Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30]>>[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)N1CCNCC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure E for Displacement of alkyl bromide with amines, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 1-isopropylpiperazine were reacted to give 441. LCMS m/z: 490.3 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:33][CH3:34])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:36]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:33][CH3:34])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(Cl)c2)cc2c1CCN2S(=O)(=O)c1cccc(F)c1
Product: COC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(F)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3-fluoro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 505.29 (M+H+.), was prepared in analogy to example 21, steps 1 to 6. Step 5 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3-fluoro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10](OCC)OCC)[CH:3]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:10]=[CH:9][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(COc1cccc(Br)c1)OCC
Solvent: Cc1ccccc1
Product: Brc1ccc2ccoc2c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of the acetal 15-2 in toluene (200 mL) was added polyphosphoric acid (20 g). The biphasic mixture was heated to 100° C. and stirred at this temperature for 4 h. The mixture was cooled to room temperature, poured onto ice, and extracted with Et2O (2×200 mL). The combined organic extracts were washed with saturated aq NaHCO3 and brine. The solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (100% hexanes) to give the product 15-3 as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>C1COCC1.CN(C)C1C=CN=CC=1>[O:23]=[C:15]1[C:14](=[C:10]2[C:11]3[C:7](=[CH:6][C:5]([NH:4][CH2:3][CH2:2][O:1][C:24](=[O:26])[CH3:25])=[CH:13][CH:12]=3)[CH2:8][O:9]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccccc2C1=C1OCc2cc(NCCO)ccc21
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCCNc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a stirred mixture of 3-[5-(2-hydroxy-ethylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (50 mg, 0.16 mmol) and acetic anhydride (20 mg, 0.20 mmol) in THF (3 ml), was added 4-dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was stirred for 30 minutes and was then poured into water (75 ml). The solid was filtered, washed with water and dried under vacuum to give acetic acid 2-[1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-ylamino]-ethyl ester as a yellow solid (39 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:26]4[CH2:27][CH2:28][O:24][C:25]4=[O:29])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)c(C)c1
Yield: 74.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (591 mg) described in Preparation Example 77 and oxazolidin-2-one (134 mg), the title compound (396 mg) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[CH3:31][S:32][CH2:33][C:34](Cl)=[O:35].[OH-].[Na+]>CC(C)=O>[CH3:31][S:32][CH2:33][C:34]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:17][N:18]=[N:19][N:20]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12)=[O:35]
Reactant: CSCC(=O)Cl
Reactant: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CSCC(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCC(N)=O)Sc3nnn[nH]3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (-20°) solution of 10.2 g. (0.026 mol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 220 ml. of 3% sodium bicarbonate and 220 ml. of acetone is dropwise added a solution of 3.66 g. (0.029 mol.) of methylmercaptoacetyl chloride in 52 ml. of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml. of ethyl acetate is added and the slurry is acidified with 3N hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:22]2[N:23]=[N:24][N:25]([CH2:27][Si](C)(C)C)[CH:26]=2)[NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:22]2[N:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)=[N:6][CH:7]=1
Reactant: CC(C)c1ccc(CC(=O)N[C@H](c2ccc(Br)cn2)c2cn(C[Si](C)(C)C)nn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1ccc(CC(=O)N[C@H](c2ccc(Br)cn2)c2cn(C)nn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of N-((S)-(5-bromopyridin-2-yl){1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-2-(4-isopropylphenyl)acetamide (0.4 g, 0.80 mmol) in THF (5.0 mL) was added a solution of TBAF in THF (0.84 mL, 1 M). The reaction was stirred at room temperature for 1 h. The solvent was removed and the residue was purified by silica flash chromatography (gradient, 10-100% EtOAc in hexanes) to give N-[(S)-(5-bromopyridin-2-yl) (1-methyl-1H-1,2,3-triazol-4-yl)methyl]-2-(4-isopropylphenyl)acetamide (0.22 g, 65%). ES-MS [M+1]+: 428.0. 1H NMR (CDCl3, 400 MHz) δ 8.53 (d, J=2.0 Hz, 1H), 7.76 (dd, J=2.4, 8.0 Hz, 1H), 7.4w (s, 1H), 7.36 (d, J=6.8 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.22 (s, 4H), 6.26 (d, J=6.8 Hz, 1H), 4.01 (s, 3H), 3.62 (s, 2H), 2.94-2.85 (m, J=6.8 Hz, 1H), 1.25 (d, J=7.2 Hz, 6H). HRMS (ES) [M+1]+ calcd for C20H22BrN5O: 428.1081. Found: 428.1112.
Reaction SMILES: [CH:1]1([CH:4]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:5]([OH:7])=O)[CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:5](=[O:7])[CH:4]([CH:1]2[CH2:2][CH2:3]2)[O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:22][CH:21]=1
Reactant: O=C(O)C(Oc1cccc2ccccc12)C1CC1
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)C(Oc1cccc2ccccc12)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
To a solution of 2-cyclopropyl-2-(1-naphthalenyloxy)acetic acid (120 mg, 0.49 mmol) and 4-chloroaniline (44.0 μL, 0.49 mmol) in anhydrous DCM (10 mL) under N2 cooled at 0° C. was added EDCI-HCl (187.9 mg, 0.98 mmol) portion wise. The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using ethyl acetate/n-hexane (a gradient of 5-10%) to furnish 119 (148 mg, 86%) as a white solid. mp 204-206° C.; 1H NMR (CDCl3, 400 MHz) δ 0.65-0.78 (m, 4H0, 1.52 (m, 1H), 4.41 (d, J=6.4 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 7.25 (d, J=6.0 Hz, 3H), 7.43 (d, J=8.4 Hz, 2H), 7.61-7.70 (m, 3H), 7.97 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 2.70, 3.16, 14.42, 82.72, 108.01, 115.68, 121.47, 122.03, 122.96, 127.64, 128.43, 129.28, 129.63, 130.07, 132.96, 135.61, 152.83, 169.27; ESI-HRMS for C21H17ClNO2 (M−H)+calcd. 350.0948. Found 350.0956.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1
Reactant: CCCCCCCC(=O)Nc1ccc(CC(OC)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCNc1ccc(CC(OC)OC)cc1

Procedure:
N-(4-(2,2-dimethoxyethyl)phenyl)octanamide (1.11 g, prepared as in example 21) is reduced with lithium aluminum hydride (1.4 equivalents) in refluxing THF (15 ml) to provide 1-(2,2-dimethoxyethyl)-4-(octylamino)benzene as a pale yellow oil after the usual work-up. This material (0.96 g) is dissolved in dichloromethane (10 ml) and treated with acetic anhydride (0.32 ml), triethylamine (0.5 ml) and DMAP (50 mg). The mixture is stirred at room temperature for 4 hr, then washed in turn with 10% aqueous citric acid and saturated sodium bicarbonate. The organic solution is dried, filtered, and concentrated to provide N-(4-(2,2-dimethoxyethyl)phenyl)-N-octylacetamide as a colorless oil (1.05 g). This is condensed with glyoxylic acid by the method of example 2 above, to provide the title compound, mp 103°-105° after recrystallization from dichloromethane-hexane.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:14]3[CH:15]=[C:16]4[CH:22]=[CH:21][N:20]([S:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)(=[O:25])=[O:24])[C:17]4=[N:18][CH:19]=3)=[N:11][NH:12][CH:13]=2)[CH:6]=[CH:5][N:4]=1.Br[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:26]1([S:23]([N:20]2[C:17]3=[N:18][CH:19]=[C:14]([C:10]4[C:9]([C:7]5[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=5)=[CH:13][N:12]([CH2:33][C:34]#[N:35])[N:11]=4)[CH:15]=[C:16]3[CH:22]=[CH:21]2)(=[O:24])=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N#CCBr
Reactant: CSc1nccc(-c2c[nH]nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cn(CC#N)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Temperature: 75 °C
Reaction time: 18 h
Yield: 63.6 %

Procedure:
To a solution of the 5-{4-[2-(methylthio)pyrimidin-4-yl]-1H-pyrazol-3-yl}-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (C-1-3) (638 mg, 1.42 mmol) and bromoacetonitrile (0.5 mL, 7 mmol) in DMF was added freshly ground Potassium Carbonate (254 mg, 1.84 mmol). The resulting suspension was stirred at 75° C. for 18 hr. LCMS showed complete consumption of starting material. The mixture was partitioned between ethyl acetate and saturated aqueous NaCl. The aqueous layer was extracted with ethyl acetate twice. The combined organics were washed with water twice, saturated aqueous NaCl, dried over MgSO4 and reduced to minimum volume. The residue was purified on silica gel using a gradient of 25 to 100% methyl tert-butyl ether in hexanes as eluent to give [3-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-methylsulfanyl-pyrimidin-4-yl)-pyrazol-1-yl]-acetonitrile (C-1-4) (440 mg, 63%) as a crisp foam. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.46 (d, J=2.02 Hz, 1H), 8.36 (d, J=5.31 Hz, 1H), 8.31 (s, 1H), 8.11-8.16 (m, 2H), 8.09 (d, J=2.02 Hz, 1H), 7.83 (d, J=4.04 Hz, 1H), 7.64-7.71 (m, 1H), 7.57 (t, J=7.71 Hz, 2H), 7.01 (d, J=5.31 Hz, 1H), 6.75 (d, J=4.04 Hz, 1H), 5.26 (s, 2H), 1.88 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][C:17]([C:23]([N:25]3[CH2:30][CH2:29][C:28]4([CH2:38][C:37](=[O:39])[C:36]5[N:35]([CH:40]([CH3:42])[CH3:41])[N:34]=[CH:33][C:32]=5[CH2:31]4)[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:19]=2)[N:14]=1)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][C:17]([C:23]([N:25]3[CH2:26][CH2:27][C:28]4([CH2:38][C:37](=[O:39])[C:36]5[N:35]([CH:40]([CH3:42])[CH3:41])[N:34]=[CH:33][C:32]=5[CH2:31]4)[CH2:29][CH2:30]3)=[O:24])=[CH:18][CH:19]=2)[N:14]=1
Reactant: CC(C)n1ncc2c1C(=O)CC1(CCN(C(=O)c3ccc4ccc(NC(C)(C)C)nc4c3)CC1)C2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncc2c1C(=O)CC1(CCN(C(=O)c3ccc4ccc(N)nc4c3)CC1)C2
Temperature: 70 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
Trifluoroacetic acid (0.90 mL, 12 mmol) was added to 1′-(2-(tert-butylamino)quinoline-7-carbonyl)-1-isopropyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(1H)-one (50 mg, 0.11 mmol). The reaction was heated to 70° C. for 3 hours, then cooled to room temperature and left stirring overnight. The reaction was concentrated to dryness and purification by reversed-phase HPLC gave the title compound (41 mg, 93%). +ESI (M+H) 418.2; HPLC retention time 2.11 minutes (Method A). 1H NMR (500 MHz, CD3OD, δ) 8.36 (d, J=9.27 Hz, 1 H), 7.97 (d, J=8.05 Hz, 1 H), 7.66 (s, 1 H), 7.53 (dd, J=8.17, 1.34 Hz, 1 H), 7.44 (s, 1 H), 7.12 (d, J=9.27 Hz, 1 H), 5.39 (quint, J=13.23, 6.68 Hz, 1 H), 3.91 (br. s., 1 H), 3.76 (br. s., 1 H), 3.46 (br. s., 2 H), 2.92 (s, 2 H), 2.67 (d, J=7.81 Hz, 2 H), 1.74 (br. s., 2 H), 1.59 (br. s., 2 H), 1.43 (br. s., 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.S(Cl)([Cl:25])(=O)=O>C(O)(=O)C>[Cl:25][C:4]1[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7]2[C:12]([C:3]=1[O:2][CH3:1])=[C:11]([S:13]([N:16]([CH3:17])[CH3:18])(=[O:15])=[O:14])[CH:10]=[CH:9][CH:8]=2
Reactant: COc1ccc(C(=O)O)c2cccc(S(=O)(=O)N(C)C)c12
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: COc1c(Cl)cc(C(=O)O)c2cccc(S(=O)(=O)N(C)C)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
4-Methoxy-5-(dimethylaminosulfonyl)-1-naphthalenecarboxylic acid (15.26 g, 50 mmoles), described in Example 1a) was suspended in acetic acid (46 ml). Sulfuryl chloride (6 ml, 75 mmoles) was added portionwise to the suspension at such a rate that the temperature did not exceed 32° C. The resulting solution was stirred at 20°-22° C. for 2 hr and then poured into 460 ml of ice water. The mixture was stirred for 30 min. The precipitate was collected and dried over P2O5 to give 16.7 g of the title compound; mp 127°-137° C.; NMR (CDCl3) δ 3.05 (s, 6H), 4.12 (s, 3H), 8.0 (broad, 1H), 7.7 and 9.25 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[N:7]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[CH2:20]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[N:5]=[C:4]([CH3:19])[CH:3]=[C:2]([CH3:1])[N:7]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(N)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NCc3ccccc3)cc2)n1

Procedure:
100 mg (0.36 mmol) sulfamethazine and 70.8 μl (0.60 mmol) benzyl bromide were dissolved in 4 ml methanol. Caesium carbonate (113.4 mg, 0.35 mmol) was added and solution was refluxed overnight with stirring. The reaction mixture was then evaporated to dryness, and purified on silica using gradient elution (chloroform to 2% methanol in chloroform) to obtain white crystals in a yield similar to that described in example 1 for step III. 1H NMR (CDCl3, 500 MHz): 7.93 (2H, m), 7.31 (5H, m), 6.58 (3H, m), 4.36 (2H, s), 2.34 (6H, s); MS (ESI+): m/z 369 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][CH:11]=1)([CH2:8][OH:9])[CH2:6][OH:7])(=[O:3])[CH3:2].CO[C:28](OC)([CH3:30])[CH3:29].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[C:1]([NH:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][CH:11]=2)[CH2:8][O:9][C:28]([CH3:30])([CH3:29])[O:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(C)(C)OC
Reactant: CCCCCCCCCCc1ccc(C(CO)(CO)NC(C)=O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: CCCCCCCCCCc1ccc(C2(NC(C)=O)COC(C)(C)OC2)cc1

Procedure:
2-Acetylamino-2-(4-decylphenyl)-1,3-propanediol (224 mg) and 2,2-dimethoxypropane (0.3 ml) were dissolved in benzene (5 ml) and the mixture was refluxed under heating in the presence of a catalytic amount of toluenesulfonic acid. After cooling, the reaction mixture was washed with an aqueous sodium hydrogencarbonate solution and dried over sodium sulfate. The solvent was distilled away and the residue was purified by preparative thin layer chromatography (silica gel) to give 99 mg of the amorphous subject compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FF.F[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[CH:11][C:12]=1[F:1]
Reactant: Fc1cccc(F)c1
Agent: FF
Solvent: Fc1ccccc1
Product: Fc1ccccc1F

Procedure:
According to Sams et al, "Molecular Sieve Fluorination of Fluorobenzene Using Elemental Fluorine," J. Org. Chem. 43(11), 2273 (1978), attempts were made to prepare 1,3-difluorobenzene using a molecular sieve fluorination technique. Fluorination of monofluorobenzene resulted in the isolation of various isomers of difluorobenzene in 19% yield; the highest reported yield for the meta isomer was 1.2%.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH2:22][CH2:21]3)[CH:17]=[CH:16][CH:15]=1)=[O:13])[CH2:8]2.Cl>CO>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:21]3)[CH:17]=[CH:16][CH:15]=1)=[O:13])[CH2:8]2
Reactant: COC(=O)CCN1CCN(c2cccc(C(=O)NC3C4CC5CC(C4)CC3C5)n2)CC1
Agent: Cl
Solvent: CO
Product: O=C(O)CCN1CCN(c2cccc(C(=O)NC3C4CC5CC(C4)CC3C5)n2)CC1
Yield: 64.8 %

Procedure:
Methyl 3-(4-(6-(adamantan-2-ylcarbamoyl)pyridin-2-yl)piperazin-1-yl)propanoate (43 mg, 0.101 mmol) was added into 4N aqueous HCl solution (2 ml), and heated at reflux for 2 hours. The resulting reaction liquid was concentrated under reduced pressure, and then neutralized by slow addition of a saturated aqueous NaHCO3 solution, followed by extraction with a mixture solution (10 ml×2) of THF:MC=4:1. The organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (10% MeOH/MC), to obtain 27 mg of pale yellow oil (65%). MS (ESI): 413 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:3]([S:19][CH:20]([CH2:24][CH3:25])[C:21](=[O:23])[CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.CO.C(O)(=O)C>[Br:1][C:2]1[C:3]([S:19][CH:20]([CH2:24][CH3:25])[CH:21]([OH:23])[CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CCC(Sc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCC(Sc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br)C(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
26 mg (0.058 mmol) of 5-[5-bromo-4-(1-ethyl-2-oxo-propylsulfanyl)-pyrimidin-2-ylamino]-pyridine-2-sulfonic acid amide, dissolved in 1.5 ml of THF/MeOH 1:1, is mixed with 10 mg of sodium borohydride and stirred for 3 hours at room temperature. While being cooled, 2-3 drops of glacial acetic acid are added and concentrated by evaporation. Uptake in acetonitrile and suctioning-off yield 17 mg (65% of theory) of 5-[5-bromo-4-(1-ethyl-2-hydroxy-propylsulfanyl)-pyrimidin-2-ylamino]-pyridine-2-sulfonic acid amide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][NH:25][CH3:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([C:19](=[O:21])[N:25]([O:24][CH3:23])[CH3:26])[CH2:17][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
A 1 L flask was charged with 25.02 g (85.9 mmol) trans-4-(benzyloxycarbonylamino-methyl)-cyclohexanecarboxylic acid, 9,21 g (94.5 mmol) O,N-dimethylhydroxyl amine HCl, 41.8 g (94.5 mmol) BOP, 750 mL methylene chloride and 75 mL diisopropylethyl amine. The reaction mixture was then stirred under nitrogen overnight. The solution was then washed with water, 5% citric acid (2×300 mL), saturated sodium bicarbonate (2×300 mL), brine (1×300 mL) and dried over Na2SO4 and concentrated to an oil. The oil was chromatographed on silica gel eluted with 50% ethyl acetate/50% hexanes to give 27.2 g of a clear oil that solidified on standing.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]#[N:13].C(OC(=O)C)(=O)C.[N+:21]([O-])([OH:23])=[O:22]>>[CH3:11][N:10]1[C:6]([C:2]2[O:1][C:5]([N+:21]([O-:23])=[O:22])=[CH:4][CH:3]=2)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]1
Reactant: O=[N+]([O-])O
Reactant: Cn1ncc(C#N)c1-c1ccco1
Solvent: CC(=O)OC(C)=O
Product: Cn1ncc(C#N)c1-c1ccc([N+](=O)[O-])o1

Procedure:
Following the procedure of Example 21, react 1.3 g of 5-(2-furyl)-1-methylpyrazole-4-carbonitrile [German Offenlegungsschrift (DOS) 1,809,386] with 11.5 ml of acetic anhydride and 3 ml of 65% nitric acid to obtain 1-methyl-5-(5-nitro-2-furyl)pyrazole-4-carbonitrile [m.p. 149.5° to 151.5° C].