.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][C:11]1=[O:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:2]([N:13]1[CH2:14][CH2:15][NH:10][C:11](=[O:16])[CH2:12]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CNCCN1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CN(CCc2ccccc2)CCN1
Temperature: 80 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
A suspension of (2-bromoethyl)benzene (4.10 mL, 30.0 mmol), piperazin-2-one (3.00 g, 30.0 mmol) and K2CO3 (4.90 g, 36.0 mmol) in DMSO (60.0 mL) was stirred at 80° C. for 5 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was then washed with water (200 mL) and extracted with methylene chloride (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The result yellow solid was then dissolved in 1 N HCl (120 mL) and washed with methylene chloride. The aqueous layer was separated, basified with 6 N NaOH, and extracted with methylene chloride (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was titrated with hexanes and filtered. The filtered solid was dried under reduced pressure to give the title compound (4.50 g, 74%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 7.31-7.28 (m, 2H), 7.23-7.19 (m, 3H), 6.17 (brs, 1H), 3.40-3.37 (m, 2H), 3.23 (s, 2H), 2.83-2.79 (m, 2H), 2.73-2.67 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].C1C=CC=CC=1.[CH2:18]([S:34](Cl)(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(N(CC)CC)C>[CH2:18]([S:34]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1CO
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)OCc1ccccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To a stirred solution of 7.65 g (0.05 mol) of 2-nitrobenzyl alcohol in 75 ml of benzene containing 5.05 g (0.05 mol) of triethylamine was added 16.25 g (0.05 mol of hexadecanesulfonyl chloride. The mixture was stirred an additional four hours. The mixture was evaporated to dryness in vacuo and the solid taken up into a mixture of ether and water. The ether layer was separated and dried over MgSO4. Evaporation of the ether gave a solid which was crystallized from absolute ethanol (yield 14.3 g, m.p. 63°-65° C.).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:19]O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:21]1([N:24]2[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[NH:26][C:25]2=[O:33])[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[CH:21]1([N:24]2[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[N:26]([CH2:19][C:7]3[N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[C:14]4[C:9]([N:8]=3)=[N:10][C:11]([C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=4)[C:25]2=[O:33])[CH2:23][CH2:22]1
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Reactant: CC(C)CCn1c(CO)nc2nc(C(F)(F)F)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
To a suspension of (1-isopentyl-5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 44-3 (1.0 g, 3.5 mmol (73% purity)), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (731.8 mg, 4.2 mmol) and triphenylphosphine (1.1 g, 4.2 mmol) in 24 ml dry THF was added (E)-diisopropyl diazene-1,2-dicarboxylate (1.0 ml, 5.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness and purified by preparative column chromatography to obtain 44 as a white solid (578.0 mg, 37%). m/z=445 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02 (m, J=6.50 Hz, 8H) 1.13-1.24 (m, 2 H) 1.48-1.64 (m, 2 H) 1.73 (dquin, J=13.19, 6.49, 6.49, 6.49, 6.49 Hz, 1 H) 2.92 (tt, J=6.81, 3.48 Hz, 1 H) 4.35-4.52 (m, 2 H) 5.41 (s, 2 H) 7.13 (d, J=5.27 Hz, 1 H) 7.61 (d, J=8.28 Hz, 1 H) 7.79 (d, J=8.28 Hz, 1 H) 8.34 (d, J=5.27 Hz, 1 H) 8.68 (s, 1 H).