Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[N:7][C:6]=1Cl)[CH3:2].[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[N:7][C:6]=1[O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:33])[F:34])[CH:27]=1)[CH3:2]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1cc(F)c(Oc2ccc(C#N)cc2)nc1Cl
Product: CCOC(=O)c1cc(F)c(Oc2ccc(C#N)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Yield: 52 %

Procedure:
2-chloro-6-(4-cyano phenoxy)-5-fluoro nicotinic acid ethyl ester (2.4 g, 7.49 mmol) and 3-trifluoromethoxyphenol (1.33 g, 7.49 mmol) were coupled using the procedure of Example 17(b) to afford 1.8 g of the required product. 1H NMR (DMSO-d6): δ 1.35 (3H, t), 4.4 (2H, q), 7.22 (2H, d), 7.3 (3H, d), 7.34 (1H, m), 7.54 (2H, d), 8.38 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:26])[N:6]2[C:11]1[CH:12]=[C:13]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.[O:27]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:37]1[CH:38]=[CH:39][C:34]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:35][CH:36]=1)[C:5](=[O:26])[N:6]2[C:11]1[CH:12]=[C:13]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(-n2c(=O)[nH]c3c(N)ncnc32)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Temperature: 37 °C

Procedure:
To a mixture of tert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (24) (600 mg, 1.68 mmol) and 4 A MS (800 mg) in dry DMF (10 mL) were added 4-phenoxyphenylboronic acid (1.08 g, 5.06 mmol), Cu(OAc)2 (307 mg, 1.68 mmol) and pyridine (1 mL). The reaction mixture was heated to 37° C. overnight under O2 atmosphere, and filtered through a Celite pad. The filtrate was diluted with water (30 mL), extracted with EtOAc (10 mL×3). The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in methylene chloride) to give tert-butyl 3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl(methyl)carbamate as a light yellow solid (31) (450 mg, 51%). LC-MS (ESI): m/z (M+1) 525.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[S:12]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:13]=[C:11]([C:10]2[CH:9]=[C:8]([OH:7])[CH:16]=[CH:15][CH:14]=2)[S:12][CH:5]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1cccc(O)c1
Solvent: Cc1ccccc1
Product: Oc1cccc(-c2nc(CCl)cs2)c1
Temperature: 120 °C
Yield: 38.1 %

Procedure:
To a solution of 1,3 dichloroacetone (0.42 g, 3.26 mmol) in toluene (5 mL) was added 3-hydroxythiobenzamide (0.25 g, 1.63 mmol) and the reaction mixture was heated at 120° C. for 1 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness, added water and extracted with EtOAc (×3). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 10% EtOAc-Hexane) to get the desired product (0.14 g, 38%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)(O)[O-].[Na+].O>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>[C:40]1([C:2]2[CH:3]=[C:4]([CH:8]([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(-c5ccccc5)c4)c3)ncnc21
Temperature: 80 °C
Yield: 95.8 %

Procedure:
To a solution of 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (from Example 429) (60 mg, 0.0001 mol) in 1,4-dioxane (2 mL, 0.02 mol), phenylboronic acid (15 mg, 0.00012 mol) and sodium bicarbonate (30 mg, 0.0003 mol) in water (0.5 mL, 0.03 mol) were added. The resulting mixture was degassed using nitrogen. Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.00001 mol) was added and nitrogen was bubbled through the reaction again. The reaction was heated at 80° C. in oil bath for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (50 mg, 80%) as a crude product. MS (ES): 522 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:20])(=[O:19])[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[CH2:21]=[O:22].[Li][Li].Cl>O1CCCC1>[CH3:17][CH:16]([CH3:18])[CH2:15][CH:14]([CH2:21][OH:22])[C:13]([OH:20])=[O:19]
Reactant: CC(C)CCC(=O)O
Reactant: C=O
Agent: Cl
Agent: [Li]CCCC
Agent: [Li][Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)CC(CO)C(=O)O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
Diisopropylamine (20.6 g) is dissolved in 80 ml of dry tetrahydrofuran. This solution is cooled to -30° C. n-Butyllithium (77 ml of 2.6 M in hexane) is added dropwise in a nitrogen atmosphere at a rate that maintains the reaction at -30° to -20° C., and this solution is stirred at -20° C. for 30 minutes. Isocaproic acid (11.6 g) in 10 ml of tetrahydrofuran is added dropwise at -20° to -10° C., then stirred at -10° C. for 30 minutes. In a separate flask, paraformaldehyde (28 g) is heated to about 200° C. and the vapors are carried in a stream of nitrogen over the surface of the tetrahydrofuran solution of the dilithium salt of isocaproic acid. During this procedure the temperature is kept between -10° and +10° C. After all of the paraformaldehyde has vaporized the reaction mixture is cooled to 0° C. and 10% hydrochloric acid is added dropwise until the reaction mixture becomes acidic. Product is extracted with 2 portions of ether (400 ml each). The ether is dried with magnesium sulfate, filtered and concentrated in vacuo to yield 13.2 g of crude material. Product is vacuum distilled to yield 9.0 g, boiling point 135°-142° C./9 mm of Hg.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8](=[O:10])[CH3:9].[Cr](Cl)([O-])(=O)=[O:13].[NH+]1C=CC=CC=1.N1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:13])[C:8](=[O:10])[CH3:9]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC(=O)Cc1ccccc1C
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(=O)c1ccccc1C
Yield: 15.4 %

Procedure:
A mixture of 7 g (47.23 mmol) 1-o-Tolyl-propan-2-one, 30.5 g (0.141 mol) pyridinium chlorochromate and 11.2 g (0.141 mol) pyridine in 200 ml DCM was heated to reflux for 16 h. The mixture was filtered through a pad of silica and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with ethyl acetate/n-hexane 1:4. The product fractions were evaporated to yield 1.178 g (15%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][C@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3][C@@H:2]1[C:11]([O:13]C)=[O:12].C(=O)C1C(=CC=CC=1)O>C(O)(=O)C>[CH3:10][O:9][C:7]([C@H:5]1[CH2:6][NH:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4]1)=[O:8]
Reactant: COC(=O)[C@@H]1CC[C@H](C(=O)OC)NC1
Solvent: CC(=O)O
Solvent: O=Cc1ccccc1O
Product: COC(=O)[C@@H]1CC[C@H](C(=O)O)NC1
Temperature: 100 °C

Procedure:
Dimethyl cis-piperidine-2,5-dicarboxylate (112 g, 0.56 mol), salicylaldehyde (3 ml, 0.056 mol) and glacial acetic acid (600 ml) were combined and the resulting mixture heated at about 100° C. for 60 hours. The mixture was cooled, than stripped in vacuo to a thick oil from which 61.7 g (59%) of title products crystallized upon stirring with 800 ml of isopropyl alcohol. Product ratio was determined by 1H-NMR (D2O, 300 MHz), a peak at 3.13 pp, (t, 1 H, J=14.5 Hz) being diagnostic of trans, and a peak at 3.3 ppm (dd, 1H) being diagnostic of cis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.C1C(=O)N([Br:24])C(=O)C1.O>FC(F)(F)C(O)=O>[Br:24][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added con. sulfuric acid (12.5 mL) followed by NBS (17.2 g, 96.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was poured into ice and water and stirred for 15 min. Extracted with ethyl acetate and the organic layer was washed with brine, dried, concentrated to get compound 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (15.0 g, 100%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) 2.41 (s, 3H), 7.96 (dd, J=8.0, 2.4 Hz, 1H), 8.02 (dd, J=8.0, 2.4 Hz, 1H). A mixture of above prepared compound (15.0 g, 64.4 mmol), Fe (18.0 g, 0.32 mol), con. HCl (2 mL) in MeOH (150 mL) and water (30 mL) was stirred at reflux for 4 h. Then the mixture was adjusted to pH 12 with aqueous NaOH solution and filtered. The solvent was removed and diluted with water. Extracted with ethyl acetate, dried, concentrated. The residue was purified by column chromatograph (ethyl acetate in petroleum ether, 7%) to get compound 0104-69 (5.8 g, 44%) as yellow oil. LCMS: 204 [M+1]+, 1H NMR (400 MHz, DMSO-d6) 2.12 (s, 3H), 5.57 (s, 2H), 6.45 (dd, J=11.2, 2.4 Hz, 1H), 6.60 (dd, J=8.0, 2.4 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:19][O:20][CH:21]([O:25][CH3:26])[CH:22]([NH2:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CS(C)=O>[CH3:19][O:20][CH:21]([O:25][CH3:26])[CH:22]([NH:24][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH3:23]
Reactant: COC(OC)C(C)N
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(OC)C(C)Nc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of benzyl 3-chloro-4-nitrophenyl ether (48.2 g, 0.183 mole), 2-aminopropionaldehyde dimethyl acetal (65.3 g, 0.55 mole), potassium carbonate (101 g, 0.73 mole) and toluene in dry dimethyl sulfoxide, under nitrogen, is stirred at 99°-105° C. for 20 hours, cooled to room temperature and filtered. The filter cake is washed with ether. The combined filtrates are mixed with ice water. The phases are separated and the aqueous phase is extracted with ether. The ether extracts are combined with the organic phase. The combined organic phase is washed with six portions of water, dried (Na2SO4) and concentrated in vacuo to give an oil residue which is crystallized in methanol to afford the title product as a yellow solid, 39.6 g (64.5%). A sample is recrystallized from methanol to afford a yellow solid, mp 57°-62° C., identified by elemental and NMR analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([CH2:14][C:15](=O)[CH3:16])[CH2:10][C:9]=3[C:18](=[O:20])[O:19][C:4]=2[CH:3]=1.[CH3:21][NH:22][CH3:23]>>[CH3:21][N:22]([CH3:23])[CH:15]([CH3:16])[CH2:14][N:11]1[CH2:12][CH2:13][C:8]2[C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[O:19][C:18](=[O:20])[C:9]=2[CH2:10]1
Reactant: CC(=O)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1
Reactant: CNC
Product: Cc1ccc2c3c(c(=O)oc2c1)CN(CC(C)N(C)C)CC3
Yield: 57.1 %

Procedure:
Prepared by the method described for Example 38 from 1,2,3,4-tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 0.007 moles) and dimethylamine (5 g, 0.111 moles). Recrystallization from ethanol gave the product (1.2 g) as the dihydrochloride 10:7 hydrate, mp 224° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13]O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.S(Cl)([Cl:17])=O.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:17][CH2:13][C:3]1[C:2]([CH3:1])=[N:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nn(-c2ccccc2)nc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1nn(-c2ccccc2)nc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
5.0 g of (5-methyl-2-phenyl-1,2,3-triazol4-yl)methan-1-ol was dissolved in 35 ml of dichloromethane, then 6.3 g of thionyl chloride was added dropwise thereto under cooling with ice. After stirring for 1 hour at room temperature, 100 ml of water was added. The resulting solution was made alkaline with 8 g of potassium carbonate, then extracted with chloroform. The organic phase was washed with water and a saturated salt solution, then dried over anhydrous sodium sulfate. After the solvent was distilled off, 5.2 g of the aimed compound was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1.O.[NH2:22][NH2:23]>CO>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:22][NH2:23])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1
Reactant: CSc1ccc2c(c1)C(c1ccccn1)=NCC(=S)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CSc1ccc2c(c1)C(c1ccccn1)=NCC(NN)=N2

Procedure:
According to the procedure of Preparation 1, 7-methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-thione is reacted with hydrazine hydrate in methanol to give 7-methylthio-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl hydrazine.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13]COCC.[Br:18][C:19]1[CH:20]=[C:21]2[C:31](=[CH:32][CH:33]=1)[O:30][C:24]1[CH:25]=[N:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:22]2=[N:34]S(C(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[NH2:34][C:22]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[C:23]2[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:24]=2[O:30][C:31]2[C:21]1=[CH:20][C:19]([Br:18])=[CH:33][CH:32]=2
Reactant: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Reactant: CCOCOc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1(c2ccccc2O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Butyllithium solution, 2.5m in hexanes (1.257 mL, 3.14 mmol) was added dropwise to a solution of 1-bromo-2-(ethoxymethoxy)benzene (0.726 g, 3.14 mmol) in THF 20 mL at −78° C. The reaction was stirred for 25 min. Then N-(7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide (1.0 g, 2.417 mmol) in THF was added. The reaction was warmed up to RT and stirred for an hour. The reaction was quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic phase was separated and washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography with gradient of 15-50% EtOAc/Hexane. The resulting material was dissolved in dry MeOH 10 mL and cooled in an ice bath. Hydrochloric acid, 4.0M solution in 1,4-dioxane (20 mL, 80 mmol) was added and mixture was stirred at RT for 4 h. The reaction was quenched with 10% sodium carbonate solution and extracted with DCM three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated to give the desired product which was used without further purificationMS m/z=402.8 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][O:5][C:6](=[O:21])[C:7]([CH2:9][C:10]([O:12]CC(CC)CCCC)=O)=[CH2:8])[CH3:2].[CH2:26]([CH:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29][NH2:30])[CH3:27]>>[CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][O:5][C:6]([CH:7]1[CH2:9][C:10](=[O:12])[N:30]([CH2:29][CH:28]([CH2:26][CH3:27])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:8]1)=[O:21])[CH3:2]
Reactant: C=C(CC(=O)OCC(CC)CCCC)C(=O)OCC(CC)CCCC
Reactant: CCCCC(CC)CN
Product: CCCCC(CC)COC(=O)C1CC(=O)N(CC(CC)CCCC)C1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Bis(2-ethylhexyl)itaconate (400 g; 1.13 Mol) was charged to a 1 L reaction vessel and the material stirred mechanically under nitrogen while heating to 45° C. 2-Ethylhexylamine (1.02 equiv.: 1.15 Mol; 148.7 g) was charged to a pressure-equalizing addition funnel and the amine added dropwise to the stirred diester over the course of one hour. During the addition, a moderate exotherm was observed and the mixture was allowed to heat to 70° C. When the addition was complete, the mixture was heated to 75° C. and held for one hour before cooling to room temperature overnight. The following day, the vessel was equipped with a distillation sidearm/condenser and heated to 120 to 125° C. under reduced pressure (−30″ Hg) (−762 mm) in order to remove 2-ethylhexanol and excess amine. When stripping was complete, the apparatus was backfilled with nitrogen and cooled to room temperature. The amount of 2-ethylhexanol collected was 141.7 g (1.09 Mol; 96.5% of theoretical recovery). The stripped product was warmed to 50° C. and filtered through a 1″ (2.5 cm) plug of silica gel, giving the final product as a light yellow liquid. H-NMR analysis of the product was consistent with the expected product. Sample materials were collected from this preparation and designated 1-(2-ethylhexyl)-5-oxo-3-pyrrolidinecarboxylic acid 2-ethylhexyl ester for comparison testing described in the Examples below.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:19]=[C:11]3[C:12]4[C:17]([CH2:18][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1.[O-][CH2:21][CH3:22].[Na+].C(I)C>C(O)C>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:19]=[C:11]3[C:12]4[C:17]([CH2:18][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1)[CH3:22]
Reactant: CC[O-]
Reactant: Oc1cccc(-c2nc3n(n2)Cc2ccccc2-3)c1
Agent: [Na+]
Solvent: CCI
Solvent: CCO
Product: CCOc1cccc(-c2nc3n(n2)Cc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
2-(3-Hydroxyphenyl)-5H-s-triazolo[5,1-a] isoindole (1.25 g, 0.05 mole) is added to 20 ml of ethanol containing one equivalent proportion of sodium ethoxide. To this mixture is added 0.49 ml (0.06 mole) of ethyl iodide in 5 ml of ethanol. After stirring for one hour at room temperature, a further amount of 0.49 ml of ethyl iodide is added. After refluxing for one hour the solvent is distilled off and the residue is washed with water and extracted with dichloromethane. Evaporation of the solvent and crystallization of the residue from ethanol gives 1 g (73%) of the title product, m.p. 166°-7° C.
Reaction SMILES: CS(O)(=O)=O.O[CH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:28]2[CH2:29][CH2:30][N:31]([CH2:7][CH2:8][CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[CH2:32][CH2:33]2)=[CH:39][CH:38]=1
Reactant: O=c1[nH]c2ccccc2n1CCCO
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 2.7 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 2.88 parts of 1-[bis(p-fluorophenyl)methyl]piperazine, 2.66 parts of sodium carbonate and 100 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 1-[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 197.3° C.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:2].[CH2:16]([Zn]CC)C.ICI.C([O-])(=O)C.[NH4+]>C(OCC)C>[CH:1]1([O:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][CH2:2]1
Reactant: CC[Zn]CC
Reactant: C=COCCCCOCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ICI
Solvent: CCOCC
Product: c1ccc(COCCCCOC2CC2)cc1

Procedure:
To a solution of {[4-(vinyloxy)butoxy]methyl}benzene (3.16 g) in diethyl ether (63 mL) was added diethyl zinc (1.0M, hexane solution) (30.6 mL) under nitrogen atmosphere, and a solution of diiodomethane (8.49 g) in diethyl ether (13 mL) was added dropwise thereto. The reaction liquid was stirred under reflux for 1 hour, followed by stirring at room temperature for 12 hours. A saturated aqueous ammonium acetate solution (80 mL) was added to the reaction liquid, followed by extraction with diethyl ether (400 mL). The organic layer was washed sequentially with a saturated aqueous ammonium acetate solution and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=95/5) to obtain {[4-(cyclopropyloxy)butoxy]methyl}benzene (2.41 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([OH:10])=[C:2]([N:1]=[CH:14][C:13]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=2[F:11])[CH:7]=1
Reactant: Nc1cc(Br)c(F)cc1O
Reactant: O=Cc1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1cc(F)c(Br)cc1N=Cc1ccc(F)cc1F
Temperature: 25 °C

Procedure:
A solution of 2-amino-4-bromo-5-fluorophenol (10.1 g, 49 mmol), 2,4-difluorobenzaldehyde (5.36 mL, 49 mmol) and p-toluenesulfonic acid (100 mg, 0.52 mmol) in toluene (250 mL) was heated to reflux in a Dean-Stark apparatus for 0.5 h and then allowed to cool to ambient temperature. After adding triethylamine (1 mL) the reaction mixture was concentrated under reduced pressure to give the crude compound which was used without further purification. (16.1 g, 99%). 1H-NMR (400 MHz, CDCl3) 6.83 (d, J=10.2, 1H), 6.93 (m, 1H), 7.01 (m, 1H), 7.49 (d, J=7.6, 1H), 8.13 (m, 1H), 8.85 (s, 1H).