Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4].[C:8]([O:12][C:13](=[O:21])[NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:8]([O:12][C:13](=[O:21])[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:2][C:3]([CH:5]2[CH2:7][CH2:6]2)=[O:4])[CH2:17][CH2:16]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(CBr)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CC(=O)C2CC2)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 104.5 %

Procedure:
2-Bromo-1-cyclopropyl-ethanone (244 mg, 1.44 mmol, 1.0 eq) is added at room temperature to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (300 mg, 1.44 mmol, 1.0 eq) in N,N-dimethylformamide (12 mL), followed by potassium carbonate (200 mg, 1.44 mmol, 1.0 eq). After 4 hours stirring at 60° C., solvent is evaporated and the residue is extracted with dichloromethane (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford [1-(2-cyclopropyl-2-oxo-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a light yellow solid (425 mg, 99% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:26][C:25]2[C:20]([O:19][CH3:18])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:7]=1
Reactant: COc1ncccc1N
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ncccc1Nc1cc(Cl)ncn1
Temperature: 90 °C
Yield: 31.5 %

Procedure:
To a solution of 4,6-dichloropyrimidine (660.04 mg, 4.43 mmol) in 1-butanol (10 mL) was added DIPEA (0.67 ml, 4.03 mmol) followed by 2-methoxypyridin-3-amine (500 mg, 4.03 mmol). The reaction mixture was then heated to 90° C. for 2 hr. The reaction mixture was then concentrated in vacuo and partitioned between DCM and water. A precipitate was removed by filtration and the organics extracted (2×20 ml DCM). The combined organic extracts were then washed with 0.5M HCl (5 ml) and then dried (Na2SO4), filtered and concentrated in vacuo to give the title intermediate (300 mg, LC-MS purity=83%); LC-MS: m/z=+236.95/238.90 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH2:35])=[N:23][C:24]([C:26]2[C:31]([NH2:32])=[N:30][C:29]([NH2:33])=[C:28]([Cl:34])[N:27]=2)=[O:25])=[CH:13][CH:12]=1)(C)(C)C.Cl.C(Cl)Cl.CO>CO>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:23][C:24]([C:26]2[C:31]([NH2:32])=[N:30][C:29]([NH2:33])=[C:28]([Cl:34])[N:27]=2)=[O:25])=[NH:35])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: N=C(NCCCCc1ccc(OCCN)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Reaction time: 1 h
Yield: 125.9 %

Procedure:
[2-(4-{4-[N′-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)ethyl]-carbamic acid tert-butyl ester 3 (2.63 g, 5.0 mmol) was dissolved in methanol (25 mL). 12N HCl (30 mL) was added in 10 ml portions. After stirring for 1 h, the reaction was complete by TLC (silica gel, methylene chloride/methanol/concentrated ammonium hydroxide, 100:10:1). The solvent was evaporated and methanol (300 mL) was added and, this process was repeated. The residue was placed under high vacuum overnight to afford the product (2.65 g, 99%) as a yellow solid, which was used without further manipulation. 1H NMR (300 MHz, DMSO-d6) δ 1.58 (m, 4H), 2.57 (m, 2H), 3.16 (m, 2H), 3.37 (m, 2H), 4.18 (t, 2H), 6.91 (d, 2H), 7.15 (d, 2H), 7.45 (m, 4H), 8.45 (br s, 3H), 9.03 (br s, 2H), 9.46 (t, 1H), 10.63 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([Cl:22])[N:3]=1>[OH-].[Na+]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[CH:5]=[C:4]([Cl:22])[N:3]=[C:2]([NH2:1])[N:7]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Yield: 86 %

Procedure:
0.885 9 (0.0026 mol) of N-[4-(2-amino-6-chloropyrimidin-4-ylsulfamoyl)phenyl]-acetamide was dissolved in 31 ml of 0.5N NaOH and boiled at reflux for 3 hours. The mixture was extracted with ethyl acetate, the aqueous phase was saturated with sodium chloride and the remaining ethyl acetate was distilled off on a rotary evaporator. Then, the aqueous phase was made acid with 3N HCl and the precipitate which separated was filtered off under suction. After drying there was obtained 0.76 g (86%) of 4-amino-N-(2-amino-6-chloro-pyrimidine-4-yl)-benzenesulfonamide as beige crystals; m.p.: >265° C. (dec.).
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C1OCCOCCOCCOCCOCCOC1.[Br:37][C:38]1[N:43]=[C:42]([CH:44]=O)[CH:41]=[CH:40][CH:39]=1>CN(C)C=O.C(O)C>[Br:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42](/[CH:44]=[CH:1]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:43]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1cccc(Br)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Brc1cccc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl benzylphosphonate (4.57 mL, 21.91 mmol) in dimethylformamide (50 mL) at room temperature was added sodium methoxide (2.367 g, 43.8 mmol) and 18-Crown-6 (2.316 g, 8.76 mmol). After stirring at room temperature for 5 min, the reaction was cooled to 0° C. and treated with 6-bromopicolinaldehyde (4.89 g, 26.3 mmol) as a solid in one portion. The ice bath was removed and the reaction stirred at room temperature for 1 h. The reaction was gradually warmed to 120° C. and held there for 2 h. The reaction was cooled to room temperature and poured into water (500 mL) with vigorous stirring. The resulting suspension was extracted with diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to an oil. The oil was dissolved in hexanes and reconcentrated to give something that appeared to be crashing out as a solid. The resulting residue (solid in oil) was suspended in ethanol, concentrated, and pumped under high vacuum to give a dark-colored, moist solid. The resulting residue was suspended in ethanol (total volume (solid+solution)=20 ml). The resulting suspension was placed in the freezer and held there overnight. The resulting precipitate was collected by filtration to give 2.46 g (43%) as a faint tan powder. 1H-NMR (CDCl3, 500 MHz) δ 7.69 (d, J=16.2, 1H), 7.60 (d, J=8.9, 2H), 7.53 (dd, J=7.9, 7.6, 1H), 7.41 (dd, J=7.6, 7.3, 2H), 7.31-7.38 (m, 3H), 7.11 (d, J=16.2, 1H). 13C-NMR (CDCl3, 126 MHz) δ 157.2, 142.3, 138.8, 136.3, 134.5, 128.9, 128.8, 127.4, 126.4, 126.2, 120.7.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1)=[O:4].[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[CH2:28][NH:29][CH2:30][CH3:31].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:30]([N:29]([CH2:28][C:27]1[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=1[F:25])[C:20](=[O:22])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:24][CH:23]=1)[CH3:31]
Reactant: CCNCc1ccccc1F
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
[4-(2-{[2-(Methoxycarbonyl)phenyl]thio}ethyl)phenoxy]acetic acid (0.250 g, 0.722 mmol) was dissolved in DCM (10 ml), N-(2-fluorobenzyl)ethanamine (0.105 g, 0.686 mmol) was added. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.255 g, 0.0.794 mmol) and N-ethyl-N,N-diisopropylamine (0.187 g, 1.443 mmol) were added. The solution was stirred for 2 hours at room temperature. The crude was purified by flash chromatography (started with isocratic DCM 100% and then the MeOH concentration was increased from 0.5% to 20%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation. The substance needed to be purified once more and it was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. The ammonium acetate was removed by freeze drying the product overnight to give 0.1 g of methyl 2-{[2-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoate (yield 29.1%).
Reaction SMILES: C([N:8]1[C:16]2[CH:15]=[C:14]([O:17][CH3:18])[CH:13]=[CH:12][C:11]=2[C:10]2[N:19]=[C:20]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:21]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:9]1=2)C1C=CC=CC=1>C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]2[C:10]3[N:19]=[C:20]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:21]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:9]=3[NH:8][C:16]=2[CH:15]=1
Reactant: COC(=O)c1cc(N2CCCCC2)nc2c3ccc(OC)cc3n(Cc3ccccc3)c12
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(N2CCCCC2)nc2c1[nH]c1cc(OC)ccc12
Reaction time: 0.67 h
Yield: 36.7 %

Procedure:
A solution of methyl 5-benzyl-7-methoxy-2-(piperidin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (51 mg, 0.12 mmol) in TFA (2 mL) and two drops of trifluoromethanesulfonic acid was heated at reflux for 30 min. Another two drops of trifluoromethanesulfonic acid was added and heating continued for another 40 min. Preparative HPLC (100×30 mm Luna C18 column, Solvent A=10 mM NH4OAc in 95% water:5% acetonitrile; B=10 mM NH4OAc in 5% water:95% acetonitrile; gradient of 15 to 100% B over 20 min at 42 mL/min) followed by removal of the solvents afforded methyl 7-methoxy-2-(piperidin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (15 mg, 0.044 mmol, 37% yield). MS (ESI) m/z 340.2 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 9.02 (1H, br. s.), 8.09 (1H, d, J=8.85 Hz), 7.22 (1H, s), 6.89 (1H, s), 6.85 (1H, d, J=8.55 Hz), 4.02 (3H, s), 3.90 (3H, s), 3.53-3.64 (4H, m), 1.69-1.80 (4H, m), 1.56-1.67 (2H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: BrCc1ccccc1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(Cc2ccccc2)c2cc([N+](=O)[O-])c(N)cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using benzyl bromide (0.46 ml; 3.9 mmol) and K2CO3 (1.5 g; 10.9 mmol) at RT for 20 h. After filtration and evaporation of the solvent the crude material is de-acetylated under reflux conditions in 2-propanol (10 ml) and hydrochloric acid (6 N, 30 ml). Pure 5-amino-1-benzyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.04 g) precipitates by pouring the reaction mixture into ice-water.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: COc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Product: COc1ccc(Nc2nc3cccc(-c4ccc(S(C)(=O)=O)cc4)n3n2)cc1
Yield: 10.8 %

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methoxy-phenyl)-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (115 mg, 0.40 mmol) and p-bromoanisole (82 mg, 0.44 mmol) in a manner analogous to Example 77 to yield [5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methoxy-phenyl)-amine (17 mg, 11%) as a yellow powder following purification on a 12 g Isco silica gel column using methanol in dichloromethane (0-10%) as eluent. MP=229° C. (dec.). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.43 (s, 1H), 8.32 (d, J=7.50 Hz, 2H), 8.14 (d, J=7.50 Hz, 2H), 7.54-7.71 (m, 4H), 7.27 (d, J=6.4 Hz, 1H), 6.87 (d, J=7.5 Hz, 2H), 3.71 (s, 3H), 3.34 (s, 3H). MS=395 (MH)+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH3:19][N:20]([CH3:49])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[CH:33]=[C:32]([CH2:43]OS(C)(=O)=O)[N:31]=2)=[CH:26][CH:25]=1)=[O:22]>C(#N)C>[CH3:19][N:20]([CH3:49])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[CH:33]=[C:32]([CH2:43][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:31]=2)=[CH:26][CH:25]=1)=[O:22]
Reactant: Sc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1COCCN1c1cc(CSc2ccccc2)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Thiophenol (0.062 mL) was dissolved in acetonitrile (5 mL). DBU (0.141 mL) was then added to the solution and was allowed to stir at RT for 5 minutes. 1,1-Dimethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]urea (154 mg) was suspended in acetonitrile (5 mL) and added to the thiol. The reaction was left to stir at RT of 1 hour then concentrated in vacuo to give the desired material which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[O:26]([C:23]1[CH:22]=[CH:21][C:20]([C:17]2[N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[O:19][N:18]=2)=[CH:25][CH:24]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(COc2ccc(-c3nc(-c4ccc(Oc5ccccc5)cc4)no3)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)no2)cc1
Temperature: 55 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
To 5-(4-(benzyloxy)phenyl)-3-(4-phenoxyphenyl)-1,2,4-oxadiazole (50 mg, 120 μmol) was added 10% Pd/C (1 mg, 8 μmol) and the mixture was suspended in methanol (3.0 mL) and THF (3.0 mL). The solution was stirred under H2 at 55° C. for 24 hours. The solution was filtered through Celite and the solvent was removed under reduced pressure and then purified by column chromatography EtOAc/Hex (1:6→1:4) to give the product as a white solid (12 mg, 31%). 1H NMR (500 MHz, CDCL3) δ(ppm): 5.83 (1H, bs), 6.98 (2H, d, J=8.2 Hz), 7.09 (4H, m), 7.18 (1H, t, J=7.6 Hz), 8.12 (2H, t, J=7.7 Hz), 8.12 (2H, d, J=6.8 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 116.3 (CH), 117.2, 118.6 (CH), 119.9 (CH), 121.8, 124.4 (CH), 129.5 (CH), 130.2 (CH), 130.6 (CH), 156.4, 159.8, 160.3, 168.5, 175.7. MS (FAB+): 331 (MH+). HRMS for C20H14N2O3 (MH+): calculated: 331.1083; found 331.1056.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:13](=[O:26])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[C:4]([F:29])[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:39][C:40]1[CH:41]=[C:42]([N:46]=[C:47]=[O:48])[CH:43]=[CH:44][CH:45]=1>O1CCOCC1>[Cl:39][C:40]1[CH:41]=[C:42]([NH:46][C:47]([NH:1][C:2]2[CH:28]=[CH:27][C:5]([O:6][C:7]3[C:16]4[CH2:15][N:14]([CH2:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=5)[C:13](=[O:26])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[C:4]([F:29])[CH:3]=2)=[O:48])[CH:43]=[CH:44][CH:45]=1
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)cc4F)ccnc3NC2=O)cc1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)Nc5cccc(Cl)c5)cc4F)ccnc3NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
57 (20 mg, 0.05 mmol), DIEA (304, 0.15 mmol), and 3-chlorophenyl isocyanate (9.4 mg, 0.06 mmol) were suspended in dioxane (2 mL), and stirred overnight at room temperature. The crude product was purified directly via HPLC. LC-MS (M+H=548, obsd.=548).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13]([C:18]1[CH:30]=[C:29]([C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])[CH:28]=[CH:27][C:19]=1[O:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])([CH2:16][CH3:17])([CH3:15])[CH3:14]>C(OCC)(=O)C>[C:13]([C:18]1[CH:30]=[C:29]([C:31]([CH2:34][CH3:35])([CH3:32])[CH3:33])[CH:28]=[CH:27][C:19]=1[O:20][CH:21]([CH2:25][CH3:26])[C:22]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12])=[O:23])([CH2:16][CH3:17])([CH3:15])[CH3:14]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1O

Procedure:
In 100 ml of ethyl acetate was dissolved 25 g (133×10-3 mole) of 2-amino-4-chloro-5-nitrophenol. To the solution was added 50 g of 2-(2,4-di-t-amylphenoxy)butanoic acid chloride at room temperature, and then the mixture was refluxed under heating for 2 hours. After the reaction, a solvent was evaporated under reduced pressure and the residue was recrystallized from hexane to obtain products. Yield: 61 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][NH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH2:3]1.F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1([CH3:15])[CH2:7][N:6]2[C:17]3[C:18]([N+:27]([O-:28])=[C:8]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:5]2=[N:4][CH2:3]1)=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC1(C)CN=C(Cc2ccccc2)NC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CN=C2C(c3ccccc3)=[N+]([O-])c3cc(C(F)(F)F)ccc3N2C1
Temperature: 40 °C
Yield: 26.8 %

Procedure:
A mixture of 1,4,5,6-tetrahydro-5,5-dimethyl-2-phenylmethylpyrimidine (1.69, 8 mmol), 1-fluoro-2-nitro-4-trifluoromethylbenzene (1.679, 8 mmol) and potassium carbonate (550 mg, 4 mmol) in acetonitrile (25 ml) was heated overnight at 40° C. The solvent was removed in vacuo and the resulting yellow solid recrystallised from ethyl acetate to yield 2,3-dihydro-2,2-dimethyl-5-phenyl-8-trifluoromethyl-1H-pyrimido[1,2-a]quinoxaline 6-oxide (800 mg) as a yellow crystalline solid, m.p. 225°-227° C. (Found: C, 64.42, H, 4.95, N, 11.23%; C20H18F3N3O requires C, 64.34, H, 4.86, N, 11.25%) and represented by the structural formula: ##STR6##
Reaction SMILES: CS([C:5]1[N:17]=[C:8]2[N:9]=[C:10]([CH2:15][CH3:16])[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=1)(=O)=O.[O:18]([CH2:25][CH2:26][NH2:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:15]([C:10]1[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=[C:5]([NH:27][CH2:26][CH2:25][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]=[C:8]2[N:9]=1)[CH3:16]
Reactant: CCc1cc(CC)n2nc(S(C)(=O)=O)nc2n1
Reactant: NCCOc1ccccc1
Product: CCc1cc(CC)n2nc(NCCOc3ccccc3)nc2n1
Temperature: 115 °C
Reaction time: 72 h

Procedure:
A mixture of 2-methanesulfonyl-5,7-diethyl-[1,2,4]-triazolo[1,5-a]pyrimidine (4.5 g, 17.7 mmol) and 2-phenoxyethylamine (24.3 g, 177.2 mmol) was added to a 100 mL RBF with a magnetic stirring bar, and the flask was fitted with a condenser. The mixture was allowed to stir at 110-120° C. for 72 hours. Progress of the reaction was monitored by analytical HPLC with UV detection where the title compound eluted with retention time of 5.1 min. The reaction was allowed to cool to room temperature and partitioned between dichloromethane (150 mL) and 2 N HCl (100 mL). The acidic layer was extracted with dichloromethane (100 mL), and the combined organic layers were washed with saturated aqueous NaCl (75 mL). The NaCl layer was extracted with dichloromethane (75 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was added to chloroform (25 mL) and methanol (0.5 mL), and a precipitate was removed by filtration. The material in the organic layer was purified by silica gel chromatography with a gradient elution of 0.75-3.0% ethanol in chloroform. Fractions were pooled and concentrated under reduced pressure, and the solid material was crystallized from hot ethanol (35 mL) to afford the title compound as an off white solid (3.26 g, 59% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.27 (m, 2H), 7.03 (t, 1H), 6.96 (m, 3H), 6.85 (s, 1H), 4.13 (t, 2H), 3.61 (q, 2H), 2.96 (q, 2H), 2.75 (q, 2H), 1.31 (t, 3H), 1.24 (t, 3H). EM (calc.): 311.2; MS (ESI) m/e: 312.3 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl.CO>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH:14][C:19]2[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Reactant: Clc1nc2ccccc2s1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1cc(CN2CCCC2)cc(OCCCNc2nc3ccccc3s2)c1

Procedure:
3-[3-(Pyrrolidinomethyl)phenoxy]propylamine (2.0 g) and 2-chlorobenzthiazole (1.45 g) were fused at 130° C. for 21/2 hours. The cooled reaction mixture was subjected to column chromatography on silica using chloroform and then chloroform:methanol (10:1) as eluants to give the title compound as a yellow oil. This was treated with maleic acid in ethanol to give 2-[3-[3-(pyrrolidinomethyl)phenoxy]propylamino]benzthiazole dimaleate (0.35 g), m.p. 91°-92° C. (recrystallised from isopropanol/ether).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[I-:11].[Na+]>[Cu](I)I>[I:11][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: N#CCc1ccc(Br)cc1
Agent: I[Cu]I
Agent: [Na+]
Product: N#CCc1ccc(I)cc1
Temperature: 110 °C

Procedure:
A round bottomed flask fitted with a magnetic stirrer was charged with 1.22 g of copper iodide (Sigma Aldrich), 25 g of 4-bromophenylacetonitrile (Apollo Scientific) and 38.37 g of sodium iodide (Sigma Aldrich) under argon. The round bottomed flask was evacuated and backfilled with argon three times. N,N′-Dimethylethylenediamine (1.38 mL, Sigma Aldrich) and 25 mL dioxane were added and the mixture was heated to 110° C. for 2 hours (h). The reaction was allowed to cool to room temperature (rt) and 125 mL of 30% aqueous ammonia was added. The mixture was then poured onto 500 mL water and extracted three times with dichloromethane (DCM) and the combined organics dried over MgSO4. The solvent was removed under reduced pressure to afford the title compound as brown oil that solidified on standing. Yield: 29.97 g. 1H NMR (400 MHz, CDCl3), δ 7.71 (2H, d, Ar—H), 7.08 (2H, d, Ar—H), 3.66 (2H, s, CH2).