Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[C:6](Cl)(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[C:6]([O:3][CH2:2][C:1]([OH:5])=[O:4])(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: O=C(O)CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(O)COC(=O)C=Cc1ccccc1
Yield: 25.2 %

Procedure:
To a solution of glycolic acid (15.2 g.) in pyridine (100ml.) was added cinnamoyl chloride (33.4 g.) with stirring under cooling. The reaction mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure at 50° to 60° C. The residue was adjusted to pH 1 with concentrated hydrocloric acid and extracted with ether. The extract was washed with water and a sodium chloride aqueous solution, in turn and concentrated under reduced pressure to give colorless crystals (45 g.). These crystals were dissolved in a sodium bicarbonate aqueous solution and adjusted to pH 3 to 3.5 with aqueous hydrochloric acid and extracted with ether. The extract was treated with a conventional manner to give crude product (16.5 g.). The product was recrystallized from benzene to give a product of 2-cinnamoyloxyacetic acid (10.4 g.), m.p. 116° to 121° C.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:46]=[CH:45][CH:44]=[CH:43][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][C@@H:25]([S:40][S:41][CH3:42])[CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([OH:31])=[O:30])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:46]=[CH:45][CH:44]=[CH:43][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][C@@H:25]([S:40][S:41][CH3:42])[CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([O:31][CH2:2][C:1]#[N:4])=[O:30])=[O:22])=[N+:15]=[N-:16]
Reactant: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)O)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Reaction time: 1.25 h
Yield: 80.4 %

Procedure:
N,N-Diisopropylethylamine (34 μL, 0.197 mmol) and subsequently bromoacetonitrile (62 μL, 0.896 mmol) were added to a solution of (2S,5S)-6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoic acid (Compound tk15) (89.5 mg, 0.179 mmol) in acetonitrile (0.3 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1.25 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (2S,5S)-cyanomethyl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk16) (77.5 mg, 80%).
Reaction SMILES: [NH3:1].[Na].[F:3][C:4]1[CH:18]=[CH:17][C:7]([C:8](/[C:10](=[C:13](/OC)\[CH3:14])/[C:11]#[N:12])=[O:9])=[CH:6][CH:5]=1>>[NH2:1]/[C:13](/[CH3:14])=[C:10](/[C:8](=[O:9])[C:7]1[CH:17]=[CH:18][C:4]([F:3])=[CH:5][CH:6]=1)\[C:11]#[N:12]
Reactant: N
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1
Agent: [Na]
Product: C/C(N)=C(/C#N)C(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
Approximately 50 ml. of liquid ammonia is condensed in a three-neck flask cooled to -78° in a dry ice-acetone bath. To this is added 200 mg. of sodium metal, followed by 100 mg. of ferric chloride hexahydrate. When the blue color had vanished, 6.2 g. of 2-(p-fluorobenzoyl)-3-methoxycrotononitrile is added. After stirring for one hour, the reaction is allowed to warm and the solvent evaporate. The residue is dissolved in hot ethyl acetate and filtered through Celite®. The filtrate is concentrated on the steam bath and diluted with hexane. Upon cooling, the crystalline product precipitates, is filtered and dried.
Reaction SMILES: [NH:1]=[C:2]1[C:15]([NH:16][C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])=[S:18])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.[H-].[Ca+2].[H-].[CH3:36]OS(OC)(=O)=O>COCCOC>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:19][C:20]([O:22][CH3:23])=[O:21])[S:18][CH3:36])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: COC(=O)NC(=S)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccc(OC)cc2)C1=N
Reactant: COS(=O)(=O)OC
Agent: [Ca+2]
Agent: [H-]
Solvent: COCCOC
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccc(OC)cc2)C1=N)SC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-imino-(4-methoxyphenyl)methyl-4-(3-carbomethoxythioureido)benzophenone (4.47 g.; 0.01 mol) in 1,2-dimethoxyethane (50 ml.) there is added calcium hydride (0.42 g.; 0.01 mol). The mixture is refluxed for one hour and is cooled to room temperature. To the mixture there is added dimethylsulfate (1.26 g.; 0.01 mol). The mixture is stirred at room temperature for one hour and is poured into an excess of ice water. The suspension formed is filtered and the filter cake dried to afford 3-imino-(4-methoxyphenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]([C:21]([O:23][CH3:24])=[O:22])[C:4]1=[O:25])[CH3:2].[CH2:26](N1C2C(=CC(C(=O)C3C=CC(F)=CC=3)=CC=2)C(C(OC)=O)C1=O)C.C(N1C2C(=CC(C(=O)C3C=CC(C)=CC=3)=CC=2)C(C(OC)=O)C1=O)C>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]([C:21]([O:23][CH2:24][CH3:26])=[O:22])[C:4]1=[O:25])[CH3:2]
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C(=O)c3ccc(F)cc3)ccc21
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: CCN1C(=O)C(C(=O)OC)c2cc(C(=O)c3ccc(C)cc3)ccc21
Product: CCOC(=O)C1C(=O)N(CC)c2ccc(C(=O)c3ccccc3)cc21

Procedure:
In a similar manner were prepared methyl 1-ethyl-5-(4-chlorobenzoyl)oxindole-3-carboxylate, m.p. 115°-118° C.; methyl 1-ethyl-5-(4-fluorobenzoyl)oxindole-3-carboxylate, m.p. 90°-100° C. (dec.); and methyl 1-ethyl-5-(4-methylbenzoyl)oxindole-3carboxylate, m.p. 110°-115° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.CS(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCN(CC(F)(F)F)CC4)c3)nn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 7-fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 180, 50 mg, 0.117 mmol), 2,2,2-trifluoroethyl methanesulfonate (55 μL, 0.468 mmol) and Cs2CO3 (76 mg, 0.234 mmol) in THF (1 mL) was stirred at 70° C. for 2 h. 2,2,2-trifluoroethyl methanesulfonate (69 μL, 0.585 mmol) was then added and the RM was stirred at reflux for 24 h. 2,2,2-trifluoroethyl methanesulfonate (69 μL, 0.585 mmol) was added again and the RM was stirred at reflux for 18 h more. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) to afford the title compound (tR 3.74 min (conditions 3), 1H-NMR in DMSO-d6: 8.85 (m, 1H); 8.54 (s, 1H); 8.34 (d, 1H); 8.07 (m, 3H); 7.77 (d, 1H); 7.61 (s, 1H); 7.54 (d, 1H); 7.47 (dd, 1H); 4.55 (s, 2H); 4.39 (m, 1H); 3.67 (m, 2H); 2.94 (m, 4H); 2.16 (m, 2H); 2.00 (m, 2H)).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)CC=C(C2C=CC(O[Si](CC(C)C)(C)C)=CC=2)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 142.6 mg (0.339 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1) and 35.6 mg (0.848 mmol) of LiOH—H2O in 12 ml of THF/water (4:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the hexane fraction extracted with 5% aqueous NaOH. The aqueous layers .were combined and acidified with 1M HCl, and then extracted with EtOAc and Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ7.91 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.47 (2H, s), 7.23 (4H, q, J=8.1 Hz), 7.01 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.35 (3H, s), 2.33 (2H, d, J=4.8 Hz), 1.30 (6H, s).
Reaction SMILES: [N+:1]([O-])([O-])=O.[NH4+].[CH3:6][CH:7]([N:9]1[S:19](=[O:21])(=[O:20])[N-:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11])[CH3:8].[Na+]>O>[CH3:8][CH:7]([N:9]1[S:19](=[O:21])(=[O:20])[NH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11])[CH3:6].[NH4+:1]
Reactant: CC(C)N1C(=O)c2ccccc2[N-]S1(=O)=O
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Temperature: 20 °C
Yield: 73.2 %

Procedure:
8 g of ammonium nitrate were introduced at 50° C. with stirring into a solution of 26.3 g of bentazone-sodium in 21.7 g of water, and the reaction mixture was subsequently stirred for a further hour. After cooling to 20° C., the precipitate was filtered off, washed twice with 5 ml of ice water in each case and dried under reduced pressure and at 50° C. 18.9 g of bentazone-ammonium of 99% purity were obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]>CO>[OH:3][N:2]=[C:5]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: NO
Reactant: COC(=O)C(=O)c1cccc2ccccc12
Agent: Cl
Solvent: CO
Product: COC(=O)C(=NO)c1cccc2ccccc12
Reaction time: 8 h
Yield: 45 %

Procedure:
Hydroxylamine hydrochloride (834 mg) was added to a stirred solution of methyl 2-oxo-2-(1-naphthyl)acetate (1.72 g) in methanol. The mixture was left overnight then the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The title oxime (828 mg) was obtained by recrystallisation of the residue from ethyl acetate/hexane. (Found: M+ 229.0743. C13H11NO3 requires 229.0739). νmax (CHCl3) 3311, 1725. δH (250 MHz, CDCl3), 3.84 (3H, s), 7.43 (1H, dd, J 1.21 and 7.12), 7.46-7.64 (4H, m), 7.89-7.97 (2H, m); m/z (EI) 229 (M+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>OS(O)(=O)=O>[C:5]([N:9]1[CH:13]=[C:12]([N+:1]([O-:4])=[O:2])[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)n1cccn1
Agent: O=S(=O)(O)O
Product: CC(C)(C)n1cc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
HNO3 (11.7 g, 185 mmol) was added dropwise to a mixture of 1-tert-butyl-1H-pyrazole (23 g, 185 mmol) in cone. H2SO4 (30 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min and was poured onto crashed ice. The aqueous mixture was extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1-tert-butyl-4-nitro-1H-pyrazole (20 g, 64% yield). 1H NMR (400 MHz, DMSO-d6): δ8.85 (s, 1H), 8.23 (s, 1 H), 1.52 (s, 9 H).
Reaction SMILES: CO.[CH2:3]([Cl:5])Cl.C(OC(=O)[C@@H](NC(OC(C)(C)C)=O)CC1C=CC(N[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[N:26]C=3)[CH:22]=[CH:21][N:20]=2)=CC=1)C>C(OC(O)C)C>[Cl:5][C:3]1[C:22]2[C:23](=[CH:28][CH:19]=[N:20][CH:21]=2)[CH:24]=[CH:25][N:26]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3ccncc23)cc1)NC(=O)OC(C)(C)C
Agent: CCOC(C)O
Solvent: CO
Product: Clc1nccc2ccncc12

Procedure:
A solution of ethyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino] propanoate (638 mg, 2.07 mmol) and Intermediate 12 (310 mg, 1.88 mmol) in ethoxyethanol (2 ml) was stirred at 120° for 15 min and at 100° for 1 h under nitrogen. The volatiles were removed in vacuo and the dark residue partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (10 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a dark foam. Chromatography (SiO2; 5 to 10% MeOH/DCM) afforded a mixture of ethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[(t-butoxycarbonyl) amino]propanoate and some of the title compound (730 mg). This mixture was treated with a solution of trifluoroacetic acid (5 ml) and DCM (5 ml) at room temperature for 1 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (75 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford an orange solid. Chromatography (silica; 10% MeOH/DCM) afforded the title compound as a straw-coloured solid (420 mg, 60% over two steps). δH (CDCl3) 10.70 (1H, s), 10.31 (1H, s), 9.44 (1H, d, J 5.6 Hz), 8.94 (1H, d, J 5.6 Hz), 8.55 (1H, d, J 7.3 Hz), 8.54 (2H, d, J 8.5 Hz), 8.46 (1H, d, J 5.6 Hz), 7.94 (2H, d, J 8.5 Hz), 4.84 (2H, q, J 7.1 Hz), 4.35 (1H, t, J 6.6 Hz), 4.10 (2H, br s), 3.64 (1H, dd, J 13.5, 6.4 Hz), 3.56 (1H, dd, J 13.5, 7.0 Hz) and 1.95 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 337 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>CS(C)=O.O>[CH:23]1([NH:28][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: NC1CCCC1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCCC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (250 mg, 0.79 mmol) in DMSO (3 mL) was added cyclopentylamine (402.6 mg, 4.73 mmol), and the resulting solution was stirred overnight at 100° C. The resulting mixture was diluted with water (15 mL) and extracted with dichloromethane (3×10 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2%-5% ethyl acetate in petroleum ether) to afford methyl 3-(cyclopentylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (240 mg, 69%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1.[Br:20][CH2:21][CH2:22][CH2:23]Br>>[Br:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: BrCCCBr
Reactant: CCCCC(CC(=O)OC)c1ccc(O)cc1OC
Product: CCCCC(CC(=O)OC)c1ccc(OCCCBr)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using methyl 3-(4-hydroxy-2-methoxyphenyl)heptanoate (prepared as described in Preparation 58A) and 1,3-dibromopropane, methyl 3-[4-(3-bromopropoxy)-2-methoxyphenyl]heptanoate was obtained as an oily substance.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH:6]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:10][CH:9]=1)=[O:7].Cl>C(OCC)C.O1CCCC1>[OH:7][CH:6]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(O)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
A 1.0M solution (200 ml, 200 ml) of allylmagnesium bromide in diethyl ether was dropped into a solution of t-butyl 4-formylbenzoate (30.9 g, 150 mmol) in anhydrous tetrahydrofuran, while stirring the latter under cooling with ice in a nitrogen stream. After the completion of the dropping, the obtained mixture was further stirred for 30 minutes, followed by the addition of 220 ml of 1N hydrochloric acid cooled with ice. The obtained mixture was vigorously stirred. The aqueous layer was further extracted with diethyl ether. The organic layers were combined, washed with an aqueous solution of common salt, dried and concentrated. The residue was purified by silica gel column chromatography to give t-butyl 4-(1-hydroxy-3-butenyl)benzoate. Yield: 8.2 g.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.FC(F)(F)C(O)=O.[Pd]>[NH2:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[N:9][CH:10]=1
Reactant: N#Cc1ccc(NC2CCCCC2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NCc1ccc(NC2CCCCC2)nc1
Yield: 63.1 %

Procedure:
Charge a solution of 6-cyclohexylamino-nicotinonitrile (1.4 g, 7.1 mmol) in methanol (70 mL) and trifluoroacetic acid (5 mL) to a pressure vessel containing 10% Pd/C (Degussa type E101, 600 mg). Pressurize the vessel to 40 psi with hydrogen and stir for 2 h. Filter the mixture through Celite®, wash with warm ethanol, and dichloromethane. Concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with dichloromethane/2M ammonia in methanol (99:1 to 90:10 gradient) to obtain the title compound (920 mg, 54%). MS (ES+) m/z: 206.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[C:5]([O:20][CH3:21])=[CH:6][C:7]([O:16][CH2:17][CH2:18][CH3:19])=[CH:8][C:9]=1[C:10]2=[O:15].Cl.Cl[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28].C[O-].[Na+]>CO.ClC1C=CC=CC=1>[CH2:25]([N:26]([CH2:29][CH3:30])[CH2:27][CH2:28][O:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[C:5]([O:20][CH3:21])=[CH:6][C:7]([O:16][CH2:17][CH2:18][CH3:19])=[CH:8][C:9]=1[C:10]2=[O:15])[CH3:24]
Reactant: CCN(CC)CCCl
Reactant: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(O)c1-2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Clc1ccccc1
Product: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(OCCN(CC)CC)c1-2
Yield: 47.1 %

Procedure:
In a manner analagous to Example 9B, react 5-hydroxy-2-propoxy-4-methoxy-fluoren-9-one (1.75 g, 6.1) in 5 mL methanol and 100 mL chlorobenzene with 2-chloroethyldiethyl amine hydrochloride (4.4 g, 25 mmole) and sodium methoxide (0.51 g, 9.5 mmole) and reflux for 2 hours then continue as in Example 9B to give 1.1 g. of the title compound (2.9 mmole, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:27]1[O:36][C:35]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=2[O:28]1>>[CH2:27]1[O:36][C:35]2[CH:34]=[CH:33][C:31]([NH:32][CH:23]3[CH2:22][CH2:21][N:20]([CH2:19][C:17]4[CH:16]=[CH:15][N:14]=[C:13]([C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH:18]=4)[CH2:25][CH2:24]3)=[CH:30][C:29]=2[O:28]1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Reactant: Nc1ccc2c(c1)OCO2
Product: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl-4-piperidone (1.40 g) and 3,4-methylenedioxyaniline (646 mg) were treated in the same manner as described in Preparation Example 29 to give the title compound.
Reaction SMILES: CN(C)C=O.[C:6]([NH:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:36]/[OH:37])/[C:32]([O:34][CH3:35])=[O:33])[N:30]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46]>O>[C:6]([NH:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:36]/[O:37][CH2:46][CH:45]=[CH2:44])/[C:32]([O:34][CH3:35])=[O:33])[N:30]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CCBr
Reactant: COC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCO/N=C(\C(=O)OC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 91.1 %

Procedure:
To 70.5 ml of N,N-dimethylformamide are added 7.05 g of methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-hydroxyiminoacetate and 3.3 g of potassium carbonate. Then, under ice-cooling and stirring 2.12 g of allyl bromide is added dropwise over a period of 5 minutes. The mixture is further stirred under ice-cooling for 4 hours. To this reaction mixture are added 1.65 g of potassium carbonate and 1.06 g of allyl bromide, and the mixture is stirred for an additional 4 hours. The reaction mixture is diluted with 150 ml of water and extracted three times with 100 ml portions of ether. The ether extract is washed twice with 100 ml portios of aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is purified by column chromatography [silica gel: 300 g; eluent: hexane-ethyl acetate (1:1)] and crystallized from ether-hexane to give 7.0 g of methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-allyloxyiminoacetate, m.p. 115°- 116° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:10]([C:8]1[S:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:18]2
Reactant: O=C(O)c1cc2cc(Br)ccc2s1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2s1

Procedure:
133.7 mg (0.52 mmol) of 5-bromo-1-benzothiophene-2-carboxylic acid (Example 13A), 155.4 mg (0.78 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 296.7 mg (0.78 mmol) of HATU, 369.8 mg (2.86 mmol) of N,N-diisopropylethylamine and 1.5 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. The product is dissolved in acetonitrile, and an excess of 1N hydrochloric acid is added. Finally, the solvent is removed. 175 mg (84% of theory) of the title compound are isolated.