Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1.O.[H][H]>C(#N)C.[C].[Pd]>[O:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[NH2:17]
Reactant: NCC1CCCO1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CC#N
Solvent: O
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NCC1CCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (0.40 mg, 1.5 mmol) in acetonitrile (8 mL) was added 2-aminomethyltetrahydrofuran (0.36 g, 3.6 mmol), and this was heated to reflux for 7 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a solution of the residue obtained in a solvent mixture of methanol/tetrahydrofuran=1:1 (40 mL) was added 10% palladium-carbon (40 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 3 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (0.40 g, 84% yield) as a brown syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([O:16][CH3:17])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: COC(CN)c1coc(-c2ccc(F)cc2)n1
Product: COC(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 22 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methoxyethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (44 mg, yield 22%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.56-8.55 (t, J=1.6 Hz, 1H), 8.29-8.26 (dt, J=7.9 Hz, 1.3 Hz, 1H), 8.11-8.06 (m, 3H), 7.73 (s, 1H), 7.67-7.63 (t, J=7.7 Hz, 1H), 7.22-7.19 (m, 1H), 7.17-7.13 (t, J=8.7 Hz, 2H), 4.54-4.51 (dd, J=5.9 Hz, 5.1 Hz, 1H), 4.12-4.06 (ddd, J=13.9 Hz, 6.5 Hz, 4.9 Hz, 1H), 3.87-3.81 (ddd, J=13.9 Hz, 6.1 Hz, 4.8 Hz, 1H), 3.45 (s, 3H). MS (ESI) m/z: Calculated for C22H16F4N4O4: 476.11. found: 475.6 (M)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1.C(OC(=O)[NH:27][CH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)(C)(C)C.C(O)(=O)C(O)=O.C(N(CC)CC)C>C(Cl)Cl>[NH2:27][CH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[OH:20])[N:3]=2)[CH2:30]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCCNC1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (1.0 g, 3.46 mmol) was dissolved in 15 mL anhydrous CH2Cl2 under an N2 atmosphere and cooled using an ice bath and (S)-piperidin-3-ylmethyl-carbamic acid tert-butyl ester/oxalic acid (1.16 g, 3.81 mmol) was added in portions, followed by triethylamine (1.05 g, 1.45 mL, 10.4 mmol). The reaction was allowed to warm to room temperature and was complete after 1.5 hour. The mixture was partitioned between CH2Cl2 and H2O and separated, and the aqueous layer was extracted once more with CH2Cl2. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to a yellow solid. This solid was suspended in 40 mL CH2Cl2 and 20 mL of TFA were added. The reaction was complete after 1 hour. The solvent and the excess TFA were removed in vacuo, the residue was re-dissolved in CH2Cl2, and the pH was adjusted to 7 using an aqueous 1 M solution of NaOH. The reaction was partitioned between CH2Cl2 and H2O and separated, and the aqueous layer was extracted once more with CH2Cl2. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to yield of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (900 mg, 71% overall yield) as a yellow solid. LC/MS: m/z 367.3 (M+H)+ at 1.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][CH2:2]N=C=NCCCN(C)C.Cl.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:23]=1[O:24][CH2:25][C:26]([OH:28])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=CC2N(O)N=[N:40]C=2C=1.Cl.C(N)C.CN1CCOCC1>CN(C=O)C>[CH2:1]([CH:25]([O:24][C:23]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:22]=1[CH2:21][NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[C:26]([NH2:40])=[O:28])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1OCC(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(Oc1ccc(Cl)cc1CNC(=O)OC(C)(C)C)C(N)=O
Reaction time: 16 h

Procedure:
EDC Hydrochloride (249 mg, 1.3 mmol) was added to a stirred mixture of 2-t-butoxycarbonylaminomethyl-4-chlorophenoxyacetic acid (316 mg, 1.0 mmol), HOBT (176 mg, 1.3 mmol), ethylamine hydrochloride (106 mg, 1.3 mmol) and N-methylmorpholine (0.396 ml, 3.6 mmol) in DMF (4 ml) and the mixture was stirred for 16 h. The reaction was partitioned between ethylacetate and 5% KHSO4 solution and the organic layer was washed with 5% KHSO4 solution, water, NaHCO3 solution and brine, dried (Na2SO4) and evaporated in vacuo to a solid (333 mg) which was used for the next step.
Reaction SMILES: CC#N.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH3:14])=[CH:7][C:6]=1[OH:22].[CH2:23]1[O:26][CH:24]1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH3:14])=[CH:7][C:6]=1[O:22][CH2:23][CH:24]([OH:26])[CH3:25]
Reactant: CC1CO1
Reactant: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(O)COc1cc(CN[C@H](C)c2cccc(Cl)c2)ccc1Cl
Yield: 61.8 %

Procedure:
A microwave compatible vial was charged with 2 mL of CH3CN, (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 96 (115 mg, 388 μmol), propylene oxide (33 μL, 466 μmol), and cesium carbonate (139 mg, 427 μmol). The vial was sealed and was subjected to microwave irradiation at 140° C. for 30 min. The reaction was checked for completion by TLC. The reaction solution was diluted with EtOAc and it was washed with water (2×) and then brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 10% to 70% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give 1-(2-chloro-5-(((R)-1-(3-chlorophenyl)ethylamino)methyl)phenoxy)propan-2-ol 97 (85 mg, 62% yield), as a colorless oil and as a mixture of diastereomers. 1H NMR (400 MHz, d4-methanol) δ ppm 1.32 (d, J=6.46 Hz, 3H) 1.73 (d, J=6.85 Hz, 3H) 3.92-4.02 (m, 3H) 4.13-4.21 (m, 2H) 4.49 (q, J=6.78 Hz, 1H) 6.98 (dd, J=8.12, 1.66 Hz, 1H) 7.43-7.49 (m, 2H) 7.49-7.53 (m, 2H) 7.58 (s, 1H). Mass spectrum: calculated for C18H21Cl2NO2 354.3. found 355.4 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH:7]=[C:8]([N:13]=[N+]=[N-])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]2[C:6]([CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[NH:13]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C(=Cc1ccc(OC)cc1)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(OC)cc2[nH]1

Procedure:
Toluene (185 ml) is added to methyl 4-methoxy-α-azidocinnamate (PREPARATION 61, 7.73 g) and the reaction is brought to reflux and maintained at reflux for 3 hr. Then the reaction is concentrated under reduced pressure and triturated with hexane. The solids are filtered and dried under reduced pressure to give the title indole, HRMS Calcd. for C11H11NO3 : 205.0739, found: 205.0736; NMR (300 MHz, CDCl3) 8.75, 7.47, 7.11, 6.76-6.73, 3.86, and 3.79 δ.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[C:4]([CH3:10])[CH:3]=1.[N+:11]([CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)([O-])=[O:12].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:14]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:9]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: C#Cc1ccc(Br)cc1C
Reactant: O=[N+]([O-])CCOC1CCCCO1
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(Br)ccc1-c1cc(COC2CCCCO2)no1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a flask containing a solution of 4-bromo-1-ethynyl-2-methylbenzene (875 mg, 4.49 mmol) (may be prepared according to the procedures in Journal of Chemical Research (2007), 12 728-732) in toluene (20 mL), was added 2-(2-nitroethoxy)tetrahydro-2H-pyran (1.34 g, 7.63 mmol), phenyl isocyanate (1.82 g, 15.3 mmol), and triethylamine (1.50 mL, 10.8 mmol). The reaction was heated at 100° C. and stirred under nitrogen overnight. The reaction was cooled, quenched with methanol and filtered. The filtrate was evaporated in vacuo onto silica gel. Chromatography on silica gel with a heptane-ethyl acetate gradient (0-35% ethyl acetate) eluted 5-(4-bromo-2-methylphenyl)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]isoxazole as an orange oil (581 mg, 36.8%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.57-1.71 (m, 4 H) 1.73-1.82 (m, 1 H) 1.82-1.91 (m, 1 H) 2.51 (s, 3 H) 3.56-3.62 (m, 1 H) 3.89-3.96 (m, 1 H) 4.69 (d, J=12.88 Hz, 1 H) 4.76-4.79 (m, 1 H) 4.86 (d, J=12.88 Hz, 1 H) 6.51 (s, 1 H) 7.42-7.46 (m, 1 H) 7.48 (d, J=1.56 Hz, 1 H) 7.59 (d, J=8.20 Hz, 1 H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23]>>[CH2:25]([O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[CH2:26][CH3:27]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: CCCOC(=O)Cl
Product: CCCOC(=O)N=C(OCC)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and propyl chloroformate, there is obtained ethyl N-propoxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 352 (8), 323 (14), 293 (14), 263 (78), 194 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:32](=[O:33])[C:31]5[CH:30]=[CH:29][CH:28]=[N:27][C:26]=5[CH3:25])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ncccc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cccnc1C
Yield: 31.7 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (120 mg, 0.371 mmol), 2-methylpyridine-3-carboxylic acid (76 mg, 0.557 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (114 mg, 0.594 mmol), 1-hydroxybenzotriazole (81 mg, 0.600 mmol), triethylamine (0.09 mL, 0.631 mmol) and N,N-dimethylformamide (6.0 mL), and by a reaction in the same manner as in Example 187, the title compound (52 mg, 31%) was obtained as pale-pink crystals.
Reaction SMILES: BrC1N(C)C=NC=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(C1C=C(NS(C)(=O)=O)C(OC)=C(NC(=O)C2C=CC(C)=C(N3[CH:40]=[C:39]([C:41]4[N:42]([CH3:50])[C:43](C(O)(C)C)=[N:44][CH:45]=4)N=N3)C=2)C=1)(C)(C)C>>[C:39]([C:41]1[N:42]([CH3:50])[C:43]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:15])=[N:44][CH:45]=1)#[CH:40]
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C(C)(C)O)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cn1cncc1Br
Product: C#Cc1cnc(C(=O)c2ccccc2)n1C

Procedure:
(5-Ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanone was prepared from 5-bromo-1-methyl imidazole and benzoyl chloride in the same manner as 1-methyl-5-ethynyl-1H-imidazole-2-carboxylic acid ethyl ester (Example 27).
Reaction SMILES: O[C:2]1([C:18]2[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=2)[C:8]2[N:9]=[C:10]([CH3:12])[S:11][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]1=2.[H-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O.C(O)(=O)C>[CH3:12][C:10]1[S:11][C:7]2[CH:6]=[CH:5][C:4]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]=3[CH:2]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[N:22]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:23]=3)[C:8]=2[N:9]=1
Reactant: Cc1ccc2c(c1)CCc1sc(C)nc1C2(O)c1c[nH]c(=O)[nH]c1=O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(CCN2CCCC2)c(=O)[nH]c1=O
Temperature: 50 °C

Procedure:
The product from example 18 step (ii) (1.44 g) was dissolved in dry N,N-dimethylformamide (20 ml) and treated cautiously with sodium hydride (60% dispersion by wt, 0.5 g) under nitrogen. After 10 min 1-(2-chloroethyl)pyrrolidine hydrochloride (0.8 g) was added and the whole heated at 50° C. for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was collected, dried over magnesium sulphate and solvent evaporated under reduced pressure. Purification was by flash chromatography eluting with 9:1 dichloromethane/methanol. The product obtained was dissolved in acetic acid (10 ml) and heated at 100° C. for 2 h. The solvent was removed under reduced pressure. Purification was by flash chromatography eluting with dichloromethane/methanol mixtures to give the subtitle product as pale yellow foam.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11].[C:17]([Cl:20])(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)(=[O:19])[CH3:18].[ClH:20].[CH2:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11]
Reactant: OCCN1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(CCO)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Piperazinoethanol (7.81 g, 60 mmoles) and triethylamine (8.36 ml, 66 mmoles) were dissolved in 100 ml of methylene chloride and cooled to 0°-5° C. Acetyl chloride (4.28 ml, 60 mmoles) in 20 ml of methylene chloride was added and the reaction mixture warmed to room temperature, held for 2 hours, and then evaporated in vacuo to dry solids. The solids were triturated with four portions of warm ether. The triturates were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 2-(4-acetylpiperazino)ethanol as an oil [7.5 g; free of triethylamine and triethylamine hydrochloride by pnmr assay; Rf 0.3 (methanol/10% acetic acid)].
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18](O)=[O:19].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:43]1([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([F:15])([F:16])[F:17])=[CH:11][CH:12]=2)[C:3]=1[C:18]([N:46]1[CH2:45][CH2:44][N:43]([C:49]2[CH:50]=[CH:51][C:52]([OH:55])=[CH:53][CH:54]=2)[CH2:48][CH2:47]1)=[O:19]
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 68.5 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (566 mg, 1.26 mmol, 69%) was obtained.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2.[NH2:16][CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19].S(O)(O)(=O)=O.[CH2:28]([N:30]([CH2:38][CH3:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1N)[CH3:29]>O>[CH2:38]([N:30]([CH2:28][CH3:29])[C:31]1[CH:36]=[CH:35][C:34]([NH:16][CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[CH:33][CH:32]=1)[CH3:39].[CH2:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH2:9][C:10]1([C:13]([NH2:30])=[O:15])[C:18]([NH2:20])=[O:19]
Reactant: CN(C)C(=O)CN
Reactant: CCN(CC)c1ccccc1N
Reactant: COc1cccc2c1CC(C(=O)O)CC2
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN(CC)c1ccc(NCC(=O)N(C)C)cc1
Product: NC(=O)C1(C(N)=O)CCc2ccccc2C1

Procedure:
The titled compound was prepared according to the procedure described in Example 1, substituting 2-(4-diethylamino-phenylcarbamoyl)-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid from Example 16B for 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid, and 2-amino-N,N-dimethyl-acetamide for N,N-diethylphenylene diamine sulfate used in Example 1. 1H NMR (300 MHz, DMSO-D6) δ 9.70 (s, 1H), 8.21 (t, J=5.4 Hz, 1H), 7.46 (t, J=9.0 Hz, 2H), 7.01–7.09 (m, 4H), 6.60 (d, J=9.0 Hz, 1H), 3.92 (d, J=5.7 Hz, 2H), 3.28 (q, J=6.9 Hz, 4H), 3.20 (d, J=17.4 Hz, 1H), 2.95 (s, 3H), 2.87 (s, 3H), 2.78 (m, 2H), 2.30 (m, 2H), and 1.05 (t, J=6.9 Hz, 6H). (one proton (ArCHaHbC(C═O)) overlapped with water)). MS (ESI) positive ion 451 (M+H)+; negative ion 449 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:18])[CH3:17])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)Cl>CO.C1COCC1>[Br:19][CH2:17][C:16]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:18]
Reactant: COCCOc1cc(C(C)=O)cc(C(C)(C)C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cc(C(=O)CBr)cc(C(C)(C)C)c1
Yield: 292.5 %

Procedure:
1-[3-tert-Butyl-5-(2-methoxyethoxy)phenyl]ethanone (O2.043; 1 g) was dissolved in methanol/THF (25 ml/25 ml), admixed with phenyltrimethylammonium tribromide (882 mg) while stirring and stirred at RT overnight. Then 50 ml of 20% citric acid solution were added and the mixture was stirred for 1 h. Subsequently, DCM (200 ml) was added and the mixture was extracted three times with DCM. Then the combined DCM phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-30% in 30 min). 1.31 g of the title compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])OC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.O>C1(C)C(C)=CC=CC=1.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: NCc1cccnc1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CO
Product: O=C(NCc1cccnc1)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of 5.88 g (0.03 mole) of methyl N-(4-nitrophenyl)-carbamate, 2.70 g (0.025 mole) of 3-aminomethyl-pyridine, 9.6 ml of Gemanin CS 302D (a mixture of N,N-dimethyl-C10-18 alkylamines sold by the firm Hoechst AG) and 50 ml of xylene is filled into a flask equipped with a 20 cm Vigreux column and a Dean-Stark trap, and the mixture is boiled for 2 hours. During this period 6 ml of a mixture of water, methanol and xylene accumulate in the trap. The mixture is filtered when hot, the crystalline end-product is washed twice with 5 ml of hot xylene, each, and then with a few amount of acetone and dried. 6.0 g (88.2%) of N-(4-nitrophenyl)-N'-(3-pyridylmethyl)-urea are obtained; m.p.: 223°-225° C.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10].C(N(CC)CC)C.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][NH:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH3:34]
Reactant: NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CNCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a solution of N-(2-aminoethyl)-2-nitro-benzenesulfonamide acetic acid salt (15.15 g, 49.6 mmol) and triethylamine (15.16 g, 0.15 mol) in dichloromethane (100 mL) was added ethyl bromoacetate (16.7 g 0.100 mol) with stirring at room temperature. After additional stirring for 1 h, the reaction mixture was washed with brine (100 mL). The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and the residue was triturated in ethyl ether (100 mL) to afford the titled compound as a white solid (8.1 g, 49%). 1H-NMR (500 MHz; DMSO-d6) δ 8.02˜7.96 (m, 2H), 7.87˜7.84 (m, 2H), 4.05 (q, 2H), 3.23 (s, 2H), 2.95 (t, 2H), 2.57 (t, 2H) 1.16 (t, 3H).