Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[N+:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:2]
Reactant: c1ccccc1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccccc1

Procedure:
feeding fresh benzene and nitric acid in about stoichiometric proportions to produce nitrobenzene into a first-stage reaction vessel containing nitrobenzene, benzene and sulfuric acid;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[H-].[Na+].[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17](F)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([CH:5]([C:6]#[N:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: CCOC(=O)CC#N
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethylcyanoacetate (1.14 g, 10.0 mmol, 2 eq) in 1 mL DMF was added at 0° C. to a suspension of sodium hydride (0.4 g, 60% in mineral oil, 5.02 mmol) in 3 mL DMF under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes before the dropwise addition of 4-fluoro-3-nitro-benzoic acid methyl ester (1.05 g, 22.7 mmol) in 5 mL DMF. After stirring for 2 hours at room temperature, 2 M HCl (20 mL) and ethyl acetate (20 mL) were added to the red solution. The organic layer was washed with water and brine, dried over sodium sulphate and concentrated to give the title compound as an orange oil, which was used without further purification (1.47 g, 5.03 mmol). 1H NMR (CDCl3) δ 8.83 (1H, d, J=1.5), 8.38 (1H, dd, J=8.0, 1.8), 7.89 (1H, d, J=8.1), 5.74 (1H, s), 4.30 (2H, q, J=7.1), 4.00 (3H, s), 1.32 (3H, t, J=7.0).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]([O:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:12][C:11]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[NH:26][C:25]2=[O:35])=[C:10]([F:36])[CH:9]=1.[N+:37](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:37][N:26]1[C:27]([C:31]([F:33])([F:34])[F:32])=[CH:28][C:29](=[O:30])[N:24]([C:11]2[CH:12]=[C:13]([O:14][C:15]3[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]([Cl:7])=[CH:9][C:10]=2[F:36])[C:25]1=[O:35]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ncccc2[N+](=O)[O-])c(Cl)cc1F
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3[N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A suspension of potassium carbonate (0.23 g), 3-[4-chloro-2-fluoro-5-(3-nitro-2-pyridyloxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (0.5 g) and 2,4-dinitrophenoxyamine (0.32 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The solution was processed and the resulting oil chromatographed on silica gel eluting with methanol:methylene chloride, 2:98. The product was isolated as a yellow semi-solid (0.3 g), mp 90-6° C.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:41])[C@H:24]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:41])=[O:22])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to Nε-Cbz-L-lysine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=1)[C:19]#[N:20].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=2)[C:19]#[N:20])[CH2:4][CH2:3]1
Reactant: CN1CCC(CCCCO)CC1
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(CCCCOc2cc(C#N)ccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
To a stirred solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (1.0 g, 5.85 mmol) in DMF (12 mL) at 0° C. was added NaH (60%; 280 mg, 7.02 mmol). The mixture was warmed to rt for 1 h, then cooled to 0° C. A solution of 2-chloro-isonicotinonitrile (810 mg, 5.85 mmol) in DMF (4 mL) was added dropwise. The mixture was stirred at rt for 18 h, and then was diluted with water (5 mL) and satd. aq. NaHCO3 (25 mL). The mixture was extracted with CHCl3 (3×25 mL), dried (Na2SO4), filtered, and. Purification by Method 1 afforded 440 mg (28%) of a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2C(=O)C3=CC=CC=[C:17]3[C:16]2=[O:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[C:16]([NH:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)(=[O:25])[CH3:17]
Reactant: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(=O)NCC1CN(Cc2ccccc2)CCO1
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
A mixture of N-[(4-benzyl-2-morpholinyl)methyl]phthalimide (162 g), 85% hydrazine hydrate (43.3 g), and ethanol (100 ml) is refluxed with stirring for 20 minutes. The reaction mixture is filtered, and the filtrate is diluted with water and extracted with chloroform. The organic layer is separated, washed with a small amount of water and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. To the filtrate is added slowly acetic anhydride (98.3 g), and the resulting mixture is stirred at 25° C. for 2 hours. The reaction mixture is washed successively with aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is recrystallized from toluene to give the title compound (101 g), mp 110°-111° C.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([NH2:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[NH2:12][C:13]1[CH:18]=[C:17]([C:2]2[C:6]3[N:7]=[C:8]([NH2:11])[N:9]=[CH:10][C:5]=3[S:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Nc1ncc2scc(Br)c2n1
Product: Nc1cccc(-c2csc3cnc(N)nc23)c1
Yield: 75.9 %

Procedure:
7-(3-Aminophenyl)thieno[3,2-d]pyrimidin-2-amine (160 mg, 75% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromothieno[3,2-d]pyrimidin-2-amine (200 mg, 0.87 mmol) and 3-aminophenylboronic acid (120 mg, 0.87 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[CH2:13])[CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[CH2:13])[CH:10]=2)/[C:5](=[N:17]/[OH:18])/[CH2:4][CH2:3]1
Reactant: NO
Reactant: C=Cc1ccc2c(c1)C(C)(C)CCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=Cc1ccc2c(c1)C(C)(C)CC/C2=N\O
Yield: 97.1 %

Procedure:
To a mixture of 4,4-dimethyl-6-vinyl-3,4-dihydronaphthalen-1(2H)-one (Preparation 1C, 0.201 g, 1.004 mmol) and hydroxylamine hydrochloride (0.084 g, 1.20 mmol) in methanol (3 mL) at room temperature was added sodium acetate (0.099 g, 1.20 mmol). The heterogeneous reaction mixture was heated at reflux for 1.5 h. The heterogeneous mixture was concentrated, and the solid residue was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (E)-4,4-dimethyl-6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (0.210 g, 0.975 mmol, 97% yield) as a pale yellow solid. The product had an HPLC ret. time=2.64 min. (condition A); LC/MS M+1=216.0.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:31][C:32]#[N:33])[CH:23]=[CH:22]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Reaction time: 1.17 h
Yield: 100.1 %

Procedure:
In a similar manner as described in step 1 of Example 3, the title compound was prepared from 6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.250 g, 0.665 mmol), prepared in step 2 of Example 2, bromoacetonitrile (0.096 g, 0.80 mmol) and cesium carbonate (1.08 g, 3.33 mmol) with the exception that the reaction was complete after 70 minutes at ambient temperature. The crude material was dissolved in methylene chloride and filtered through silica gel (45 g, 200–300 mesh). The solvent was removed under reduced pressure to give {[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile as a beige solid (0.276 g, 100%), mp 156–157° C. Elemental Analysis for C29H22N2O Calc'd: C, 84.03; H, 5.35; N, 6.76. Found: C, 83.15; H, 5.46; N, 6.54.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@H:5]([NH2:7])[CH3:6].N1C=CC=CC=1.[Cl:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19]>C1COCC1>[Cl:14][CH2:15][CH2:16][NH:17][C:18]([NH:7][C@@H:5]([CH3:6])[CH2:4][O:3][CH3:2])=[O:19]
Reactant: O=C=NCCCl
Reactant: COC[C@@H](C)N
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC[C@H](C)NC(=O)NCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A mixture of (R)-1-methoxypropan-2-amine hydrochloride (500 mg, 3.98 mmol) and pyridine (315 mg, 3.98 mmol) in THF (15 mL) was treated drop-wise with 2-chloroethylisocyanate (420 mg, 3.98 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, partitioned between EtOAc and brine and the organic layer dried over Na2SO4 and concentrated to dryness to afford (S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea (393 mg, 50%). 1H NMR (400 MHz, DMSO-d6): δ 6.08 (s, 1 H), 5.93 (d, J=8.1 Hz, 1 H), 3.71 (m, 1 H), 3.56-3.51 (m, 3 H), 3.30-3.23 (m, 3 H), 3.22 (s, 3 H), 0.98 (d, J=6.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[C:26]([CH3:34])=[CH:27][C:28]([Cl:33])=[C:29]([CH:32]=3)[C:30]#[N:31])[C@@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[CH3:36])=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[C:29]([C:30]#[N:31])[C:28]([Cl:33])=[CH:27][C:26]=1[CH3:34])([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1cc(Cl)c(C#N)cc1N[C@@H](c1nnc(-c2ccc(N)cc2)o1)[C@H](C)O[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3cc(C#N)c(Cl)cc3C)[C@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a pre-cooled (0° C.) solution of 5-((1R,2S)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-4-methylbenzonitrile (intermediate 77d) (200 mg, 0.40 mmol) in CH2Cl2 (4.0 mL) and pyridine (1.04 mL) was added, portion wise, acetyl chloride (0.14 mL, 2.0 mmol). Upon complete addition the reaction mixture was warmed slowly to room temperature and stirred for 23 h. The reaction mixture was then cooled to 0° C. and quenched with 10% ap HCl (5 mL) then H2O (15 mL) was added. The solution was extracted with CH2Cl2 (2×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange oil, which was used without further purification (199 mg, 92%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.11 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.6 Hz, 2H), 7.80 (br s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 5.57 (d, J=8.9 Hz, 1H), 4.99 (dd, J=1.8, 8.9 Hz, 1H), 4.76-4.68 (m, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 1.62 (d, J=6.3 Hz, 3H), 1.07 (s, 9H), 0.27 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)#[N:20]>CN(C)C=O.C1CCCCC1>[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH3:3])=[C:5]2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C#N)cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.9 g (0.06 mole) of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide under nitrogen at 0°-5° was added dropwise over 20 minutes a solution of 10.4 g (0.05 mole) of 3-methyl-2-(3-pyridyl)indole in 60 ml of dimethylformamide. The reaction mixture was stirred for 0.5 hour at 0°-5° followed by dropwise solution of 9.8 g (0.05 mole) of p-cyanobenzyl bromide in 50 ml of dimethylformamide. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture was poured into ice-water (600 ml). The resulting solid was collected, dried, washed with petroleum ether and redissolved in ether (500 ml). The ether solution was first washed with water, then with saturated sodium bicarbonate solution, dried over MgSO4, treated with charcoal and filtered. Evaporation of the ether extract to dryness yielded a yellow solid. This product was slurried in hot cyclohexane and collected by filtration to give 1-(4-cyanobenzyl)-3-methyl-2-(3-pyridyl)indole, m.p. 127°-9°.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:13]1([CH2:19][CH2:20][C:21](Cl)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:7]1([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][CH2:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)Nc1cc(-c2ccccc2)[nH]n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-Amino-5-phenylpyrazole (160 mg) was dissolved in pyridine (1 ml) to which was subsequently added 3-phenylpropionyl chloride (0.15 ml), and the mixture was stirred at room temperature for 14 hours and then at 50° C. for 30 minutes. The reaction solution was diluted with ethyl acetate (15 ml), washed with water (15 ml), 10% citric acid (15 ml), 1 N aqueous sodium hydroxide solution (15 ml) and saturated brine (15 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled away under a reduced pressure, and the resulting residue was crystallized from ethanol to obtain the title compound (139 mg) as white crystals (melting point: 168 −170° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C.[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C1(C)C=CC(S(O[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)(=O)=O)=CC=1>O>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc(OCCc2ccc(Cl)cc2)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
Potassium carbonate (54.9 g, 397 mmol) was added to a N,N-dimethylacetamide (330 mL) solution of methyl 4-hydroxybenzoate (25.2 g, 165 mmol) and 2-(4-chlorophenyl)ethyl p-toluenesulfonate (compound described in J. Am. Chem. Soc., (1978), 100, 228-246, 61.7 g, 199 mmol) at room temperature. The mixture was stirred at 120° C. for 1.5 hours. The reaction solution was cooled to room temperature, and water (1 L) was added thereto. The resulting mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with water (three times) and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate, 10:1, V/V) to give 43.2 g of methyl 4-[2-(4-chlorophenyl)ethoxy]benzoate (white solid). All this solid was dissolved in ethanol (430 mL), and a 2 M lithium hydroxide aqueous solution (148 mL, 297 mmol) was added thereto. The mixture was stirred at 60° C. for 2 hours, and the solvents (mainly ethanol) were evaporated. The residue was suspended in water (300 mL), and 2 N hydrochloric acid (160 mL) was added thereto under ice-cooling with stirring. The precipitated white solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure to give 41.0 g of the title compound (white solid, yield: 90%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:27])[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[N:14][C:15]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]([CH3:19])[C:17]=2[CH3:18])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CCO.O>[CH2:20]([C:15]1[N:14]=[N:13][C:12]([N:9]2[CH2:10][CH2:11][C:6]([CH3:27])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[C:17]([CH3:18])[C:16]=1[CH3:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1(C)CCN(c2nnc(Cc3ccccc3)c(C)c2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(C)(C(=O)O)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-4-methyl-piperidine-4-carboxylic acid ethyl ester (0.60 g, 1.6 mmol) in EtOH (5 mL) is added sodium hydroxide (0.5 g, 13.2 mmol) in H2O (5 mL). After being stirred at 25° C. for two hr, the mixture is concentrated, and extracted with CH2Cl2 (2×10 mL) to remove impurities. The aqueous layer is acidified by 1N HCl to pH˜5, and extracted with CH2Cl2 (6×20 mL). The combined organic solution is dried over Na2SO4, filtered and concentrated to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-4-methyl-piperidine-4-carboxylic acid (0.49 g, 89%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[ClH:23].[NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccc(Cl)cc1)OCC
Agent: Cl
Product: NCC(CP(O)O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 5.0 g of ethyl 3-amino-2-(4-chlorophenyl)propyl(diethoxymethyl)phosphinate in 60 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 1 hour. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure, and co-evaporated three times with 20 ml of water under reduced pressure to give 3-amino-2-(4-chlorophenyl)propylphosphonous acid hydrochloride, as a hygroscopic solid, 31P=+30.1 ppm (D2O).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH:32]1[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]1>>[O:38]=[S:35]1(=[O:39])[CH2:36][CH2:37][N:32]([C:3]([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[N:17][O:18][C:19]=4[C:20]([F:22])([F:23])[F:21])[N:12]=[CH:11]3)=[CH:8][CH:9]=2)=[O:2])[CH2:33][CH2:34]1
Reactant: O=S1(=O)CCNCC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1)N1CCS(=O)(=O)CC1
Yield: 97.4 %

Procedure:
As described for Example 38b, 6-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using thiomorpholine 1,1-dioxide (124.9 mL, 0.9 mmol) instead of cyclopropanemethylamine, to the title compound (120 mg, 97%) which was obtained as a colourless oil. MS: m/e=535.8 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([CH3:15])[N:7]2[C:12](=[O:14])[CH3:13].[Br:16]N1C(=O)CCC1=O>C(#N)C>[Br:16][C:11]1[C:2]([OH:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12](=[O:14])[CH3:13])[C@@H:6]([CH3:15])[CH2:5][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N1c2cccc(O)c2CC[C@@H]1C
Solvent: CC#N
Product: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A solution of (S)-1-(5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (1.2 g, 5.85 mmol) in acetonitrile (24 mL) was cooled to 0° C. and treated with N-bromosuccinimide (1.041 g, 5.85 mmol) in one portion. The solution turned dark yellow-orange in color initially, then faded to a pale orange color over the next 10-15 min. After 30 min, the solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 8:1 dichloromethane-ethyl acetate followed by 7:1 dichloromethane-ethyl acetate) to afford (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (1.37 g, 82%). MS (ESI, pos. ion) m/z 284, 286 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:4][C:3]2[C:2]([Br:1])=[CH:8][CH:7]=[CH:6][C:5]=2[Br:9])=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1c(Br)cccc1Br
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(C(=O)Nc2c(Br)cccc2Br)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
2,6-Dibromoaniline (1.0 g, 3.98 mmol) was dissolved in dioxane (20 mL) and treated with diisopropylethylamine (1.39 mL, 7.96 mmol) followed by 4-tert-Butylbenzoyl chloride (1.70 g, 7.96 mmol). The solution was warmed to 60° C. and stirred overnight. The mixture was concentrated under reduced pressure and the residue was re-dissolved in ethyl acetate (50 mL). The organic solution was washed with 10% HCl (2×50 mL), saturated sodium carbonate (50 mL) and saturated sodium chloride (50 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, eluting with 20% acetone/hexane to yield 1.33 g (81%) of product. MS (ESI) m/z 409.9772; HPLC Method B, purity 92.3% at 210-370 nm, 10.4 min.; 89.7% at 232 nm, 10.4 min.; HRMS: calcd for C17H17Br2NO+H+, 409.97496; found (ESI, [M+H]+), 409.9772.