Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:4])([OH:3])[OH:2].[S:5](=[O:9])(=[O:8])([OH:7])[OH:6].C[N:11](C)C1C=CC=CC=1>S(=O)=O>[S:1](=[O:2])([OH:4])[OH:3].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[NH4+:11].[NH4+:11]
Reactant: O=S(=O)(O)O
Reactant: CN(C)c1ccccc1
Agent: O=S(O)O
Agent: O=S=O
Product: O=S(=O)([O-])[O-]
Product: [NH4+]

Procedure:
The effluent gas from absorber section 5 is impoverished in sulfur dioxide and enriched in gaseous dimethylaniline and passes sequentially through sulfurous acid scrubbing section 9 and sulfuric acid scrubbing section 10 and leaves scrubbing section 10 through line 18 very low in sulfur dioxide content and free or substantially free of absorbent. In sulfurous acid scrubbing section 9 sulfur dioxide gas and liquid aqueous ammonium sulfate solution withdrawn from the bottom of the regenerator are separately fed into the lower and upper portion respectively of scrubber section 9 beneath the lowermost tray and above the uppermost tray respectively through lines 19 and 20 respectively. Liquid water per se may be supplied in the upper portion of the sulfurous acid-ammonium sulfate scrubbing section 9 through line 22 for the sulfurous acid production in the event additional water is needed to supplement the water introduced into this scrubbing section in the aqueous ammonium sulfate solution, and to maintain the water balance in the process. The uprising sulfur dioxide gas is dissolved in the water of the descending current of aqueous ammonium sulfate solution to form a dilute aqueous solution of sulfurous acid and ammonium sulfate which flows downwardly from tray to tray in scrubber section 9. The presence of the ammonium sulfate in sulfurous acid scrubbing section 9 results in a considerably enhanced dissolution of the SO2 gas in the water to form sulfurous acid as is previously disclosed herein. The uprising effluent gas bubbles through the descending current of thus-formed dilute sulfurous acid-and ammonium sulfate-containing solution which flows downwardly from tray to tray in scrubber 9, and a major portion, i.e. more than 50%, and typically more than 90%, of the gaseous dimethylaniline present in the gas is removed from the gas in scrubbing section 9 by reaction with the sulfurous acid in the presence of the ammonium sulfate to form dimethylaniline sulfite. The aqueous sulfurous acid-and ammonium sulfate-containing scrubbing solution also containing the thus-formed dimethylaniline sulfite is withdrawn from the lower portion of scrubbing section 9 through line 62 and passed to collection tank 63.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:8]1[CH2:12][CH2:11][C:10](=O)[CH:9]=1)([CH3:7])([CH3:6])[CH3:5].Cl>C(OCC)C>[CH3:1][C:11]1[CH2:10][CH:9]=[C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])[CH:12]=1
Reactant: CC(C)(C)C1=CC(=O)CC1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CC1=CC(C(C)(C)C)=CC1
Temperature: 0 °C

Procedure:
To a 500 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 100 ml of dehydrated diethyl ether and 57 ml (170 mmol) of diethyl ether solution of 3.0 M methyl magnesium bromide were charged under a nitrogen atmosphere. In the ice bath, 19.6 g (142 mmol) of 3-tert-butylcyclopentenone was added dropwise over 1 hour. The resultant solution was stirred at room temperature for 20 hours, and then the reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with 50 ml of ether. The obtained organic layers were combined, washed twice with a saturated aqueous solution of sodium hydrogencarbonate, twice with water, and twice with saturated brine and dried over magnesium sulfate and the solvent was distilled off. Thereafter, the purification was conducted by distillation under reduced pressure to obtain 13.5 g of a pale yellowy transparent liquid. The yield constant was 70%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:33])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:34][C@@H:35]([CH2:48][NH2:49])[CH2:36][O:37][C:38]1[C:46]2[NH:45][C:44](=[O:47])[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1>>[CH2:1]([NH:7][C:8]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:27][CH2:28][CH:29]([NH:49][CH2:48][C@H:35]([OH:34])[CH2:36][O:37][C:38]4[C:46]5[NH:45][C:44](=[O:47])[NH:43][C:42]=5[CH:41]=[CH:40][CH:39]=4)[CH2:30][CH2:31]3)=[CH:22][CH:21]=2)(=[O:17])=[O:18])=[CH:12][CH:11]=1)=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 225) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=6.8 Hz, 3 H), 1.20–1.60 (m, 10 H), 1.90–2.05 (m, 2 H), 2.50–3.50 (m, 9 H), 3.50–3.65 (m, 1 H), 3.95–4.05 (m, 2 H), 6.43 (t, J=5.6 Hz, 1 H), 6.58 (d, J=7.8 Hz, 1 H), 6.61 (d, J=8.2 Hz, 1 H), 6.70–6.89 (m, 5 H), 7.46(d, J=9.0 Hz, 2 H), 7.51(d, J=9.0 Hz, 2 H), 9.06 (s, 1 H), 9.60 (brs, 1 H), 10.60 (s, 1 H), 10.75 (s, 1 H); MS (ES) m/z: 680.3 (MH+); HRMS Calcd. for C34H46N7O6S (MH+): 680.3230. Found: 680.3221.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C)C=O>[N:13]1([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-bromomethylbenzoate (14.75 g) in dimethylformamide (50 ml), cooled to 5° C., was added rapidly morpholine (13.8 ml). The mixture was stirred at room temperature for 2 h. The mixture was partitioned between diethyl ether and water. The organic layer was washed with water, dried (MgSO4), evaporated and purified by column chromatography eluting with ethyl acetate/iso-hexane (20:80) to give methyl 4-(morpholin-4-ylmethyl)benzoate (14.13 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][C:11]23[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2NO)[CH:5]=[CH:6][CH:7]=1.O.[NH2:25]N>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([NH2:25])[C:11]23[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: ONC1CCCCC12C=Nc1ccc(-c3cccc(Cl)c3)cc12
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: NC1=Nc2ccc(-c3cccc(Cl)c3)cc2C12CCCCC2
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 65.2 %

Procedure:
To a turbid solution of 5′-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3 -[3H]indol]-2-amine (0.500 g; 1.53 mmol) in 25 mL of ethanol was added hydrazine hydrate (0.600 mL; 12.24 mmol). The solution was warmed to 55° C., where Raney-nickel (50% in water) was added to the reaction to keep a constant evolution of gas. After 45 minutes, the hot reaction mixture was filtered through a Celite plug and rinsed with a copious amount of hot methanol. The filtrate was concentrated in vacuo to give 0.890 g of an opaque solid. The product was purified by flash silica gel chromatography, (eluant, 2% to 8% methanol-methylene chloride with 0.1% ammonium hydroxide) to afford 0.310 g (65%) of the desired product as a white solid. Mp. 118-120° C. 1H NMR δ (300 MHz, DMSO-d6) 1.31-1.46 (m, 2H), 1.70-1.93 (m, 8H), 7.0 (d, 1H), 7.1 (br, 2H 2NH), 7.31-7.34 (dt, 1H, J=8 Hz), 7.41-7.46 (t, 2H), 7.55-7.58 (d, 1H), 7.62 (s, 1H), 7.72 (s, 1H); MS (ECI(+ve)) m/z 311 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[NH:11][C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.[Br:33][CH2:34][CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:33][CH2:34][CH2:35][N:11]1[C:10]2[N:9]=[C:8]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=3)[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=3)[C:15]=2[C:14](=[O:16])[N:13]([CH3:17])[C:12]1=[O:18]
Reactant: BrCCBr
Reactant: Cn1c(=O)[nH]c2nc(Oc3cccc(OC(F)(F)F)c3)n(Cc3ccc(Cl)cc3)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(CCBr)c1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.215 mmol) in DMF (3 mL) was added 1,2-dibromoethane (0.2 mL, 2.32 mmol), followed by potassium carbonate (60 mg, 0.435 mmol). The mixture was stirred at 50° C. for 16 h. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over sodium sulfate, filtered and concentrated to give the crude product (110 mg, 91.6% yield) as white solid. LCMS retention time 2.099 min; LCMS MH+ 573.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=2[N:14]=1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:35])=O.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH:33]([CH3:35])[CH3:32])[CH:5]=[CH:4][C:3]=1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=2[N:14]=1
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCN4)cc3F)nc12
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 50F (80 mg) in methanol (3 mL) was added triethylamine (67 mL) and acetone (35 mL). This solution was stirred at ambient temperature for 1 hour, treated with sodium cyanoborohydride (30 mg), stirred at 50° C. for 18 hours and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN; 0-100% gradient). 1H NMR (CD3OD) δ 1.33 (d, J=6.71 Hz, 3H), 1.35 (d, J=6.71 Hz, 3H), 2.25-2.34 (m, 3H), 2.58-2.64 (m, 1H), 3.47-3.61 (m, 2H), 3.67-3.74 (m, 1H), 4.72-4.79 (m, 1H), 7.45 (t, J=7.78 Hz, 1H), 7.63 (d, J=8.24 Hz, 1H), 7.66 (d, J=11.90 Hz, 1H), 7.86 (d, J=8.24 Hz, 1H), 8.00 (d, J=7.32 Hz, 1H), 8.48 (t, J=7.78 Hz, 1H).
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]2[S:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:7][CH:6]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:3]([CH2:4][C:5]1[N:10]=[C:9]([C:11]2[S:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:7][CH:6]=1)=[O:30])[CH3:2]
Reactant: CCSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCS(=O)Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
2-[6-[(Ethylthio)methyl]-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.10 g, 0.32 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.071 g, 0.32 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.095 g, 91%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=O)(=[O:14])=[O:13])[CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH:50]1[C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][NH:52]/[C:51]/1=[N:60]\[C:61]([C:63]1[C:68]([NH2:69])=[N:67][C:66]([NH2:70])=[C:65]([Cl:71])[N:64]=1)=[O:62].CN1CCOCC1>CN(C=O)C>[CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([N:57]2[CH2:58][CH2:59][C:54]3([NH:50]/[C:51](=[N:60]/[C:61]([C:63]4[C:68]([NH2:69])=[N:67][C:66]([NH2:70])=[C:65]([Cl:71])[N:64]=4)=[O:62])/[NH:52][CH2:53]3)[CH2:55][CH2:56]2)=[O:20])(=[O:14])=[O:13])[CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3]
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Reactant: CC(C)COC1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)COC1CCN(S(=O)(=O)c2cccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Isobutoxy-piperidine-1-sulfonyl)-benzoic acid (0.03 mmol, 10.2 mg) is treated with a solution of HATU (11.4 mg, 0.03 mmol) in DMF (1 ml) followed by a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (11.9 mg, 0.03 mmol) and N-methyl morpholine (0.010 ml, 0.03 mmol) in DMF (1 ml) and shaken at room temperature overnight. The solution is evaporated under vacuum, redissolved in DMSO (0.5 ml) and purified by mass-directed preparative HPLC. The purified fractions are evaporated under vacuum to afford the title compound; [M+H]+ 648.4
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]1[CH:36]=[CH:35][C:34]2[C@@H:33]3[C@H:24]([C@H:25]4[C@@:29]([CH2:31][C@H:32]3[OH:37])([CH3:30])[C@@H:28]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:27][CH2:26]4)[CH2:23][CH2:22][C:21]=2[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19]1[CH:36]=[CH:35][C:34]2[C@@H:33]3[C@H:24]([C@H:25]4[C@@:29]([CH2:31][C:32]3=[O:37])([CH3:30])[C@@H:28]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:27][CH2:26]4)[CH2:23][CH2:22][C:21]=2[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@]12C[C@@H](O)[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@]12CC(=O)[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
Dichloromethane (92.25 ml) was added to oxalyl dichloride (3.54 ml, 40.59 mmol) under nitrogen atmosphere and the resulting mixture was cooled to −78° C. To this mixture, a solution of dimethyl sulfoxide (5.76 ml, 81.18 mmol) diluted in dichloromethane (18.45 ml) was added dropwise. After the mixture was stirred for 2 minutes at −78° C., a solution of 3,17β-bis(benzyloxy)estra-1,3,5(10)-trien-11α-ol (17.29 g, 36.90 mmol) in dichloromethane (36.90 ml) was added dropwise, followed by stirring for 15 minutes at −78° C. Triethylamine (25.7 ml, 184.5 mmol) was added dropwise to the reaction mixture, which was then stirred for 5 minutes at −78° C. and warmed to room temperature. The reaction mixture was cooled again on ice, quenched by addition of ice and water, and then extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure using an evaporator to give crude 3,17β-bis(benzyloxy)estra-1,3,5(10)-trien-11-one (crude 18.76 g, quant from crude 1H-NMR).
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.O=P(Cl)(Cl)[Cl:18]>C(N(CC)C1C=CC=CC=1)C>[Cl:18][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(SC)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)Cc1c(C)nc(SC)nc1Cl
Yield: 72 %

Procedure:
Methyl (4-hydroxy-6-methyl-2-methylmercapto-5-pyrimidinyl)-acetate (4.0 g, 17 mmol) is heated in a mixture of phosphoroxychloride (40 ml) and N,N-diethylaniline (5.5 ml) for 2 hours at 100° C. The excess phosphoroxychloride was removed by evaporation under vacuum and the residue poured into ice-water. Extraction with ethyl acetate, drying and filtration over silicagel gives methyl (4-chloro-6-methyl-2-methylmercapto-5-pyrimidinyl)-acetate as a crystalline solid (3.1 g, 72%), having a m.p. of 88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[CH:3][CH:4]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 4-aminopyridine (1.00 g, 10.6 mmol) and pyridine (1.01 ml, 12.7 mmol) in tetrahydrofuran (35 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.76 ml, 12.7 mmol), and the mixture was stirred at room temperature for 2 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.05 g (36.6%) of the desired product as a solid was separated by filtration.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][O:11][C:10](=[O:13])[C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1>CN(C=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[C:10](=[O:13])[O:11][CH2:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([CH2:22][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)COC2=O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(CCc4ccc5ccccc5n4)cc3)COC2=O)cc1
Temperature: 80 °C
Yield: 0 %

Procedure:
To a stirred solution of 4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (280 mg, 0.99 mol) in DMF (5 mL) were added K2CO3 (274 mg, 1.98 mol) and 2-(chloromethyl)quinoline (255 mg, 1.19 mol) at RT. The reaction mixture was then heated at 80° C. for 3 h, quenched with ice and then extracted with EtOAc (2×20 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography using 20% ethyl acetate in hexanes to afford 3-(4-methoxyphenyl)-4-(4-(2-(quinolin-2-yl)ethyl)phenyl)furan-2(5H)-one (50 mg, 12%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:26][OH:27])=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:26][O:27][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:9]([CH2:11][N:12]3[CH2:13][CH2:14][N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[CH2:16][CH2:17]3)[N:10]=2)[CH:7]=1
Reactant: OCc1c(CN2CCN(c3ccc(Cl)cc3Cl)CC2)nc2ccc(Cl)cn12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(N2CCN(Cc3nc4ccc(Cl)cn4c3COCc3ccccc3)CC2)c(Cl)c1
Reaction time: 0.12 h

Procedure:
To 6-chloro-2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]imidazo[1,2-a]pyridine-3-methanol (Example 44; 0.0651 g) in THF (1 mL) is added sodium hydride (Aldrich, 60% dispersion in mineral oil; 0.0067 g). After 7 min, benzyl bromide (Aldrich; 0.020 mL) is added and the mixture is stirred for an additional 4.5 h, at which time it is partitioned between dichloromethane and aq. sodium bicarbonate/brine. The organic layers are filtered through sodium sulfate and concentrated, and the residue is chromatographed on silica gel using methanol/dichloromethane (2/98) to give 0.061 g of 6-chloro-2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-3-[(phenylmethoxy)methyl]imidazo[1,2-a]pyridine. The methanesulfonic acid salt is prepared by dissolving the product in dichloromethane and adding methanesulfonic acid (1 equivalent) and concentrating the mixture under reduced pressure. Crystallization from ethyl acetate/hexane affords 0.050 g of the title compound; mp 159-160.5° C.; MS m/z 514, 516; IR (mineral oil) 806, 1170, 1042, 1188, 1480 cm-1. 1H NMR (CDCl3) δ 2.68, 3.02, 3.75, 4.57, 4.91, 6.92, 7.17, 7.36, 7.53, 8.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:27]([C:29]1[C:30](F)=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28])[CH:20]=[CH:19]2.C([O-])([O-])=O.[K+].[K+].[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][OH:46]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:27]([C:29]1[C:30]([O:46][CH2:45][CH2:44][N:43]([CH3:47])[CH3:42])=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28])[CH:20]=[CH:19]2
Reactant: CN(C)CCO
Reactant: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5cccnc5F)ccc4c3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5cccnc5OCCN(C)C)ccc4c3)c2cc1OC
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a mixture of N-[6-(6,7-dimethoxy-(4-quinolyloxy)) (2-naphthyl)](2-fluoro-(3-pyridyl))carboxamide (Step a, 62 mg, 0.13 mmol) and K2CO3 (166 mg, 1.3 mmol) in dry NMP (5 mL, Aldrich) was added N,N-dimethylethanolamine (35 mg, 0.36 mmol, Aldrich) at RT. The reaction was stirred at 110° C. for 16 h. The mixture was cooled and diluted with 60 mL of EtOAc, then washed with water and brine. The organic phase was dried over MgSO4 and concentrated. The residue was purified by prep-HPLC to give title compound as a white solid. MS (ESI, pos. ion) m/z: 539 (M+1). Mass Calc'd for C31H30N4O5: 538.22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13].O>COCCOC.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.[Zn]>[CH3:13][CH:12]([CH3:14])[C:11](=[O:15])[CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CBr)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(CC(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of Pd(PPh3)2Cl2 (0.86 g, 1.22 mmol) and zinc powder (3.19 g, 48.8 mmol) in 1,2-dimethoxyethane (DME, 100 mL) at room temperature was slowly added a solution of 3-methoxybenzyl bromide (5.0 g, 24.4 mmol) and isobutyryl chloride in DME (25 mL). The mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with ether. The combined ether extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (20:1) to give 3.03 g (64) of compound (§4 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.09 (d, J=7.0 Hz, 6H), 2.70-2.75 (m, 1H), 3.70 (s, 2H), 3.79 (s, 3H), 6.70-6.85 (m, 3H), 7.23 (t, J=8.0 Hz, 1H).