Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH:49]([NH2:51])[CH3:50])=[CH:45][CH:44]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:51][CH:49]([C:46]2[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=2)[CH3:50])=[O:40])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(N)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (20 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The reaction solution was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (2 mg, yield 8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>ClCCl>[C:2]1([NH:1][S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Yield: 54.3 %

Procedure:
To a mixture of aniline (0.35 g, 3.75 mmol) and pyridine (1 ml) a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (42) (0.45 g, 1.82 mmol) in dichloromethane (3 ml) was added and the resultant solution was stirred at 40° C. for 1 hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 6N HCl. The organic layer was washed successively with water, saturated NaCl and dried (Na2SO4). The solvent was evaporated under reduced pressure to give the title compound (0.30 g, 54%). 1H NMR (DMSO-d6, HMDSO), δ: 6.60 (1H, d, J=16.0 Hz); 6.93-7.43 (5H, m); 7.60 (1H, d, J=16.0 Hz); 7.79 (2H, d, J=8.0 Hz); 7.87 (2H, d, J=8.0 Hz); 10.35 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13](C3C=C([N+]([O-])=O)C=CC=3S([O-])(=O)=O)[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1.[BrH:44].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([Br:44])[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(c2cc([N+](=O)[O-])ccc2S(=O)(=O)[O-])=NN1c1ncccc1Cl)C1CC1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Reaction time: 144 h

Procedure:
400 mg of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl-4-nitrobenzene sulfonate was dissolved in 0.7 mL of acetic acid, and 0.2 mL of a 47 mass % hydrogen bromide aqueous solution was dropwise added, followed by stirring for about 6 days. After completion of the reaction, ethyl acetate, water and 2 mL of 1 N sodium hydroxide were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to obtain 250 mg of the desired product in a paste form.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:47][CH2:48][CH2:49][NH:50][C:51]1[N:56]=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:54]=[C:53]([NH:63][CH2:64][CH2:65][NH:66][C:67](=[O:69])[CH3:68])[C:52]=1[CH3:70]>CN1C(=O)CCC1>[C:67]([NH:66][CH2:65][CH2:64][NH:63][C:53]1[N:54]=[C:55]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[N:56]=[C:51]([NH:50][CH2:49][CH2:48][NH:47][C:1]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:13])[C:52]=1[CH3:70])(=[O:69])[CH3:68]
Reactant: CC(=O)NCCNc1nc(-c2ccccc2)nc(NCCN)c1C
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1nc(-c2ccccc2)nc(NCCNC(=O)c2ccc3ccccc3n2)c1C
Reaction time: 12 h

Procedure:
A solution of quinaldic acid (30 μl of a 0.3M solution in NMP), HATU (30 μl of a 0.3M solution in NMP) and diisopropylethylamine (30t1 of a 0.3M solution in NMP) was shaken at ambient temperature in a well of a 96 position microtitre plate for 45 min. N-[2-({6-[(2-aminoethyl)amino]-5-methyl-2-phenylpyrimidin-4-yl}amino)ethyl]acetamide (30 μl of a 0.3M solution in NMP) was then added and the mixture shaken for a further 12 hrs. Purification via ion exchange silica (SCX) yields the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4](=[N:6][OH:7])[NH2:5].[C:8]1(=[O:18])O[C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.C(N(CC)CC)C.Cl.[N:27]1([CH2:34][C:35]2[S:39][C:38]([C:40](Cl)=[O:41])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN1CCN(C)C1=O.[Cl-].[Na+].O>[N:27]1([CH2:34][C:35]2[S:39][C:38]([C:40]([C:9]34[CH:17]=[CH:16][CH:15]=[CH:14][CH:10]3[C:11]([N:1]([CH2:2][CH2:3][C:4](=[N:6][OH:7])[NH2:5])[C:8]4=[O:18])=[O:12])=[O:41])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCCC(N)=NO
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C(Cl)c1ccc(CN2CCCCCC2)s1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: NC(CCN1C(=O)C2C=CC=CC2(C(=O)c2ccc(CN3CCCCCC3)s2)C1=O)=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
9.59 g (93.0 mM) of 3-aminopropionamidoxime was dissolved in 288 ml of 1,3-dimethyl-2-imidazolidinone, 14.46 g (97.65 mM) of phthalic anhydride was added, and the mixture was stirred at room temperature for 1 hour and then at 140° C. for 2 hours. The reaction solution was cooled to room temperature, and 15.6 ml (111.6 mM) of triethylamine and 16.4 g (55.8 mM) of 5-(hexahydro-1H-azepin-1-yl)methyl-2-thiophene carbonylchloride hydrochloride were added. The mixture was stirred -overnight at room temperature, and 720 ml of saturated brine was added. Then, the thus precipitated crystals were collected by filtration and washed with distilled water to give 19.96 g of 0-[5-(hexahydro-1H-azepin-1-yl)methyl-2-thenoyl]-3-phthalimidopropionamidoxime (79% in yield from (hexahydro-IH-azepin-1-yl)methyl-2-thiophene carbonylchloride hydrochloride).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[C:15]([OH:16])=[CH:14][C:13]([F:17])=[CH:12][C:8]=2[C:9]([O-:11])=[O:10])=O)[CH2:3][CH2:2]1.O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH:1]1([C:4]2[O:16][C:15]3[C:7](=[C:8]([C:9]([O:11][CH3:19])=[O:10])[CH:12]=[C:13]([F:17])[CH:14]=3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])c1cc(F)cc(O)c1NC(=O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)cc2oc(C3CC3)nc12
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A mixture of 2-(cyclopropanecarboxamido)-5-fluoro-3-hydroxybenzoate from Step D (180 mg, 0.71 mmol), p-toluenesulfonic acid monohydrate (202 mg, 1.07 mmol) and toluene (5 mL) was heated at reflux under nitrogen for 3 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, washed with a saturated solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by Combi-flash chromatography (silica gel, 60:40 hexanes/ethyl acetate) to afford methyl 2-cyclopropyl-6-fluorobenzoxazole-4-carboxylate (115 mg, 69%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.68 (dd, J=10.2, 2.4 Hz, 1H), 7.34 (dd, J=7.5, 2.4 Hz, 1H), 4.02 (s, 3H), 2.39-2.29 (m, 1H), 1.35-1.29 (m, 2H), 1.26-1.17 (m, 2H); 19F NMR (282 MHz, CDCl3) δ −116.29; MS (ESI+) m/z 236 (M+H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:28]1([CH3:27])[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:36]
Reactant: Cc1ccccc1N=C=O
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
In a 25 mL flask, to a solution of 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (0.160 g, 0.442 mmol) in dichloromethane (2 mL) was added 2-methyl phenylisocyanate (0.06 g, 0.497 mmol) in dichloromethane (5 mL) followed by triethylamine (0.044 g, 0.414 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and adsorbed onto Celite®. Purification by flash column chromatography (reverse phase) 5% acetonitrile/water provided the title compound as a white solid (0.11 g, 53%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[S:20])[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1)([OH:3])=[O:2].[H-].[Na+].[H][H].Cl.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][Cl:30]>CN(C)C=O>[ClH:30].[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([S:20][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: O=C(O)c1ccc(-c2cc3ccccc3[nH]c2=S)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCSc1nc2ccccc2cc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(p-Carboxyphenyl)quinolin-2-thione (6.87 g.) was added to a suspension of sodium hydride (3.9 g. of a 50% w/w dispersion in mineral oil) in dimethylformamide (50 ml.) at 0°-5°. When all the hydrogen had evolved, 2-dimethylaminoethyl chloride hydrochloride (3.5 g.) was added and the mixture was stirred at ambient temperature for 16 hr. The mixture was poured into ice-water (300 ml.), filtered, and the filtrate adjusted to pH 7 with 2 M-hydrochloric acid. The resulting mixture was filtered and the solid residue was dissolved in 2 M-hydrogen chloride in methanol at 0°. The solvent was evaporated and the solid residue was crystallised from methanol-ethyl acetate to give 3-(p-carboxyphenyl)-2-(2-dimethylaminoethylthio)quinoline hydrochloride, m.p. 246°-7°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[CH:16]1([C:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[O:20])[CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2CC2)cc1
Yield: 85 %

Procedure:
6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone, 3.4 g (32.5 millimoles) of cyclopropanecarboxylic acid chloride and 100 ml of absolute toluene are kept for 6 hours at 80° C. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized from dimethylformamide/water. 6.8 g (85% of theory) of 6-(p-cyclopropylcarbonylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are obtained as beige crystals, of melting point 267°-268° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])C=O)([CH3:4])([CH3:3])[CH3:2].[O:18]=[C:19]1[NH:23][N:22]=[C:21]([CH2:24][C:25](O)=O)[NH:20]1.N1CCCCC1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:2][C:1]([C:5]1[CH:6]=[C:7]([CH:25]=[CH:24][C:21]2[NH:20][C:19](=[O:18])[NH:23][N:22]=2)[CH:10]=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:12]=1[OH:13])([CH3:4])[CH3:3]
Reactant: O=C(O)Cc1n[nH]c(=O)[nH]1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C=Cc2n[nH]c(=O)[nH]2)cc(C(C)(C)C)c1O
Yield: 40 %

Procedure:
A solution of 3,5-di-t-butyl-4-hydroxybenzaldehyde (3.5 g, 15 mmol), 2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) acetic acid (N. W. Jacobsen, B. L. McCarthy, and S. Smith, Aust. J. Chem., 32 161-5 (1979] (2.15 g, 15 mmol), and piperidine (1.3 g, 15 mmol) in pyridine (15 ml) and toluene (45 ml) is heated at reflux (with removal of water) for 40 hours. The reaction mixture is cooled, filtered, and evaporated. The residue is partitioned between ethyl acetate (100 ml) and 1N HCl (400 ml). The organic layer is washed two additional times with 1N HCl (400 ml) and then is dried (MgSO4) and evaporated. The residue crystallized upon addition of hot dichloromethane. Recrystallization from isopropyl ether/ethyl acetate gives 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (2.49 g, 40%), mp 280°-284° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[CH3:15][S:16][CH3:17].[Cl:18]N1C(=O)CCC1=O>ClCCl.C(#N)C>[ClH:18].[CH3:14][O:13][C:5]1[N:4]2[N:3]=[C:2]([N:1]=[S:16]([CH3:17])[CH3:15])[N:10]=[C:9]2[C:8]([O:11][CH3:12])=[CH:7][N:6]=1
Reactant: COc1cnc(OC)n2nc(N)nc12
Reactant: CSC
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CC#N
Product: COc1cnc(OC)n2nc(N=S(C)C)nc12
Product: Cl
Temperature: -25 °C
Yield: 91 %

Procedure:
2-Amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (5.6 g, 0.029 mol) was slurried in dichloromethane (100 mL) and methyl sulfide (1.9 g, 0.031 mol) was added. The mixture was cooled to −25° C., and a solution of N-chlorosuccinimide (4.2 g, 0.031 mol) in acetonitrile (40 mL) was added to the reaction slurry over one hour, keeping the internal temperature at −22 to −28° C. When the addition was complete, the reaction was allowed to warm to room temperature over several hours. The new slurry was filtered and the solids washed with acetonitrile (2×40 mL). The solids were dried in a vacuum oven to provide 7.7 g of N-(5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-S,S-dimethylsulfilimine hydrochloride as a light tan solid, m.p. 170-174° C. The material was 95 area % pure by HPLC, with the remainder being the amine starting material.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24]([O:26]CC)=O)=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:29]1([CH2:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30]1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24]([N:40]3[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][CH2:34][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[CH2:42][CH2:41]3)=[O:26])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1nnc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: C1CCN(CCCN2CCNCC2)C1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nnc(C(=O)N3CCN(CCCN4CCCC4)CC3)o2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.07 mmol), 1-[3-(pyrrolidin-1-yl)propyl]piperazine (31 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). A portion of the crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[O:29][CH:28]=[N:27][CH:26]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>C(Cl)Cl>[NH:20]1[CH:24]=[C:23]([C:25]2[O:29][CH:28]=[N:27][CH:26]=2)[N:22]=[CH:21]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(-c3cnco3)c2)cc1
Solvent: ClCCl
Solvent: O=CO
Product: c1nc(-c2cnco2)c[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A solution of 5-(1-trityl-1H-imidazol-4-yl)oxazole (14.5 g, 38.4 mmol) was treated with a 90% aq. solution of formic acid (90 mL) and the mixture was stirred at RT for 18 h. The mixture was then diluted with DCM, and washed with H2O and sat. aq. solution of NaHCO3. The combined aqueous layers were washed with DCM and then concentrated in vacuo. The residue obtained was placed in a Soxlet apparatus and continuously extracted with DCM for 12 h. The organic phase was then concentrated and the crude product was crystallized in DCM to give the title compound (2.68 g). UPLC-MS: MS 136.1 (M+H+); UPLC rt 0.25 min.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[C:6]([F:10])[C:5]([F:11])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.P(Br)(Br)[Br:26]>C(Cl)Cl>[Br:26][CH2:8][C:7]1[C:2]([F:1])=[C:3]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:4]=[C:5]([F:11])[C:6]=1[F:10]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(F)c(CO)c2F)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(F)c(CBr)c2F)CC1

Procedure:
tert-butyl 4-(2,4,5-trifluoro-3-(hydroxymethyl)phenyl)piperazine-1-carboxylate (180 mg, 0.52 mmol) was reacted under the standard conditions with PBr3 in DCM (see Example 189, Step ii) to give tert-butyl 4-(3-(bromomethyl)-2,4,5-trifluorophenyl)piperazine-1-carboxylate (57 mg).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[NH2:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:24][NH:23][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccnc1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NNc1cccnc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 3-hydrazinopyridine dihydrochloride 237 (0.120 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 238 (0.20 g, 60%) as a white foam.
Reaction SMILES: N1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.O1CCC[CH2:11]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH2:28][C:29]1[NH:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1>O.C(N(CC)CC)C>[N:4]1[CH:5]=[CH:6][CH:11]=[C:2]([C:7]([NH:28][C:29]2[NH:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[O:9])[CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: O=C(Nc1nc2ccccc2[nH]1)c1cccnc1
Reaction time: 5 h

Procedure:
3.7 G. of 2-pyrazinecarboxylic acid is suspended in 20 ml. of dry tetrahydrofuran and 6.3 g. of trifluoroacetic anhydride is added thereto. To the resulting solution, at 20°-25°C., there is added 8.5 ml. of triethylamine and 4 g. of 2-aminobenzimidazole (II) and the thus-obtained reaction mixture is stirred at 20°-25°C. for about 5 hours. 200 Ml. of water is then added, followed by filtration and the residue is recrystallized from aqueous acetic acid to yield 2-(2-pyrazinylcarbonylamino)-benzimidazole [(III), R = 2-pyrazinyl].
Reaction SMILES: ClC1C=CC=CC=1[N+:8](=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[O-:9].[OH-:18].[Na+].O.NN>CO.[Ni].O>[Cl:17][C:12]1[CH:13]=[C:14]([C:14]2[CH:15]=[CH:16][C:11]([NH2:10])=[C:12]([Cl:17])[CH:13]=2)[CH:15]=[CH:16][C:11]=1[NH2:10].[N:8]([OH:9])=[O:18]
Reactant: [O-][N+](=Nc1ccccc1Cl)c1ccccc1Cl
Reactant: [OH-]
Agent: [Ni]
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2ccc(N)c(Cl)c2)cc1Cl
Product: O=NO
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
53.4 g of 2,2'-dichloroazoxybenzene are stirred in 60 ml of methanol. 0.6 g of sodium hydroxide and 11.8 ml of hydrazine hydrate are added and the mixture is warmed to 65° C. After Raney nickel has been added (a total of about 0.05 g in 2-3 portions) vigorous evolution of nitrogen starts. The reduction has ended after 30 minutes. The mixture is cooled to 10° C. and diluted with water and the 2,2'-dichlorohydrazobenzene which has crystallised out is filtered off and washed with water until neutral. After the rearrangement to 3,3'-dichlorobenzidine and tetrazotisation with nitrous acid, a yield of 86% of theory is obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:27])[CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:15]=2)C(O)=O)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:47]([CH2:50]C)CC)C.[OH2:52]>O1CCCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:27][C:50](=[O:52])[NH:47][CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:25])([F:26])[CH:22]([F:23])[F:24])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O
Reactant: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2ccc(F)nc2)O1
Yield: 93 %

Procedure:
To a solution of (2RS,3RS)-3-(6-fluoropyridin-3-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionic acid (3.6 g, 9.20 mmol, (2RS,3SR) form: (2RS,3RS) form=10:1) in tetrahydrofuran (90 ml) were added diphenylphosphoryl azide (2.18 ml, 10.1 mmol) and triethylamine (1.93 ml, 13.8 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was allowed to cool and water (200 ml) was added. The mixture was extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give (4RS,5SR)-5-(6-fluoropyridin-3-yl)-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one (3.31 g, (4RS,5SR) form: (4RS,5RS) form=10:1, 93%) as an amorphous compound.