Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH3:16].C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.[Cl-].[NH4+]>C1COCC1>[CH3:15][C:11]1[C:10]2[N:9]([C:20](=[O:19])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:16]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccnc1C
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(C)cccn2c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of lithium diisopropylamide (1.8 M in THF, 64.8 mL, 117 mmol) in 135 mL of THF at −78° C. was added a solution of 2,3-lutidine (10.0 g, 93.0 mol) in 62 mL of THF dropwise over 10 min. After an additional 40 min, a solution diethyl ethoxymethylenemalonate (21.7 mL, 107 mmol) in 30 mL of THF was added slowly over 15 min, and the reaction was slowly warmed to rt. After 2.5 h, the mixture was treated with saturated aqueous ammonium chloride and extracted 3× with dichlormethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude intermediate was dissolved in 100 mL of o-xylene and heated to reflux for 16 h. The reaction was concentrated in vacuo and the resultant residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide ethyl 9-methyl-4-oxo-4H-quinolizine-3-carboxylate that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 232.1 for [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([OH:26])=O)[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.[CH3:58][NH:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][N:66]=[CH:65][CH:64]=1>CN(C=O)C>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:59]([CH3:58])[CH2:60][CH2:61][O:62][C:63]3[CH:64]=[CH:65][N:66]=[CH:67][CH:68]=3)=[O:26])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CNCCOc1ccncc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)CCOc3ccncc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (50 mg, 0.13 mmol), EDCI (50 mg, 0.26 mmol), HOBt monohydrate (40 mg, 0.26 mmol), DIPEA (90 μL, 0.52 mmol), N-methyl-2-(pyridin-4-yloxy)ethanamine (20 mg, 0.13 mmol) and DMF (1 mL). The resulting crude compound was purified using prep method D.
Reaction SMILES: Br[C:2]1C=CC(OC)=C(C=1)C(Cl)=O.Br[C:14]1[CH:15]=[CH:16][C:17]([O:37][CH3:38])=[C:18]([CH:36]=1)[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]CC)=[O:32])=[CH:26][CH:25]=1)=[O:20].BrC1C=CC(OC)=C(C=1)C(NCCC1C=CC(CC(O)=O)=CC=1)=O>>[CH3:38][O:37][C:17]1[CH:16]=[CH:15][C:14]([CH3:2])=[CH:36][C:18]=1[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=1)=[O:20]
Reactant: COc1ccc(Br)cc1C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(CCNC(=O)c2cc(Br)ccc2OC)cc1
Agent: COc1ccc(Br)cc1C(=O)NCCc1ccc(CC(=O)O)cc1
Product: COc1ccc(C)cc1C(=O)NCCc1ccc(CC(=O)O)cc1

Procedure:
with 5-bromo-2-methoxybenzoyl chloride, via ethyl 4-[2-(5-bromo-2-methoxybenzamido)-ethyl]-phenylacetate (oil), 4-[2-(5-bromo-2-methoxybenzamido)-ethyl]-phenylacetic acid; m.p. 148°-150° C., after recrystallization from isopropanol.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:11]1([CH2:17][C:18](Cl)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C1COCC1>[C:11]1([CH2:17][CH2:18][NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC1CC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: c1ccc(CCNC2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cyclopropanamine (1 eq.) in dichloromethane (0.13 M) was added sequentially at 0° C. pyridine (1.5 eq.) and phenylacetyl chloride (9 eq.). The resulting mixture was slowly warmed to RT and stirred at RT for 3 h. After quenching with 1 N aq. HCl, the reaction mixture was extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. The crude amide thus obtained was taken up in THF (0.3 M) and added BH3.SMe2 complex (3 eq.). The reaction was heated to reflux and the volatiles were slowly distilled off. The resulting distillation residue was carefully quenched with 1 N aq. HCl and allowed to stir at 50° C. overnight. The reaction was cooled to 0° C. and the pH of the solution was brought to ˜12 with 1 N aq. NaOH before it was extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. The crude product thus obtained could be further purified by way of column chromatography (SiO2, 2:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:18])[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Cl[C:20]1[N:25]=[N:24][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+].O1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:18])[CH:6]=[CH:7][C:8]=1[C:20]1[N:25]=[N:24][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:33])([CH3:34])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:22][CH:21]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(O)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 110 °C
Yield: 48 %

Procedure:
To a 25 mL microwave vial was added 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.90 g, 10.8 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 2.55 g, 9.00 mmol), NaHCO3 (2.27 g, 27.0 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.520 g, 0.450 mmol). Dioxane (45 mL) and water (15 mL) were added, and the reaction mixture was purged with nitrogen for 10 minutes. The reaction mixture was heated under microwave irradiation at 110° C. for 16 h. After cooling to RT, the mixture was filtered through celite, washing the filter pad sequentially with ethyl acetate, DCM, and MeOH. Concentration of the filtrate afforded a brown solid which was purified by flash chromatography (80 g silica, 0-20% 2 M ammonia in MeOH gradient, in DCM) to provide 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (1.6 g). MS (M+1)=371.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=O)=[CH:4][CH:3]=1.NC1C=CC(CC(N)=O)=CC=1.CSC.B.Cl.[OH-].[Na+]>C1COCC1>[CH2:14]([N:11]([CH2:12][CH3:13])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)[CH3:15]
Reactant: CCN(CC)C(=O)Cc1ccc(N)cc1
Agent: B
Agent: Cl
Agent: NC(=O)Cc1ccc(N)cc1
Solvent: CSC
Solvent: C1CCOC1
Product: CCN(CC)CCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 2-(4-aminophenyl)-N,N-diethylacetamide, (2-NB-2-A13; 1.5 g, 7.28 mmol) from Step 2 in anhydrous THF (15 mL) kept at 0° C. was added a 2 M solution of borane dimethylsulfide in THF (14.5 mL, 29 mmol) slowly. The reaction was allowed to warm to room temperature and stirred for 18 h. Hydrochloric acid (6N, 10 mL) was carefully added and the reaction was refluxed for 1 hour followed by cooling to room temperature and neutralization with 3N sodium hydroxide solution. Aqueous layer was separated and extracted with ethyl acetate (4×30 mL). Combined organic layer was dried over sodium sulfate, filtered and evaporated to provide 4-(2-(diethylamino)ethyl)aniline as a light-brown oil (1.25 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.[CH3:24][Si:25]([CH3:71])([CH3:70])[CH2:26][CH2:27][O:28][CH2:29][N:30]([CH2:62][O:63][CH2:64][CH2:65][Si:66]([CH3:69])([CH3:68])[CH3:67])[C:31]1[N:36]2[N:37]=[CH:38][C:39]([C:40]3[CH:41]=[N:42][C:43](Cl)=[CH:44][CH:45]=3)=[C:35]2[N:34]=[C:33]([CH:47]2[CH2:53][CH:52]3[N:54]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH:49]([CH2:50][CH2:51]3)[CH2:48]2)[CH:32]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:69][Si:66]([CH3:67])([CH3:68])[CH2:65][CH2:64][O:63][CH2:62][N:30]([CH2:29][O:28][CH2:27][CH2:26][Si:25]([CH3:24])([CH3:71])[CH3:70])[C:31]1[N:36]2[N:37]=[CH:38][C:39]([C:40]3[CH:41]=[N:42][C:43]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=4)=[CH:44][CH:45]=3)=[C:35]2[N:34]=[C:33]([CH:47]2[CH2:53][CH:52]3[N:54]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH:49]([CH2:50][CH2:51]3)[CH2:48]2)[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n1)C2
Reactant: COc1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(-c3cnn4c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)cc(C5CC6CCC(C5)N6C(=O)OC(C)(C)C)nc34)cn2)cc1F
Temperature: 150 °C
Reaction time: 1 h

Procedure:
3-Fluoro-4-methoxyphenylboronic acid (2.79 mmol, 475.7 mg), K3PO4 (4.20 mmol, 890.4 mg), and PdCl2(dppf).CH2Cl2 (0.14 mmol, 114.3 mg) were added to a solution of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.40 mmol, 1000 mg) in dioxane (12 mL) and H2O (1.5 mL). The resulting solution was stirred at 150° C. under microwave condition for 1 h. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, LCMS tR=3.31 Min (5 min run, UV254nm) Mass calculated for, M+H 805.42, observed LC/MS m/z 805.17 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F-].[K+].[F:16][C:17]([Si](C)(C)C)([F:19])[F:18]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]([OH:13])[C:17]([F:19])([F:18])[F:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(C=O)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [F-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)cc(C(O)C(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
To a stirred mixture of methyl 3-bromo-5-formylbenzoate (0.60 g, 2.5 mmol), tetra-N-butylammonium bromide (0.90 g, 2.8 mol), potassium fluoride (10 mg, 0.17 mmol), and toluene (10 mL) at −20° C. was added (trifluoromethyl)trimethylsilane (0.74 mL, 5.0 mmol). The reaction mixture was stirred for 20 min, and then quenched with water. To the mixture were added 1 M HCl aqueous solution (2 mL) and 1,4-dioxane (12 mL), and the mixture was stirred for 30 min. The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash column to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].C([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])#C>>[OH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: C#Cc1ccccc1O
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccccc2O)c1)c1ccccc1
Yield: 7 %

Procedure:
In a manner similar to that describe in Example 431 a mixture of (S)-5-ethynyl-N—[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 1-ethynyl-2-hydroxybenzene were reacted to give the title compound as a white solid (6 mg, 7%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[C:26]([CH3:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[CH3:31].C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[C:27]([OH:32])[C:26]=1[CH3:33])=[O:6]
Reactant: Cc1ccc(O)c(C)c1N
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(O)c(C)c1NC(=O)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a mixture of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (632 mg, 2.7 mmol, 1.0 eq) and oxalyl chloride (1.03 g, 8.1 mmol, 3.0 eq) in DCM (30 mL) was added DMF (0.3 mL). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated to remove the solvent and excess oxalyl chloride then the residue obtained was dissolved in THF (20 mL). This solution was added dropwise to a suspension of 3-amino-2,4-dimethyl-phenol (370 mg, 2.7 mmol, 1.0 eq) and NaHCO3 (680 mg, 8.1 mmol, 3.0 eq) in THF (20 mL). After addition was complete, the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was adjusted to pH 3 by addition of 1M HCl and the aqueous layer extracted with EtOAc. The organic extract was dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:1) to give the title compound as a yellow solid (400 mg, 42%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.[C:11]([C:15]1[CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[C:11]([C:15]1[CH:16]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][CH2:6]3)[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Brc1cccc2c1C=CC2
Reactant: CC(C)(C)c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(C)(C)C)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(-c2cccc3c2C=CC3)cc(C(C)(C)C)c1
Temperature: 80 °C
Yield: 62.9 %

Procedure:
Mixture of compound 4 (60 g, 308 mmol, 1 equiv), 2-(3,5-di-tert-butylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (126 g, 400 mmol, 1.3 equiv), powdered potassium carbonate (128 g, 924 mmol, 3 equiv) and bis(triphenylphosphine)palladium(II)dichloride (25.3 g, 31 mmol, 0.1 equiv), 1,4-dioxane (300 mL) and water (150 mL) was heated overnight at 80° C. The reaction was poured into 700 mL of water and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with saturated brine (1 L), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified over silica gel (1 Kg) eluting with heptanes to give compound 5 (59 g, 63% yield) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH2:7][C:6]1=[O:17])=[O:4].[Li+].[CH3:19][CH:20]([N-]C(C)C)[CH3:21].C(Br)C=C>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH:7]([CH2:21][CH:20]=[CH2:19])[C:6]1=[O:17])=[O:4]
Reactant: COC(=O)C1C(=O)CCc2cccc(OC)c21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1Cc2cccc(OC)c2C(C(=O)OC)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 10.2 g (43.5 mmol) 1,2,3,4-tetrahydro-8-methoxy-2-oxo-1-naphthalene carboxylic acid methyl ester in 108 mL of THF in a three-neck, round-bottomed flask, equipped with a dropping funnel, was added dropwise 63.8 mL (95.7 mmol) of LDA (1.5M in cyclohexane) at -30° C. to -40° C. under a nitrogen atmosphere. The solution was allowed to warm to 0° C. and 6.0 mL (69.6 mmol) of allylbromide was added. After stirring the mixture for one hour at room temperature, TLC analysis showed no starting material remaining. The reaction was quenched with 3N hydrochloric acid to pH 2-3 and extracted with ethyl acetate (2×1 L). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by liquid chromatography on 800 g silica gel 60 (230-400 m), eluting with hexane-acetone (3:1), and collecting 40 mL fractions. Fractions 36-63 gave 10.3 g (87%) of pure title compound as a yellow oil.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH:23]1[CH2:28][N:27]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25][NH:24]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:55]1([N:61]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:62](Cl)=[O:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C)C=O>[C:55]1([N:61]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:62]([N:24]2[CH2:25][CH2:26][N:27]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:28][CH:23]2[CH2:22][CH2:21][O:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:63])[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: c1ccc(C(OCCC2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCN2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N(c1ccccc1)c1ccccc1)N1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.2 %

Procedure:
To a suspension of 364 mg (0.59 mmol) of (±) 2-(2-trityloxyethyl)-4-N-tritylpiperazine in 10 ml of N,N-dimethylformamide was added 170 ml (1.22 mmol) of triethylamine in one portion and 140 mg (0.60 mmol) of diphenylcarbamyl chloride in portions and the mixture was allowed to stir under nitrogen at room temperature for 20 hours. The solution was cooled and concentrated in vacuo. Flash chromatography on 40 g of silica gel using 25:75 v/v ethyl acetate/hexane as the eluant afforded 240 mg (50%) of a yellow oil.
Reaction SMILES: [Na].CN(C)[C:4]1[CH2:8][CH2:7][CH2:6][N+:5]=1[CH3:9].COS([O-])(=O)=O.[CH2:17]([O:19][C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:18].O>C(O)C.CCOCC>[CH2:17]([O:19][C:20]([C:21](=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:28])[CH3:18]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CN(C)C1=[N+](C)CCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=C1CCCN1C)c1ccccc1

Procedure:
Add a solution of 6.9 g of sodium in 140 ml of ethanol dropwise at 90°, with stirring, in a stream of nitrogen, to 84 g of 2-dimethylamino-1-methyl-1-pyrrolinium-methylsulfate and 37.9 g of phenylacetic acid ethyl ester. Stir the thus-prepared reaction mixture for a further 30 minutes at 90° and then distribute it between water and diethyl ether (300 ml of each). Isolate the product from the ether phase and distil it to obtain a yield of 48 g (85% of theory) of title compound (b.p. 106° to 107° at 0.008 mm of Hg).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[CH:6][C:7]([C:11]([OH:13])=O)=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][NH2:53])[CH2:47][CH2:46]1>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([C:11](=[O:13])[NH:53][CH2:52][CH2:51][N:48]2[CH2:49][CH2:50][O:45][CH2:46][CH2:47]2)=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(C(=O)O)nc1C
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(C(=O)NCCN2CCOCC2)nc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a solution of 5-acetyl-6-methyl-4-(3-nitrophenyl)-2-pyridinecarboxylic acid (0.95 g) in tetrahydrofuran (10 ml) was added N-hydroxybenzotriazole (0.43 g) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g) at 5° C. After the mixture was stirred at the same temperature for 1 hour, 2-morpholinoethylamine (0.41 g) and triethylamine (0.32 g) was added thereto. The mixture was stirred at ambient temperature for 2 hours and diluted with ice-cold water (20 ml) and ethyl acetate (20 ml). The separated organic layer was washed with brine, dried and concentrated in vacuo. The residue was triturated with diethyl ether to give 3-acetyl-2-methyl-6-(2-morpholinoethylcarbamoyl)-4-(3-nitrophenyl)pyridine (0.45 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11](O)[CH3:12]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CCO
Reactant: Cc1cnc(C(=O)O)cn1
Product: CCOC(=O)c1cnc(C)cn1
Yield: 67 %

Procedure:
A solution of 5-methylpyrazine-2-carboxylic acid (15.0 g, 0.109 mol) in ethanol (70.0 mL) containing (1.5 g, 0.0079 mol) was heated to reflux for 4 h under argon atmosphere. The dark colored solution was cooled, added sod.bicarbonate (1.0 g) and concentrated under reduced pressure. The residue was partitioned between water (50 mL) and EtOAc (100 mL). The organic layer was washed with water (2×25 mL), dried (Na2SO4), and concentrated under reduced pressure to afford ethyl 5-methylpyrazine-2-carboxylate (12.05 g, 67%) as an orange colored liquid: 1H NMR (CD3OD/400 MHz) δ 9.1 (d. 1H, J=1.2 Hz), 8.62 (d, 1H, J=1.2 Hz), 4.45 (q, 2H, J=7.2 Hz), 2.63 (s, 3H), and 1,41 (t, 3H, J=7.2 Hz); ES MS m/z 167 (M+H). Step 2 Ethyl 5-(bromomethyl)pyrazine-2-carboxylate