Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]C(C)(C)C.CCCCC.[CH:31](N1CCCCC1)=[O:32].[NH4+].[Cl-]>C1COCC1.CCCCCC.CCOCC>[CH:12]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH:31]=[O:32])[CH:3]=[C:4]2[CH:10]=[CH:9]1)([CH3:14])[CH3:13]
Reactant: O=CN1CCCCC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C=O)cnc21
Temperature: -78 °C
Yield: 74.4 %

Procedure:
Bromide x254 (1.1 g, 3.11 mmol) is dissolved in freshly distilled absolute THF (40 ml). A 1.7 M solution of t-BuLi in pentane (1.92 ml, 1.05 eq) is added dropwise at −100° C. under vigorous stirring in a flow of argon. The reaction mixture is stirred for 45 min and meanwhile allowed to heat up slowly to −78° C. After this, a solution of N-formylpiperidine (0.42 g, 1.2 eq, 3.73 mmol) in freshly distilled absolute THF (5 ml) is added dropwise for 5 min. The mixture is allowed to heat up to 0° C. under stirring in the cooling bath, and then poured into a mixture of saturated aqueous NH4Cl (20 ml) and 1:1 hexane/ether mixture (100 ml). The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is purified by chromatography on silicagel, CCl4/MeCN) to afford 0.7 g of 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde x255.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3]([OH:5])=[O:4].[C:11](O)(=[O:13])C.O>C(O)=O>[CH:11]([NH:1][CH:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3]([OH:5])=[O:4])=[O:13]
Reactant: NC(C(=O)O)c1cccs1
Reactant: CC(=O)O
Solvent: O
Solvent: O=CO
Product: O=CNC(C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of amino-thiophen-2-yl-acetic acid (5 g) in formic acid (50 ml) was added acetic acid (18 ml). After stirring at room temperature for 6 h, water (25 ml) was added. The reaction mixture was stirred for 30 min. The mixture was concentrated in vacuo and triturated with water. The solids were collected by filtration and dried in vacuo (50° C.).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[CH:23][CH:22]=1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)(=[O:13])=[O:12].P([O-])([O-])([O-])=O>CC(C)=O>[N:27]1([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][N:10]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:26][CH:25]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: COC(=O)CCCCCCN(Cc1ccc(-n2ccnc2)cc1)S(=O)(=O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: O=C(O)CCCCCCN(Cc1ccc(-n2ccnc2)cc1)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.3 %

Procedure:
A mixture of 7-[(4-imidazol-1-yl-benzyl)-(pyridine-2-sulfonyl)-amino]-heptanoic acid methyl ester (52 mg), porcine pancreas lipase (81 mg), acetone (1 mL), and phosphate buffer (pH=7, 5 mL) was stirred at room temperature for 20 h. The product was extracted into CH2Cl2 (3x). The organic solution was dried (MgSO4), filtered, and concentrated to provide the title compound (44 mg). 1H NMR (400 MHz, CD3OD) δ 8.71 (m, 1H), 8.24 (s, 1H), 8.07-7.98 (m, 2H), 7.64-7.54 (m, 6H), 7.19 (s, 1H), 4.57 (s, 2H), 3.29 (t, 2H), 2.15 (t, 2H), 1.41 (m, 2H), 1.33 (m, 2H), 1.13 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:14][CH3:15])[C:8](=[O:13])[CH2:9][CH2:10][S:11][CH3:12])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.B1([O-])O[O:23]1.O.O.O.O.[Na+].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[C:6]([N:7]([CH2:14][CH3:15])[C:8](=[O:13])[CH2:9][CH2:10][S:11]([CH3:12])=[O:23])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CCN(C(=O)CCSC)c1cn(-c2cccnc2)nc1Cl
Reactant: [O-]B1OO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCN(C(=O)CCS(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 60 °C
Yield: 36.7 %

Procedure:
To N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylthio)propanamide (0.08 g, 0.24 mmol) in glacial acetic acid (0.82 mL) was added sodium perborate tetrahydrate (0.05 g, 0.25 mmol), and the mixture was heated at 60° C. for 1 hour. The reaction mixture was carefully poured into a separatory funnel containing saturated aqueous NaHCO3 resulting in gas evolution. When the gas evolution had ceased, ethyl acetate was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate, and all the organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-10% methanol/dichloromethane) to give the desired product as a clear oil (0.03 g, 40%): IR (thin film) 1655 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.95 (t, J=9.2 Hz, 1H), 8.63 (dd, J=4.7, 1.4 Hz, 1H), 8.20-7.86 (m, 2H), 7.59-7.33 (m, 1H), 3.73 (ddt, J=20.5, 13.4, 6.8 Hz, 2H), 3.23-3.06 (m, 1H), 2.94-2.81 (m, 1H), 2.74-2.62 (m, 2H), 2.59 (s, 3H), 1.25-1.07 (m, 3H); ESIMS m/z 341 ([M+H]+).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]>[Cu]I.O1CCOCC1>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1Br
Reactant: NC(=O)c1ccccc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccccc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 23 h
Yield: 82.7 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (6.0 mg, 0.0315 mmol, 1.0 mol %), benzamide (460 mg, 3.80 mmol), K2CO3 (850 mg, 6.15 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (40 μL, 0.333 mmol, 11 mol %), 2-bromoanisole (0.38 mL, 3.05 mmol) and dioxane (0.50 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 5:1; 20 mL fractions). Fractions 10-15 provided 573 mg (83% yield) of the product as a colorless oil. The 1H NMR spectrum was in accord with that reported by Narasaka et al. Tsutsi, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1999, 72, 1869.
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](I)[CH:26]=[CH2:27].Cl>CN(C=O)C.O>[CH2:27]([N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:26]=[CH2:25]
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: C=CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)c1ccccc1)N(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (3 g, 0.011M) in DMF (30 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.5 g, 0.012M). The mixture was stirred at room temperature for 0.5 hours, and then allyl iodide (1.8 g, 0.01M) was added dropwise. The reaction mixture was warmed to 60° C. and stirred for 2 hours. The mixture was then diluted with water (50 ml), neutralized with 10% HCl and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate and the methylene chloride removed under vacuum to afford N-allyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Sc2ccccc2)ccn1
Yield: 93.9 %

Procedure:
Using the method of Example 3, Step A, thiophenol (1.04 g, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9.46 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide 2-chloro-4-(phenylthio)pyridine (1.97 g, 94% yield) as an oil. 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.45-7.58 (m, 5H), 6.90 (s, 1H), 6.85 (d, 1H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.CC(C)=O>ClCCl>[OH:4][CH2:3][CH2:2][N:1]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: COc1ccc(CCl)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(CCO)CCO)cc1
Temperature: 2.5 °C
Yield: 94.7 %

Procedure:
25 gms (0.2380 moles) of diethanolamine and 60 ml (0.4312 moles) triethylamine in 75 ml dichloromethane were taken in a reaction vessel and cooled to 0-5° C. with stirring. 40 gms (0.2554 moles) of p-methoxy benzyl chloride in 50 ml of dichloromethane was added thereto slowly. Further, the reaction mass was stirred with dichloromethane and maintained at a temperature of 25-30° C. for about 16 hours. The resulting solution was concentrated to get a residue. 200 ml of acetone was added to the residue, cooled to 0-5° C. for about one hour and filtered. The filtrate was concentrated to obtain the title compound as an oil (50.8 gms).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[OH-:11].[K+]>>[O:3]=[C:1]([CH3:2])[CH2:4][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:10])=[O:11]
Reactant: CC(=O)C1CCCCC1=O
Reactant: [OH-]
Agent: [K+]
Product: CC(=O)CCCCCC(=O)O

Procedure:
7-Oxooctanoic acid was prepared by treatment of 2-acetyl cyclohexanone with aqueous potassium hydroxide (S. Hunig et al; Chem Ber 91, 129-133 (1958)).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][N:11](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Cl)ncc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)ncc1F
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
A microwave tube was charged with 2-chloro-5-fluoro-4-methylpyridine (5.5 mmol), Zn(CN)2 (16.6 mmol), Pd(PPh3)4 (1.1 mmol) in DMF (20 mL). The mixture was stirred at 150° C. for 5 min in a microwave reactor. The mixture was combined with other crudes obtained following the procedure described above. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc, washed (sat. NH4Cl), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (SiO2, 5:95 to 15:85 EtOAc/petroleum ether) to yield the desired product.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]([O:21]C)=[O:20].Cl>O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 90 °C
Yield: 70 %

Procedure:
2 N Aqueous NaOH solution (10 mL) was added to a suspension of methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXVII) (1.30 g, 3.83 mmol) in water (20 mL) and heated at 90° C. for 1 h. The solution was cooled to room temperature, diluted with ice water and acidified to pH 3.0 with 10% aqueous HCl. The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXVIII) as a white solid (0.87 g, 2.68 mmol, 70% yield). ESIMS found for C13H13BrN2O3 m/z 326.0 (M+H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[O:4]=[CH:5][C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.C(O)C.Cl>O>[OH:4][CH:5]([C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1)[C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(O)C#N)ccc1O
Temperature: 0 °C

Procedure:
Sodium cyanide (10.2 g) is dissolved in water (40 ml) and cooled to 0° C. A second solution comprising vanillin (15.5 g) and ethanol (30 ml) is added at 0° C. Now, concentrated hydrochloric acid (28.5 g 32%) is added to the mixture at 0 to +5° C. within 30 to 45 minutes and the dropping funnel is rinsed with water (10 ml). After confirming that the conversion has proceeded to a satisfactory level by HPLC, the mixture is worked up by extracting repeatedly with t-butyl methyl ether (3×50 ml). The collected organic phases are washed twice with 10% aqueous bisulfite (50 ml) and once with water (40 ml). Finally, the product solution is dried and the solvent is evaporated in vacuum to yield the crude product as a yellow oil, which crystallized on standing (mp 80-81° C.). If the already pure product needs further purification, it can be crystallized from ether/hexane (m.p82-83° C.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[F:22][C:19]([F:20])([F:21])[C:16]1[S:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc(N2CCNCC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.83 mmol 4-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml of dichloromethane was treated with 6.6 mmol trifluoroacetic acid and stirred for 2 hours at room temperature. The reaction mixture is concentrated to give the title compound as yellowish gum. MS (m/e): 239.1 (M+H+, 100%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:12]([NH:15][C:16]3[N:21]=[CH:20][C:19]([S:22][CH2:23][CH2:24][C:25](OC)=O)=[CH:18][C:17]=3[O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:13][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClC1C=C[N:40]=[C:39]([C:43]([NH:45][CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])=[O:44])[CH:38]=1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[N:11]=[C:12]([NH:15][C:16]3[N:21]=[CH:20][C:19]([S:22][C:23]4[CH:24]=[CH:25][N:40]=[C:39]([C:43]([NH:45][CH2:46][CH2:47][N:48]([CH3:49])[CH3:50])=[O:44])[CH:38]=4)=[CH:18][C:17]=3[O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:13][CH:14]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN(C)CCNC(=O)c1cc(Cl)ccn1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(C)=O)CC3)cs2)c(Oc2ccccc2)c1
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc(C(=O)NCCN(C)C)c4)cc3Oc3ccccc3)n2)CC1

Procedure:
Prepared from methyl 3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate and 4-chloro-N-(2-(dimethylamino)ethyl)picolinamide as described in Example 3, Step C. 1H NMR (CDCl3) δ 1.62-1.70 (m, 2H), 2.07-2.12 (m, 2H), 2.11 (s, 3H), 2.28 (s, 6H), 2.51 (t, 2H), 2.71 (t, 1H), 2.88 (tt, 1H), 3.19 (t, 1H), 3.52 (dd, 2H), 3.90 (d, 1H), 4.71 (d, 1H), 6.51 (s, 1H), 7.00 (dd, 1H), 7.09-7.15 (m, 3H), 7.21 (t, 1H), 7.40 (t, 2H), 7.80 (d, 1H), 8.22 (bs, 1H), 8.24 (d, 1H), 8.28 (d, 1H), 8.84 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[F:9].Cl[CH2:11][CH:12]=O>>[Br:1][C:2]1[N:7]2[CH:11]=[CH:12][N:8]=[C:6]2[CH:5]=[CH:4][C:3]=1[F:9]
Reactant: O=CCCl
Reactant: Nc1ccc(F)c(Br)n1
Product: Fc1ccc2nccn2c1Br
Temperature: 100 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A mixture of 6-bromo-5-fluoropyridin-2-ylamine (25 mg, 0.13 mmol) and chloroacetaldehyde (0.1 mL, 50 wt. % in water) in IMS (2 mL) was stirred at 100° C. in a sealed tube for 18 hours, then cooled to room temperature and loaded onto an Isolute® SCX-2 cartridge (5 g). The desired product was washed with MeOH then eluted with 2 M NH3 in MeOH to give 5-Bromo-6-fluoroimidazo[1,2-a]pyridine as a yellow oil (25 mg, 89%). 1H NMR (400 MHz, CHCl3-d): δ 7.84 (s, 1 H); 7.76 (m, 1 H); 7.61 (ddd, J=9.73, 4.67, 0.71 Hz, 1 H); 7.21-7.16 (m, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1>>[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: Cc1ccc(CO)cc1
Product: Cc1ccc(COc2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)cc1

Procedure:
Mitsunobu coupling of phenol 58 with 4-methylbenzylalcohol followed by flash chromatography (5 to 30% EtOAc-hexanes gradient) gave 2-(3-(3-(4-methylbenzyloxy)phenyl)propyl)isoindoline-1,3-dione as a white waxy solid. Yield (2.6 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=3.2 Hz, 2H), 7.67 (d, J=3.2 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 7.16 (dd, J=8.0 Hz, 3H), 6.75-6.85 (m, 3H), 4.98 (s, 2H), 3.74 (t, J=8.0, 2H), 2.67 (t, J=8.0 Hz, 2H), 2.35 (s, 3H), 2.04 (dddd, J=8.0, 2H).
Reaction SMILES: [Br:1][C:2]1[N:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1)[C:7]2=[O:14].[N+]1([O-:30])C=CC=CC=1>>[Br:1][C:2]1[NH:11][C:10](=[O:30])[C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1)[C:7]2=[O:14]
Reactant: [O-][n+]1ccccc1
Reactant: COc1cnc(Br)c2c1C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Product: COc1c2c(c(Br)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O

Procedure:
5-Bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione was prepared in a manner similar to that described in Example 12, step 7 to 9, except the oxidation of 5-bromo-2-(3-chloro-4-fluorobenzyl)-8-methoxy-3,4-dihydro-2,6-naphthyridin-1(2H)-one to the corresponding pyridine N-oxide was oxidized with hydrogen peroxide urea complex (Caron et al., Tetrahedron Lett., 2299, 2000).
Reaction SMILES: C[Si]([C:5]#[C:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:6]([CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8])#[CH:5]
Reactant: C[Si](C)(C)C#CC(O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Place a mixture of α-[(trimethylsilyl)ethynyl]-benzenemethanol (1.87 g, 9.13 mmol) and tetrahydrofuran (11 mL) under argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (11 mL of a 1M solution in tetrahydrofuran, 11 mmol). Stir for 1 hour at room temperature and partition between ethyl ether and water. Separate the organic phase, wash with saturated aqueous sodium chloride, dry (MgSO4), filter, and concentrate in vacuo to yield the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=4[F:41])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:41][C:32]1[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:31]=1[C:23]1[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[N:26]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:22]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[6-(2-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (0.24 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.2 g, 49%). MS (ISP) 543.1 [(M+H)+]; mp 210° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.Cl[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>[N+](C1C=CC=CC=1)([O-])=O.[Cu]=O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1)([OH:18])=[O:17]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: O=C(O)c1ccccc1-n1nc(C(=O)O)c2ccccc21
Yield: 30.3 %

Procedure:
3-Indazolecarboxylic acid (4.10 g), 3.90 g of 2-chlorobenzoic acid, 3.90 g of potassium carbonate and 0.18 g of copper(II) oxide were stirred in 150 ml of nitrobenzene at 170° to 180° C. for 3 hours. After cooling, 100 ml of water was added to the reaction mixture, and the insoluble substance was removed by filtration. The resulting solution was washed with chloroform, and the aqueous layer was decolored with active charcoal and then filtered. The filtrate was made acidic with 50 ml of 1N hydrochloric acid and then extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from methanol-chloroform-ether to obtain 2.13 g (30.2%) of 1-(2-carboxyphenyl)-3-indazolecarboxylic acid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].OO>C(O)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:10][O:9][C:7]([CH2:6][C:5]1[O:1][N:2]=[C:3]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Mn+4]
Agent: OO
Agent: [O-2]
Solvent: CC(=O)O
Product: COC(=O)Cc1onc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A 1.2 g (3.38 mmols) quantity of methyl 5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenoate was dissolved in 19 ml of acetic acid, and the solution was added dropwise to a suspension composed of 0.44 g (5.1 mmols) of manganese dioxide and 5 ml of acetic acid at 60° C. After the completion of addition, the mixture was stirred at 60° C. for one hour. After the completion of reaction, hydrogen peroxide was added to the reaction mixture to decompose excess manganese dioxide. The same procedure as in Example 3 was thereafter repeated to obtain 0.78 g (yield 65%) of the above-identified product.