Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14]>CN1C(=O)N(C)CCC1>[CH:1]1([O:7][CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: COC(COC1CCCCC1)OC
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Cyclohexanol (11.00 g) was added slowly over 2 hours to a stirred suspension of sodium hydride (4.80 g, 50% w/w dispersion in oil) in dry DMPU (100 ml) at 50° C. under argon. The mixture was stirred for an additional 30 minutes, then cooled to 5° C. and treated with 2-bromo-1,1-dimethoxyethane (16.9 g). Stirring was continued for 18 hours at ambient temperature. The mixture was then poured into ice-water (250 ml). The aqueous mixture was extracted with ether (4×100 ml). The combined extracts were washed successively with water (3×100 ml) and saturated brine (100 ml), then dried (MgSO4) and evaporated. Flash chromatography of the residue, eluting successively with hexane, 5% v/v ethyl acetate hexane and 10% v/v ethyl acetate/hexane, gave 2-cyclohexyloxy-1,1-dimethoxyethane as an oil (A) (7.32 g). This was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[Br:7][C:6]1[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[N:3][O:4][C:5]=1[CH3:8]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1onc(N)c1Br
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1onc(NC(=O)OCC(Cl)(Cl)Cl)c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-amino-4-bromo-5-methylisoxazole (2.58 g, 14.6 mmol) and DMAP (893 mg, 7.3 mmol) in 60 mL dichloromethane at −78° C. was added pyridine (6 ml, 74.1 mmol) followed by 2,2,2-trichloroethyl chloroformate (8 ml, 58 mmol). The reaction was allowed to warm to room temperature while stirring over ca. 4 hours. Ice water was added, the aqueous phase neutralized with saturated aq. NaHCO3, and the product extracted with ether (3×), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (20% ethyl acetate/hexane) to afford 2,2,2-trichloroethyl 4-bromo-5-methylisoxazol-3-ylcarbamate.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl[Sn]Cl>CCO>[CH2:6]([O:5][P:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOP(=O)(OCC)c1cccc(N)c1
Yield: 69.8 %

Procedure:
A solution of diethyl(3-nitrophenyl)phosphonate (520 mg, 2.0 mmol) and SnCl2 (1.8 g, 8 mmol) in EtOH (50 mL) was heated at reflux for 12 h. The mixture was then filtered and the filtrate concentrated in vacuo to yield a crude product, which was purified by preparative HPLC to afford 320 mg of desired diethyl(3-aminophenyl)phosphonate (yield: 69%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:6][CH:5]=1.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[Cl:19][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([NH:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:14]=1)[NH:11][C:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1)=[CH:18]2
Reactant: COC(=O)c1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1
Reaction time: 3 h
Yield: 8.5 %

Procedure:
The compound obtained in Example 64 (760 mg, 2.06 mmol) was dissolved in 30 ml of tetrahydrofuran and 2M-lithiumborohydride solution in tetrahydrofuran (2.06 ml, 4.12 mmol) was added. The mixture was at 80° C. for 3 hours. Saturated ammoniumchloride solution was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to obtain the title compound 60 mg (Yield 9%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:12].Br[CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:3]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:12])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCBr
Reactant: O=C1CCCCCCCN1
Agent: [H-]
Agent: [Na+]
Product: CCCCN1CCCCCCCC1=O
Yield: 74.1 %

Procedure:
Following example 10, 16.32 g of 50% sodium hydride-mineral oil dispersion (8.16 g NaH, 0.34 M), 40 g (0.283 M) of azacyclononan-2-one and 43 g (0.311 M) of 1-bromobutane was refluxed for 22 hours. The reaction mixture was diluted with benzene-tolune and was extracted with water. The organic phase was separated, dried and concentrated to a yellow oil. Distillation afforded 41.4 g (74%) of product; b.p. 166°-170°/0.2 mm.
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH:5]1[C:17]2[C:12](=[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]3=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[C:7]1[CH:33]=[CH:32][CH:31]=[CH:30][C:8]1=[C:9]1[CH:29]=[CH:28][CH:27]=[CH:26][C:10]1=2.[C:36](Cl)([Cl:38])=[O:37]>ClCCl>[Cl:38][C:36]([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]3=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[C:7]1[CH:33]=[CH:32][CH:31]=[CH:30][C:8]1=[C:9]1[CH:29]=[CH:28][CH:27]=[CH:26][C:10]1=2)=[O:37]
Reactant: C[Si](C)(C)OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 17-(trimethylsilyl)oxymethyl-tetrabenzo(a,c,g,i)fluorene (0.177 g, 0.38 mmol) in dichloromethane (5 ml) was added phosgene (1.5 ml, 2.9 mmol; 7.5 equiv; 1.93M in toluene). The reaction mixture was heated under reflux for 2 h and then stirred at room temperature for 48 h, under nitrogen. The solvent was removed in vacuo to give compound (37) as a yellow solid which was recrystallized from dichloromethane/n-hexane (36.9 mg, 21%); m.p. 188-189° C.; (Found: C, 80.9; H, 4.29; N, 0.45; C31H19O2Cl requires: C, 81.1; H, 4.14%); νmax (CH2Cl2) 3060 (CH stretching, aromatic), 1775 (CO, chloroformate), 1610, 1500 (aromatic rings), 1160, 1140 (CO stretching) cm−1; δH (CDCl3, 200 MHz) 8.79-8.60 (6H, m, aromatic), 8.20-8.15 (2H, m, aromatic), 7.76-7.57 (8H, m, aromatic), 5.17 (1H, t, 3J=5.7 Hz, CH), 4.77 (2H, d, 3J=5.7 Hz, CH2); δc (CDCl3, 50 MHz) 150.5 (CO, chloroformate), 140.3, 137.2, 131.6, 130.5, 128.2, 127.7 (quaternary aromatic C's), 127.5, 127.0, 126.3, 126.2, 125.1, 124.5, 123.5, 123.4 (aromatic CH's), 74.6 (CH2), 46.5 (CH).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[C:8](=[O:23])[N:9]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:10]([CH3:16])=[N:11][C:12]=2[CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)#[N:27].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.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].ClCCl>[CH3:16][C:10]1[N:9]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:8](=[O:23])[C:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([C:29]3[C:28]([C:26]#[N:27])=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:3][CH:4]=2)=[C:12]([CH2:13][CH2:14][CH3:15])[N:11]=1
Reactant: CCCc1nc(C)n(C2CCOCC2)c(=O)c1Cc1ccc(Br)cc1
Reactant: N#Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(C2CCOCC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
A mixture of 5-(4-bromobenzyl)-2-methyl-6-propyl-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-4(3H)-one (0.7 g), (2-cyanophenyl)boronic acid (0.36 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.07 g), 2 M aqueous sodium carbonate solution (1.5 mL) and 1,4-dioxane (15 mL) was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.61 g, 83%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[I:12].[H-].C([Al+]CC(C)C)C(C)C.CO.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[F:10][C:8]1[CH:7]=[C:6]([CH3:11])[C:5]([I:12])=[C:4]([CH2:3][OH:2])[CH:9]=1
Reactant: COC(=O)c1cc(F)cc(C)c1I
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)cc(CO)c1I
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a solution of 5-fluoro-2-iodo-3-methyl-benzoic acid methyl ester (11.2 g) in dichloromethane (80 mL) was added dropwise over 25 minutes diisobutyl aluminium hydride (113 mL, 1.02 mol/L hexane solution) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dropwise methanol (10 mL) at the same temperature, and the mixture was stirred for 10 minutes. To the reaction mixture was added a saturated potassium sodium tartrate tetrahydrate aqueous solution (300 mL) under ice-cooling, and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give (5-fluoro-2-iodo-3-methyl-phenyl)methanol (7.15 g). To a suspension of the obtained compound (7.15 g) in chloroform (53 mL) and acetone (5.2 mL) was added manganese dioxide, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=0-15%) to give the title compound (3.54 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19](Cl)=[O:20].Cl.CCCCCC.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][N:24]=[C:16]([Cl:15])[CH:17]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)NC(=O)c2ccnc(Cl)c2)cc1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
2.3 g (0.01 mol) of 4-methylsulfonylbenzenesulfonamide were dissolved in 20 ml of pyridine, and added dropwise by 1.7 g (0.01 mol) of 2-chloroisonicotinoyl chloride at room temperature, followed by agitation for 2 hrs. at the same temperature. After acidified by adding aqueous hydrochloric acid, the precipitate was extracted by ethyl acetate. The organic layer obtained was dried and then concentrated to precipitate crude crystals, which were recrystallized by n-hexane/ethyl acetate to 2.8 g (yield: 74.7%) of N-(4-methylsulfonylphenylsulfonyl)-2-chloroisonicotinamide as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[Br-:12].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:12][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[N:2]([CH3:11])[CH3:1])[CH:7]=[O:8]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CN(C)c1ccc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 4-(dimethylamino)-benzaldehyde (10.0 g, 67.03 mmol) in dichloromethane (250 mL) was added pyridinium tribromide (21.4 g, 67.03 mmol). The reaction mixture was stirred at room temperature overnight. The solution was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Choromatography on silica gel (15% EtOAc in hexane) afforded 14.06 g of 3-bromo-4-(dimethylamino)-benzaldehyde (92%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([CH:8]([O:15][C:16](OC2C=CC=CC=2)=[O:17])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:31]>C(O)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]2[NH:31][C:16](=[O:17])[O:15][C:8]=2[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)CCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COC(=O)CCc1oc(=O)[nH]c1-c1ccc(Cl)cc1
Yield: 80 %

Procedure:
A mixture of methyl 4-(4-chlorobenzoyl)-4-phenoxycarbonyloxybutyrate (61.2 g), ammonium acetate (62.2 g) and acetic acid (300 ml) was stirred under reflux for 1.5 hours. The reaction mixture was concentrated, water was added to the resulting residue, and the crystals thus precipitated were collected by filtration. These were recrystallized from methanol to give colorless needles of methyl 3-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]propionate (36.6 g, 79%). m.p. 147-148° C.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36]Cl)[CH2:31][CH2:30]1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:25])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: CC(=O)N1CCN(CCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 90 °C
Yield: 84.9 %

Procedure:
A mixture of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (250 mg, 0.74 mmol), 1-acetyl-4-(2-chloroethyl)piperazine (144 mg, 0.81 mmol) and potassium carbonate (12 mg, 0.81 mmol) in N-methylpyrrolidinone (6 ml) was heated at 90° C. for 2 hours. The mixture was cooled and water added. After 30 minutes the solid was filtered off and dried under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4) to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (310 mg, 58%) as a white solid.
Reaction SMILES: C(N(CC)[C:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:17][C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[O:5])C.[OH-:30].[K+]>O.C(O)C>[C:23]([O:22][C:21]([NH:20][C@H:18]([CH3:19])[CH2:17][C:13]1[C:12]2[C:16](=[C:8]([O:7][CH2:6][C:4]([OH:30])=[O:5])[CH:9]=[CH:10][CH:11]=2)[NH:15][CH:14]=1)=[O:27])([CH3:24])([CH3:26])[CH3:25]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC(=O)OC(C)(C)C)c[nH]c12
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC(=O)OC(C)(C)C
Yield: 99 %

Procedure:
A solution of tert-butyl (R)-[2-(7-diethylcarbamoylmethoxy-1H-indol-3-yl)-1-methylethyl]carbamate (0.35 g, 0.87 mmol) and potassium hydroxide (0.39 g, 7 mmol) in water (4 mL) and ethanol (6 mL) is stirred at 60° C. for 8 hours. After cooling, the mixture is concentrated and acidified by addition of water (30 mL) and acetic acid. The resultant is extracted with chloroform, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give the desired (R)-[3-(2-(tert-butoxycarbonylamino)propyl)-1H-indol-7-yloxy]acetic acid (0.30 g, yield: 100%).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][C:13]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][CH:7]=1.[OH-].[K+]>CO.C1COCC1>[C:23]1([C:13]2[CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:12]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:29])=[O:2])=[CH:11][CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of ester (2d) (4.2 g, 11.0 mmol) in methanol (370 mL) and THF (225 mL) was added 1N KOH (188 mL). After stirring overnight the mixture was heated to 50° C. for 0.5 h and was allowed to cool to room temperature. After stirring 2 h the solvent was partially removed under reduced pressure, the mixture was acidified with 1N HCl, and was extracted with EtOAc. The combined organic layers were washed with water, brine and were dried (MgSO4). The solvent was removed under reduced pressure and the residue was triturated (EtOAc) to give the acid (2e) as a white solid (3.86 g, 96%): 1H NMR (CD3OD) δ 7.54 (d, J=15.7 Hz, 1H), 6.28 (d, J=8.1 Hz, 2H), 7.27-7.08 (m, 8H), 6.89 (d, J=8.1 Hz, 2H), 6.76 (dd, J=7.3, 1.1 Hz, 1H), 6.34 (d, J=15.7 Hz, 1H), 2.83 (t, J=7.0 Hz, 2H), 2.37 (t, J=7.0 Hz, 2H), 2.14 (m, 2H); ESI m/z: 365 (M−H−, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[S:29])[C:8]=2[CH:30]=1)([O-:3])=[O:2].[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH:14]([O:15][CH3:16])[O:17][CH3:18])([CH3:13])[C@H:10]([O:19][C:31](=[O:33])[CH3:32])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[S:29])[C:8]=2[CH:30]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
200 mg (0.46 mmol) of the compound obtained in Example 1 was dissolved in 2 ml of dichloromethane, to which 87 μl (0.93 mmol) of acetic anhydride, 0.13 ml (0.93 mmol) of triethylamine and 17 mg (0.14 mmol) of 4-dimethylaminopyridine were added in that order. The reaction was stirred for 2 hours at room temperature, 10 ml of saturated NaHCO3 solution was added and extraction was performed with 30 ml of dichloromethane. The extract was washed with brine and dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), to give 211 mg (yield: 97%) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: OO
Reactant: Cc1nccnc1C
Solvent: CC(=O)O
Product: Cc1ncc[n+]([O-])c1C
Temperature: 35 °C
Reaction time: 48 h
Yield: 94.6 %

Procedure:
A mixture of 2,3-dimethylpyrazine (25 g, 0.23 mol) and 30% H2O2 (52.4 g, 0.46 mol) in acetic acid (74 mL) was stirred for two days at 35° C. The solvent was removed under vacuum. Water was added and the mixture evaporated again. The residue was basified with aqueous K2CO3 and extracted with EtOAc. The organic phases were dried over Na2SO4 and concentrated. The resulting solid combined from two batches was recrystallized from cyclohexane to give 2,3-dimethylpyrazine 1-oxide (27 g, 47%). 1HNMR (CDCl3, 300 MHz) δ 8.18 (d, J=3.9 Hz, 1H), 8.02 (d, J=4.2 Hz, 1H), 2.58 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[O:14]([CH2:21][CH2:22][NH2:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:14]([CH2:21][CH2:22][NH:23][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCOc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCOc1ccccc1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-phenoxyethylamine. The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a yellow solid. δH (CD3OD): 3.79 (2H, t), 4.17 (2H, t), 6.88-6.97 (3H, m), 7.08 (1H, s), 7.16 (2H, t), 7.67 (1H, s), 8.58 (1H, s); m/z (ES+)=316 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH2:14])[CH3:10].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:14][CH2:13][CH:12]([O:15][CH2:16][CH3:17])[O:11][CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(CN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(CNCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Benzaldehyde (1.27 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.75 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=2)=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.S(Cl)(Cl)(=O)=O.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:30](=[O:32])[CH3:31])=[N:22][CH:23]=2)=[CH:13][CH:12]=3)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cnc3ccc(-c4ccc(N)nc4)cc3n2)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)Nc1ccc(-c2ccc3ncc(N4CCN(C)CC4)nc3c2)cn1
Temperature: 50 °C
Reaction time: 48 h
Yield: 58.8 %

Procedure:
A solution of 5-[3-(4-methyl-1-piperazinyl)-6-quinoxalinyl]-2-pyridinamine (0.46 mmol) in pyridine (3 ml) was treated with a sulfonyl chloride, acyl chloride or anhydride such as acetic anhydride (0.56 mmol) and heated at 50° C. for 18 hour. The reaction mixture was treated with another portion of acetic anhydride (0.10 mmol) and stirred for another 2 days. The reaction mixture was diluted with water and saturated sodium bicarbonate (aq) and extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 filtered and concentrated under reduced pressure. The residue was taken into hot ethyl acetate and diluted with hexanes and cool to 0° C. The reaction mixture was filtered and washed with hexanes to give the title compound (98 mg, 58%). MS(ES)+ m/e 321 [M+H]+.