Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C1C=CC=CN=1)C.[OH:10][CH:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:12]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].[C:33](OC(=O)C)(=[O:35])[CH3:34].Cl>N1C=CC=CC=1>[C:33]([O:10][CH:11]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:12]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])(=[O:35])[CH3:34]
Reactant: CC(C)OC(=O)CCC(C(=O)OC(C)C)C(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccccc1)C(CCC(=O)OC(C)C)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
70 mg of dimethylaminopyridine was added to a mixed solution comprising 6.13 g of diisopropyl 4-hydroxy-4-phenyl-1,3-butanedicarboxylate, 30 ml of pyridine and 6 ml of acetic anhydride, followed by stirring at room temperature for 1.5 hours. 2N hydrochloric acid was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with 2N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 4.68 g of the above-identified compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[N:14][CH:15](Cl)[C:16]([Cl:19])([Cl:18])[Cl:17])[C:12](=[O:21])[N:11]([CH3:22])[C:10]2=[O:23])[CH:6]=[CH:7][CH:8]=1.[F:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29].C(N(CC)CC)C.C(Cl)Cl>C(#N)C>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[N:14][CH:15]([NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[F:26])[C:16]([Cl:19])([Cl:18])[Cl:17])[C:12](=[O:21])[N:11]([CH3:22])[C:10]2=[O:23])[CH:6]=[CH:7][CH:8]=1
Reactant: CN1C(=O)C(=NC(Cl)C(Cl)(Cl)Cl)N(c2cccc(C(F)(F)F)c2)C1=O
Reactant: Nc1ccccc1F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1C(=O)C(=NC(Nc2ccccc2F)C(Cl)(Cl)Cl)N(c2cccc(C(F)(F)F)c2)C1=O
Reaction time: 0.08 h

Procedure:
In this Example 1-(3-trifluoromethylphenyl)-3-methyl-5-(1,2,2,2-tetrachloroethyl)imino-1,3-diazolidine-2,4-dione; (0.05 mol) is dissolved in 20 ml of acetonitrile. One equivalent of 2-fluoroaniline (0.05 mol) is added with stirring over a five minute period. Temperature is maintained at 25°-35° C. Triethylamine (0.05 mol) is then added with stirring over a 10-minute period. The temperature is maintained at 25°-35° C. for one hour. Methylene chloride (50 ml) is added and the solution is washed 3 times with 50 ml of water, dried over magnesium sulfate and filtered. The solvent is removed under high vacuum affording 1-(3-trifluoromethylphenyl)-3-methyl-5-(1-2'-fluorophenylamino-2,2,2-trichloroethyl)imino-1,3-diazolidine-2,4-dione.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:22][C:23]([F:51])([C:47]([F:50])([F:49])[F:48])[C:24]([F:46])([F:45])[C:25]([F:44])([F:43])[O:26][C:27]([F:42])([F:41])[C:28]([F:40])([F:39])[O:29][C:30]([F:38])([F:37])[CH2:31][O:32][CH2:33][CH2:34][CH2:35]Br>O>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]([O:29][C:28]([F:39])([F:40])[C:27]([F:41])([F:42])[O:26][C:25]([F:43])([F:44])[C:24]([F:45])([F:46])[C:23]([F:22])([F:51])[C:47]([F:50])([F:49])[F:48])([F:38])[F:37])=[CH:19][CH:20]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: FC(F)(COCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: O
Product: CCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as described in Example 1 by combining 5-heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 10.0 mmol) and 3-(2-(2-(nonafluorobutoxy) tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromopropane (6.6 g, 12.0 mmol, Example 10). The product was isolated by addition of water (60 mL) to the resulting mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by Kugelrohr distillation (b.p. 180°-190° C. at 2 torr; yield 5.6 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[ClH:13].[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[NH2:25])=[CH:17][CH:16]=1>ClCCl>[ClH:13].[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[NH:25][C:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH3:12])=[NH:11])=[CH:17][CH:16]=1
Reactant: Nc1cccc2ccc(F)cc12
Reactant: CCc1cccc(N(C)C#N)c1
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(N(C)C(=N)Nc2cccc3ccc(F)cc23)c1
Temperature: 160 °C
Yield: 53.1 %

Procedure:
A mixture of N-(m-ethylphenyl)-N-methylcyanamide (195 mg, 1.21 mmol) and 7-fluoro-1-aminonaphthalene hydrochloride (200 mg, 1.01 mmol) was heated in a preheated oil bath at 160° C. for 2.5 hours and then allowed to cool to room temperature. The resulting solid was taken up in dichloromethane and washed with 5% NAOH solution. The organic layer was concentrated and the resulting residue was treated at room temperature with 0.5M methanol-HCl solution (10 ml). It was concentrated and the resulting purple glass was purified by flash chromatography on silica gel to give N-(7-fluoro-1-naphthyl)-N'-(m-ethylphenyl)-N'-methylguanidine hydrochloride (192 mg, 53%) as off-white crystals. M.p.: 187°-90° C. IR (CHCl3): 1630, 3400 cm-1. 1H NMR (CD3Cl3): δ 1.259 (t, 3H, J=7.9 Hz), 2.431 (q, 2H, J=7.9 Hz), 3.564 (s, 3H), 6.76-7.94 (m, 10H). Anal. Calcd for C20H21N3FCl: C, 67.12; H, 5.92; N, 11.74. Found: C, 67.28; H, 6.00; N, 11.87.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:24])[CH:3]=1.FC(F)(F)C(O)=O.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([SiH](CC)CC)C>C(Cl)(Cl)Cl>[CH2:17]([NH:16][C:14]([C:10]1[S:9][C:8]([N:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:3][C:4]2=[O:24])=[N:12][C:11]=1[CH3:13])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nc(-n2ccc(N)cc2=O)sc1C(=O)NCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-n2ccc(NCc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.2 %

Procedure:
To a solution of 2-(4-amino-2-oxopyridin-1(2H)-yl)-N-benzyl-4-methylthiazole-5-carboxamide (0.30 g, 0.88 mmol) and trifluoroacetic acid (15 mL) in chloroform (20 mL) was added benzaldehyde (0.10 mL, 0.98 mmol). The reaction mixture was stirred for 15 minutes at ambient temperature, then triethylsilane (0.15 mL, 1.00 mmol) was added. The reaction mixture was kept stirring for 2 hours at ambient temperature, then another portion of benzaldehyde (0.10 mL, 0.98 mmol) and triethylsilane (0.15 mL, 1.00 mmol) was added. The reaction mixture was kept stirring for another 2 hours at ambient temperature. The solvent was removed in vacuo, and the residue was washed with saturated aqueous sodium bicarbonate solution, water and t-butylmethyl ether to afford the title compound (0.30 g, 79%): mp 253-255° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.68 (t, J=5.7 Hz, 1H), 8.39 (d, J=7.8 Hz, 1H), 7.87 (s, 1H), 7.44-7.21 (m, 10H), 6.21 (d, J=7.8 Hz, 1H), 5.31 (s, 1H), 4.36 (d, J=5.7 Hz, 2H), 4.31 (d, J=4.5 Hz, 2H), 2.50 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.1, 160.9, 155.9, 154.5, 150.2, 140.0, 138.3, 130.6, 128.9, 128.7, 127.7, 127.6, 127.1, 122.8, 103.6, 88.6, 46.0, 43.0, 17.5; MS (ES+) m/z 431.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>C(O)C.[Pd]>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(F)cc1C(=O)O
Reaction time: 16 h
Yield: 0.8 %

Procedure:
To a pressure flask capable of withstanding, 150 psi. was added 5-fluor-2-nitrobenzoic acid (2.0 g, 0.01 1 mol) dissolved in ethanol (40 mL) and 10% palladium on carbon (200 mg). The reaction was placed in a Parr apparatus and the flask flushed three times with hydrogen leaving an internal pressure of 65 psi. The reaction was continued for 16 hours while maintaining a pressure of 65 psi. The reaction was filtered through celite, washed with ethanol and the filtrate evaporated to dryness to give 2-amino-5-fluorobenzoic acid (1.22 g, 73%) as an off-white solid.: m.p. 183°-184°; 1H NMR (400 MHz, DMSO-d6) δ 6.75 (dd, 1H), 7.16 (dt, 1H), 7.36 (dd, 1H); 13C NMR (100 MHz, DMSO-d6) δ 109.3, 109.4, 115.4, 115.6, 117.8, 117.9, 121.5, 121.9, 148.3, 150.8, 153.8, 168.6, 168.7.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)C(C)C)(C)C.[C:19](Cl)([Cl:21])=[O:20].C1(C)C=CC=CC=1>C(OCC)C>[Cl:21][C:19]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:20]
Reactant: OCc1ccccc1Cl
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)OCc1ccccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2-chlorobenzyl alcohol (1.0 g, 7.0 mmol) in diethyl ether (15 ml) at 0° C. was added N,N-diisopropylethyl amine (2.4 ml, 14.0 mmol), and phosgene solution in toluene (7.5 ml, 14.0 mmol). The mixture was allowed to warm up to room temperature in 2 h while stirring, then it was filtered. The diethyl ether was removed by rotary evaporator, and the solution of 2-chlorobenzyl chloroformate in toluene was carried on for the next step reaction.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH:40]([CH3:42])[CH3:41].ClCCl>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:30][CH2:31]6)=[O:28])[CH2:23]5)=[N:19][N:18]([CH:40]([CH3:42])[CH3:41])[C:17]4=[O:32])=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)n1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (60 mg, 0.434 mmol, 3.1 eq) and 2-iodopropane (34 mg, 0.200 mmol, 1.4 eq). The vial was capped and purged with nitrogen gas, and the reaction was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had progressed only 15%. To the reaction mixture was added another equivalent of 2-iodopropane and the solution was irradiated in the microwave at 160° C. for 30 min. Analysis by LC/MS displayed the reaction had progressed to 35% completion. The reaction mixture was subjected to several iterations of microwave conditions, increasing the reaction temperature and reaction time, until the final conditions of 180° C. for 3 h was reached. It was determined via analysis by LC/MS that the reaction had proceeded to 90% completion. The reaction mixture was poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-65% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (18 mg, 27%). MS(ES)+ m/e 471.3 [M+H]+.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:60][OH:61])[C:27]([NH:29][CH:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:63][C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65]>[Ag]=O.CN(C)C=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:60][O:61][CH2:63][C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C:27]([NH:29][CH:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reaction time: 0.08 h

Procedure:
A mixture of 0.85 g of the product of Step D, 0.8 ml of tert.-butyl bromoacetate and 4 ml of dimethylformamide stood in an ice bath for 5 minutes and then 1.7 g of silver oxide were added thereto. The mixture was stirred for one hour after removal of the bath and the mixture was vacuum filtered. The filter was rinsed with ethyl acetate and 80 ml of water were added to the filtrate which was decanted. The aqueous phase was extracted twice with 20 ml of ethyl acetate and the combined organic phases were washed twice with 50 ml of aqueous sodium chloride solution, dried, treated with 80 mg of activated carbon and vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in isopropyl ether and after efflorescence, the mixture was vacuum filtered. The product was rinsed with isopropyl ether and dried to obtain 0.724 g of the syn isomer of diphenylmethyl 7-[2-(2-tritylamino-4-thiazolyl)-2-(tert.-butoxycarbonylmethyloxyimino)-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylate with Rf=0.34 (methylene chloride containing 5% of ether).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH2:23][OH:24])[CH2:12][CH2:13][N:14]1[CH2:21][CH2:20][C:17]2([CH2:19][CH2:18]2)[C@H:16]([OH:22])[CH2:15]1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][C@H:11]([CH2:23][OH:24])[CH2:12][CH2:13][N:14]1[CH2:21][CH2:20][C:17]2([CH2:19][CH2:18]2)[C@H:16]([OH:22])[CH2:15]1
Reactant: O=C(N[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Yield: 100.3 %

Procedure:
A solution of [(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-carbamic acid benzyl ester (350 mg, 1.00 mmol) in MeOH (5 mL) was stirred for 1½ h at room temperature under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on activated charcoal, 35 mg), then insoluble material was removed by filtration through diatomaceous earth. The filtrate was evaporated to afford the title compound (215 mg, 100%) Colourless gum, MS (ISP)=215.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([CH3:17])[CH:16]=[C:4]2[N:3]=1.O.[NH2:19][NH2:20]>O1CCOCC1.O>[CH3:17][C:15]1[CH:16]=[C:4]2[N:3]=[C:2]([NH:19][NH2:20])[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]2[N:14]=1
Reactant: NN
Reactant: Cc1cc2nc(Cl)cc(N3CCOCC3)n2n1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2nc(NN)cc(N3CCOCC3)n2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
There was dissolved, in 1,4-dioxane (3 mL), 5-chloro-2-methyl-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (179 mg, 0.708 mM), then hydrazine monohydrate (343 μL, 7.08 mM) was added to the solution, and the mixture was stirred at 90° C. overnight. This reaction liquid was then diluted with water and the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (88.7 mg, yield: 51%).
Reaction SMILES: [C:1]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)N=CC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]1[CH:32]([C:33]([OH:35])=[O:34])[CH2:31][CH2:30][C:28](=O)[CH2:27]1.Cl>C(O)(=O)C>[C:1]([N:9]1[C:28]2[CH2:27][CH2:26][CH:32]([C:33]([OH:35])=[O:34])[CH2:31][C:30]=2[C:19]2[C:18]1=[CH:23][CH:22]=[C:21]([O:24][CH3:25])[CH:20]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(C(=O)O)CC1
Reactant: COc1ccc(N(N=Cc2ccccc2)C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c1c(n2C(=O)c2ccccc2)CCC(C(=O)O)C1
Temperature: 0 °C

Procedure:
A solution of 75 g. of benzaldehyde 1-benzoyl-1-(4-methoxyphenyl)hydrazone and 42.6 g. of cyclohexanone-4-carboxylic acid in one liter of acetic acid saturated with hydrogen chloride was heated under reflux for three hours during which time hydrogen chloride was continually passed through the solution. The solution was poured into four liters of ice-water and the resulting solid was collected by filtration to give 47.4 g. of the title compound; m.p. 218°-220°C. (methyl alcohol).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[CH:13][C:8]=2[O:7][CH2:6]1>CC(O)=O>[N+:1]([C:11]1[C:12]([NH:14][C:15](=[O:17])[CH3:16])=[CH:13][C:8]2[O:7][CH2:6][O:5][C:9]=2[CH:10]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)OCO2
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 20 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
A solution of 70% HNO3 (15.5 mL, 244 mmol) in HOAc (40 mL) was added dropwise to a stirred solution of acetamide 218 (29.17 g, 163 mmol) in HOAc (150 mL) at 15-20° C. and the mixture stirred at 20° C. for 16 h. The precipitate was filtered, washed with water and dried to give nitroacetamide 219 (36.0 g, 99%) as a yellow powder: mp 207-208° C. (Krasso, A. & Ramuz, H., U.S. Pat. No. 4,599,347, 1986) mp 212-213° C.]; 1H NMR δ 10.78 (br s, 1H, NH), 8.36 (s, 1H, H-7), 7.66 (s, 1H, H-4), 6.10 (s, 2H, H-2), 2.27 (s, 3H, CH3).
Reaction SMILES: [O:1]1[C@:5]([CH3:22])([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:21])[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:2]1[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[O:1]1[C@:5]([CH3:22])([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:21])[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[C@@H:2]1[CH:3]=[O:4]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@]1(C)O[C@@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@]1(C)O[C@H]1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
1.70 g (5.45 mmol) of (2R,3R,7R,11R)-2,3-epoxy-3,7,11,15-tetramethylhexadecanol in 5 ml of methylene chloride was added dropwise while stirring at room temperature to a suspension of 1.6 g (5.45 mmol) of pyridinium chlorochromate in 50 ml of methylene chloride and the mixture was stirred at room temperature overnight. Celite was then added and the mixture was stirred with 100 ml of ether for 1 hour, subsequently filtered and rinsed with ether. The crude product was chromatographed on silica gel with toluene. There was obtained 1.46 g (87%) of (2R,3R,7R,11R)-2,3-epoxy-3,7,11,15-tetramethylhexadecanal, [α]D20 =-5.87° (c=1.5% in chloroform).
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:11]=1[O:24][CH3:25])(C)[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>C(O)C.O>[CH3:25][O:24][C:11]1[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[CH:13][CH:14]=[CH:15][C:10]=1[CH:3]([CH3:1])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(C#N)c1cccc(Oc2ccccc2F)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(Oc2ccccc2F)cccc1C(C)C(=O)O
Yield: 73.4 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(2-fluorophenoxy)phenyl]propionate (6.2 g) and potassium hydroxide (2.1 g) in a mixture of ethanol (60 ml) and water (30 ml) was refluxed under heating for 72 hours, and the reaction mixture was evaporated. Water was added to the residue, washed with diethyl ether, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and then evaporated to give oily 2-[2-methoxy-3-(2-fluorophenoxy)phenyl]propionic acid (3.85 g).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([S:27]([CH:30]=[CH2:31])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41]>>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([O:20][CH:21]3[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH2:31][N:46]4[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:44][CH2:45]4)(=[O:29])=[O:28])[CH2:25][CH2:26]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: C=CS(=O)(=O)N1CCC(Oc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(OC2CCN(S(=O)(=O)CCN3CCN(S(C)(=O)=O)CC3)CC2)nc(N2CCOCC2)n1
Yield: 28 %

Procedure:
Reaction of 2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{[1-(vinylsulfonyl)-4-piperidinyl]oxy}-1,3,5-triazin-2-yl)-1H-benzimidazole with 1-(methylsulfonyl)piperazine as in Example 12 gave 2-(difluoromethyl)-4-methoxy-1-[4-{[1-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole in 28% yield: mp (MeOH) 251-254° C.; 1H NMR (DMSO-d6) δ7.96 (d, J=8.3 Hz, 1H), 7.71 (t, JHF=52.8 Hz, 1H), 7.45 (t, J=8.3 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H), 5.28-5.22 (m, 1H), 3.98 (s, 3H), 3.85-3.84 (m, 4H), 3.74-3.70 (m, 4H), 3.52-3.46 (m, 2H), 3.34-3.20 (m, 4H), 3.13-3.11 (m, 4H), 2.86 (s, 3H), 2.78-2.74 (m, 2H), 2.56-2.54 (m, 4H), 2.13-2.08 (m, 2H), 1.88-1.80 (m, 2H); Anal. Calcd. for C28H39F2N9O7S2: C, 47.0; H, 5.5; N, 17.6. Found: C, 47.2; H, 5.4; N, 17.4%.