Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.CCOC(C)=O.[Cl:26][C:27]1[CH:32]=[C:31](CCl)[CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[C:31]([CH2:1][N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:18])[N:15]([CH3:16])[CH3:17])[CH2:12][CH2:13]2)[CH:30]=[CH:29][N:28]=1
Reactant: CN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCc1ccnc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1-Boc-4-(N,N-dimethylcarbamoyl)piperazine was treated with 8 M HCl/EtOAc to afford a salt, then the salt (1.0 equiv) was mixed with 2-chloro-4-(chloromethyl)pyridine (1.0 equiv) (Preparation B-11) and K2CO3 (4 equiv) in DMF. The mixture was stirred for 1 h at rt. After removing most of the solvent, the residue was partitioned in water and EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid (˜90% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]=[C:9]=[O:10])[CH:5]=[C:4]([F:11])[CH:3]=1.[F:12][C:13]1[C:14](=[NH:21])[N:15]([CH3:20])[C:16](=[O:19])[NH:17][CH:18]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([N:17]2[CH:18]=[C:13]([F:12])[C:14](=[NH:21])[N:15]([CH3:20])[C:16]2=[O:19])=[O:10])[CH:5]=[C:4]([F:11])[CH:3]=1
Reactant: Cn1c(=O)[nH]cc(F)c1=N
Reactant: O=C=Nc1cc(F)cc(F)c1
Solvent: CN(C)C=O
Product: Cn1c(=N)c(F)cn(C(=O)Nc2cc(F)cc(F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Difluoro-5-isocyanatobenzene (119 mg, 0.769 mmol) was added to a solution of 5-fluoro-4-imino-3-methyl-3,4-dihydropyrimidin-2(1H)-one (100 mg, 0.699 mmol) in DMF (1.8 mL) and stirred overnight at room temperature. The solution was then concentrated under vacuum and the resulting residue stirred in dichloromethane (2 mL) for 30 min. The solids were filtered and washed with dichloromethane (2×3 mL) and dried under vacuum to afford the title compound; mp 203.0-204.5° C.; 1H NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 9.87 (s, 1H), 7.68 (d, J=6.2 Hz, 1H), 7.25 (d, J=7.4 Hz, 2H), 6.80 (s, 1H), 3.25 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 163.77, 163.62, 161.36, 161.21, 158.57, 149.14, 146.14, 145.90, 142.72, 142.58, 142.44, 138.68, 136.41, 122.85, 122.52, 101.05, 100.76, 97.32, 97.06, 96.79, 29.43; ESIMS m/z 299.0 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:31]4[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1cncc(F)c1
Product: C[C@@H](c1ccc(-c2cncc(F)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 5-fluoropyridin-3-ylboronic acid following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.5 min, m/z=453 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][C:12]1(O)[CH2:17][CH2:16][CH2:15][CH2:14]C1.[C:19](Cl)(=O)[C:20]([CH3:23])([CH3:22])[CH3:21].O.C1(C)C=CC(S(O)(=O)=[O:34])=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][C:11]3([OH:34])[CH2:12][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[N:1][C:2]=2[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cc(Br)ccc1NCCC1(O)CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1nc2cc(Br)ccc2n1CC1(O)CCCCC1
Reaction time: 0.25 h
Yield: 21 %

Procedure:
To a solution of 1-{[(2-amino-4-bromophenyl)amino]ethyl}cyclohexanol (Step B, 892 mg, 2.8 mmol) in toluene (15 mL) was added pivaloyl chloride (379 μL, 3.1 mmol) at room temperature. After stirring for 15 min, p-toluenesulfonic acid monohydrate (533 mg, 2.8 mmol) was added and the mixture was stirred under reflux for 17 h with Dean-Stark apparatus. Water (5 mL) and saturated sodium hydrogencarbonate aqueous solution were added and the mixture was extracted with ethyl acetate (15 mL×3). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1 then 4:1 as eluent) to afford the title compound (215 mg, 21%).
Reaction SMILES: [CH2:1]([S:6]([OH:9])(=O)=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[Na].S(Cl)([Cl:13])=O>>[CH2:1]([S:6]([Cl:13])(=[O:9])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCCS(=O)(=O)O
Agent: [Na]
Product: CCCCCS(=O)(=O)Cl
Temperature: 60 °C
Yield: 61 %

Procedure:
1-Pentanesulfonic acid, sodium salt (10 g, 57.5 mmol) was charged into a 250 ml round bottom flask (allow headroom). Thionyl chloride (20 mL) is added; gas evolves, and a while solid forms. The mixture is heated at 60° C. for 3 hours. The solvents are removed in vacuo; toluene is added and removed in vacuo to remove residue of SOCl2. The residue is partitioned between CH2Cl2 and ice water; the organic layer is dried over Na2SO4. The crude product is purified by distillation (bp 54–56° C. @ 0.5 mm Hg) to give a clear oil, 61% yield.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].Br[C:10]1[S:11][CH:12]=[CH:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[S:11]1[CH:12]=[CH:13][N:14]=[C:10]1[N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: Brc1nccs1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CCCN1c1nccs1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 80 mg (0.70 mmol) of L-Proline in 3 mL of anhydrous N,N-dimethylformamide at ambient temperature was added 0.062 ml (0.70 mmol) of 2-bromothiazole, 288 mg (2.09 mmol) of potassium carbonate, and 13 mg (0.068 mmol) of copper(I)iodide. The reaction mixture was heated to 100° C. overnight then filtered through a plug of Celite®. The crude residue was purified by reverse-phase HPLC (TMC Pro-Pac C18; 0-60% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to give the title compound as a light brown solid. (0.065 g, 50%). LC-MS: m/z (ES) 199.2 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:8]([C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(CN[C@H](CC(C)C)C(N)=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 39.5 %

Procedure:
(2R)-2-[N-(4-Methoxybenzyl)amino]-4-methylpentanoic acid amide (3.57 g, 14.3 mmol) was dissolved in CH2Cl2 (100 mL) and treated with Et3N (4.2 mL, 29 mmol) and 4-chlorobenzenesulfonyl chloride (3.6 g, 17 mmol) at rt for 18 h. The solvents were removed and the residue was taken into EtOAc (500 mL). The organic solution was washed with H2O, brine, dried over MgSO4, and concentrated. The resulting material was then further purified by flash chromatography (SiO2, 1% MeOH/CH2Cl2) to afford the title compound (2.4 g) as a slightly colored solid in 40% yield. MS (ESI), (M−H)−422.9; 1H NMR (CDCl3) δ 7.63 (d, 2H, J=7.0), 7.42 (d, 2H, J=7.0), 7.25 (d, 2H, J=8.0), 6.79 (d, 2H, J=8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.36 (dd, 2H, J=5.0, 15), 4.26 (t, 1H, J=7.2), 3.78 (s, 3H), 1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0); IR (KBr) 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm−1.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:29]([OH:31])=O.[O:32]1CCC[CH2:33]1>>[CH:33]([O:25][C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[C@H:19]([CH2:18][C@@H:17]([O:27][CH:29]=[O:31])[C@@H:16]3[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:28])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24]1)=[O:32]
Reactant: O=CO
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1CCOC1
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](OC=O)C[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 96 %

Procedure:
CDCA (II) (15.0 g, 38.27 mmol) was dissolved in 83 ml of tetrahydrofuran and treated with 18 drops of 70% HClO4. Formic acid (50 ml) was then added dropwise in 40 min and the resulting mixture was reacted at 54° C. for 8 h. The mixture was then concentrated under vacuum and the residue was taken up in water. The white precipitate was filtered, washed several times with water, triturated in water at 5° C. for 20 min, and dried under high vacuum to obtain 16.5 g (36.83 mmol, 96%) of pure compound (V).
Reaction SMILES: [BH4-].[Na+].Cl[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:5]([F:8])([F:7])[F:6]>C1COCC1>[F:6][C:5]([F:7])([F:8])[CH2:4][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: Oc1ccccc1C(Cl)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccccc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium borohydride (0.930 g) was added to a solution of 2-(1-chloro-2,2,2-trifluoroethyl)phenol (2.6 g) in THF (30 ml). The reaction mixture was then stirred for 14 hrs at room temperature under an atmosphere of nitrogen, after which time the reaction was quenched with 1N HCl (50 ml) and partitioned between 1N HCl (100 ml) and ethyl acetate (200 ml), the organics were separated and dried over magnesium sulfate, filtered and solvent evaporated in vacuo to afford title compound as a semi solid (2.4 g). 1H NMR (CDCl3): δ 3.50 (q, J=21.06 Hz 2H), 6.80 (m, 1H), 7.00 (m, 1H), 7.25 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].N1C=CC=CC=1.[CH2:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[C:19]([F:26])[CH:18]=1)[CH3:16]>C1C=CC=CC=1>[CH2:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[O:22])=[C:19]([F:26])[CH:18]=1)[CH3:16]
Reactant: CCc1ccc(C(=O)Cl)c(F)c1
Reactant: Nc1ccccc1O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCc1ccc(C(=O)Nc2ccccc2O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 13.08 gm. of o-aminophenol in 150 cc. of dry pyridine which is cooled in ice water is added a solution of 4-ethyl-2-fluorobenzoyl chloride (prepared from 20.0 gm. of acid and thionyl chloride) in 30 cc. of dry benzene. The mixture is stirred at room temperature overnight and then concentrated in vacuo. The residue is treated with water and the precipitate collected by filtration to give crude 4-ethyl-2-fluoro-2'-hydroxybenzanilide which was characterized by infra red spectra and then used in the following step.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][S:9][C:5]=2C(O)=[N:3][C:2]=1O.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:25])=O.C1COCC1.Cl[CH2:34][Cl:35]>O>[Cl:25][C:2]1[N:3]=[C:34]([Cl:35])[C:5]2[S:9][CH:8]=[CH:7][C:6]=2[N:1]=1
Reactant: ClCCl
Reactant: Oc1nc(O)c2c(n1)CCS2
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)c1ccccc1
Product: Clc1nc(Cl)c2sccc2n1
Temperature: 110 °C
Reaction time: 0.58 h
Yield: 88 %

Procedure:
800 g of solid Compound VI (4.66 mol) was charged into to an inert and dry jacketed reactor (reactor 1) equipped with a temperature probe, mechanical stirrer and a dropping funnel. 1.5 litre (9.31 mol) Diethylaniline was charged over 30 min to 1 h keeping the temperature at or below 25° C. The internal temperature was brought up to 105-110° C. and 0.68 equiv. (868 ml, 34% of the total) of phosphorus oxychloride was added into the reactor (reactor 1) over 5-10 min. When the inside temperature began to decrease, the internal temperature was maintained at 110° C. and addition of the remaining POCl3 (1.32 equiv. or 66% of the total) resumed over a period of 30-40 min. The internal temperature was adjusted to 105-110° C. and the mixture was stirred for 18-24 h or until complete (HPLC analysis). The mixture was cooled to 45° C. and THF (400 mL) was charged at 45° C. The above crude mixture was placed into a secondary dry vessel or reactor (vessel or reactor 2). 4.8 l of water was charged into the reactor 1 and cooled to 5° C. The crude reaction mixture (in reactor or vessel 2) is then slowly charged into reactor 1 containing water keeping the temperature at 5-10° C. The mixture was stirred at 5° C. for 30 min to 1 h and the resulting solid was collected by filtration. The cake was rinsed with water twice (1.6 l per rinse) and the cake was air dried in the funnel for 6-8 h to afford 964 g (92% w/w; 88% yield) of crude Compound VII. Dichloromethane (4.6 L) is charged into a 10 L reactor. Crude Compound VII and activated carbon (46.2 g) were charged into the reactor, the mixture is heated to 40° C. and stirred for 20 min. The resulting solution was collected by filtration through a filter media to remove charcoal. The cake was rinsed with dichloromethane twice (175 ml per rinse). The solution was concentrated under reduced pressure to a minimum stirrable volume and the remaining dichloromethane was chased away by distillation with a minimum amount of petroleum ether. Additional petroleum ether (1.3 l) was charged into the reactor, the mixture was cooled to 10° C. and stirred for 1 hr. The resulting solid was collected by filtration and the cake was rinsed with petroleum ether twice (150 ml per rinse). The cake was air dried in the funnel (suction) until it appeared dry. The resulting solid Compound VII was transferred to a suitable tared container and dried in an oven at 50° C. for 6 hr to get final product: 1H NMR (400 MHz, DMSO-d6) δ 3.45-3.56 (m, 4H); 13C NMR (400 MHz, DMSO-d6) δ 29.3, 36.5, 134.8, 151.0, 154.1, 175.9.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[N:32]=[C:33]=[O:34].Cl>C(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[NH:32][C:33]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2)=[O:34]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cc(C(F)(F)F)ccc4Cl)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-chloro-2-isocyanato-4-trifluoromethyl-benzene (0.15 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding the 1-(2-chloro-5-trifluoromethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (240 mg, 49%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN 0.1% H3PO4 in H2O: tR=7.88 min (99%); mp. 240-242° C.; 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H, CHH), 2.39 (qd, J=4.3, 13.2 Hz, 1H, CHH), 2.63 (br. s., 1H, CHH), 2.82-3.02 (m, 1H, CHH), 4.24-4.55 (m, 4H, CH2+CH2), 5.12 (dd, J=5.0, 13.1 Hz, 1H, NCH), 7.30 (dd, J=1.6, 8.4 Hz, 1H, Ar), 7.47 (d, J=7.9 Hz, 1H, Ar), 7.55 (s, 1H, Ar), 7.69 (dd, J=8.0, 15.4 Hz, 2H, Ar), 7.78 (t, J=5.7 Hz, 1H, Ar), 8.49 (s, 1H, NH), 8.66 (s, 1H, NH), 10.99 (s, 1H, NH). 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.80, 47.13, 51.58, 116.19, 116.25, 118.54, 122.07, 123.06, 124.60, 125.64, 127.02, 127.90, 128.32, 130.23, 130.49, 137.51, 142.49, 143.95, 154.67, 167.89, 170.98, 172.85. LCMS MH=495; Anal Calcd for: C22H18ClF3N4O4+0.05 HCl: C, 53.20; H, 3.66; N, 7.49; Cl, 11.28. found: C, 53.08; H, 3.39; N, 7.64; Cl, 11.29.
Reaction SMILES: [Li+].[Br-].[CH3:3][C:4]1([O:7][CH2:6]1)[CH3:5].F[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1.[C:24](OCC)(=O)C>CN1C(=O)CCC1.O>[CH3:3][C:4]([OH:7])([CH3:5])[CH2:6][NH:23][C@@H:20]1[CH2:21][CH2:22][N:18]([C:10]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=2[CH3:24])[CH2:19]1
Reactant: CC1(C)CO1
Reactant: CCOC(C)=O
Reactant: N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2F)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1N1CC[C@@H](NCC(C)(C)O)C1
Temperature: 80 °C

Procedure:
LiBr (153.6 mg) and isobutylene oxide (85.1 mg) were added to a solution of (R)-1-(2-fluoro-4-nitro-phenyl)-pyrrolidin-3-ylamine (100 mg) in NMP (2 mL) and the reaction mixture was heated for 2 d at 80° C. Then ethyl acetate and water were added to the mixture. The aqueous phase was extracted several times with ethyl acetate. The organic phases were combined, dried over sodium sulfate and the solvent was removed in vacuum. The raw product was purified by preparative HPLC. In this way the product was obtained with molecular weight 297.15 (C14H20FN3O3); MS (ESI): 298 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=3)[S:4][C:3]=1[C:19]([NH2:21])=[O:20].[N:22]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:18][O:17][C:9]1[C:10]([O:15][CH3:16])=[CH:11][C:12]2[CH:13]=[C:14]3[C:2]4[N:1]=[N:22][NH:21][C:19](=[O:20])[C:3]=4[S:4][C:5]3=[N:6][C:7]=2[CH:8]=1
Reactant: O=N[O-]
Reactant: COc1cc2cc3c(N)c(C(N)=O)sc3nc2cc1OC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2cc3c(nc2cc1OC)sc1c(=O)[nH]nnc13
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.0 g of 3-amino-6,7-dimethoxythieno[2,3-b]quinoline-2-carboxamide in 1.5 liters of glacial acetic acid was added dropwise a solution of 4.0 g of sodium nitrite in 20 ml of water. The resulting mixture was stirred at room temperature for 16 hours. The solvent was then evaporated from the reaction mixture under reduced pressure to concentrate it to a volume of 300 ml. The solid which formed was separated by filtration to give 8,9-dimethoxy-1,2,3-triazino[4',5':4,5]thieno[2,3-b]quinolin-4(3H)-one. A small portion of this product was washed with hot tetrahydrofuran to give an off-white solid melting at greater than 230° C. with decomposition. The product obtained has the following structural formula ##STR3##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[CH:37]([N:10]1[CH:11]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)=[N:9]1)([CH3:39])[CH3:38]
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 60 °C

Procedure:
To a solution of 2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline (0.075 g) in dimethyl formamide (2 ml) was added cesium carbonate (0.098 g) and 2-iodo propane (0.030 ml) and the reaction mixture heated at 60° C. for 72 h. The reaction mixture was poured into water and extracted with methylene chloride, dried magnesium sulfate, filtered and concentrated. Purification via Prep TLC eluting with 2% methanol/1% saturated ammonium hydroxide/67% ethyl acetate/30% hexane provided the title compound (60 mg). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=6.2 Hz, 2H), 8.16 (d, J=8.7 Hz, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.70 (m, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.53 (t, J=7.1 Hz, 1H), 7.38 (d, J=9.1 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 5.38 (s, 2H) 4.51 (m, 1H), 1.54 (d, J=6.6 Hz, 6H); MS: (M+H m/z=421.2).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([NH:15][NH2:16])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>O1CCCC1>[NH2:1][C:2]1[S:3][C:4]([C:13]2[O:14][C:24](=[O:25])[NH:16][N:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: NNC(=O)c1sc(N)nc1-c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nc(-c2ccccc2)c(-c2n[nH]c(=O)o2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
2-Amino-4-phenyl-thiazole-5-carboxylic acid hydrazide (1 g, 4.3 mmol) was suspended in tetrahydrofurane (50 mL). Triethylamine (5 mL, 40 mmol) and carbonyldiimidazole (0.83, 5.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo. The crude product was purified by flash column chromatography, eluted with the ethyl acetate/hexanes (1/1) to give the product as a solid. Yield: 20%.
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])C1C=CC=CC=1.CCN([CH:40]([CH3:42])[CH3:41])C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[O:19]1[C:17]2[CH:16]=[CH:12][CH:42]=[CH:40][C:41]=2[CH:21]=[C:20]1[C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1nc(C(F)(F)F)cc1-c1csc(NC(=O)OCc2ccccc2)c1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1nc(C(F)(F)F)cc1-c1csc(NC(=O)c2cc3ccccc3o2)c1C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 288.9 %

Procedure:
Under an atmosphere of argon, acid chloride 12 (10.8 mg, 60 μmol) was added in portions to a stirred solution of 11 (24 mg, 50 μmol), Hünig's base (26 μL, 19 mg, 15 μmol), and DMAP (0.6 mg, 5.0 μmol) in dichloromethane (250 μL) at room temperature. The reaction was stirred for 10 minutes then heated to 30° C. for 20 minutes. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 13 (21.3 mg, 87%) as a solid: LRESIMS m/z 492 [M+H]+, calcd. for C23H20F3N3O4S1 492.1.