Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:20](=[O:37])[N:19]([CH2:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[N:18]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:3][C:4](=[O:7])[O:5][N:36]=3)=[CH:27][CH:28]=2)[C:20](=[O:37])[N:19]([CH2:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nn(CC2CCCCO2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nn(CC2CCCCO2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.76 g), sodium hydrogen carbonate (1.08 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[3-butyl-5-oxo-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile (0.55 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.31 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.33 g, 53%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.O>C(OCC)C>[O:4]=[C:1]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: C1CCNC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)N1CCCC1
Temperature: -50 °C
Reaction time: 12 h

Procedure:
Acryloyl chloride (9 g, 0.1 mole) was added by syringe to ethyl ether (40 ml) and the solution cooled to -50° C. A solution of pyrrolidine (7.1 g, 0.1 mole) in ethyl ether (20 ml) was added dropwise. A solution of triethylamine (15.3 ml) was added slowly over 10 minutes. The reaction was slowly allowed to warm to room temperature and stirred for 12 hours. Water (50 ml ) was added, the layers were separated and the aqueous layer extracted with ethyl ether (100 ml) and methylene chloride (2×75 ml), and combined with the organic layer above, dried over sodium sulfate, filtered, and the solvents removed to give an oil. The product was purified by chromatography on silica. The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(O[CH2:17][C:18]1[CH:23]([C:24]([OH:26])=[O:25])[N:22]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:21]2[S:20][CH:19]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]([C:24]([OH:26])=[O:25])[N:22]3[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@H:21]3[S:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1cccc2ccccc12
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(CC2=CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)c2ccccc12
Reaction time: 0.25 h

Procedure:
A solution of 0.8 g of freshly distilled 1-methoxynaphthalene in 2.2 ml of trifluoroacetic acid is mixed with 0.4 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the resulting solution is left to stand for 15 minutes at room temperature. It is then diluted with an equal amount of toluene and evaporated to dryness under reduced pressure. The residue is taken up in 50 ml of acetic acid ethyl ester and 30 ml of a 10% strength aqueous dipotassium hydrogen phosphate solution. The whole is thoroughly shaken, the organic layer is separated off and the aqueous phase is extracted with two 50 ml portions of acetic acid ethyl ester. The aqueous phase is covered with 50 ml of acetic acid ethyl ester and the pH value is adjusted to 2 by adding 2% strength aqueous phosphoric acid. After vigorous shaking, the organic solution is separated off, and the aqueous phase is twice extracted with 50 ml portions of acetic acid ethyl ester. The combined organic extracts are washed three times with 50 ml portions of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. 3-(4-Methoxy-1-naphthylmethyl)-7-(N-phenylacetylamino)-ceph-2-em-4ξ-carboxylic acid is obtained as an oily residue, which on trituration with acetic acid ethyl ester crystallises and after recrystallisation from methanol melts at 196°C; thin layer chromatogram (silica gel): Rf = 0.71 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.76 (system n-butanol/acetic acid/water, 67:10:23) and Rf = 0.52 (system n-butanol/ethanol/water, 40:10:50); ultraviolet absorption spectrum (in methanol): λmax = 225 mμ (ε = 17,600) and 298 mμ (ε = 8300) and shoulder at 308 mμ (ε = 6400) and 322 mμ (ε = 3950); infrared absorption spectrum (in mineral oil): characteristic bands at 3.02μ, 5.69μ, 5.77μ, 6.06μ and 6.59μ.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CS(=O)(=O)CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCCS(C)(=O)=O)cc1)n2C)c1ccccc1
Yield: 66 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 2-(methylsulphonyl)-ethyl chloroformate. Yield: 66% of theory, C32H36N6O7S (648.8) Rf value: 0.44 (silica gel; dichloromethane/ethanol=19:1) ##EQU65##
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[NH:9]1[C:13]2[CH:14]=CC=C[C:12]=2[N:11]=[CH:10]1.[N:18]1[C:31]2[C:22](=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)C=C[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl.[Cu]I.CO>[N:9]1([C:13]2[CH:14]=[CH:26][CH:27]=[C:28]([N:29]3[C:30]4[CH:25]=[CH:24][CH:23]=[CH:22][C:31]=4[N:18]=[CH:19]3)[CH:12]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:11]=[CH:10]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Ic1cccc(I)c1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1cc(-n2cnc3ccccc32)cc(-n2cnc3ccccc32)c1
Yield: 127.5 %

Procedure:
In a 1 L round-bottomed flask 1,3-diiodobenzene (26.43 g, 80 mmol), 1H-benzo[d]imidazole (20.82 g, 176 mmol), and 1,10-phenanthroline (5.77 g, 32.0 mmol), CuI (3.05 g, 16 mmol), and cesium carbonate (120 g, 369 mmol) were combined in anhydrous DMF (350 mL) to give a brown suspension. The reaction was purged with N2 for 20 minutes and then heated to reflux for 24 hours. The reaction mixture was passed thought a plug of silica gel (5% MeOH in DCM) to obtain the crude product. The crude product was subjected to silica gel chromatography (SiO2, 400 g, 2% MeOH to 5% MeOH in DCM) to ultimately obtain the final product (12.66 g, 51%).
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:19][C:20]1[N:21]=[C:22]([NH2:31])[S:23][C:24]=1[CH2:25][CH2:26][O:27][N+:28]([O-:30])=[O:29]>>[CH3:19][C:20]1[N:21]=[C:22]([NH:31][C:1](=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[S:23][C:24]=1[CH2:25][CH2:26][O:27][N+:28]([O-:30])=[O:29]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Product: CCCCCCCCCCCCCCCC(=O)Nc1nc(C)c(CCO[N+](=O)[O-])s1
Yield: 62 %

Procedure:
Pet-158 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using hexadecanoic acid (palmitic acid) and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 62%.
Reaction SMILES: [CH:1]([CH:11]1[CH2:16][C:15](=[O:17])[O:14][C:12]1=O)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CC.[NH2:18][CH2:19][CH2:20][O:21]CCO>>[CH2:1]([CH:11]1[CH2:16][C:15](=[O:17])[N:18]([CH2:19][CH2:20][OH:21])[C:12]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC=CC1CC(=O)OC1=O
Reactant: NCCOCCO
Product: CCCCCCCCC1CC(=O)N(CCO)C1=O

Procedure:
Preparation of n-C10 (N-CH2CH2OCH2CH2OH)--In a similar preparation, n-decenyl succinic anhydride (10.5 g; 0.1 mole) is reacted with 2-(2-aminoethoxy) ethanol (23.8 g; 0.1 mole) to provide the title compound. GC analysis indicates the reaction to be about 85% complete after 120 minutes in a 150° C. heating bath.
Reaction SMILES: Br.[CH3:2][C:3]1[NH:4][CH:5]=[C:6]([C:8](=O)[CH2:9][Br:10])[N:7]=1.C(=O)(O)[O-].[Na+].CC(C)=O.[C:21]([NH:24][C:25]([NH2:27])=[S:26])(=[NH:23])[NH2:22]>O>[BrH:10].[NH:24]([C:25]1[S:26][CH:9]=[C:8]([C:6]2[N:7]=[C:3]([CH3:2])[NH:4][CH:5]=2)[N:27]=1)[C:21]([NH2:23])=[NH:22]
Reactant: N=C(N)NC(N)=S
Reactant: Cc1nc(C(=O)CBr)c[nH]1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc(-c2csc(NC(=N)N)n2)c[nH]1
Yield: 79.3 %

Procedure:
2.8 g (9.86 mmol) of 1-(2-methyl-4-imidazolyl)-2-bromo ethanone hydrobromide was dissolved in 10 ml water. Saturated sodium bicarbonate solution was added to pH 10 and the resultant solid was collected by filtration and washed with 15 ml water. The dried free base was heated at reflux in 50 ml acetone. To the refluxing clear acetone solution was added 1.2 g (9.86 mmol) of amidinothiourea. Solution occurred immediately and within a minute a solid began to form. After 1 hour reflux the slurry was cooled and the solid was collected by filtration and was washed with acetone followed by ether to give 2.37 g (79%) of 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole hydrobromide, mp 158° (dec.); nmr (DMSO-d6) (δ): 7.71 (s shoulder on broad s, 1H); 7.56 (broad s, 4H); 4.32 (s, 1H); 2.51 (s, 3H); calcd. for C8H10N6S.HBr: C, 31.69; H, 3.66; N, 27.72; found: C, 31.46; H, 4.30; N, 27.28.
Reaction SMILES: [Na].CCOCC.C[C:8]([CH3:18])([CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[C:9]#N.[Cl-].[NH4+]>C(O)C.O1CCCC1>[CH3:18][C:8]1([CH3:9])[CH2:11][CH2:12][C:13]([CH3:16])([CH3:17])[CH:14]1[NH2:15]
Reactant: CC(C)(C#N)CCC(C)(C)C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A flask was charged with 35 g. (0.61 mole) of 40% sodium dispersion in mineral oil. The oil was removed by washing with ethyl ether and decantation. The sodium was then mixed with 400 ml. of ether and a mixture of 32.8 g (0.20 mole) 2,2,5,5-tetramethyladiponitrile, prepared by the method of Coffman et al., J. Am. Chem. Soc., 80, 2868 (1957), and 400 ml. of tetrahydrofuran was added slowly. The resulting mixture was stirred at room temperature for 4 hours, the excess sodium decomposed by dropwise addition of saturated aqueous ammonium chloride, the organic layer washed with water, dried (Na2SO4) and evaporated to afford 25.1 g. of crude 2,2,5,5-tetramethylcyclopentylimine. The imine was dissolved in 75 ml. of ethanol and added dropwise to a flask containing 23.3 g. (1 mole) sodium shot. An additional 75 ml. ethanol was added and the mixture heated at reflux until the remaining sodium metal was consumed. The reaction mixture was diluted with water, acidified to pH 1 with concentrated hydrochloric acid, the aqueous phase washed with ether then made strongly basic by addition of sodium hydroxide. The organic layer was extracted with ether, washed with brine, dried (Na2SO4) and evaporated to dryness. The residue was distilled in vacuo to afford 6.6 g. (23%) of the desired amine, B.P. 60°-61° C. (20 mm.).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Br:18]Br.N(OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:18][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N
Reactant: BrBr
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
To a solution of 20.0 g of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester and 10 ml of bromine in 200 ml of chloroform was added 15.8 g of isoamyl nitrite dropwise. The reaction mixture was allowed to stir at room temperature for about 24 hours and the volatiles were removed under reduced pressure. The residue was recrystallized from ethanol/water to provide 10.0 g of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 38%. mp=86°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:14]([O:16][CH3:17])=[O:15])([CH3:13])[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([N:10]2[CH2:11][C:12]([C:14]([O:16][CH3:17])=[O:15])([CH3:13])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9]2)=[O:28])=[CH:24][CH:25]=1
Reactant: COC(=O)C1(C)CNN=C1c1ccc(Cl)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COC(=O)C1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Yield: 95 %

Procedure:
3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole (Example O) and 4-trifluoromethylphenyl isocyanate were reacted by substantially following the procedure given in Example D to give a 95% yield of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide. NMR data was consistent with the structure.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:8]2[C:7]([C:17]#N)=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=[O:26])=CC=1.[CH2:30]([OH:33])[CH2:31][CH3:32]>COC(C)(C)C>[CH2:30]([O:33][C:17]([C:7]1[C:8]2[C:9](=[N:10][CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)=[O:26])[CH2:31][CH3:32]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCO
Reactant: CC(C)(C)n1cc(C#N)c2cc([N+](=O)[O-])cnc21
Solvent: COC(C)(C)C
Product: CCCOC(=O)c1cn(C(C)(C)C)c2ncc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a suspension of 5.0 g (20.47 mmol) of 1-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile in 125 mL of n-propanol, 7.78 g of p-toluensulfonic acid were added under stirring. The mixture was heated at reflux for 40 hours and then it was cooled to room temperature and diluted with 70 mL of tert-butyl methyl ether. The precipitate was filtered off and the clear filtrate was concentrated under vacuum to a small volume (about 40-50 mL). The suspension was cooled to −5/0° C. and kept at this temperature for 2 hours. The solid was filtered, washed with 20 mL of 1:1 mixture of n-propanol and tert-butyl methyl ether and dried to afford 5.50 g of the title compound as a cream-colored solid.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH:13]([CH3:16])[CH2:14][OH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[S:1]([O:15][CH2:14][CH:13]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:16])(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: CC(CO)Oc1ccccc1
Product: CC(COS(N)(=O)=O)Oc1ccccc1

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 2-phenoxypropanol. The oil obtained was further purified as in Example 38 by chromatography and recrystallization to give the title compound as colorless, viscous oil in 35% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([SH:13])[CH3:12]>>[Cl:1][C:2]1[CH:9]=[C:8]([S:13][CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CCS
Product: CCSc1ccc(C#N)c(Cl)c1

Procedure:
4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with ethanethiol to afford 2-chloro-4-(ethylthio)benzonitrile. 2 g of 2-chloro-4-(ethylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(ethylthio)benzoic acid. 1.5 g of 2-chloro-4-(ethylthio)benzoic acid was reacted via Procedure R to yield 2-chloro-4-(ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide. MS (Q1) 435.1 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[C:5]([NH:7][C:8]1[CH:17]=[C:16]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=[O:11])=[O:6].O1CCOCC1.[OH-].[K+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[C:5]([NH:7][C:8]1[CH:17]=[C:16]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:15]=[CH:14][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2OC)cc1NC(=O)c1ccccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccccc2OC)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 74.4 %

Procedure:
5 g of methyl 2,4-bis(2'-methoxybenzamido)-benzoate obtained in Example 9 was admixed with 250 ml of dioxane, 3 g of potassium hydroxide and 50 ml of water, followed by stirring the mixture at room temperature for 20 to 30 hours. The mixture was then poured into 1.5 l of ice-water containing 20 ml of acetic acid to precipitate crystals. The crystals were recovered by filtration, washed with water and recrystallized from ethanol-water to yield 3.6 g of 2,4-bis(2'-methoxybenzamido)-benzoic acid having a melting point between 232° - 233°C.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=O)C1C=CC=CC=1.[NH:37]1[C:45]2[CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41][C:40]=2[CH:39]=[N:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(#N)C>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([Cl:35])[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:17][N:46]([CH:43]3[CH2:44][C:45]4[NH:37][N:38]=[CH:39][C:40]=4[CH2:41][CH2:42]3)[C:14]2=[O:36])=[C:25]([Cl:26])[CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC1CCc2cn[nH]c2C1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1C1CCc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Add a solution of (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde, Preparation 38, (8.17 g, 15.5 mmol) in CH2Cl2 (100 mL) to a solution of 4,5,6,7-tetrahydro-1H-indazol-6-ylamine (2.13 g, 15.5 mmol) in acetonitrile (200 mL) and stir for 30 minutes at room temperature under N2. Add sodium triacetoxyborohydride (9.89 g, 46.7 mmol) to the reaction and stir for 18 hours. Remove the solvent in vacuo and extract solid with ethyl acetate, water and saturated NaHCO3. Dry the organic layer (Na2SO4), filter and concentrate under vacuum. Purify the residue by silica gel chromatography with a gradient of 0 to 10% methanol in CH2Cl2 to afford 3.93 g (54%) of the title compound. MS (m/z): 470 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[I:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([I:15])[CH:17]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCc1cccc(I)c1
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21

Procedure:
2-Chloro-6-[(3-iodobenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 15 for preparation), 3-iodobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:2]=[C:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCCCC1COCc1ccccc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCCC1COCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
An oven-dried 250 mL one-necked round bottomed flask was charged with methyltriphenylphosphonium bromide (4.3 g, 12.3 mmol) and dry THF (20 mL) and then cooled to −78° C. To this solution was added n-BuLi (2.8 M in hexane, 4.3 mL, 12.3 mmol) over 10 min by syringe. The resultant red ylide solution was then warmed to rt, stirred for 3 hours, and cooled to −78° C. To this ylide solution was added 2-((benzyloxy)methyl)cyclohexanone (1.8 g, 8.6 mmol) in dry THF (5 mL) via syringe over 10 min. After being stirred for 1 hour at −78° C., the reaction mixture was warmed to rt slowly and stirred for 10 hours. After that the reaction mixture was cooled to 0° C., quenched with aq. NaHCO3 (60 mL), and extracted with ether (3×60 mL). The organic layer was washed with brine (60 mL) and dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed with hexane-Et2O isocratic 10% as eluant to give the title compound as clear oil. MS m/z 217.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[N:21]O)[NH2:20])=[CH:17][CH:16]=1.O>C1C=CC=CC=1>[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2[N:21]=[C:7]([C:3]3[O:4][CH:5]=[CH:6][C:2]=3[CH3:1])[O:9][N:20]=2)=[CH:17][CH:16]=1
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: Cc1ccoc1C(=O)O
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccoc1-c1nc(-c2ccc(Cl)cc2)no1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A solution of 3-methyl-furan-2-carboxylic acid (252 mg, 2 mmol), thionyl chloride (0.5 mL) in benzene (5 mL) was stirred at 60° C. for 8 h and evaporated to dryness. The residue was dissolved in pyridine (10 mL), and to the solution was added 4-chloro-benzamidoxime (340 mg, 2 mmol). The solution was refluxed for 10 h and then cooled to room temperature. The solution was diluted by water (20 mL) to produce a precipitate. The solid was collected by filtration and washed with water, then dried to yield 201 mg (39%) of the title compound. 1H NMR (CDCl3): 8.12 (d, J=8.4 Hz, 2H), 7.62 (d, J=1.5 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 6.50 (d, J=1.5 Hz, 1H).