Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3](=[O:15])[O:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[As](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>C1C=CC=CC=1.[OH-].[Na+]>[C:16]1([C:2]2[C:3](=[O:15])[O:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1ccc(C2=C(I)C(=O)OC2)cc1
Reactant: OB(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)OC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4 g of the product of Step 3, 3.7 g of PhB(OH)2, 0.4 g of Ph3As, 0.4 g of PdCl2 (PhCN)2 in 100 mL of benzene and 15 mL of 2N NaOH is refluxed for 6 h. After cooling to r.t., Et2O (200 mL) is added to the reaction mixture and the mixture is washed with 100 mL of saturated NaHCO3. The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash chromatography on silica gel eluted with 4:1 hexane/EtOAc to give the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2OC)[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H:42]1CCCCN(C2C=CC=CC=2C)C1=O>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:15](=[O:16])[NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:42])[C:19]1=[O:33])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1N1CCCC[C@H](N)C1=O
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-6-oxo-6-((S)-2-oxo-1-o-tolylazepan-3-ylamino)hexanoic acid (65 mg, 0.12 mmol) was synthesized as described for the preparation of Intermediate 70 using (S)-3-amino-1-o-tolylazepan-2-one. Anal. Calcd. for C33H38N2O4 m/z 526.4. found: 527.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.37-6.84 (m, 16H), 4.84-4.72 (m, 1H), 4.01-3.78 (m, 1H), 3.51 and 3.28 (dd, J=15.0, 4.8 Hz, 1H), 3.04-2.81 (m, 2H), 2.79-2.61 (m, 3H), 2.50-2.37 (m, 1H), 2.18 (s, 1H), 2.13 (s, 2H), 2.03-1.44 (m, 10H).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[O-2].[O-2].[V+5].[V+5].O>[OH:2][C:1]1[C:3]([OH:4])=[CH:5][C:6]2[C:7]3[C:6](=[CH:5][C:3]([OH:4])=[C:1]([OH:2])[CH:8]=3)[C:7]3[C:6](=[CH:5][C:3]([OH:4])=[C:1]([OH:2])[CH:8]=3)[C:7]=2[CH:8]=1
Reactant: Oc1ccccc1O
Agent: [V+5]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: Oc1cc2c3cc(O)c(O)cc3c3cc(O)c(O)cc3c2cc1O
Temperature: 30 °C
Yield: 33.6 %

Procedure:
Catechol (22.0 g, 0.2 moles) and divanadium pentoxide (vanadium (V) oxide) (36.4 g, 0.2 moles) were added into water (110 mL), and 98% sulfuric acid (440 g, 4.4 moles) was added dropwise to the solution while temperature of the solution was maintained at 30° C. or lower, to adjust the concentration in percent by weight of sulfuric acid in the reaction system at 80%. The solution was reacted at 30° C. for 6 hours with stirring. After completion of the reaction, water (500 mL) was added dropwise to the reaction solution while temperature of the solution was maintained at 30° C. or lower, and the reaction solution was stirred at the same temperature for another 30 minutes. The resultant precipitate was collected by filtration, and the obtained crude crystal was washed with water. The crude crystal was further dispersed in water (1 L), and the dispersion liquid was stirred for 30 minutes, and then filtered to collect crystal. After the collected crystal was dispersed in acetone (400 mL), the dispersion liquid was stirred for 30 minutes. After that, the dispersion liquid was filtered to filter off insoluble matter, and the filtrate was concentrated under reduced pressure to distill off an excess amount of acetone. Subsequently, water (160 mL) was poured into the concentrated filtrate (solution of about 160 mL). This solution was slowly heated up from 56° C. under normal pressure to concentrate the solution. Crystal precipitated when temperature of the concentrated solution became 70 to 80° C. Concentration was further continued, and stopped when temperature of the concentrated solution became 90° C. The crystal thus precipitated was collected by filtration, and then dried, to give 2,3,6,7,10,11-hexahydroxytriphenylene (7.27 g, theoretical yield from catechol: 33.6%) in black powder form. Also, the obtained compound in black powder form was identified to be 2,3,6,7,10,11-hexahydroxytriphenylene by measuring 1H-NMR in the same way as in Example 1.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C[Li].[CH3:15]COCC.Cl>[Cl-].[Na+].O.C1COCC1>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: COc1cccc(C(=O)O)c1O
Reactant: CCOCC
Agent: Cl
Agent: [Cl-]
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(C)=O)c1O
Yield: 71.8 %

Procedure:
In a 250 mL dry flask was charged with 2-hydroxy-3-methoxybenzoic acid (6.0 g, 36.0 mmol) and anhydrous THF (20 mL) under N2. Methyl lithium in an ether solution (1.6 M, 73.5 mL, 117.6 mmol) was added dropwise over 20 min. The reaction mixture was heated to reflux for 20 h. After cooling the mixture was poured into 25 mL of brine with 6 N HCl and extracted with 100 mL of EtOAc. The organic layer was further washed with brine three times and dried over sodium sulfate. The solvent was evaporated and the residue was purified by column (hexane:EtOAc 2.5:1) to give 1-(2-hydroxy-3-methoxy-phenyl)-ethanone (4.3, 71.8%). 1-(2-Hydroxy-3-methoxy-phenyl)-ethanone (1.0 g, 6.0 mmol), 4-acetoxybenzoic acid (1.08 g, 6.0 mmol) and phosphorus oxychloride (0.923 g, 6.0 mmol) in 10 mL pyridine were stirred at rt overnight. The reaction mixture was poured into water (100 mL) and the isolated solid was washed with water. The solid was dissolved in dichloromethane and purified by column chromatography (hexane:EtOAc 2:1) to give the intermediate (1.05 g, 53.13%). Potassium tert-butoxide (0.4 g, 3.5 mmol) was added to this intermediate (1.05 g, 3.2 mmol) in 20 mL anhydrous THF. The reaction mixture was stirred for 4 h at rt. The mixture was poured into water (100 mL) with 1 mL AcOH (adjusted pH to 6-7.0). The solid was further rinsed with water and dissolved in dichloromethane. The organic layer was wash with brine and dried over sodium sulfate. The crude compound was treated with AcOH and two drops of concentrated HCl solution and heated to 110° C. for 1 h. The AcOH was evaporated and the solid residue was dissolved in MeOH and potassium carbonate (3.8 mmol) was added. The reaction mixture was stirred for 1 hour at rt. The reaction mixture was neutralized with AcOH and the solvent was evaporated. The residue was poured into water and the solid was collected by filtration and purified by column to give 150 mg of 2-(4-hydroxyphenyl)-8-methoxy-4H-chromen-4-one (17.4%). MS (ES) m/z: 269.93 (M+1), 268.91 (M); Mp. 281-283° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([NH:12][C:13]([N:15]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17][CH2:16]2)=[O:14])([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]([NH:12][C:13]([N:15]3[CH:21]4[CH2:20][CH2:19][N:18]([CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[O:14])([CH3:10])[CH3:11])[CH:3]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(NC(=O)N1CCN2CCC1CC2)c1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)N1CCN2CCC1CC2)c1ccc(F)c(-c2ccc(F)cc2)c1
Yield: 61.4 %

Procedure:
Using general procedure E, N-[2-(3-bromo-4-fluorophenyl)propan-2-yl]-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide (100 mg, 0.261 mmol), 4-fluorophenyl boronic acid (91 mg, 0.65 mmol) and palladium (II) acetate gave the title compound as an off-white solid (64 mg, 62%). 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 2H), 7.37-7.30 (m, 2H), 7.10-7.03 (m, 3H), 4.77 (s, 1H), 3.99 (br s, 1H), 3.58 (m, 2H), 3.10-2.90 (m, 6H), 1.98 (m, 2H) 1.71 (m, 8H) ppm. 13C NMR (100 MHz, CDCl3) δ 163.7, 161.3, 159.5, 157.1, 155.6, 144.6, 131.0, 130.9, 127.4, 127.2, 125.7, 116.1, 115.6, 57.9, 55.2, 48.2, 46.4, 46.4, 41.5, 30.6, 30.6, 27.6, 27.6 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.90 min; (M+1) 400.
Reaction SMILES: [C:1]([N:9]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[C:1]([N:9]1[CH2:16][C@@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of lactone from Example 1, part A(5) (10.05 gm, 46.31 mmole) in THF-H2O (100 ml -18 ml) was treated slowly with 1M lithium hydroxide (60 ml). The reaction was stirred at room temperature under argon for 2 hours, concentrated and acidified to pH 6 with HCl. The solution was washed several times with ethyl acetate, acidified to pH 1 with HCl, saturated with sodium chloride and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to an oil which was crystallized from dichloromethane-hexane to afford 7.7 gm (71%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([CH2:23][F:24])[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([CH2:23][F:24])[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c(CF)c(F)c2=O)c(F)cc1Cl
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c(F)c(CF)n(C)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-fluoro-4-fluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-fluoro-4-fluoromethyl-3methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 85°-89° C.,
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:19])[CH:3]=1.Br[C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:16]1([CH2:15][O:14][C:7]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]3[C:6]=2[NH:5][C:4](=[O:19])[CH:3]=[C:2]3[NH:1][C:21]2[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=2[CH3:28])[CH2:17][CH2:18]1
Reactant: Cc1cncc(C)c1Br
Reactant: COc1ccc2c(N)cc(=O)[nH]c2c1OCC1CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCC1CC1
Temperature: 110 °C
Yield: 23.3 %

Procedure:
A mixture of 4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one (500 mg, 1.92 mmol), 4-bromo-3,5-dimethylpyridine (350 mg, 1.88 mmol), Pd2(dba)3 (88 mg, 0.19 mmol Pd), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (181 mg, 0.38 mmol), sodium tert-butoxide (370 mg, 3.85 mmol), and toluene (20 mL) was heated at 110° C. for 3 h under N2, and then allowed to cool to room temperature. The reaction was filtered and washed with 5% methanol in dichloromethane (500 mL×3). The filtrate was concentrated and purified by silica gel chromatography (40:1; ethyl acetate/methanol) and then reverse-phase HPLC to give 0.16 g of 8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one as white solid. MS (ESI): 366.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:13][CH2:14]Br.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCBr
Reactant: N#CCc1ccc(F)c(Cl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2ccc(F)c(Cl)c2)CC1
Reaction time: 8 h

Procedure:
To a mixture of 3-chloro-4-fluoro-phenylacetonitrile (8.48 g), 1,2-dibromoethane (13 ml) and benzyltriethylammonium chloride (0.46 g) was added sodium hydroxide solution (50% in water, 20 ml) at room temperature. The mixture was vigorously stirred overnight. Water was added and the aqueous phase was extracted twice with diethyl ether. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (SiO2; heptane/EtOAc) to give 1-(3-chloro-4-fluorophenyl)-cyclopropanecarbonitrile as light yellow liquid (3.91 g). 1H-NMR (300 MHz, CDCl3, δ): 1.35-1.40 (m, 2H), 1.72-1.76 (m, 2H), 7.10-7.21 (m, 2H), 7.26-7.34 (m, 1H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:18]([N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCCI
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.8 %

Procedure:
Mix ethyl 4-iodobutyrate (43.5 g, 0.18 mol), dibenzylamine (35.5 g, 0.18 mol), potassium carbonate (24.9 g, 0.18 mol) and ethanol (114 mL dried over 4A molecular sieves). Reflux for 24 hours then stir at room temperature for 48 hours. Add methylene chloride (100 mL) and filter. Evaporate the filtrate to a residue and purify by silica gel chromatography (methylene chloride) to give the title compound (47 g).
Reaction SMILES: [ClH:1].[C:2]([CH:10]1[C:15](=O)[N:14]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[S:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:26][Mg+].[Br-]>CCOCC>[ClH:1].[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:14]1[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[S:11][CH:10]([C:2]([CH3:26])([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[OH:9])[CH2:15]1
Reactant: C[Mg+]
Reactant: CN(C)CCN1C(=O)C(C(=O)c2ccccc2)Sc2ccccc21
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Product: CN(C)CCN1CC(C(C)(O)c2ccccc2)Sc2ccccc21
Temperature: 0 °C

Procedure:
Interaction of the free base of the product of example 1 with 1 equivalent of CH3MgBr in ether at room temperature forms a Grignard complex which is decomposed with ice water and the ethereal solution dried over anhydrous MgSO4, filtered and the filtrate treated with anhydrous HCl to yield the title product.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:18])=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:12]=1)#[N:6].N1C=CC=CC=1.O>C(OCC)C>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:18][S:1](=[O:2])[O:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:11]=2[CH:12]=1)#[N:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CO)c1cc(C#N)ccc1O
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)COS(=O)Oc2ccc(C#N)cc21
Reaction time: 3 h
Yield: 32.2 %

Procedure:
Thionyl chloride (4.2 g) in diethyl ether (10 ml) was added dropwise with stirring at 0°-5° C. to a solution of 2-(5-cyano-2-hydroxyphenyl)-2-methyl-1-propanol (5 g) prepared as in Example 26, and pyridine (5.5 g) in diethyl ether (80 ml). The mixture was stirred for 3 hours at 0°-20° C. Water was then added and the mixture was filtered. The ether solution was then washed with dilute hydrochloric acid, then with aqueous sodium bicarbonate and water (twice), then dried over magnesium sulphate and run down. The residue was recrystallised from ethanol, giving the title product (2.0 g) as white crystals, mp 87°-88° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1>O=[Mn]=O>[CH:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1
Reactant: O=C1CCCCN1c1cccc2c1CCNC2
Agent: O=[Mn]=O
Product: O=C1CCCCN1c1cccc2c1CCN=C2
Yield: 95.6 %

Procedure:
33B (0.38 g, 1.650 mmol) was oxidized with MnO2 to afford 0.36 g of 33C as a dark oil. MS (ESI) m/z: 229.0 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([CH2:24][N:25]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[N:26]2)[CH2:23][CH2:22]1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:31][CH2:30][C:27]2[CH:28]=[CH:29][N:25]([CH2:24][CH:21]3[CH2:23][CH2:22]3)[N:26]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCc1ccn(CC2CC2)n1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(NCc1ccn(CC2CC2)n1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (100 mg, 0.35 mmol) and C-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-methylamine (53 mg, 0.35 mmol) as starting materials; off white solid (60 mg, 41.1%). MS (ESI): 423 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6][C:7]([CH:9]=[C:10]([N:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O.[O-]CC.[Na+].C(O)(=O)C>C(O)C.C(OCC)(=O)C>[CH3:24][N:17]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:7]([CH2:6][O:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([CH3:1])[CH:3]=2)[CH:9]=[C:10]1[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)CN(C)C(=CC(=O)COc1cccc(C)c1)COC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(COc2cccc(C)c2)cc(COC(C)(C)C)n1C
Temperature: 25 °C

Procedure:
To a solution of 1-(3-methylphenoxyacetyl)-2-(N-ethoxycarbonylmethyl-methylamino)-3-t-butoxy-1-propene (40 g, 0.1 mol) in absolute ethanol (250 ml) is added sodium ethoxide (1.0 g, 0.015 mol) under N2. The reaction is stirred at room temperature and monitored by TLC until all starting material has disappeared. Then acetic acid (0.9 g, 0.015 mole) is added and the mixture taken to dryness in vacuo. The residue is dissolved in ethyl acetate (200 ml) and washed with water (100 ml), then saturated brine (100 ml) and dried over anhydrous sodium sulfate. The solvent is removed and the crude product is purified by preparative HPLC to afford pure ethyl 1-methyl-2-(t-butoxymethyl)-4-(3-methylphenoxymethyl)pyrrole-5-carboxylate
Reaction SMILES: C(O)(C(F)(F)F)=O.NC1(C2C=CC(C3C(=O)C4C=CC=CC=4OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:42][C:43]1([C:47]2[CH:52]=[CH:51][C:50]([C:53]3[C:58](=[O:59])[C:57]4[CH:60]=[CH:61][C:62]([NH2:64])=[CH:63][C:56]=4[O:55][C:54]=3[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44]1)(C)(C)C>>[NH2:64][C:62]1[CH:61]=[CH:60][C:57]2[C:58](=[O:59])[C:53]([C:50]3[CH:51]=[CH:52][C:47]([C:43]4([NH2:42])[CH2:46][CH2:45][CH2:44]4)=[CH:48][CH:49]=3)=[C:54]([C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)[O:55][C:56]=2[CH:63]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(N)ccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1
Yield: 156.9 %

Procedure:
TFA: Following the procedure used to make 3-[4-(1-amino-cyclobutyl)-phenyl]-2-phenyl-1-benzopyran-4-one, {1-[4-(7-amino-4-oxo-2-phenyl-4H-1-benzopyran-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (6.3 mg, 0.017 mmol) was reacted to give the title compound as a yellow solid (10.2 mg, 100%). 1H-NMR (400 MHz, D2O) δ 7.30 (d, 1H), 7.05-7.18 (m, 4H), 6.85 (dd, 2H), 6.59-6.65 (m, 4H) 5.65 (s, 1H) 2.33-2.47 (m, 4H), 1.95-2.02 (m, 1H), 1.52-1.59 (m, 1H). LCMS (Method I): RT=3.97 min, [M+H]+=384.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH3:21][N:22]([CH3:31])[CH2:23][CH2:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.CI>O1CCCC1>[CH3:31][N:22]([CH3:21])[CH2:23][CH:24]([C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)[CH3:1]
Reactant: CN(C)CCc1cnccn1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CC(CN(C)C)c1cnccn1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To 0.56 mole of lithium diisopropylamide, prepared from n-butyllithium and diisopropylamine in tetrahydrofuran, was added at -10° C. 84.6 g (0.56 mole) of β-dimethylaminoethylpyrazine in 1200 ml of tetrahydrofuran over a period of 30 minutes. The reaction mixture was stirred for additional 30 minutes. The deep red-coloured reaction mixture was cooled to -30° C. and 95.4 g (0.56 mole) of methyl iodide was added over a period of 20 minutes and the reaction mixture was stirred for three additional hours at room temperature. The mixture was poured onto ice and extracted with ether. The combined extracts were dried over sodium sulphate and the ether removed by distillation. The residue was distilled to give 91.0 g of β-dimethylamino-α-methylethylpyrazine, b.p. 90°-93° C. at 9 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH3:13])[CH:5]=1)([O-:3])=[O:2].CC1C=CC(S([CH2:24][N+:25]#[C-:26])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].CO>O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[O:9][CH:26]=[N:25][CH:24]=2)=[C:6]([O:12][CH3:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a 5 L three necked round bottom flask equipped with a condenser and a mechanical stirrer was placed 1B (146.3 g, 0.8076 mol), TOSMIC (157.7 g, 0.8077 mol), K2CO3 (116.6 g, 0.8075 mol) and MeOH (2.5 L). The mixture was heated to reflux under N2 and stirred for 3 hours. Water (1.25 L) was added drop-wise while maintaining the pot temperature between 59–69° C. The resulting slurry was cooled to room temperature, and then to 5° C. with an ice-water bath. After stirring for 30 minutes at 5° C., the slurry was filtered. The resulting cake was washed with water (3×400 mL) and dried in a vacuum oven at 45° C. for 20 hours to give 1C (148.5 g, 84%) as a yellow-reddish solid. 1H NMR (CDCl3) d 8.02 (s, 1H), 7.97 (d, J=2 Hz, 1H), 7.95 (d, J=2 Hz, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 4.11 (s, 3H).