Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([I:23])C(=O)C1>CN(C=O)C>[I:23][C:15]1[C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12][CH:11]=[N:10][C:9]=2[NH:13][CH:14]=1
Reactant: c1ccc(-c2ncnc3[nH]ccc23)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ncnc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-phenyl-7H-pyrrolo[2,3-d]pyrimidine (5.28 g, 27.0 mmol) in DMF (100 mL) was added NIS (6.57 g, 29.2 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with water (150 mL) and the resulting precipitated product was filtered and washed with water. The filtrate cake was dried under vacuum to afford 5-iodo-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid. LRMS (ESI) calcd for C12H8IN3 [M]+: 321, found 321. 1H NMR (600 MHz, DMSO-D6) δ 12.71 (s, 1H), 8.83 (s, 1H), 7.87 (d, J=2.45 Hz, 1H), 7.68 (t, J 1.45 Hz, 1H), 7.67 (d, J=3.42 Hz, 1H), 7.54 (d, J=1.96 Hz, 2H), 7.53 (t, J=1.46 Hz, 1H).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[N:10][C:11]3[C:16]([C:17]=2O)=[CH:15][CH:14]=[CH:13][C:12]=3[C:19]([F:22])([F:21])[F:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=N[C:27]2[C:32](C=1O)=[CH:31][CH:30]=[CH:29][C:28]=2C(F)(F)F.C1(S)C=CC=CC=1.[Na].O>CN(C=O)C>[C:27]1([C:17]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Oc1c(Br)cnc2c(C(F)(F)F)cccc12
Reactant: Oc1c(Sc2ccccc2)cnc2c(C(F)(F)F)cccc12
Agent: Sc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(Sc3ccccc3)cnc12
Temperature: 120 °C
Yield: 57 %

Procedure:
3-(phenylthio)-8-(trifluoromethyl)quinolin-4-ol: A solution of 3-bromo-8-(trifluoromethyl)quinolin-4-ol (0.240 g, 0.830 mmol), sodium thiophenol (0.293 g, 45.1 mmol), is dissolved in DMF and heated in a microwave reactor for 10 min at 120° C. After which, the reaction is poured into water and extracted with ethyl acetate. The combined extracts are washed with sat aq NaHCO3, water, brine, and dried with magnesium sulfate. The extracts are concentrated and the residue is chromatographed with 1:9 ethyl acetate:hexanes to afford the title compound as a white solid (0.151 g, 57%). mp 153-155° C.; MS (ESI) m/z 322; MS (ESI) m/z 320; HRMS: calcd for C16H10NF3OS+H, 322.05134; found (ESI, [M+H]+), 322.0486.
Reaction SMILES: [CH2:1]([CH:3]([NH:19][CH3:20])[CH:4]([CH2:17][CH3:18])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)[CH3:2].C=O.[CH:23](O)=O>CN(C=O)C>[CH2:1]([CH:3]([N:19]([CH3:23])[CH3:20])[CH:4]([CH2:17][CH3:18])[C:5]1[CH:6]=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=1)[CH3:2]
Reactant: O=CO
Reactant: CCC(NC)C(CC)c1cc(OC)c(OC)c(OC)c1
Agent: C=O
Solvent: CN(C)C=O
Product: CCC(c1cc(OC)c(OC)c(OC)c1)C(CC)N(C)C
Yield: 91.3 %

Procedure:
A solution of 35.4 g (0.126 mole) of α,β-diethyl-3,4,5-trimethoxy-N-methylbenzeneethanamine, 25.6 g (0.316 mole) formalin, 15 g (0.316 mole) formic acid in 350 ml DMF was heated under reflux for five hours. The mixture was partitioned between water and methylene chloride. The organic layer was dried with MgSO and evaporated in vacuo. The residue was warmed at 0.75 Torr for one hour. There was obtained 34 g (91% yield) of α,β-diethyl-3,4,5-trimethoxy-N,N dimethylbenzeneethanamine as an oil 1H NMR (CHCl3): 6.7 (s, 2H); 3.8 (s 9H); 2.7-2.2 (m, 2H); 2.2 (s, 6H); 2.0-1.2 (m, 4H); 0.9 (t, 3H); 0.7 (t, 3H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]1[S:24][CH:23]=[C:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=[O:28])[CH:21]=1.[F:33][C:34]([Si](C)(C)C)([F:36])[F:35].Cl>C1COCC1>[F:33][C:34]([F:36])([F:35])[CH:27]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:22]1[CH:21]=[C:20]([CH3:19])[S:24][CH:23]=1)[OH:28]
Reactant: Cc1cc(-c2ccccc2C=O)cs1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2C(O)C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 185.1 %

Procedure:
Tetrabutylammonium fluoride (0.028 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 2-(5-methylthiophen-3-yl)-benzaldehyde (550 mg, 1.29 mmol) and trifluoromethyltrimethylsilane (TMSCF3) (483 μl, 3.27 mmol) in 10 ml of THF at 0° C. The formed mixture was warmed up to room temperature and stirred at room temperature for 4 hours. The reaction mixture was then treated with 10 ml of 1N HCl and stirred at room temperature overnight. The product was extracted with ethyl acetate (3×50 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 650 mg of 2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethanol, yield: 87%. A mixture of 2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethanol (100 mg, 0.37 mmol), 2-amino-4,6-dichloro-pyrimidine (54 mg, 0.33 mmol), cesium carbonate (481 mg, 1.48 mmol) and 1,4-dioxane (2 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 90 mg of 4-chloro-6-{2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine, yield: 68%
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:17](O)[CH2:18][OH:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]3([C:12]([CH3:13])([CH3:15])[CH3:14])[O:19][CH2:18][CH2:17][O:16]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OCCO
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)C1(c2c[nH]c3ncc(Br)nc23)OCCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (1.5 g, 5.3 mmol) was partly dissolved in 18 ml toluene, and ethylene glycol (0.9 ml, 15.9 mmol) and then p-toluenesulfonic acid hydrate were added. The mixture was refluxed with a Dean-Stark-type trap attached for 24 hr. The reaction was cooled to room temperature and ammonium chloride solution, water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined ethyl acetate layers were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration and evaporation the residue was purified by silica gel chromatography(ethyl acetate/hexanes to give 1.44 g (83%) of 2-bromo-7-(2-tert-butyl-[1,3]dioxolan-2-yl)-5H-pyrrolo[2,3-b]pyrazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][F:22].O>C(#N)C>[F:22][CH2:21][CH2:20][N:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[N:9]=[N:10]1
Reactant: FCCBr
Reactant: Cc1ccc(-c2nn[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-c2nnn(CCF)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 5.0 grams (0.031 mole) 4-(4-methylphenyl)-1,2,3,5-(1H)-tetrazole and 4.8 grams (0.035 mole) of potassium carbonate in 150 mL of acetonitrile was heated to reflux and then cooled to ambient temperature. To this was slowly added 10.0 grams (0.078 mole) of 1-bromo-2-fluoroethane. Upon completion of the addition the reaction mixture was placed in a water bath and cooled to 0° C., where it stirred for one hour. After this time the reaction mixture was heated to reflux, where it stirred for three hours, and then cooled to 0° C., where it stirred for about 18 hours. At the conclusion of this period the reaction mixture was poured into 50 mL of water. The resulting solution was extracted with three 50 mL portions of ethyl acetate. The combined extracts were concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel. Elution was accomplished with methylene chloride and acetone. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.8 grams 1-(2-fluoroethyl)-(4-methylphenyl)-1,2,3,5-(1H)-tetrazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[C:20]3=[N:21][C:22]([N:26]4[CH2:32][CH:31]5[O:33][CH:28]([CH2:29][CH2:30]5)[CH2:27]4)=[CH:23][C:24](=[O:25])[N:19]3[CH2:18][C@@:17]2([CH3:38])[C:34]([F:37])([F:36])[F:35])=[CH:10][CH:9]=1.Cl[CH2:40][CH2:41][N:42]([CH3:44])[CH3:43]>CN(C=O)C>[CH3:43][N:42]([CH3:44])[CH2:41][CH2:40][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[C:20]3=[N:21][C:22]([N:26]4[CH2:27][CH:28]5[O:33][CH:31]([CH2:30][CH2:29]5)[CH2:32]4)=[CH:23][C:24](=[O:25])[N:19]3[CH2:18][C@@:17]2([CH3:38])[C:34]([F:37])([F:36])[F:35])=[CH:10][CH:9]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CC4CCC(C3)O4)cc2=O)N1CCc1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(CCN2c3nc(N4CC5CCC(C4)O5)cc(=O)n3C[C@@]2(C)C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
282 mg (0.87 mmol) of cesium carbonate are added to a solution of 130 mg (0.29 mmol) of (S)-1-[2-(4-hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 10 mL of DMF. After heating at 80° C. for 20 minutes, 62.40 mg (0.43 mmol) of (2-chloroethyl)dimethylamine are added. The reaction medium is heated at 80° C. overnight. The reaction medium is evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 25 min 10% B, t 30 min 10% B), 116 mg of (S)-1-{2-[4-(2-dimethylaminoethoxyl)phenyl]ethyl}-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:15])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH3:28]I.CO>C1COCC1.C(Cl)Cl>[CH:3]1[C:12]2[C:7](=[C:8]([N:13]([CH3:28])[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=3)=[O:15])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2cnccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)NCc1ccc(C(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
Sodium hydride (60% dispersion in oil, 7 mg, 0.17 mmol) was added to a suspension N-isoquinolin-5-yl-N′-[4-(trifluoromethyl)benzyl]urea (Example 14; 48 mg, 0.14 mmol) in THF (3 mL) at room temperature and the reaction was stirred until effervescence ceased (20 minutes). Methyl iodide (11 μL, 0.17 mmol) was added and the reaction stirred at room temperature for 3 hours. TLC analysis (10% MeOH in CH2Cl2) indicated only one major product. The reaction was evaporated in vacuo and the product isolated by preparative TLC (4% MeOH in CH2Cl2) to give the title compound. m/z (ES+) 360 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])=[CH:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([NH:19][CH3:20])=[CH:14][C:13]=3[C:12]3[CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:11]2=3)=[CH:4][CH:3]=1.C(O[C:31](=[O:33])[CH3:32])(=O)C.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:26])=[CH:9]/[N:10]2[C:18]3[CH:17]=[CH:16][C:15]([N:19]([CH3:20])[C:31](=[O:33])[CH3:32])=[CH:14][C:13]=3[C:12]3[CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:11]2=3)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc2c(c1)c1c(n2C=C(C)c2ccc(F)cc2)CCN(C)C1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(C)c1ccc2c(c1)c1c(n2/C=C(\C)c2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-(2-(4-Fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-N,2-dimethyl-1H-pyrido[4,3-b]indol-8-amine (30 mg) was charged in a round bottom flask. Acetic anhydride (0.5 mL) was added and the contents stirred at RT for 30 min. The reaction mixture was then basified with 1N NaOH and extracted with EtOAc (2×25 mL). The organic layer was concentrated under vacuum and purified through reverse phase column chromatography to yield 19.38 mg of the desired compound. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.70 (m, 2H), 7.50 (s, 1H), 7.36 (d, 1H), 7.18 (m, 3H), 7.0 (s, 1H), 4.78 (d, 1H), 4.41 (d, 1H), 3.90 (m, 1H), 3.62 (m, 1H), 3.28 (s, 3H), 3.20 (m, 2H), 3.10 (s, 3H), 1.96 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].Br[C:18]([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)Br
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 15 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a mixture of 5-nitro-1H-indole (6.0 g, 37 mmol) and AlCl3 (24 g, 0.18 mol) in CH2Cl2 (100 mL) at 0° C. was added 2-bromo-2-methyl-propane (8.1 g, 37 mmol) dropwise. After being stirred at 15° C. overnight, the mixture was poured into ice (100 mL). The precipitated salts were removed by filtration and the aqueous layer was extracted with CH2Cl2 (30 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to obtain the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to give 3-tert-butyl-5-nitro-1H-indole (2.5 g, 31%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J=1.6 Hz, 1H), 8.31 (brs, 1H), 8.05 (dd, J=2.0, 8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.42 (d, J=1.6 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9][CH:8]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CCO>[C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CNCCN1c1ccccc1
Reaction time: 10 h
Yield: 94.2 %

Procedure:
An EtOH (75 mL) solution of ethyl 1-phenyl-4-(phenylmethyl)-2-piperazinecarboxylate (2.20 g, 6.8 mmol) and 500 mg of 4% Pd/C was subjected to hydrogenolysis in a standard Parr apparatus. The reaction was carried out for 10 hours at 55° C. and under a hydrogen pressure of 5 psi. After the catalyst was removed by filtration and the solvent by stripping under reduced pressure, 1.5 g of ethyl 1-phenyl-2-piperazinecarboxylate was obtained as a clear oil.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH:37]([NH2:47])CC2C=CC=CC=2OC)[CH:6]=1.NCC[CH2:51][O:52][C:53]1[CH:81]=[C:80](OC)[CH:79]=[CH:78][C:54]=1[C:55](NC1C=C([N+]([O-])=O)C=CC=1C(NC1C=CC(OC)=CC=1)=O)=O.COC1C=CC=CC=1C=O>>[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH2:37][NH:47][CH2:55][C:54]2[CH:78]=[CH:79][CH:80]=[CH:81][C:53]=2[O:52][CH3:51])[CH:6]=1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCC(N)Cc2ccccc2OC)cc1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCN)cc1
Agent: COc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCNCc2ccccc2OC)cc1

Procedure:
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-[3-(2-methoxybenzyl)-aminopropoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (52 mg, 0.085 mmol, 56%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-methoxybenzaldehyde.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:22][CH2:23]1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CC=C(c2ccncc2[N+](=O)[O-])CC1
Temperature: 75 °C
Yield: 63 %

Procedure:
To a solution of 4-chloro-3-nitro-pyridine (350 mg, 2.208 mmol) in Toluene (7.00 mL), Ethanol (1.75 mL) and sodium carbonate solution (aq) (2.21 mL of 1 M, 2.21 mmol) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (985.3 mg, 4.416 mmol), Pd2(dba)3 (60.66 mg, 0.07 mmol) and triphenyl phosphine (115.8 mg, 102.3 μL, 0.44 mmol). The mixture was stirred at 75° C. (reflux) for 18 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between water (30 mL) and DCM (2×30 mL). The combined organics were washed with water (30 mL) and brine (30 mL), dried and evaporated to dryness to afford a dark brown oil which was purified by column chromatography on silica gel eluting with petroleum ether (A): ethyl acetate (B) (20-100% (B), 24 g, 30.0 CV, 35 mL/min) then ethyl acetate (A): methanol (B) (0-10% (B)) to afford 4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-3-nitro-pyridine as a red oil (305 mg, 63%). MS (ES+) 220.1.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH2:18]([NH2:20])[CH3:19].CCO>C(CC(C)(C)C)(C)C>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:20][CH2:18][CH3:19])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: CCN
Solvent: CCO
Solvent: CC(C)CC(C)(C)C
Product: CCNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1
Temperature: 130 °C

Procedure:
A mixture of 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), ethanamine (0.5 ml, 2 M in MeOH) and EtOH (3 ml) was heated under microwave radiation at 130° C. for 30 min. MS m/z (rel. intensity, 70 eV) 289 (M+, 0.3), 176 (7), 141 (8), 95 (9), 75 (10), 58 (bp).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[NH:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26](Cl)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>C(C(C)=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:4]2[CH2:5][CH2:6][NH:7][C:2]([CH3:1])([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=3)[CH2:3]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CC2(C)CNCCN2)cc1OC
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Solvent: CCC(C)=O
Product: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccc(Cl)cc3)CCN2)cc1OC
Yield: 80 %

Procedure:
If 3-methyl-3-(3,4-dimethoxybenzyl)-piperazine is reacted with p-chlorophenyl-phenylmethyl chloride in methyl ethyl ketone according to Example 2, 1-(p-chlorophenyl-phenylmethyl)-3-methyl-3-(3,4-dimethoxybenzyl)-piperazine is obtained in 80 percent yield after a 12-hour reaction period. The hydrochloride has a melting point of 235°-237° C. (isopropanol).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[ClH:31]>O>[ClH:31].[C:24]1([CH2:23][NH:30][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(/C=C\COCCCCCCBr)cc1
Agent: Cl
Solvent: O
Product: CS(=O)(=O)Nc1ccc(/C=C\COCCCCCCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Z)-N-[4-[3-[(6-Bromohexyl)oxy]-1-propenyl]phenyl]methanesulphonamide (2.0 g) was added to benzylamine (6 ml) at 125°, under nitrogen. The reaction mixture was stirred at 125° for 3 h, cooled to room temperature and added to 2N hydrochloric acid (50 ml) and water (20 ml). The resultant white solid was collected by filtration, washed in turn with 2N hydrochloric acid, water and ether then dried in vacuo at 50° to give the title compound as a white powder (1.0 g) m.p. 133°-134°.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:40]1[CH2:45][CH2:44][N:43]([C:46]2[N:51]=[C:50]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[N:49]=[C:48]([C:58]3[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=3)[N:47]=2)[CH2:42][CH2:41]1>CN(C=O)C>[N:43]1([C:46]2[N:51]=[C:50]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[N:49]=[C:48]([C:58]3[CH:64]=[CH:63][C:61]([NH:62][C:3](=[O:4])[CH:2]([F:6])[F:1])=[CH:60][CH:59]=3)[N:47]=2)[CH2:42][CH2:41][O:40][CH2:45][CH2:44]1
Reactant: O=C(O)C(F)F
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1)C(F)F
Temperature: 60 °C
Yield: 45.6 %

Procedure:
To a mixture of 2,2-difluoroacetic acid (20 mg, 0.21 mmol), HBTU (76 mg, 0.2 mmol), and DIEA (52 mg, 0.40 mmol) in 2 mL of DMF was added 4-(4,6-dimorpholino-1,3,5-triazin-2-yl) aniline (40 mg, 0.12 mmol). The reaction was stirred at 60° C. 16 hr. Then the reaction mixture was cooled to room temperature and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamide (23 mg, 46% yield). HPLC: Rt=2.19 min; MS 421 [M+H].
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(C#N)cn5)cc4)CC3)n2CCS1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C#N)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
To a solution of the compound (33.1 g, 62.0 mmol) obtained in Example 60-4) in tetrahydrofuran (500 mL), tetrabutylammonium fluoride (74.4 mL, 1 M tetrahydrofuran solution) was added, and the mixture was stirred at room temperature for 1.5 h. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate:methanol=4:1) to obtain the title compound (22.5 g, 87%) as a white solid.