Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[N:12]1([C:17]([S-:19])=[S:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.[NH4+].C(O)(=O)C>CO>[N:12]1([C:17]([S:19][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[S:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: S=C([S-])N1CCCC1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])CC(SC(=S)N1CCCC1)c1ccccc1
Temperature: 10 °C
Yield: 77 %

Procedure:
β-Nitrostyrene (7.5 grams, 0.050 mole) was added to a cooled (10° C.) stirred slurry of ammonium 1-pyrrolidinecarbodithioate (8.2 grams, 0.050 mole) in methanol (50 ml.). The temperature of the mixture fell to 5° C., then rapidly climbed to 10° C. The cooling bath was removed and the reaction temperature rose slowly to 22° C. Acetic acid (3.0 grams, 0.05 mole) was added, the slurry was cooled to 10° C. and the solid was filtered off, washed with water, and dried in air. The crude product melted at 108° C.-116° C. and weighed 11.4 grams (77% yield). Repeated recrystallizations from cool acetone-methanol, hot acetone-2-propanol, and cool methylene chloride-toluene-hexane solutions gave pure α-(nitromethyl)benzyl 1-pyrrolidinecarbodithioate melting at 116° C.-120° C. (sintering at 113° C.).
Reaction SMILES: [NH2:1][C:2]1[C:18]([Br:19])=[CH:17][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Br:20].ClC(OCC)=O.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Br:20])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:8]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:10])=[CH:17][C:18]=1[Br:19]
Reactant: Nc1c(Br)cc(C(=CC(=O)O)c2ccccc2)cc1Br
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Br)cc(C(=CC(=O)N2CCOCC2)c2ccccc2)cc1Br

Procedure:
This compound was prepared from 4-amino-3,5-dibromo-β-phenyl-cinnamic acid (isomer ratio A:B=1:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 1(c). Melting point of the 1:1 mixture of isomers A and B: 156°-174° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1.Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22]>CCCCCC.C1COCC1>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])[C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CCN(C)CC3)CC1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
The title compound was prepared by following general procedure 7. Sodium hydride (34 mg, 0.43 mmol) washed with hexane for removal of oil and dried under vacuum and taken in THF. To this solution 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.43 mmol) in THF was added dropwise at 0° C. Then the reaction mixture was stirred for 0.5 h. The solution of 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (89 mg, 0.51 mmol) in THF was added dropwise in reaction mixture. Then the reaction mixture was stirred at RT for 2 h. The reaction monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water. THF was evaporated and aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to gives 95 mg of desired compound, which was stirred with ethanolic HCl to give the HCl salt of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methylpiperidin-1-yl)ethanone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: Nc1ccccc1S
Reactant: N#Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Sc1ccccc1N
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
In 10 ml of DMF was dissolved 1.25 g of orthoaminothiophenol followed by addition of 1.38 g of potassium carbonate. The mixture was preheated at 100° C. and after 1.45 g of o-chlorobenzonitrile was added, the mixture was stirred in an argon gas stream at 100° C. for 1 hour. To the reaction mixture was added ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water twice and dried over magnesium sulfate and the solvent was distilled off. The residue was crystallized from n-hexane-isopropyl ether to give 1.91 g of the title compound as white crystals, m.p. 88°-90° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:18]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[CH:31]=4)[CH:12]=3)[N:9]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: COc1cccc(CBr)c1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of 3-(8-amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (28 mg, 0.1 mmol) in anhydrous DMF (1 ml) was added cesium carbonate (49 mg, 0.15 mmol) followed by a solution of 3-methoxybenzyl bromide (20 mg, 0.1 mmol) in DMF (0.5 ml). The reaction was stirred at room temperature overnight. The reaction was poured onto saturated NaHCO3 (10 ml) and extracted with EtOAc (2×10 ml). The combined organics were washed with water (10 ml) and aqueous brine solution (3×10 ml), dried (MgSO4), filtered and concentrated in vacuo, to give 3-cyclobutyl-1-[3-(3-methoxy-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-8-ylamine as a brown solid (24.1 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.42 (t, 1H, J=7.8 Hz), 7.35-7.27 (m, 3H), 7.13 (d, 1H, J=5.1 Hz), 7.08-7.03 (m, 4H), 6.90 (d, 1H, J=8.6 Hz), 5.17 (s, 2H), 3.84 (s, 3H), 3.86-3.79 (m, 1H, obscured), 2.72-2.62 (m, 2H), 2.56-2.47 (m, 2H), 2.25-2.14 (m, 1H), 2.11-2.02 (m, 1H), 2H not observed (NH2); LCMS (ES+) m/z 401.34 [MH+] at Rt 3.20 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:13]Br>C(O)(=O)C.O>[Br:13][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:3]=[C:2]([Cl:1])[C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1cc(Cl)c(O)c(Br)c1

Procedure:
To a solution of 3-chloro-4-hydroxyphenylacetic acid (2.5 g) in glacial acetic acid (35 mL) was added 0.8 mL of neat bromine carefully while stirring. The mixture was stirred in dark at ambient temperature for 51 h. The resulting mixture was diluted with water, extracted with ethyl acetate, dried and concentrated in vacuo to afford 3-bromo-5-chloro-4-hydrox-yphenylacetic acid. This crude product was dissolved in methanol (15 mL), treated with concentrated sulfuric acid (1 mL) carefully, stirred at reflux for 18 h. Cooled reaction mixture was concentrated under reduced pressure, diluted with water carefully, extracted with dichloromethane. The combined organic layers were dried and concentrated. Flash column chromatography on silica gel with ethyl acetate/hexane (0-50% gradient elution) afforded 3-bromo-5-chloro-4-hydroxyphenylacetic acid methyl ester (2.5 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]3[N:10]=[C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]4[C:18](=[O:20])[C:19]=3[C:6]=2[CH2:5][CH2:4][C:3]=1[CH:21]=[O:22].[CH2:23]([O:25][C:26](C1CCN2C(=O)C3C4CCCC(=O)C=4SC=3N=C2CC1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([CH:15]1[CH2:14][CH2:13][N:12]2[C:18](=[O:20])[C:19]3[C:6]4[CH2:5][CH2:4][C:3]([CH:21]=[O:22])=[C:2]([Cl:1])[C:7]=4[S:8][C:9]=3[N:10]=[C:11]2[CH2:17][CH2:16]1)=[O:27])[CH3:24]
Reactant: O=CC1=C(Cl)c2sc3nc4n(c(=O)c3c2CC1)CCCCC4
Reactant: CCOC(=O)C1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O
Product: CCOC(=O)C1CCc2nc3sc4c(c3c(=O)n2CC1)CCC(C=O)=C4Cl
Reaction time: 192 h

Procedure:
Compound 21 was synthesized by the method described for 4a using compound 19 as a starting material, with the exception that the reaction mixture was stirred for 8 days.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[S:11][C:10]=1[C:18]([O:20]C)=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1COCC1.CO.[OH-].[Na+]>O>[C:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[S:11][C:10]=1[C:18]([OH:20])=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C)sc1C(=O)O
Temperature: 60 °C
Yield: 64.6 %

Procedure:
To a solution of methyl 3-(N-carbo-tert-butoxyamino)-5-tert-butylthiophene-2-carboxylate (10.7 g, 34.1 mmol) in a 2:1:1 mixture of THF, MeOH and H2O (340 mL) was added NaOH (4.09 g, 102.3 mmol, 3.0 equiv). The resulting solution was heated at 60° C. for 18 h, cooled to room temp. and concentrated under reduced pressure. The residue was separated between H2O (500 mL) and EtOAc (250 mL). The aqueous phase was adjusted to pH 2 with a 10% HCl solution, then extracted with EtOAc (2×400 mL). The organic phase was washed with a saturated NaCl solution (250 mL), dried (MgSO4), and concentrated under reduced pressure to afford 3-(N-carbo-tert-butoxyamino)-5-tert-butylthiophene-2-carboxylic acid as an orange solid (6.6 g, 65%). This material was used in the next step without further purification. An analytical sample of the carboxylic acid was further purified: mp 187-8° C., TLC (10% MeOH/CH2Cl2) Rf0.17; 1H NMR (CDCl3) δ1.40 (s, 9H), 1.54 (s, 9H), 7.73 (s, 1H), 9.19 (s, 1H); 13C NMR (CDCl3) δ28.2 (3C), 31.8 (3C), 35.4, 81.3, 104.6, 116.7, 146.7, 151.9, 166.6, 169.3; FAB-LRMS m/z (rel abundance) 300 (M+H, 30%).
Reaction SMILES: [N+:1]([C:4]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:23][CH3:24])=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.C(OC1[C:47](OC)=[CH:46][C:42](C(Cl)=O)=[C:41]([N+:50]([O-])=O)[C:40]=1[O:53]C)C1C=CC=CC=1.N1(CO)CCCC1>CN(C=O)C.CC#N.C(Cl)Cl>[CH2:16]([O:15][C:11]1[C:10]([O:23][CH3:24])=[CH:9][C:5]([C:6]([N:50]2[CH2:47][CH2:46][CH2:42][CH:41]2[CH2:40][OH:53])=[O:8])=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=1[O:13][CH3:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C(=O)Cl)c([N+](=O)[O-])c(OC)c1OCc1ccccc1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: OCN1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1OCc1ccccc1
Reaction time: 8 h
Yield: 70 %

Procedure:
A catalytic amount of DMF (5 drops) was added to a stirred solution of 124 (10 g, 30.0 mmol) and oxalyl chloride (4.65 g, 36.0 mmol) in dry CH3CN (115 mL) under a nitrogen atmosphere. The reaction mixture was allowed to stir overnight and the resulting acid chloride used directly in the next part of the procedure. 4-benzyloxy-3,5-dimethoxy-2-nitro-benzoyl chloride in anhydrous CH3CN (115 mL) was added dropwise over 0.5 hours to a stirring solution of pyrrolidine methanol (3.34 g, 33.03 mmol, 1.1 eq) and TEA (7.58 g, 75.1 mmol, 2.5 eq) in anhydrous DCM (100 mL) at 0° C. under a nitrogen atmosphere and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was washed with 1N HCl (2×100 mL), and the organic layer was washed with distilled H2O (2×100 mL), brine (2×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent yielded a brown glass (8.71 g, 20.9 mmol, 70%); 1H NMR (270 MHz, CDCl3) δ 1.7-2.2 (m, 4H), 3.3-3.5 (m, 2H), 3.7-3.9 (m, 2H), 3.9 (s, 3H), 4.0 (s, 3H), 4.2-4.3 (m, 1H), 5.1 (s, 2H), 6.85 (s, 1H), 7.3-7.5 (m, 5H); 13C NMR (67.8 MHz, CDCl3) δ 167.3, 156.8, 148.2, 142.3, 136.4, 136.0, 129.0, 128.5, 128.4, 104.8, 75.6, 65.7, 62.8, 61.4, 56.6, 50.2, 28.3, 24.5.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:45]=[CH:44][C:38]2[O:39][CH2:40][CH2:41][CH2:42][O:43][C:37]=2[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[O:39]1[C:38]2[CH:44]=[CH:45][C:35]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[CH:21][CH:22]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)=[CH:36][C:37]=2[O:43][CH2:42][CH2:41][CH2:40]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCCCO2
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc5c(c4)OCCCO5)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3,4-dihydro-2H-1,5-benzodioxepin-7-yl borate (123 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 66) (194 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10]([CH3:11])=[C:9]2[C:12](=[C:16]=[O:17])[CH:13]=[CH:14][CH:15]=[C:8]2[O:7]1)=[O:5])[CH3:2].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Oc2cccc(=C=O)c2=C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1oc2cccc(CO)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 0.123 g (0.530 mmol) of 4-carbonyl-3-methylbenzofuran-2-carboxylic acid ethyl ester in 10 mL of ethanol was added 0.019 g (0.505 mmol) of sodium borohydride. The reaction was stirred at room temperature for 2 h and than diluted wuth water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide 0.113 g of 4-hydroxymethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[C:6]([CH:14]=1)[CH:7]=[C:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)=[C:6]([CH:14]=1)[CH2:7][CH:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13]
Reactant: CN1CCN(c2ccc(F)cc2C=C2CCNC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(F)cc2CC2CCNC2=O)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
To a solution of 3.9 g (13.5 mmol) of 3-[5-Fluoro-2-(4-methyl-piperazin-1-yl)-benzylidene]-pyrrolidin-2-one in 150 mL of methanol is added 1.0 g of Pd/C. Hydrogenation at 50 psi with heating to 50° C. was complete after 24 hours. The reaction was filtered over Celite™ using methanol and concentrated. The resultant residue was purified by silica gel chromatography to provide 3.8 g (98% yield) of 3-[5-Fluoro-2-(4-methyl-piperazin-1-yl)-benzyl]-pyrrolidin-2-one. Diagnostic C13 NMR (100 MHz, CDCl3) 27.3, 31.7, 40.5, 42.1, 46.2, 53.0, 55.8, 113.7, 113.9, 116.6, 116.8, 122.3, 122.4, 137.9, 148.0, 161.0; MS m/z 292.2 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:20]([F:22])[F:21])=[C:14]([CH:19]=1)[C:15]([O:17]C)=[O:16].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[F:21][CH:20]([F:22])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:19][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cc(CN)ccc1C(F)F
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1ccc(C(F)F)c(C(=O)O)c1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Add isobutyryl chloride (0.571 mL, 5.42 mmol, 1.05 equiv) to a mixture of methyl 5-(aminomethyl)-2-(difluoromethyl)benzoate hydrochloride (1.30 g, 5.17 mmol, 1.0 equiv) and triethylamine (1.51 mL, 10.85 mmol, 2.1 equiv) in DCM (50 mL) at room temperature and stir the mixture for one hour. Dilute the mixture with DCM; wash with water; then with a saturated sodium chloride aqueous solution. Separate the organic layer; dry over sodium sulfate; filter; and concentrate the filtrate under reduced pressure. Dissolve the resulting crude material in 1,4-dioxane (10 mL), and add sodium hydroxide (5 N, 2 mL, 10 mmol, 1.93 equiv). Stir the resulting suspension at 40° C. overnight. Concentrate the mixture under reduced pressure, and treat the resulting residue with 1 N aqueous hydrochloric acid until the pH reaches 3. Extract the resulting suspension with EtOAc (2×30 mL). Wash the combined organic layers with a saturated sodium chloride aqueous solution (50 mL); dry over sodium sulfate; filter; and concentrate the filtrate under reduced pressure to give the title compound as a white solid (1.32 g, 94% yield). ES/MS (m/z) 272 (M+1).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22](Br)[CH:23]=[CH:24][CH:25]=1>C(Cl)Cl>[F:18][C:19]([F:28])([F:27])[C:20]1[CH:25]=[C:24]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:23]=[CH:22][CH:21]=1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: FC(F)(F)c1cccc(Br)c1
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cccc(C(F)(F)F)c1)O2

Procedure:
This compound was similarly prepared by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 3-trifluoromethylbromobenzene as described in Example 26. The product was isolated by chromatography over 50 fold amount of silica gel using methylene chloride for elution. Crystallization of the combined clean fractions from petroleum ether gave colorless crystals with m.p. 81°-83°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.CC#N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:1][C:2]2[CH:7]=[N:6][N:5]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:4](=[O:14])[CH:3]=2)=[CH:18][CH:19]=1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1cc(OCc2ccc(Cl)cc2)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a mixture of 5-hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg), 1-bromomethyl-4-chlorobenzene (209 mg), CH3CN (8 ml) and DMF (1 ml) was added potassium carbonate (282 mg), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated in vacuo and diluted with water. The mixture was extracted with EtOAc, and extract was washed successively with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with n-hexane to give the title compound (210 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCCCCCCC>C1COCC1>[CH3:5][C:4]([CH3:6])([CH:3]=[CH2:2])[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:14]
Reactant: O=Cc1ccccc1
Reactant: CC(C)=CCCl
Solvent: C1CCOC1
Solvent: CCCCCCCCCC
Product: C=CC(C)(C)C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
4-Chloro-2-methyl-2-butene (3.2 mmol) was weighed into a vial and sealed with a septum. Using a freeze-pump-thaw technique, air was removed and replaced with argon. THF (4 ml) was added to the vial and then cooled to -78° C. The allyl chloride was then cannulated to the active coppersolution (8.00 mmol) at -108° C. The solution was stirred at -108° C. for 10 minutes and then warmed to -78° C. Benzaldehyde (1.60 mmol) and decane (3.20 mmol) were admixed with 4 ml of THF in a vial, cooled to -78° C. and then cannulated to the organocopper solution at -78° C. and stirred for 30 minutes. The solution was then quenched with saturated NH4Cl(aq), extracted with ether (3×20 ml), washed with brine (3×50 ml), and the organic layer dried over MgSO4. Flash silica gel chromatography usinggradient mixtures of hexanes/EtOAc afforded 2,2-dimethyl-1-phenyl-3-butene-1-ol (1.28 mmol), for an 80% yield: IR (neat) 3451, 3083, 3062, 3029, 2964, 2929, 2869, 1637, 1452, 1413, 1378, 1361, 1187, 1024, 998, 730, 701. 1H NMR (300 MHz) 7.24-7.28 (m, 5H),5.84-5.93 (dd, J1 =17.41 Hz, J2 =10.73 Hz, 1H), 5.00-5.12 (m, 2H), 4.37 (s, 1H), 2.23 (s, 1H), 0.98 (s, 3H), 0.93 (s, 3H). 13C NMR(300 MHz) 144.9, 140.6, 127.7, 127.3, 113.6, 80.4, 42.0, 24.2, 20.9.
Reaction SMILES: [Na].[C:2]1([C:8]2[N:9]=[C:10]([CH2:19]P(=O)(OC)OC)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([C:28]1[CH:29]=[C:30]([CH:37]=[CH:38][CH:39]=1)[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=O.P(=O)([O-])[O-]>CO>[C:2]1([C:8]2[N:9]=[C:10]([CH:19]=[CH:26][C:28]3[CH:29]=[C:30]([CH:37]=[CH:38][CH:39]=3)[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cccc(C=O)c1
Reactant: COP(=O)(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)OC
Agent: O=[PH]([O-])[O-]
Agent: [Na]
Solvent: CO
Product: COC(=O)COc1cccc(C=Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium metal (260 mg, 11 mg atom) was dissolved in methanol (50 mL) and dimethyl [(4,5-diphenyl-2-oxazolyl)methyl]phosphonate (3.89 g, 11 mmol) added followed by methyl (3-formylphenoxy)acetate (2 g, 10 mmol). The mixture was stirred at room temperature for 20 minutes before being concentrated and diluted with 2N HCl solution. The mixture was extracted with CH2Cl2, the organic phase dried over sodium sulfate and the solvent evaported to leave a yellow oil. This was combined with the crude material from a reaction performed on 2 g of the phosphonate and 985 mg of aldehyde and chromatographed on a column of silica gel. Elution with a mixture of hexanes and diethyl ether (3:2) furnished methyl [3-[2-(4,5-diphenyl-2-oxazolyl)ethenyl]phenoxy]acetate as the diethyl ether solvate (2.92 g, 46%) after recrystallization from diethyl ether, m.p. 79°-82° C.