Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1.CC#N>CN1C(=O)CCC1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2nnc(N3CCNCC3)c3ccccc23)cc1
Reactant: N#Cc1cnc(Cl)nc1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: N#Cc1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1

Procedure:
Using the general protocol, 1-benzyl-4-piperazin-1-yl-phthalazine (56 mg, 0.184 mmol) and 2-chloro-5-cyanopyrimidine (44.5 mg, 0.239 mmol) are added into a microwave vial, equipped with a stir bar, and MeCN (0.5 ml) and NMP (0.5 ml) are dispensed. The vial is sealed and the reaction was irradiated at high level absorption in the microwave at 180° C. for 15 min. The product is observed as the main peak (m/z; M+1=408). The compound is purified by preparative HPLC using a C8-254 nm method.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)=[CH:17][C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])=[CH:12][N:11]=1.[H-].[Na+]>>[CH2:1]([O:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)=[CH:17][C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[O:19])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)nc2)cc1OC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(OCc3ccccc3)nc2)cc1OC
Yield: 76 %

Procedure:
In the same manner as in Example 2, using benzyl alcohol (554 mg), 4-[3-(2-chloro-5-pyridyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine (1 g) and 60% sodium hydride (205 mg), 4-[3-(2-benzyloxy-5-pyridyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine (Compound No.63) (0.9 g) was obtained as a resinous solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][NH:10][CH2:11][CH2:12][OH:13]>>[CH2:1]([N:10]([CH2:11][CH2:12][OH:13])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CNCCO
Product: CN(CCO)Cc1ccccc1

Procedure:
The title compound was prepared from benzyl bromide (4 g) and 2-(methylamino)ethanol (18.6 ml) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [CH3:1]CCCCC.C[Si](C=[N+]=[N-])(C)C.[OH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[C:17](=[O:26])[C:16]=1[I:27]>CO>[I:27][C:16]1[C:17](=[O:26])[N:18]([CH3:25])[C:19]2[C:24]([C:15]=1[O:14][CH3:1])=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: Cn1c(=O)c(I)c(O)c2ccccc21
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COc1c(I)c(=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1M hexane solution of trimethylsilyldiazomethane (10 ml) and methanol (5 ml) were added to 4-hydroxy-3-iodo-1-methyl-2(1H)-quinolinone (500 mg) and stirred at room temperature for one hour. The reaction solution was concentrated and purified with a silica gel chromatography (hexane-ethyl acetate) to obtain the title compound (479 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C=O)cn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
A solution of methyl 6-methylnicotinate (0.5 g, 3.3 mmol) in THF (16 mL) at 0° C. was treated dropwise with lithium aluminum hydride in THF (6.6 mL, 1 M), stirred at 0° C. for 1.5 hours, treated with ethyl acetate (3 mL), and stirred at 25° C. The reaction was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the residue (0.395 g) in dichloromethane (16 mL) was treated with MnO2 (2 g), stirred at 25° C. for 68 hours, and filtered through celite® to give the title compound (0.326 g, 80% yield), which was used without further purification.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.Cl.[NH2:41][O:42][CH:43]([CH3:45])[CH3:44].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:44][CH:43]([O:42][N:41]=[C:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:6][CH2:7]1)[CH3:45]
Reactant: CC(C)ON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=NOC(C)C)CC2)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), 2-(aminooxy)propane hydrochloride (0.43 g) and pyridine (10 mL) was stirred at 100° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH3:29][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:29])=[O:25])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1

Procedure:
4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzoic acid from Step A (32 mg, 0.077 mmol) was dissolved in MeOH (0.5 mL) and DCM (0.5 mL). Trimethylsilyl diazomethane (2.0 M in ether) was slowly added at 0° C. until a yellow color persisted. The volatiles were evaporated to give methyl 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzoate which was used without further purification. LCMS: m/z 421.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:5]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[CH:4]=1.[CH:25](=O)[CH2:26][CH2:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:25]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[CH2:10][CH2:11]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC=O
Reactant: COc1ccc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCN1CCN(c2ccc(OC)cc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (10 mg, 0.030 mmol) produced in Example (85c) in tetrahydrofuran (1 mL) were added butyraldehyde (3.3 mg, 0.045 mmol), sodium triacetoxyborohydride (13 mg, 0.061 mmol) and acetic acid (1.8 mg, 0.030 mmol) in that order, followed by stirring for 60 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-butyl-4-[4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:6][C:7]1[CH:14]=[C:13]([F:15])[C:10]([CH:11]=O)=[C:9]([F:16])[CH:8]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[F:15][C:13]1[CH:14]=[C:7]([OH:6])[CH:8]=[C:9]([F:16])[C:10]=1[CH2:11][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1c(F)cc(O)cc1F
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cc(F)c(CN2CCCC2)c(F)c1
Yield: 19.6 %

Procedure:
Pyrrolidine (6.6 mL, 80 mmol) was added to a solution of intermediate 20, 4-hydroxy-2,6-difluorobenzaldehyde (9.7 g, 61.3 mmol) in dichloromethane (100 mL). The reaction mixture was cooled on ice bath, and sodium triacetoxyborohydride (19.5 g, 925 mmol) was added in portions under stirring. The reaction mixture was intensively stirred for 24 h at RT. Water (100 mL) and concentrated HCl were added to attain pH˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×100 mL), then with EtOAc (100 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜10, the obtained crystals were separated by filtration, dried in vacuo, dissolved in small amount of water, HCl was added to attain pH˜7, and water layer was extracted with CHCl3 (2×100 mL). The organic layer was separated, washed with brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (2.6 g, 20%, 12 mmol). LCMS data: 215 and 214 (M+H)+ (calculated for C11H13F2NO 213.23). 1H NMR data (DMSO-d6): 10.26 (br.s, 1H, OH), 6.38-6.46 (m, 2H, H—Ar), 3.52 (s, 2H, Ar—CH2); 2.35-2.44 (m, 4H), 1.58-1.68 (m, 4H).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([F:25])[C@H:13]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[C:12]1(O)[CH2:36]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(#N)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([F:25])[C@H:13]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[C:12]1=[CH2:36])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2c1ncn2[C@H]1[C@@H](F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C1(O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C=C1[C@@H](n2cnc3c(N)ncnc32)[C@@H](F)[C@H](OC(=O)c2ccccc2)[C@H]1COC(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
Compound 13 (260 mg, 0.50 mmol) was dissolved in moist acetonitrile (9 μL H2O was added into 10 mL anhydrous acetonitrile) and cooled to −30° C. Excess 1-bromocarbonyl-methylethylacetate (0.54 mL, 3.68 mmol) was added dropwise into the mixture and allowed to warm up to room temperature. After stirring at room temperature for 1 h, the reaction mixture was again cooled to −30° C. and additional 1-bromocarbonyl-methylethylacetate (0.2 mL, 1.47 mmol) was added. Crushed ice was added to quenched the reaction and neutralized with saturated NaHCO3 (20 mL) solution and extracted with EtOAc (100 mL×2). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in anhydrous DMF and treated with activated zinc (c.a. 2.0 g) and HOAc (0.2 mL) and stirred at room temperature for 8 h. The volatile was removed in vacuo and the residue was dissolved in isopropyl alcohol/chloroform (4:1) co-solvent and washed with saturated NaHCO3 (15 mL) solution, H2O and brine. The organic layer was colleted and dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on a silica gel (EtOAc:Hexanes=2:1 to 4:1) to give exo-cyclic alkene nucleoside 14 (165.0 mg, 68%) as a white solid. mp: 195-198° C. (dec.) [α]25D +77.66° (c 0.27, CHCl3); UV (MeOH) λmax 231.0, 259.0 nm; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.12-8.06 (m, 2H), 7.94 (d, J=3.6 Hz, 1H), 7.65-7.44 (m, 3H), 6.0 (dd, J=2.4 and 33.2 Hz, 1H), 5.86 (br, 2H, D2O exchangeable), 5.75 (d, (d, J=14.8 Hz, 1H), 5.50 (s, 1H), 5.21 (dd, J=4.0 and 50.8 Hz, 1H), 4.98 (d, J=1.2 Hz, 1H), 4.82-4.64 (m, 1H), 4.66-4.61 (m, 1H), 3.42 (m, 1H); 13C NMR (100 MHz, CDCl1) δ 166.4, 165.0, 155.5, 153.2, 150.5, 144.4, 140.9, 140.8, 133.8, 133.3, 130.0, 129.7, 129.6, 128.7, 128.6, 128.5, 118.8, 113.2, 93.6 (d, J=184.4 Hz), 75.8 (d, J=29.0 Hz), 64.4 (d, J=3.1 Hz), 58.3 (d, J=17.5 Hz), 46.5. FIR-MS Calcd. for (C26H22FN5O4+H)+488.1734, found 488.1731.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=O)[CH3:8].IC1C=CC=CC=1CCN.CC(OC(C)=O)=O>O1CCOCC1>[I:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH3:8]
Reactant: CC(=O)NCCc1ccccc1I
Agent: NCCc1ccccc1I
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: CC1=NCCc2c(I)cccc21
Temperature: 25 °C

Procedure:
N-(2-iodophenethyl)acetamide. A solution of 2-(2-iodophenyl)ethanamine (13.5 g, 54.6 mmol) and Ac2O (10.3 mL, 109 mmol) in 1,4-dioxane (200 mL) was heated to 100° C. for 45 min. The reaction was then allowed to cool to RT and concentrated in vacuo. The resulting residue was taken up in DCM and washed with a saturated aq. solution of NaHCO3—gas formation! The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellow oil (16.2 g) which was used as it is in the next step. UPLC-MS: MS 290.3 (M+H+); UPLC rt 0.96 min.
Reaction SMILES: Cl[CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[N:7]1([CH:2]([CH3:6])[CH2:3][CH2:4][OH:5])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: CC(Cl)CCO
Product: CC(CCO)N1CCOCC1

Procedure:
In a manner similar to Preparation 1, react 3-chloro-1-butanol with morpholine to obtain the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]3=[O:28])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O.Cl>C(Cl)(Cl)Cl.C(OCC)C>[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]3=[O:28])[CH2:16][CH2:17][C@@H:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](Cn3c(=O)oc4ccccc43)CC[C@H]2C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=c1oc2ccccc2n1C[C@@H]1CC[C@H]2CNCCN2C1

Procedure:
A solution of 3.1 g (8.01 mmol) of 3-[(7R,9aS)-2-BOC-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]-pyrazin-7-ylmethyl]-3H-benzooxazol-2-one in 40 mL of chloroform was stirred with excess HCl (g) in ethyl ether for 2 h at ambient temperature. The solvent was evaporated to give 2.3 g (100%). of the title compound dihydrochloride which was used for subsequent reactions without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:26](Cl)=[O:27])=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:26]([C:22]4[CH:21]=[C:20]5[C:25](=[CH:24][CH:23]=4)[N:16]=[CH:17][CH:18]=[N:19]5)=[O:27])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1ccc2nccnc2c1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc2nccnc2c1

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 6-quinoxalinecarbonyl chloride (96 mg; 0.50 mmol; 2.0 eq.) as a white powder (47.5 mg, 53%). HPLC, Rt: 2.73 min. (purity 62.3%). LC/MS, M+(ESI): 357.4, M−(ESI): 355.3.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:18]=1.[CH:19]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([CH3:26])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>O>[CH3:26][C:21]1[CH:20]=[CH:19][C:24]([O:25][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](/[CH:10]=[CH:11]/[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:7][C:6]=3[CH:18]=2)=[CH:23][CH:22]=1
Reactant: Brc1ccc2oc(/C=C/c3ccccc3)nc2c1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3oc(/C=C/c4ccccc4)nc3c2)cc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 60.2 %

Procedure:
Under an argon stream, a mixture of 5-bromo-2-[(E)-2-phenylethenyl]benzoxazole (Compound of Reference Example 43) (105 mg), p-cresol (45 mg), potassium carbonate (97 mg), copper oxide(II) (70 mg) and pyridine (1.5 ml) was stirred at 130° C. for 24 hours. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of potassium hydrogen sulfate and water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:6, v/v) was concentrated under reduced pressure, and the resulting crystals were collected by filtration to obtain 5-(4-methylphenoxy)-2-[(E)-2-phenylethenyl]benzoxazole (69 mg, 60%). The compound was recrystallized from ethyl acetate-hexane.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9]C)=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1.B(Cl)(Cl)Cl.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][N:18]=2)[CH2:15][CH2:16]1
Reactant: COc1cc(Cl)c(Br)c(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1
Agent: ClB(Cl)Cl
Agent: O=C=O
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Oc1cc(Cl)c(Br)c(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A stirred solution of 0.38 gram (0.00084 mole) of 2-bromo-3-chloro-5-methoxy-1-{4-[5-(trifluoromethyl)(2-pyridyl)]piperazinyl}benzene and 0.78 gram (0.0021 mole) of n-tetrabutylammonium iodide in 30 mL of methylene chloride was cooled in a dry-ice/acetone bath and 2.1 mL (0.0021 mole, a 1.0M solution in methylene chloride) of boron trichloride was added dropwise. Upon completion of addition the reaction mixture was kept cold in the dry-ice/acetone bath for an additional 30-minute period, then it was allowed to warm to ambient temperature where it stirred during a three-hour period. After this time the reaction mixture was cooled in an ice/water bath and 15 mL of water was added. The organic layer was separated and the aqueous layer was extracted with one 15 mL portion of methylene chloride. The organic layer and the extract were combined and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using as eluants: 50% hexane in methylene chloride, then 100% methylene chloride, and finally 2% methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.17 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C@:18]3([CH3:29])[C:23]([CH3:25])([CH3:24])[C:22](=[O:26])[N:21]([CH3:27])[C:20]([NH2:28])=[N:19]3)[CH:12]=2)[CH2:6]1.O.[Li+].[OH-]>C1COCC1.CO>[NH2:28][C:20]1[N:21]([CH3:27])[C:22](=[O:26])[C:23]([CH3:24])([CH3:25])[C@:18]([C:13]2[CH:12]=[C:11]([NH:10][CH:7]3[CH2:8][CH2:9][CH:5]([CH2:4][C:3]([OH:30])=[O:2])[CH2:6]3)[CH:16]=[CH:15][C:14]=2[F:17])([CH3:29])[N:19]=1
Reactant: COC(=O)CC1CCC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCC(CC(=O)O)C3)ccc2F)N=C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {3-[3-((S)-2-amino-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-4-yl)-4-fluoro-phenylamino]-cyclopentyl}-acetic acid methyl ester (example 95, 0.05 mmol) in THF (1 ml), MeOH (0.3 ml), and H2O (0.3 ml) was added LiOH (1N, 0.1 mmol) and the reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and the residue diluted with aqueous HCl (0.5N) until pH=5 and EtOAc. The white solid which precipitate was filtered off, washed with H2O and dried. The organic phase was dried over Na2SO4 and evaporated to yield a white solid. The combined solid material was triturated with a mixture of dichloromethane and MeOH (10:1), filtered and the filtrate was concentrated in vacuo to yield a mixture of isomers of the title compound as a white solid. MS (ESI): m/z=405.5 [M+H]+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4]C=1Cl.[NH3:10].[C:11](#[N:13])C>>[NH2:10][C:5]1[N:4]=[C:11]([NH2:13])[N:1]=[C:8]([Cl:9])[N:7]=1
Reactant: CC#N
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N
Product: Nc1nc(N)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution obtained by dissolving 184.5 g (1.0 mol) of cyanuric chloride in 800 mL of acetonitrile at room temperature and cooling down to 0° C. was dropwise added over 2 hours 303.7 g (5.0 mol) of an aqueous 28% ammonia solution with vigorous stirring, by keeping the reaction temperature at 10° C. or lower. After completion of the dropwise addition, the cooling was discontinued and the mixture was stirred at room temperature for 1 hour, followed by gradually warming the mixture up to 45° C. and allowing the mixture to react for 4 hours. After cooling, the product was filtered and washed with a large amount of water. The filtrate was dried at 50° C. for 6 hours in vacuum to obtain 115 g (yield 79%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:27]=1[NH:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([N:28]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]2[C:37]([CH3:41])=[CH:38][CH:39]=[CH:40][C:26]=2[CH3:25])=[O:21])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCNc1c(C)cccc1C
Reactant: COc1ccc(N(CCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)CCCN(C(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(p-anisidino)-butyric acid and ethyl 4-(2,6-dimethylanilino)butyrate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(p-anisidino)butyryl]-4-(2,6-dimethylanilino)butyrate (oil), saponification of which and the processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(p-anisidino)butyryl]-4-(2,6-dimethylanilino)butyric acid (M.P. 131° to 133°).