Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(O)C.[OH-].[Na+].[CH2:17](Br)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCC(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
3.0 G. 1-amino-4-hydroxy-2-nitrobenzene in 80 ml. aqueous ethanol, containing 0.80 g. sodium hydroxide, is reacted with 4.0 g. phenacyl bromide on a steam bath under nitrogen atmosphere for 2 hours, water is added and the product collected by filtration to afford 1-amino-2-nitro-4-phenacyloxybenzene. This latter compound is hydrogenated at one atmosphere pressure in 150 ml. methanol in the presence of hydrochloric acid and 2.0 g. palladized charcoal until the theoretical uptake of hydrogen has occurred. The catalyst is filtered off and the solution stripped uner vacuum to afford 1,2-diamino-4-[1-(2-hydroxy-2-phenyl)ethoxy]benzene. This latter compound is treated overnight at room temperature with 12 g. methoxy carbonyl isothiocyanate in 120 ml. acetone. The solution is evaporated and the residue triturated with water. Recrystallization from methanol yields 1,2-bis(3-methoxycarbonyl-2-thioureido)-4-[1-(2-hydroxy-2-phenyl)ethoxy]benzene.
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=O)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Product: CS(=O)(=O)NC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1

Procedure:
Prepared from the coupling of 2e and methylsulfonamide by the method described in Procedure 1, Method A. Yield (68%); 1H NMR (CDCl3) δ 7.66 (d, J=15.7 Hz, 1H), 7.18 (m, 10H), 6.95 (d, J=8.1 Hz, 2H), 6.84 (d, J=7.3 Hz, 1H), 6.28 (d, J=15.7 Hz, 1H), 3.36 (s, 3H), 2.82 (t, J=7.0 Hz, 2H), 2.41 (t, J=7.0 Hz, 2H), 2.19 (m, 2H); ESI m/z: 442 (M−H−, 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[O:7]1[CH2:8][CH2:9][O:10][C:5]2[CH:4]=[C:3]([CH2:2][C:13]#[N:14])[CH:12]=[CH:11][C:6]1=2
Reactant: [C-]#N
Reactant: ClCc1ccc2c(c1)OCCO2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12.5 g, 67.7 mmol) and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at rt for 1 h. The mixture was poured into water (150 mL) and then extracted with dichloromethane (50 mL×4). The combined organic layers were washed with water (50 mL×2) and brine (50 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column (Petroleum Ether/Ethyl Acetate 50:1) on silica gel to obtain 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile as a yellow oil (10.2 g, 86%). 1H-NMR (300 MHz, CDCl3) δ 6.78-6.86 (m, 3H), 4.25 (s, 4H), 3.63 (s, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26]3[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32]C(=O)OC(C)(C)C)[CH2:27]3)=[N:6][C:7]([N:10]3[C:18]4[CH:17]=[C:16]([C:19]5[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=5)[N:15]=[CH:14][C:13]=4[CH:12]=[N:11]3)=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[CH:1]1([C:4]2[C:5]([N:26]3[CH2:31][CH2:30][CH2:29][C@H:28]([NH2:32])[CH2:27]3)=[N:6][C:7]([N:10]3[C:18]4[CH:17]=[C:16]([C:19]5[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=5)[N:15]=[CH:14][C:13]=4[CH:12]=[N:11]3)=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C3CC3)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C3CC3)c(N3CCC[C@H](N)C3)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of tert-butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.2224 mmol; 117.1 mg) in Methanol (5 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 181 as an off-white solid (46.0 mg, 49%). 1H NMR (400 MHz, DMSO) δ 9.75-9.71 (s, 1H), 9.47-9.44 (s, 1H), 9.33-9.29 (s, 1H), 8.67-8.61 (d, J=9.6 Hz, 2H), 7.55-7.51 (d, J=8.2 Hz, 1H), 7.49-7.43 (d, J=8.2 Hz, 1H), 3.86-3.78 (d, J=10.8 Hz, 1H), 3.65-3.58 (s, 1H), 3.16-3.09 (s, 1H), 2.89-2.81 (m, 1H), 2.68-2.65 (s, 3H), 2.12-2.04 (m, 1H), 2.02-1.93 (d, J=8.9 Hz, 2H), 1.81-1.69 (m, 1H), 1.48-1.37 (d, J=8.7 Hz, 1H), 1.20-1.11 (m, 1H), 1.09-0.99 (m, 1H), 0.91-0.84 (m, 1H), 0.75-0.67 (s, 1H); MS (ESI) m/z: 427.2 [M+H]+
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.[ClH:34]>C(#N)C.CC(C)=O>[ClH:25].[ClH:34].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:10]=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[CH:29][CH:28]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC#N
Product: Cc1ccc(CN2CCN(c3cccc(-c4ccccc4)c3)CC2)cc1
Reaction time: 16 h

Procedure:
To a solution of 3-[1-piperazinyl]biphenyl (11.9 g) in aceonitrile (200 cc), there is added potassium carbonate (6.9 g) and then, in the course of 20 minutes, a solution of α-chloro-p-xylene (8 g) in acetonitrile (50 cc), at a temperature in the region of 20° C., and stirring is continued for 16 hours. The insoluble material which has formed is separated by filtration. The solution obtained is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in methylene chloride (30 cc) and the solution poured onto silica (1 kg) contained in a column 8 cm in diameter. Elution is performed with a mixture (3 liters) of methylene chloride and methanol (97.5:2.5 by volume) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in acetone (600 cc). The solution is cooled to a temperature in the region of 5° C., 2.5N ethereal hydrogen chloride (40 cc) is added and stirring is maintained for approximately 1 hour. The precipitate formed is separated by filtration and washed with acetone (2×40 cc). 3-[4-(4-Methylbenzyl)-1-piperzinyl]biphenyl dihydrochloride (17.3 g), m.p. 241° C., is thereby obtained.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH:4]=[CH:5]OC.Cl.O.[NH2:13][NH2:14].[OH-].[Na+]>O.C(O)C>[F:1][C:2]([F:10])([F:9])[C:3]1[CH:4]=[CH:5][NH:14][N:13]=1
Reactant: COC=CC(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cc[nH]n1
Yield: 92 %

Procedure:
2.71 kg of 1,1,1-trifluoro-4-methoxy-but-3-en-2-on, 2.44 kg of ethanol and 3.10 kg of water were charged into a reaction vessel. 20 ml of concentrated hydrochloric acid and 0.80 kg of hydrazine hydrate were successively added and the mixture was heated to reflux for 4 h. The mixtures was allowed to cool and neutralized by addition of 10% aqueous NaOH to about pH 4-5. Then the mixture was evaporated. Toluene was added and the mixture was again evaporated to yield 2 kg of raw 3-trifluoromethylpyrazole with a purity of >85%.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([NH2:15])[NH:8][N:7]=1.CN(C)[CH:18]=[CH:19][CH:20]=O>CCO>[NH2:15][C:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:6]2[N:5]=[CH:18][CH:19]=[CH:20][N:7]2[N:8]=1
Reactant: COC(=O)c1c(N)n[nH]c1N
Reactant: CN(C)C=CC=O
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1c(N)nn2cccnc12
Temperature: 25 °C

Procedure:
Acetic acid (0.013 mL, 0.221 mmol) was added to a mixture of methyl 3,5-diamino-1H-pyrazole-4-carboxylate (689 mg, 4.41 mmol, prepared as described in J. Prakt. Chem. 1965, 27, 239-250) and 3-dimethylaminoacrylaldehyde (531 mg, 5.36 mmol) in EtOH (9 mL), and the mixture was heated at reflux for 22 hours, and then cooled to room temperature. The slurry was concentrated under vacuum, and the residue was dissolved in hot methanol (20 mL), allowed to cool to room temperature, then filtered and dried to provide the title compound, in sufficient purity for use in the next step. MS (ESI) m/z 193 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:28](=[O:30])[CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(N2CCN(C(C)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 16 h
Yield: 97 %

Procedure:
A solution of the bis-hydrochloride salt of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine in pyridine (1 mL) was treated with acetic anhydride (32 μL, 0.34 mmol) and stirred for 16 h. The reaction mixture was evaporated and partitioned between EtOAc (2 mL) and a saturated aqueous NaHCO3 solution (2 mL). The organic component was separated, dried over MgSO4, filtered, and evaporated to residue which was purified by silica gel flash chromatography with EtOAc as eluant to afford the title compound as an oil (45 mg, 97%). LC/MS (Method A) 6.88 min, [M+1]+ 409.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>O1CCOCC1.C(N(C(C)C)CC)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[CH2:18][O:17][C:4]1[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=[C:2]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Br)cn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C#C[Si](C)(C)C)cn12
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1 g of ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 21A; 2.35 mmol; 1 equivalent) was initially charged in 52 ml of dioxane/diisopropylethylamine 1:1, and 165 mg of dichlorobis(triphenylphosphine)palladium(II) (0.24 mmol, 0.1 equivalents) and 45 mg of copper(I) iodide (0.24 mmol, 0.1 equivalents) were added. At RT, 1.3 ml of trimethylsilylacetylene (9.4 mmol, 4 equivalents) were slowly added dropwise. The resulting reaction mixture was stirred at 50° C. for 16 h. The mixture was then concentrated, water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with 10% strength aqueous sodium thiosulphate solution and then with saturated sodium chloride solution and dried over magnesium sulphate, and the filtrate was concentrated. The residue was dissolved in methanol and purified by preparative HPLC (column: Nucleodur C18 Gravity 50×200 mm, 10 μm, gradient: A=water+0.1% concentrated aqueous ammonia solution, B=acetonitrile, 0 min=30% B, 5 min=30% B, 23 min=100% B, 28 min=100% B, 28.2 min=30% B, 34 min=30% B, flow rate 110 ml/min, wavelength 220 nm). This gave 726 mg of a solid (89% pure, 62% of theory).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(O)(=O)C>ClC(Cl)C>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 89.8 %

Procedure:
Sodium triacetoxyborohydride (3.3 g, 15.4 mmol, 1.1 eq.) was added at room temperature to a solution of 4-chlorobenzaldehyde (2 g, 14 mmol), tert-butyl 2-aminoethylcarbamate (4.5 mL, 28.5 mmol, 1.2 eq.) and acetic acid (2.5 mL) in dichloroethane (20 mL). The reaction mixture was allowed to stir overnight before being quenched with 0.5M HCl (30 mL). The mixture was then extracted with dichloromethane one time and then brine was added. The precipitate was filtered and dried to give tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (3.58 g, 90%), MS (ESI) m/e (M+H+) 285.
Reaction SMILES: I[CH2:2][CH:3]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH2:4]1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C>CN(C)C=O>[C:3]1([CH2:2][N:11]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: O=C(O)C1CCNCC1
Reactant: ICC1Cc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)C1CCN(CC2=Cc3ccccc32)CC1
Reaction time: 6 h

Procedure:
0.028 mole of 1-(iodomethyl)benzocyclobutene (Process 1, stage G), 0.028 mole of 4-piperidinecarboxylic acid and 0.028 mole of triethylamine are mixed in 95 ml of dimethylformamide. The mixture is brought to 60° C. for 6 hours. It is evaporated to dryness, the residue is taken up with ethyl acetate and water and settling is allowed to take place.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].CCO[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].CCOCC>CCCCCC>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCc1ccccc1N
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C(=CNc1ccccc1CC)C(=O)OCC
Temperature: 80 °C
Yield: 94.9 %

Procedure:
A mixture of 2-ethylaniline (11.7 g) and diethyl ethoxymethylene malonate (25.0 g) were warmed together at 80° C. for one hour. After cooling, the mixture was poured with stirring into a mixture of 150 ml of ether and 75 ml of hexane. After cooling the solution in an ice bath colorless needles precipitated and were collected by filtration. There was obtained 26.7 g (95%) of the title product; tlc, Rf =0.73, silica gel, ethyl acetate:hexane (1:1).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Br[C:17]1[C:22]([F:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=1.Cl>CS(C)=O.O>[F:23][C:22]1[C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=2)=[N:18][CH:19]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:21]=1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1)C(=O)O
Temperature: 48 °C

Procedure:
2-(4-Hydroxyphenoxy)propanoic acid (1.80 g, 0.00988 mole) was dissolved in 15 ml of dimethyl sulfoxide. A solution of sodium hydroxide (0.8 g, 0.02 mole in 1 ml of water) was added and the reaction mixture was heated under nitrogen to 48° C. over a 27 minute period. 2-Bromo-3-fluoro-5-(trifluoromethyl)pyridine (2.40 g, 0.00984 mole) dissolved in 5 ml of dimethyl sulfoxide was added and the reaction mixture was heated at 75°-78° C. for 40 minutes. The mixture was poured into 150 ml of cold water and acidified with aqueous HCl. A gum came down. Upon work-up and purification, a fraction (0.45 g) was obtained which had an elemental analysis of, in percent by weight:
Reaction SMILES: [CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC3C=CC=CC=3)[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>>[CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:31]4[C:30]5[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=5)[N:34]=[CH:33][N:32]=4)[CH:42]=3)=[O:19])[N:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Nc1cc(C2CCC2)nn1-c1ccccc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CCC5)nn4-c4ccccc4)c3)c2cc1OC

Procedure:
1-(3-cyclobutyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea was prepared from phenyl 3-cyclobutyl-1-phenyl-1H-pyrazol-5-ylcarbamate and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) according to the procedure given in Example 352B. 1H NMR (400 MHz, DMSO-d6) δ9.21 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 7.51-7.55 (m, 6H), 7.34-7.42 (m, 3H), 7.18 (m, 1H), 6.92 (m, 1H), 6.36 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 3.35 (m, 1H), 2.08-2.26 (m, 4H), 1.84-1.99 (m, 2H); LC-MS (ESI) m/z 537 (M+H)+.
Reaction SMILES: C[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([OH:10])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:21][CH:20]=1>CN(C=O)C>[O:26]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][O:23][C:22]1[CH:33]=[CH:34][C:19]([CH2:18][O:10][C:4]2[N:3]=[CH:2][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)=[CH:20][CH:21]=1
Reactant: Cc1nc(O)ccc1C=O
Reactant: O=C(COc1ccc(CBr)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(OCC(=O)c3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of methyl 6-hydroxypyridine-3-carbaldehyde. (0.25 g, 2 mmol) in DMF (10 mL) was added cesium carbonate (0.97 g, 3 mmol) and stirred at RT for 30 min then added 2-[4-(bromomethyl)phenoxy]-1-phenylethanone (0.61 g, 2 mmol) this resulting mass was stirred at 80° C. for 12 h, reaction quenched with water and extracted with ethyl acetate, Organic layer was washed with water and brine solution dried over anhydrous Na2SO4 and concentrated to afford crude product which was purified by column chromatography to get pale brown solid as product (0.4 g, Yield: 60%); 1H NMR (300 MHz, CDCl3): δ 9.59 (s, 1H) 7.95-8.02 (m, 2H), 7.67-7.78 (m, 3H), 7.54-7.59 (m, 2H), 7.30-7.33 (d, 2H), 6.93-6.96 (d, 2H), 6.49-6.53 (d, 1H), 5.57 (s, 2H), 5.11 (s, 2H).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:16])[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:3])[CH3:2].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:16])[C@@H:11]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:3])[CH3:2]
Reactant: CC(C)CCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C

Procedure:
Following the procedure described in Referential Example 4, but using 4-(S)-isopropyl-3-(1-oxo-4-methylpentyl)-2-oxazolidinone (5.17 g), prepared in Referential Example 38, and tert-butyl bromoacetate (18.5 ml) as starting materials, the desired compound (6.16 g), having a m.p. of 143°-144° C. after recrystallization from aqueous methanol, was obtained.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[I-:16].[Na+].CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].Cl>CN(C=O)C.O>[CH2:6]([O:5][P:4]([C:9]1[CH:14]=[C:13]([I:16])[CH:12]=[CH:11][C:10]=1[OH:15])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: [I-]
Reactant: CCOP(=O)(OCC)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(OCC)c1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
To a cooled (0° C.) mixture of (2-hydroxy-phenyl)-phosphonic acid diethyl ester (13.1 g, 56.9 mmol) and sodium iodide (10.2 g, 68.3 mmol) in DMF (200 mL) was added chloramine-T trihydrate (19.2 g, 68.3 mmol) over 5 min. After 10 min, the reaction was allowed to warm to rt and the mixture was allowed to stir at rt for 2 h. The mixture was diluted with H2O (50 mL), acidified using 0.5 N HCl and extracted twice with EtOAc. The organic extracts were pooled and washed sequentially with satd. Na2S2O3/brine (1/1) and then brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was chromatographed over silica gel (elution with a stepwise gradient 5-15% EtOAc-hexanes) to give 14.9 g (73%) of a colorless solid after recrystallization (EtOAc-hexanes). Rf 0.30 (20% EtOAc-hexanes). Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 357 (M+H).
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:19])[C:11]([C:16](O)=[O:17])=[CH:12][NH:13][C:14]=2[CH3:15])[CH:6]=[CH:7][CH:8]=1.[CH3:21][N:22](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C>[CH3:21][NH:22][C:16]([C:11]1[C:10](=[O:19])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([F:20])[F:1])[CH:4]=2)=[C:14]([CH3:15])[NH:13][CH:12]=1)=[O:17]
Reactant: Cc1[nH]cc(C(=O)O)c(=O)c1-c1cccc(C(F)F)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c[nH]c(C)c(-c2cccc(C(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 16a, 931 mg, 3.33 mmol), TBTU (1.17 g, 3.64 mmol), triethylamine (0.94 mL, 6.70 mmol) in DMF (3 mL) is stirred for 30 min. Then, methylamine (5.23 mL of 2M solution in THF, 10.5 mmol) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is concentrated under reduced pressure and purified by preparative reversed-phase HPLC (XBridge, gradient of acetonitrile in water, 0.3% NH4OH, 60° C.). Yield: 0.25 g (25% of theory); ESI mass spectrum: [M+H]+=293; Retention time HPLC: 0.59 min (Z011_S03).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][S:13](O)(=[O:15])=[O:14].C(Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 52.75 g (0.265 mol) of (3-chloro-propoxy)-benzene in 100 ml of CH2Cl2, a solution of 19.4 ml (0.292 mol) of chlorosulfonic acid in 100 ml of CH2Cl2 is added dropwise at 0-5° C. under N2 atmosphere. The mixture is allowed to warm to ambient temperature and stirred for 2 hours. To the mixture, 29.6 ml (0.345 mol) of oxalyl chloride and 4 ml (0.052 mol) of DMF are added dropwise at r.t. and the mixture is stirred for 18 h at r.t. The reaction mixture is poured into ice-water, extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated under reduced pressure to give 58.5 g of 4-(3-chloropropoxy)benzenesulfonyl chloride; NMR (CDCl3): 2.26-2.36 (m, 2H), 3.76 (t, 2H, J=6.04 Hz), 4.24 (t, 2H, J=6.04 Hz), 7.06 (d, 2H, J=9.08 Hz), 7.98 (d, 2H, J=9.08 Hz).