Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][C@@H:18]([OH:20])[C@@H:17]([OH:21])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1.N1([C:27]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[NH:37][C:36]3=[O:44])[CH2:31][CH2:30]2)=[O:28])C=CN=C1.CC(C)([O-])C.[K+]>O1CCCC1>[O:44]=[C:36]1[NH:37][C:38]2=[N:39][CH:40]=[CH:41][CH:42]=[C:43]2[N:35]1[CH:32]1[CH2:31][CH2:30][N:29]([C:27]([O:21][C@H:17]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH2:10][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:19][C@H:18]2[OH:20])=[O:28])[CH2:34][CH2:33]1
Reactant: O[C@@H]1C[C@@H](c2cccc(F)c2F)Cc2cccnc2[C@@H]1O
Reactant: O=C(N1CCC(n2c(=O)[nH]c3ncccc32)CC1)n1ccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O[C@H]1c2ncccc2C[C@H](c2cccc(F)c2F)C[C@H]1O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.3 %

Procedure:
In an oven-dried 100 mL round-bottom flask was dissolved (6S,8R,9S)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-8,9-diol (61 mg, 0.209 mmol) (azeotroped with dry benzene) and 1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (65.4 mg, 0.209 mmol) in tetrahydrofuran (2 mL) to give a colorless solution under nitrogen. After cooling to 0° C. (ice bath), potassium t-butoxide (1M in tetrahydrofuran, 0.754 mL, 0.754 mmol) was added dropwise, and the tan suspension was warmed up to room temperature with stirring. After 2 h some SM remained. Another 20 mg of 1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one was added, and the mixture was left stirring overnight. After 18 h the reaction was quenched with sodium bicarbonate solution and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated to give a yellow oil. Purification by FCC up to 10% methanol/methylene chloride afforded the desired product (last peak, 16 mg, 14%) as a light yellow foam. MS(ESI)[M+H+]=536.26, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27-8.59 (m, 1H) 8.08 (dd, J=5.29, 1.26 Hz, 1H) 7.54 (d, J=2.52 Hz, 1H) 7.31-7.51 (m, 1H) 7.22 (dd, J=7.30, 5.04 Hz, 1H) 6.93-7.19 (m, 4H) 5.39-5.63 (m, 1H) 5.18 (br. s., 1H) 4.45-4.64 (m, 1H) 4.37 (br. s., 1H) 3.10-3.40 (m, 3H) 2.92 (d, J=13.85 Hz, 1H) 2.11-2.88 (m, 5H) 1.75-1.95 (m, 2H) 1.55-1.71 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C([Li])CCC.[C:27]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1.C(OCC)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:12]=[C:11]([C:27]3([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[S:10][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:16]=1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(-c2cc(C3(O)CCCCC3)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)thiophene (5.92 g, 20 mmole) in toluene (20 ml)/diethyl ether (120 ml) was treated with 1.6M n-butyl lithium (14 ml, 1.1 equiv.) and heated at reflux for 1.5 hours. The reaction mixture was cooled to 0° and treated with a solution of cyclohexanone (2.3 ml, 1.1 equiv.) in 5 ml of diethyl ether. The mixture was stirred for 1.5 hours at 0° and 1 hour at room temperature, quenched with water, and extracted with ethyl acetate. The organic extracts were washed with brine, dried and concentrated in vacuo. Chromatography on a Waters Prep 500 (hexane/ethyl acetate, 3:1) provided the title compound (5.8 g, 74%) as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:17]O>>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1ccccc1

Procedure:
A solution of 3-phenylpropionic acid (50 g, 0.33 mole) and conc. sulfuric acid (5 g) in methanol (220 ml) was refluxed for 1 hour with stirring, concentrated and poured into cold H2O. The mixture was extracted thrice with methylene chloride (75 ml), the organic layer was washed thrice with H2O (125 ml), dried over anhydrous MgSO4 and evaporated. The residual crude oil (54 g) was distilled under reduced pressure to give 51.5 g of methyl 3-phenylpropionate as a colorless oil having a boiling point of 94°-95° C./5 mmHg.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>>[C:7]([C:4]1[N:3]=[C:2]([CH3:1])[NH:6][CH:5]=1)(=[O:9])[CH3:8]
Reactant: Cc1ncc[nH]1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1c[nH]c(C)n1

Procedure:
The reaction of 2-methylimidazole with acetic anhydride to give 4-acetyl-2-methylimidazole over a catalyst may be represented for example by the following equation: ##STR7##
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH2:17]Cl>>[CH3:25][O:24][C:20]1[CH:19]=[C:16]([CH:15]=[C:14]([O:13][CH3:12])[C:21]=1[O:22][CH3:23])[CH2:17][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Sc1ncnc2ccccc12
Reactant: COc1cc(CCl)cc(OC)c1OC
Product: COc1cc(CSc2ncnc3ccccc23)cc(OC)c1OC
Yield: 42.2 %

Procedure:
The title compound(3.56 g) was prepared from 4-mercaptoquinazoline(4.0 g) and 3,4,5-trimethoxybenzyl chloride(7.3 g).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[N+]([O-])(O)=O.[NH2:16][NH:17][C:18](N)=N.[OH-].[Na+]>C(O)C>[NH2:5][C:4]1[C:3]([C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:1])=[CH:18][NH:17][N:16]=1
Reactant: N=C(N)NN
Reactant: N#CCC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: Nc1n[nH]cc1C(=O)c1ccccc1

Procedure:
A reaction mixture comprising 73.36 g of α-(dimethylamino)methylene]-β-oxo-2-benzenepropanenitrile, 63.45 g of aminoguanidine nitrate, 500 ml of ethanol and 36.6 ml of 10N sodium hydroxide was refluxed for 10 hours and then cooled. The resulting precipitate was collected and washed with water, giving 17.1 g of the desired product, mp 177°-179° C.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>Br>[CH2:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][CH2:11][CH2:12]2)[CH3:20]
Reactant: CCc1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc2c(c1)CCN2
Yield: 34 %

Procedure:
A mixture of 1-benzenesulfonyl-5-ethyl-2,3-dihydro-1H-indole (15 g, 0.05 mol) in HBr (48%, 162 mL) was heated at reflux for 6 h. The mixture was basified with sat. NaOH solution to pH 9 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-ethyl-2,3-dihydro-1H-indole (2.5 g, 32%).
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(OC([N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=3)[NH:22][C:21]2=[O:37])[CH2:16][CH2:15]1)=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:36][N:33]1[CH2:32][CH2:31][N:30]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:37])[N:20]([CH:17]2[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]2)[CH2:29]3)[CH2:35][CH2:34]1
Reactant: CN1CCN(c2ccc3c(c2)CN(C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc3c(c2)CN(C2CCNCC2)C(=O)N3)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
2 mL of trifluoroacetic acid were added to the ice-cooled solution of 1.1 g (2.561 mmol) of 3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-6-(4-methyl-1-piperazinyl)-2(1H)-quinazolinone in 20 mL of methylene chloride. The reaction mixture was stirred for 15 hours at ambient temperature and for 5 hours at 40° C. and then evaporated down in vacuo. The residue remaining was taken up in 5 mL of water, the solution formed was saturated with potassium carbonate and extracted exhaustively with dichloromethane. The combined extracts were evaporated down in vacuo. The residue obtained was purified by column chromatography on silica gel using dichloromethane/methanol 9/1 (v/v) to start with, then dichloromethane/methanol/concentrated ammonia 70/30/3 (v/v/v) as eluant. The appropriate fractions were evaporated down in vacuo, the residue remaining (0.5 g; 59% of theoretical) was used in the next step without further purification.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:27]=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=1>CN1CCCC1=O>[C:32]([C:29]1[N:30]=[CH:31][C:26]([N:22]2[CH2:23][CH2:24][CH:19]([N:5]([CH:2]3[CH2:4][CH2:3]3)[C:6](=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([C:13]4[O:17][CH:16]=[N:15][CH:14]=4)=[CH:11][CH:12]=3)[CH2:20][CH2:21]2)=[N:27][CH:28]=1)#[N:33]
Reactant: N#Cc1cnc(Cl)cn1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)cn1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 5-chloro-pyrazine-2-carbonitrile following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.46 min; Mass spectrum (ESI+): m/z=415 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH2:17])[CH:5]=1.CCN(CC)CC.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([NH:17][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH:9]=1
Reactant: COC(=O)c1cc(N)cc(-c2ccc(Cl)cn2)c1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
3-Amino-5-(5-chloro-pyridin-2-yl)-benzoic acid methyl ester (1.5 g, 5.71 mmol, from Preparation 2) and Et3N (2.39 mL, 17.13 mmol) were dissolved in 30 mL methylene chloride, and isobutyryl chloride (72 mL, 6.85 mmol) was added. The reaction mixture was stirred at room temperature for two hours, and then was partitioned between water and methylene chloride. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 1.29 g of 3-(5-chloro-pyridin-2-yl)-5-isobutyrylamino-benzoic acid methyl ester, MS (M+H)=333.
Reaction SMILES: [O:1]([CH2:8][C@H:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O1CCCC1.[Ru]>[CH:2]1([O:1][CH2:8][C@H:9]2[CH2:11][O:10]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: c1ccc(OC[C@H]2CO2)cc1
Agent: [Ru]
Solvent: C1CCOC1
Product: C1CCC(OC[C@H]2CO2)CC1
Yield: 58 %

Procedure:
In two separate runs, dissolve (R)-2-phenoxymethyl-oxirane (1.410 g, 9.389 mmol) in tetrahydrofuran (50 mL). Add 5% ruthenium on carbon (0.71 g) and hydrogenate at 60 psi of hydrogen gas for 40 minutes. Filter through a filtering agent, wash with tetrahydrofuran, concentrate and purify (silica gel chromatography, eluting with 5:95 to 30:70 ethyl acetate:hexanes) to give the desired compound as a clear liquid (0.850 g, 57.9% combined yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li+].[CH3:16][CH:17]([N-]C(C)C)C.C(I)C>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:16][CH3:17])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cccc(-n2c(C)ccc2C)n1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCCc1cccc(-n2c(C)ccc2C)n1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from Example 2a (7.53 g, 40.0 mmol) in 30 mL of dry THF was added dropwise with stirring to a solution of LDA (42.4 mmol) in 30 mL of dry THF at −30° C. Stirred at −30° C. for 30 min. Added EtI (3.42 mL, 42.0 mmol) in 20 mL of dry THF dropwise with stirring for 30 min then warmed to room temperature. After 2 h quenched by pouring into saturated NaCl solution and extracted with ether. Dried over MgSO4, filtered and concentrated under vacuum giving the title compound. The product was purified by silica gel column chromatography eluting with EtOAc/hexane to give the title compound (5.21 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12](OC)=[O:13])[C:3]=1[C:16]([O:18]C)=O.O.[NH2:21][NH2:22]>C(O)C>[NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12](=[O:13])[NH:21][NH:22][C:16](=[O:18])[C:3]=12
Reactant: COC(=O)c1nc2ccccc2c(N)c1C(=O)OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1c2ccccc2nc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a stirred solution of dimethyl 4-aminoquinoline-2,3-dicarboxylate (0.15 g, 0.58 mM) in ethanol (4 mL) was added hydrazine hydrate (1.46 g, 29.2 mM) and the resulting solution was refluxed for 3 hr. The reaction mixture was cooled to room temperature and filtered to separate the yellow precipitate (0.12 g). This material was stirred in refluxing acetic acid (4.5 mL) for 1 hr. After cooling to room temperature the reaction mixture was filtered and the collected solids washed with acetic acid and ethyl acetate. Air drying provided the title compound (0.13 g, 68%) as an orange solid, mp>400° C.; MS(CI): 229 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[CH2:5])[CH3:2].[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>N1C=CC=CC=1.C(Cl)Cl>[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](=[O:16])[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C(OCC)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=CC(=O)C(Cl)(Cl)Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7.49 g 1-(1-Ethoxy-vinyl)-4-Fluorobenzene in 3.6 mL of Pyridine was added at 0° C. to 8.19 g of Trichloroacetyl chloride. The suspension was diluted with 15 ml of dry methylene chloride and stirred at room temperature overnight. The resulting dark brown suspension was concentrated in vaccuo, filtered over a silica gel column with a 9:1 mixture of Heptane and Ethyl acetate as eluant. One obtains after concentration 28 g of a reddish brown oil which was repurified by chromatography on silica gel using a 19:1 mixture of Heptane and Ethyl acetate as eluant. The obtained brown oil (10.15 g) was directly used in the next step.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]1.O>C(O)C>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH2:19][CH2:20][O:21][CH:22]2[CH2:23][C:24]([CH3:31])([CH3:30])[NH:25][C:26]([CH3:28])([CH3:29])[CH2:27]2)=[CH:8][CH:7]=1
Reactant: Oc1ccc(-c2nc3ccccc3o2)cc1
Reactant: CC1(C)CC(OCCBr)CC(C)(C)N1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(OCCOc2ccc(-c3nc4ccccc4o3)cc2)CC(C)(C)N1

Procedure:
Equal molar quantities of p-hydroxybenzaldehyde and o-aminophenol in excess nitrobenzene was refluxed for five hours. The nitrobenzene was removed and the residue was washed with hot xylene. 2-(4-Hydroxyphenyl)benzoxazole was obtained by crystallization from ethanol in 64% yield (m.p. 253°). A mixture of the sodium salt of 2-(4-hydroxyphenyl)benzoxazole (0.01 mole) and 4-(2-bromoethoxy)-2,2,6,6-tetramethylpiperidine (0.01 mole) in 250 ml of ethanol was refluxed for 20 hours. The reaction mixture was cooled, 200 ml. of water was added and the product, I, was filtered out.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].[CH:10]1([C:13](=[N:15]O)[NH2:14])[CH2:12][CH2:11]1>C1(C)C(C)=CC=CC=1>[CH:10]1([C:13]2[N:15]=[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[O:8][N:14]=2)[CH2:12][CH2:11]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(Cl)c1cnccn1
Solvent: Cc1ccccc1C
Product: c1cnc(-c2nc(C3CC3)no2)cn1

Procedure:
To a mixture of 28.7 g. of pyrazinoyl chloride in 100 ml. of xylene is added slowly a solution of 20 g. of cyclopropanecarboxamidoxime in 100 ml. of xylene. This mixture is heated under reflux for 3 hours, concentrated under reduced pressure and the residue mixed with aqueous sodium hydroxide. The mixture is filtered and the filtrate is extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to give crude crystals, which are recrystallized from cyclohexane to give light yellow crystals, melting point 61°-64°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C:8]2[C:17](=[O:18])[N:16]([CH3:19])[C:15]3[C:10](=[CH:11][N:12]=[C:13]4[NH:22][CH:21]=[CH:20][C:14]4=3)[CH:9]=2)[CH:7]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=2)[C:35](O)=[O:36])[CH2:28][CH2:27]1)[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>>[CH2:24]([N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=2)[C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C:8]3[C:17](=[O:18])[N:16]([CH3:19])[C:15]4[C:10](=[CH:11][N:12]=[C:13]5[NH:22][CH:21]=[CH:20][C:14]5=4)[CH:9]=3)[CH:7]=2)=[O:36])[CH2:30][CH2:31]1)[CH3:25]
Reactant: CCN1CCN(c2cc(C(=O)O)cc(C(F)(F)F)c2)CC1
Reactant: Cc1ccc(N)cc1-c1cc2cnc3[nH]ccc3c2n(C)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCN1CCN(c2cc(C(=O)Nc3ccc(C)c(-c4cc5cnc6[nH]ccc6c5n(C)c4=O)c3)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(5-amino-2-methyl-phenyl)-9-methyl-3,9-dihydro-3,4,9-triaza-cyclopenta[a]naphthalen-8-one (22 mg, 0.07 mmol), 3-(4-Ethyl-piperazin-1-yl)-5-trifluoromethyl-benzoic acid (24 mg, 0.08 mmol), HATU (30 mg, 0.08 mmol) and DIEA (27 mg, 0.21 mmol) in 0.5 mmol DMF is stirred at room temperature for 2 hours. The solvent is removed by rotary evaporation. The crude product is purified by reverse phase HPLC to give the title compound as white solid. 1H NMR 400 MHz (DMSO-d6) δ 12.19 (s, 1H), 10.32 (s, 1H), 9.71 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.72 (s, 1H), 7.66 (m, 2H), 7.58 (s, 1H), 7.50 (t, 1H, J=2.8 Hz), 7.45 (s, 1H), 7.23 (d, 1H, J=8.4), 7.04 (s, 1H), 4.06 (m, 2H), 3.99 (s, 3H), 3.55 (b, 2H), 3.15 (m, 2H), 3.06 (m, 4H), 2.09 (s, 3H), 1.20 (t, 3H, J=7.2). MS m/z 589.2 (M+1).
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)=[N:12][CH:13]=2)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:38][O:39][C:40]([C@H:42]1[CH2:47][C@@H:46](O)[CH2:45][CH2:44][N:43]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:41]>C1COCC1>[N:14]1([C:11]2[N:12]=[CH:13][C:8]([O:7][CH2:6][C:4]3[CH:5]=[N:1][N:2]([CH:46]4[CH2:45][CH2:44][N:43]([C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[CH:42]([C:40]([O:39][CH3:38])=[O:41])[CH2:47]4)[N:3]=3)=[CH:9][CH:10]=2)[CH:18]=[N:17][N:16]=[N:15]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cn[nH]n1
Reactant: COC(=O)[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1CC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 5-((2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine (600 mg, 2.45 mmol), triphenylphosphine (1.5 eq.), and (2R,4S)—N-Boc-4-hydroxypiperidine-2-carboxylic acid methyl ester (1.5 eq.) dissolved in THF (20 mL) at 0° C. was added a solution of di-tertbutylazodicarboxylatc (1.5eq.) in THF (5 mL) drop wise. The reaction was allowed to warm to room temperature overnight and the solvents removed in vacuo The crude material was purified by flash column chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 9.44 (1H, s), 8.27 (1H, d), 8.03 (1H, d), 7.71 (1H, s), 7.58 (1H, dd), 5.27 (2H, s), 4.99-5.19 (1H, m), 4.57 (1H, m), 4.11-4.31 (1H, m), 3.79 (3H, s), 3.04-3.24 (1H, m), 2.75 (1H, m), 2.18-2.32 (2H, m), 2.05 (1H, m), 1.50 (9H, s). ES+-MS found: 486.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17]>>[C:20]([O:19][C:15]([NH:16][N:17]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)(C)OC(=O)NN=Cc1ccc(-c2ccccn2)cc1

Procedure:
WO97/40029 discloses a production method comprising reacting 4-(pyridin-2-yl)benzaldehyde with tert-butyl carbazate [tBuOC(═O)NHNH2 wherein tBu is tert-butyl] to give N-(tert-butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine, therefor 4-(pyridin-2-yl)benzaldehyde is important as an intermediate for a pharmaceutical product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>C(Cl)Cl.CO>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[O:8][C:6]1[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][N:22]3[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]3)=[CH:32][CH:31]=2)[N:7]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1Oc1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1Oc1ccc(F)c(Cl)c1
Yield: 59 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-4-fluorophenoxy)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 59% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ H 8.10 (s, 1H), 7.43 (t, 1H, J=8.4 Hz), 7.23 (d, 2H), 7.09 (d, 2H, J=8.2 Hz), 7.04 (dd, 1H, J=9.6, 2.4 Hz), 6.94 (m, 1H), 3.42 (s, 2H), 2.46 (bs, 8H) 2.27 (s, 3H), 2.18 (s, 3H); MS (ESI): 442.3 [M+H]+, 221.7 [M+2H]2+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:18]([NH:26][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Temperature: 100 °C

Procedure:
To a stirred solution of 1-fluoro-2-nitrobenzene (14.1 g, 0.1 mol) and triethylamine (14 ml, 0.1 mol) in DMF (150 ml) was added phenethylamine (12.1 g, 0.1 mol). The mixture was now heated to 100° C., and the reaction was monitored by TLC. After the reaction was completed (2 h) the solvent was removed by evaporation in vacuo. The residue was partitioned between 0.5N aqueous HCl (100 ml) and ether (100 ml). The organic phase was washed with water, dried and evaporated to give the title compound as a yellow oil.