Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)[N:10]=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (2.0 g, 5.76 mmol) in THF: water (5 mL:10 mL) was added sodium hydroxide (0.691 g, 17.27 mmol). The reaction mass was stirred at RT for 3 h. The reaction mass was diluted with water and washed the aqueous layer with diethyl ether and toluene. The aqueous layer was cooled to 15° C. and acidified with dilute HCl. The reaction mass was filtered off to afford 1.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.50 (t, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.67-7.74 (m, 1H), 8.06 (s, 4H), 12.77 (br s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[O:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:21][CH2:20][N:19]([CH:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)[CH2:24][CH2:23]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CN(C2CCOCC2)CCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(C3CCOCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (750 μL), 1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride (2.1 g), potassium carbonate (3.2 g), and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. To the reactant was added water, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 1-(4-nitrophenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine (1.83 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19](B(O)O)=[C:18]2[C:13]([N:14]([CH3:26])[C:15](=[O:25])[N:16]([CH3:24])[C:17]2=[O:23])=[CH:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].N#N.Br[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1>C(OC(=O)C)CCC.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][N:11]1[C:19]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)=[C:18]2[C:13]([N:14]([CH3:26])[C:15](=[O:25])[N:16]([CH3:24])[C:17]2=[O:23])=[CH:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c2c(B(O)O)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Reactant: Clc1cccc(Br)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Temperature: 80 °C

Procedure:
(6-(2-((tert-Butoxycarbonyl)amino)ethyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)boronic acid (step 4) (631 mg, 1.724 mmol), Pd-118 (commercial, CAS 95408-45-0) (51.1 mg, 0.078 mmol, 5 mol %) and potassium carbonate (433 mg, 3.13 mmol) were suspended in n-butylacetate (11.2 mL). The vessel was evacuated and back filled with N2 (×4). Under a stream of N2 was charged 1-bromo-3-chlorobenzene (commercial) (0.184 mL, 1.567 mmol) and water (0.056 mL, 3.13 mmol). The vessel was heated to 80° C. for 2 hrs under microwave irradiation. An additional amount of water (100 μL) and 1-bromo-3-chlorobenzene (0.184 mL, 1.567 mmol) was charged and the mixture heated to 80° C. for a further 2 hrs under microwave irradiation. The reaction mixture was diluted with water (40 mL) and EtOAc (20 mL) and the layers were separated. The aqueous was extracted with EtOAc (4×20 mL) and the combined organics were washed with brine (20 mL), dried (Na2SO4) and filtered under reduced pressure. Silica gel was added to the solution and the solvent evaporated under reduced pressure. The residue was purified via ISCO SiO2 80 g RediSep® Rf column eluting with 50-70% EtOAc/hexane. The fractions containing product were combined and evaporated to afford a pale tan solid, which was dried under vacuum at 50° C. for 3 hrs. This afforded the title product as a pale tan solid.
Reaction SMILES: [NH:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([CH3:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)[C:2]([CH3:4])=[O:3].[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C>[NH:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([CH3:17])=[O:16])=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH2:7][CH2:6]1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc2c(c1)CCN2NC(C)=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(NC(C)=O)CC2
Yield: 62.8 %

Procedure:
33 g of 1,5-diacetamino-indoline were dissolved at 70° C. in 120 ml of glacial acetic acid and nitrated dropwise with 15 ml of nitric acid (d=1.4). The reaction became vigorous and methanol/ice cooling was used. The precipitated crystals were removed by filtration under suction, dissolved in methylene chloride and washed neutral. After evaporation and crystallization from isopropanol, there were obtained 25 g (62.8% of theory) of 1,5-diacetamino-6-nitro-indoline of melting point 212°-213° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][S:18]([CH2:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])(=[O:20])=[O:19]>>[F:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[C:6]1[C:5]([F:16])=[CH:4][N:3]=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([CH2:21][S:18]([CH3:17])(=[O:20])=[O:19])[CH:23]=2)[N:7]=1
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(F)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3F)n2)c1

Procedure:
Example 16.2 was prepared under similar conditions as described in the preparation of Example 3. using 2-chloro-4-(2,4-difluorophenyl)-5-fluoropyrimidine (Intermediate 16.1) and 3-[(methylsulfonyl)methyl]aniline (Intermediate 1.3). The batch was purified by preparative HPLC.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[NH:34][C:35](=[O:37])[CH3:36])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(N2C3C=CC(C4NN=NN=4)=CC=3OC3C2=CC=CC=3)CC1)=O)(C)(C)C.[C:70]([OH:76])([C:72]([F:75])([F:74])[F:73])=[O:71].Cl>C(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[NH:34][C:35](=[O:37])[CH3:36])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:13]1.[C:70]([OH:76])([C:72]([F:75])([F:74])[F:73])=[O:71]
Reactant: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1N2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4nnn[nH]4)ccc32)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1N2C1CCNCC1

Procedure:
Using an adaptation of the method described in Procedure 6, substituting 4-[3-(2-acetylaminophenyl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 1j, for 4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 5a, and a mixture of TFA in methylene chloride for a 4N hydrochloric acid solution, the title compound N-[2-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide, 2j was obtained as a TFA salt after purification via reverse phase HPLC (eluent gradient: CH3CN in water containing 0.1% TFA). MS m/z (MH+) 400.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([N:9]2[C:13]([OH:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[N:10]2)[CH:6]=[CH:5][CH:4]=1.Br[CH2:22][N:23]1[C:27](=[O:28])[C:26]2[C:29]([CH:35]([CH3:37])[CH3:36])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:25]=2[S:24]1(=[O:39])=[O:38]>CN(C=O)C>[CH:35]([C:29]1[C:26]2[C:27](=[O:28])[N:23]([CH2:22][O:14][C:13]3[N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:8]=4)[N:10]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:12]=3)[S:24](=[O:39])(=[O:38])[C:25]=2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=1)([CH3:37])[CH3:36]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: Oc1cc(C(F)(F)F)nn1-c1cccc(C(F)(F)F)n1
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1cccc(C(F)(F)F)n1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
To a mixture 1-(6-trifluoromethyl-2-pyridyl)-3-trifluoromethyl-5-hydroxypyrazole (420 mg; 1.41 mmol) in 10 ml of DMF was added under nitrogen KF (132 mg, 2.28 mmol) and the mixture was stirred at room temperature for 10 minutes. To the above mixture was added 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (410 mg, 1.17 mmol) and the resulting mixture was stirred at room temperature for one hour, quenched with cold saturated ammonium chloride solution, and extracted with ether (3×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue (a solid) was purified by flash chromatography (silica gel; 5-20% ethyl acetate in hexane) and recrystallized from ether/hexane to afford 420 mg (63%) of 4-isopropyl-6-methoxy-2-[1-(6-trifluoromethyl-2-pyridyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =6-CF3 -2-pyridyl; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 149°-150° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([NH2:13])=[N:9][NH:10][C:11]=1[NH2:12].[Br:14][CH:15]([CH:18]=O)[CH:16]=O>C(O)C.C(O)(=O)C>[Br:14][C:15]1[CH:16]=[N:12][C:11]2[N:10]([N:9]=[C:8]([NH2:13])[C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:18]=1
Reactant: Nc1n[nH]c(N)c1-c1ccccn1
Reactant: O=CC(Br)C=O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1nn2cc(Br)cnc2c1-c1ccccn1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
4-(Pyridin-2-yl)-1H-pyrazole-3,5-diamine (2.54 g, 14.51 mmol) and 2-bromo-malonaldehyde (2.41 g, 15.97 mmol) were suspended in dry ethanol (35 mL). A small amount of glacial acetic acid (30 drops) was added and the mixture was heated at reflux for 3 hours. After allowing the reaction to cool to room temperature the mixture was concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography eluting with EtOAc containing 2% NH3(aq) solution to afford the title compound as a yellow solid (0.82 g, 19% yield). MS (ES+) 290/292. δH (DMSO-d6) 7.2 (3H, m), 7.9 (1H, t), 8.5 (1H, d), 8.6 (2H, m), 9.3 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=O.C[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[N:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:11]=1)[O-:3]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccccc1
Product: [O-][N+](=Nc1ccccc1)c1ccccc1

Procedure:
The reduction reaction was carried out in the same manner as set forth in Example 6 except for using a mixture of 1.0 mmol of nitrobenzene and 1.0 mmol of o-methyl nitrobenzene instead of using nitrobenzene alone, and using 17 mg (the amount required for swelling of the reactant, i.e., the mixture, in 100%) of Polymer supported reagent-2, and thereby an azoxybenzene derivative of a symmetrical structure and an azoxybenzene derivative of an asymmetrical structure were obtained as a main product, respectively.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)/[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:37])/[C:34](/[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)=[CH:33]/[CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:53][CH:54]=1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1F
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A solution of triphenylphosphine (262 mg, 1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (178 mg, 1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (158 mg, 0.5 mmol). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-amino-5-bromopyridine (260 mg, 1.5 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded (E)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylamide (66 mg, 28%) as an amorphous white solid: EI-HRMS m/e calcd for C21H20BrFN6OS (M+) 470.0866, found 470.0864.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[N:14]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=3)[N:6]2[N:5]=1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])[CH:26]=[CH:27][CH:28]=1>>[O:34]=[C:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:25]1[CH:24]=[C:23]([NH:22][C:4]2[N:9]=[CH:8][C:7]3=[CH:10][CH:11]=[C:12]([C:13]4[N:14]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=4)[N:6]3[N:5]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CS(=O)c1ncc2ccc(-c3cccn3CCC#N)n2n1
Reactant: Nc1cccc(N2CCCC2=O)c1
Product: N#CCCn1cccc1-c1ccc2cnc(Nc3cccc(N4CCCC4=O)c3)nn12

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 3-[2-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-pyrrol-1-yl]-propionitrile (93 mg, 0.31 mmol) was coupled to 1-(3-amino-phenyl)-pyrrolidin-2-one (77 mg, 0.44 mmol) at 120° C. for 96 h to afford the title compound. Yield of TFA salt: 23 mg (15%) of brown powder. LC/MS: 412 (M+H); HPLC: 97% pure, RT=2.16 min; mp: 60-67° C.; 1H NMR: (DMSO, δ) 9.55 (s, 1H), 8.99 (s, 1H), 7.89 (s, 1H), 7.51 (d, J=8.2, 1H), 7.28 (d, J=8.2, 1H), 7.20 (t, J=8.1, 1H), 7.14 (m, 1H), 6.95 (d, J=4.5, 1H), 6.88 (d, J=4.4, 1H), 6.49 (dd, J=3.6, 1.5 1H), 6.27 (t, J=3.6, 1H), 4.19 (t, J=6.3, 2H), 3.49 (t, J=7.0, 2H), 2.77 (t, J=6.3, 2H), 2.47 (t, J=7.0, 2H), 2.02 (p, J=7.0, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([CH3:17])[N:3]=1.O.O.O.O.O.O.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CC(C)=O.O1CCOCC1>[CH3:17][C:4]1[N:3]=[C:2]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1nc(Cl)nc(N2CCOCC2)c1[N+](=O)[O-]
Reactant: C1CNCCN1
Solvent: O
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(N2CCNCC2)nc(N2CCOCC2)c1[N+](=O)[O-]

Procedure:
A solution of 2.6 gm (0.01 mol) of 2-chloro-6-methyl-4-morpholino-5-nitro-pyrimidine (m.p. 127°-129°C, prepared from 2,4-dichloro-6-methyl-5-nitro-pyrimidine and morpholine) in 100 ml of acetone/dioxane (1:1) was added dropwise, while stirring and cooling, to a solution of 19.4 gm (0.1 mol) of piperazine hexahydrate in 300 ml of acetone/dioxane (1:1) at about 5°C. After about 1 hour the solvents were distilled off in vacuo, and the residue was taken up in about 100 ml of water. The insoluble reaction product was suction-filtered off, washed with water and dried. Yield: 3.0 gm (97% of theory). After one reprecipitation from about 0.2 N hydrochloric acid with 2 N ammonia, the reaction product of the formula ##SPC5##
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Cl)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CCOCC>[N:24]1([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: O=C(c1ccccc1)C(OCCCl)(OCCCl)c1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)C(OCCN1CCCCC1)(OCCN1CCCCC1)c1ccccc1

Procedure:
With stirring, 35 g (0.1 mole) of benzil-di-(2-chloroethyl)ketal and 77 g (0.9 mole) of piperidine are kept for 7 hours at 105° C. After cooling, the reaction mixture is diluted with ether and the piperidine hydrochloride is collected by filtration. The ether is distilled off and the residual oil is dried in a high vacuum.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.[C:22]([O:26][C:27](=[O:45])[NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:30]=1[F:44])([CH3:25])([CH3:24])[CH3:23].N#N.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:22]([O:26][C:27]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH:8]=2)=[CH:31][C:30]=1[F:44])=[O:45])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1F

Procedure:
To a mixture of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (I16) (0.504 g, 1.52 mmol), tert-butyl(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (I62) (0.496 g, 1.47 mmol), and PdCl2(PPh3)2 (0.055 g, 0.078 mmol) under a N2 atmosphere was added dioxane (15 mL) and the mixture was bubbled with N2 for 5 minutes before addition of 3.0 M aqueous sodium carbonate (1.5 mL, 4.5 mmol). The reaction was heated at reflux for 6 hours then concentrated under reduced pressure. The residue was chromatographed on silica gel (0-25% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I57) (0.409 g, 71%); 1H NMR (400 MHz, CDCl3) δ 7.12 (m, 3H), 6.09 (s, 1H), 4.08 (m, J=2.8 Hz, 2H), 3.63 (dd, J=5.6, 5.6 Hz, 2H), 2.49 (m, 2H), 1.42 (s, 18H).
Reaction SMILES: C(OC(=O)C)(=O)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:15][N:16]2[CH2:20][C:19](O)([CH3:21])[N:18]([N:23]=[CH:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:17]2=[O:31])[CH:9]=1.[OH-].[Na+]>C(O)(=O)C>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:15][N:16]2[CH:20]=[C:19]([CH3:21])[N:18]([N:23]=[CH:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:17]2=[O:31])[CH:9]=1
Reactant: CC1(O)CN(N=Cc2cccnc2)C(=O)N1N=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cn(N=Cc2cccnc2)c(=O)n1N=Cc1cccnc1
Temperature: 0 °C

Procedure:
11.2 g of acetic anhydride are added to a suspension of 32.4 g of 1,3-bis(pyridin-3-ylmethyleneamino)-4-hydroxy-4-methylimidazolidin-2-one in 75 ml of acetic acid. The reaction mixture is then heated to 50°. After 3 hours the reaction mixture is cooled to 20°, then poured onto 800 ml of ice-water and neutralised with 30% sodium hydroxide solution. The aqueous phase is then extracted three times with 200 ml of methylene chloride each time. The organic phase is dried with magnesium sulfate, filtered and concentrated by evaporation. The residue is stirred with ether. The crystals are filtered off with suction and dried. 28.2 g of the title compound having a melting point of 176°-178° are thus obtained.
Reaction SMILES: [Br-:1].[K+].N[C@@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH2:6][CH2:7][CH3:8].N([O-])=O.[Na+]>S(=O)(=O)(O)O>[Br:1][C@@H:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:9]([OH:11])=[O:10]
Reactant: [Br-]
Reactant: CCCC[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCC[C@H](Br)C(=O)O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Potassium bromide (15.9 g., 133 mmol.) was added to a stirred solution of D-norleucine (5.0 g., 38 mmol.) in 2.5N sulfuric acid (77 ml.) at room temperature. The reaction mixture was cooled to -10° C. and solid sodium nitrite (3.94 g., 57 mmol.) was added portionwise, maintaining the temperature between -10° and -5° C. After addition was complete, the foamy reaction was stirred for 1 hour and then warmed to room temperature and stirred for another hour. The reaction mixture was then extracted twice with ether, the ether extracts were washed once with water, dried (magnesium sulfate), filtered and evaporated to give 3.3 g. of crude title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:32]1[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(F)c(F)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 76.7 %

Procedure:
Ethyl N-(6,7-di fluoro-2-methoxyquinoxalin-3-yl)carbamate (25 mg, 0.088 mmol) and 1-(3-methoxy phenyl)piperazine (35 mg, 0.18 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (28 mg, 0.18 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (1:1) mixture and concentration gave 29 mg of the titled compound (yield, 76%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.76-3.77 (m, 4H), 3.81 (s, 3H), 4.12 (s, 3H), 6.48-6.49 (m, 2H), 6.56-6.58 (m, 1H), 7.20-7.23 (m, 1H), 7.29-7.30 (m, 1H), 7.50-7.53 (m, 1H), 7.60-7.62 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:3]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2cc(Cl)ccc2C#N)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Cl)cc1-c1ccc(CBr)cc1

Procedure:
6.83 g of 4-chloro-2-(4-methylphenyl)benzonitrile, 5.34 g of N-bromosuccinimide and 0.1 g of α,α'-azobis(isobutyronitrile) were heated in 220 ml of carbon tetrachloride under reflux for 2 hr. The succinimide was removed by filtration, and the filtrate was concentrated. The residue was crystallized from a mixed solvent of tetrahydrofuran-isopropyl ether. The yield was 5.6 g.