Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[CH2:7]([SnH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>>[CH3:1][C:2]([OH:6])(/[CH:4]=[CH:5]/[Sn:11]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:3]
Reactant: C#CC(C)(C)O
Reactant: CCCC[SnH](CCCC)CCCC
Product: CCCC[Sn](/C=C/C(C)(C)O)(CCCC)CCCC
Temperature: 80 °C

Procedure:
A mixture of 2-methylbut-3-yn-2-ol (2.00 g), tributyltinhydride (10.5 g) and αα′-azobisisobutyronitrile (190 mg) was heated (neat) to 80° C. under stirring. After 4 h the reaction mixture was cooled to room temperature. The crude product was purified by chromatography eluting with petroleum ether/Et2O 7:1 to afford the title compound as a liquid.
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH:14]([C:17]1[CH:18]=[C:19]([CH:23]([CH3:27])[CH2:24][CH:25]=[O:26])[CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH3:15]>C(O)(C)C.CCOCC>[CH:14]([C:17]1[CH:18]=[C:19]([CH:23]([CH3:27])[CH2:24][CH2:25][OH:26])[CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)c1cccc(C(C)CCO)c1
Yield: 73.7 %

Procedure:
To a refluxing solution of 132.8 g aluminum isopropoxide in 800 ml of isopropanol, a solution of 300 g of 3-(3-isopropylphenyl)butanal in 200 ml of isopropanol was dropped in. The resulting solution was refluxed for 1.5 hours, then cooled and diluted with ether. Then, the organic phase was washed with brine, dried, and evaporated to dryness. The resulting oil was distilled to yield 223.5 g of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[S:22]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[CH2:28][CH2:27][CH2:26]1)(=[O:24])=[O:23]>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:35]([C:32]2[CH:33]=[C:34]3[C:29]([CH2:28][CH2:27][CH2:26][N:25]3[S:22]([C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[O:14][CH3:13])(=[O:24])=[O:23])=[CH:30][CH:31]=2)=[O:36])[S:9][CH:10]=1)[CH3:2]
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCC3)n1

Procedure:
1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid was converted to the title compound in analogy to example 8, steps 3 and 4. Step 3 was performed using (2-amino-thiazol-4-yl)-acetic acid ethyl ester and 1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid and yielded (2-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester, which was hydrolyzed to (2-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-thiazol-4-yl)-acetic acid in step 4, MS (ISP): m/e=502.0 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[C:9]=1[F:22])(C)(C)C.Cl>C(OC(=O)C)C>[NH2:7][C:8]1[C:9]([F:22])=[C:10]([NH:15][S:16]([CH:19]([CH3:20])[CH3:21])(=[O:18])=[O:17])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CC(C)S(=O)(=O)Nc1ccc(F)c(NC(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)Nc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
The tert-butyl-2,6-difluoro-3-(1-methylethylsulfonamido)phenylcarbamate (100 mg, 0.3 mmol) prepared at Step 4 was added into ethylacetate solvent and, hydrogen chloride (4M solution in 1,4-dioxane) was applied and stirred at room temperature for 5 hours. After the reaction, the solvent was concentrated and vacuum filtrated, and the remaining solid was washed with diethyl ether and hexane and dried, so that 65 mg of the target compound, N-(3-amino-2,4-difluorophenyl)propane-2-sulfonamide (percentage yield: 91%), was obtained.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([C:13]3[N:14]([CH3:39])[C:15]4[CH:21]=[C:20]([C:22]([NH:24][CH2:25][CH2:26][O:27][C:28]5[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=5[C:30]([O:32]CC)=[O:31])=[O:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)[CH3:12])[NH:7][C:6]=2[C:5]([F:40])=[C:4]([F:41])[CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([C:13]3[N:14]([CH3:39])[C:15]4[CH:21]=[C:20]([C:22]([NH:24][CH2:25][CH2:26][O:27][C:28]5[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=5[C:30]([OH:32])=[O:31])=[O:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)[CH3:12])[NH:7][C:6]=2[C:5]([F:40])=[C:4]([F:41])[CH:3]=1
Reactant: CCOC(=O)c1ccccc1OCCNC(=O)c1ccc2nc(C(C)c3nc4c(F)cc(F)c(F)c4[nH]3)n(C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(c1nc2c(F)cc(F)c(F)c2[nH]1)c1nc2ccc(C(=O)NCCOc3ccccc3C(=O)O)cc2n1C

Procedure:
A mixture comprising ethyl 2-(2-{2-[I-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carbonylamino}ethoxy}benzoate (118 mg, 0.21 mmol), methanol (4 ml) and 2N sodium hydroxide (2.1 ml) was stirred at room temperature for 4 hours, neutralized with 2N hydrochloric acid (2.1 ml) and partitioned between ethyl acetate and saturated ammonium chloride. The aqueous layer was separated and extracted with ethyl acetate (X3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to a white solid. The residue was dissolved in warm ethanol (10 ml) and 4M hydrogen chloride/dioxane solution. The solution was diluted with ethyl ether to give a precipitate. The precipitate was isolated and dried to give 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid as a white solid; MS (LCMS) C27H22F3N5O4 m/e calc 537.50; found 538.4 (MH+).
Reaction SMILES: C[C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7].[CH:15]1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cu]>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[O:5][C:6]([CH3:7])=[CH:2][N:3]=2)=[CH:13][CH:12]=1
Reactant: Cc1nc(-c2ccc(O)cc2)oc1C
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Cu]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(-c2ncc(C)o2)cc1
Yield: 35.5 %

Procedure:
2-(4-Methoxyphenyl)-5-methyloxazole was prepared in 35.5% yield of decarboxylation of the compound of part (c) with copper powder in Dowtherm at reflux temperature. The isolated product was distilled, b.p. 136°-140° C. (0.1 mm).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[CH:8]=[C:9]([Br:24])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:13]=[CH:12]2)[CH3:6].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([CH2:48][OH:49])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1.C1CCCCC1>ClCCl>[Br:24][C:9]1[CH:10]=[C:11]2[C:15](=[C:7]([CH:5]([O:49][CH2:48][C:35]3([C:32]4[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=4)[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH2:40]3)[CH3:6])[CH:8]=1)[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:13]=[CH:12]2
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Reaction time: 0.25 h

Procedure:
To a solution of (±)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (780 mg, 1.512 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (468 mg, 1.512 mmol) in dichloromethane (3 mL) at 0° C. was added cyclohexane (3 mL) and tetrafluoroboric acid diethyl etherate (0.041 mL, 0.302 mmol). After 15 min, the reaction was quenched by addition of triethylamine (ca. 0.05 mL). The reaction was diluted with diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→18% EtOAc/Hex) gave 543 mg (54%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.87 (s, 1H), 7.71 (d, J=1.8, 1H), 7.21 (m, 2H), 7.18 (s, 1H), 6.97 (m, 2H), 5.58 (qAB, JAB, 11.6, 2H), 5.06 (q, J=6.1, 1H), 3.68 (m, 2H), 3.41 (m, 2H), 3.24 (qAB, JAB=8.9, 2H), 3.02 (m, 2H), 2.12 (m, 1H), 2.04 (m, 1H), 1.83 (m, 2H), 1.42 (s, 12H), 0.80 (m, 1H), 0.71 (m, 1H), −0.11 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 162.4, 160.4, 155.0, 138.6, 136.1, 133.4, 129.3, 128.7 (d, J=7.7), 128.1, 127.4, 122.5, 115.3, 115.1, 114.8, 79.8, 79.4, 76.7, 72.8, 66.1, 41.1, 40.0 (br), 32.3, 32.1, 28.6, 22.8, 17.9, −1.4. Mass spec.: 662.02 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[O:9]=[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]1[CH:20]([CH2:24][CH3:25])C(O)=O.FC(F)(F)C(O)=O.N>O.[N+]([O-])([O-])=O.[Ag+].C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[CH:20]([N:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]1=[O:9])[CH2:24][CH3:25]
Reactant: Clc1ccc(Cl)nn1
Reactant: CCC(C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: [Ag+]
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(c1cc(Cl)nnc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
3,6-Dichloropyridazine (596 mg, 4 mmol), 2-(1,3-dioxoisoindolin-2-yl)butanoic acid (1.59 g, 6.8 mmol), silver nitrate (67.9 mg, 0.4 mmol), trifluoroacetic acid (91.2 mg, 0.8 mmol) and water (10 mL) were heated at 70° C. with stirring, and to the resulting mixture, diammonium peroxodisulfate (1.64 g, 7.2 mmol) in water (2 mL) was added dropwise over 30 minutes. After the dropwise addition, the resulting reaction mixture was stirred at 70° C. for 30 minutes, then mixed with 10 mL of ethyl acetate and allowed to cool to room temperature. The reaction mixture was cooled with ice, then basified with 28% aqueous ammonia (to pH 9) and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate=1/1) to give a crude product, which was used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[N:11]=1)[C:5]([O:7]C)=[O:6].C1COCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[N:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cc(C(=O)O)cc(Cl)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinate (2 g, 7.18 mmol) in 1:1 THF:MeOH (60 mL) added a NaOH (9.3 mL, 9.3 mmol, 1N). The reaction mixture was stirred at rt for 0.5 h, acidified to pH 3-4 with 1N HCl, extracted with dichloromethane (×2), dried over sodium sulfate and concentrated in vacuo to provide 2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinic acid as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.88 (s, 1H), 7.63 (s, 1H), 3.39 (s, 3H), 3.13 (s, 3H).
Reaction SMILES: [CH:1]12[CH:8]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.CS(O[CH2:23][CH2:24][CH2:25][CH:26]([C:38]1[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=1)[O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:44]([C:41]1[CH:40]=[CH:39][C:38]([CH:26]([O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[CH2:25][CH2:24][CH2:23][N:3]2[CH2:4][CH:5]3[CH:8]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:43][CH:42]=1)#[N:45]
Reactant: COc1ccc(OC(CCCOS(C)(=O)=O)c2ccc(C#N)cc2)cc1OC
Reactant: CN(C(=O)OC(C)(C)C)C1C2CCC1CNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OC(CCCN2CC3CCC(C2)C3N(C)C(=O)OC(C)(C)C)c2ccc(C#N)cc2)cc1OC
Temperature: 90 °C
Yield: 60.1 %

Procedure:
A mixture of tert-butyl 3-azabicyclo[3.2.1]oct-8-yl(methyl)carbamate (Preparation D; 2.60 g, 10.9 mmol), 4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methanesulfonate (see step (iii) above; 4.40 g, 10.9 mmol), and potassium carbonate (1.50 g, 10.9 mmol) in DMF (50 mL) was heated at 90° C. under nitrogen for 4 h. The mixture was partitioned with water (50 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried (Na2SO4), filtered and then concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane:methanol (98:2), to afford 3.60 g (60%) of the sub-title compound as an amorphous solid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]12[O:14][CH:10]1[CH2:11][CH2:12][CH2:13]2>C1COCC1.[Cu](I)I>[C:1]1([C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CC2OC2C1
Reactant: Br[Mg]c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: O[C@@H]1CCC[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
Scheme IB, step A: A one liter three necked round bottom flask equipped with a mechanical stirrer, addition funnel, thermometer is charged with 1M THF solution of phenylmagnesium bromide (300 mL, 300.0 mmol) and copper iodide (3.8 g, 20.0 mmol). To this reaction mixture was then added cyclopentene oxide (25.23 g, 300.0 mmol) dissolved in THF (50.0 mL) dropwise over a period of 60 minutes (reaction was quite exothermic, reaching THF reflux by the end of addition). The reaction mixture was then stirred to room temperature and quenched with 25% solution of ammonium chloride (200.0 mL). Added ether (80.0 mL) and separated upper organic layer. Washed organic layer with 25% ammonium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated filtrate to provide (+,−) trans-2-phenyl-cyclopentanol as a brown oil (mass =47.7 g);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][OH:20])[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH:19]=[O:20])[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A mixture of [1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazol-4-yl]methanol (6.84 g), activated manganese dioxide (14.00 g), and tetrahydrofuran (70 ml) was stirred at room temperature for one hour. After the manganese dioxide was removed by filtration, the filtrate was concentrated. The crystals obtained were collected by filtration to yield 1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazole-4-carbaldehyde (6.50 g, yield: 95%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 138–139° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:2]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21].O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([NH:12][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[N:9][N:8]=2)[CH:2]=1
Reactant: Nc1nnc(-c2cccnc2)o1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nnc(-c2cccnc2)o1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 5-pyridin-3-yl-1,3,4-oxadiazol-2-ylamine (1.00 g, 6.17 mmol) and pyridine (1.47 ml, 18.5 mmol) in tetrahydrofuran (20 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.70 ml, 12.3 mmol), and the mixture was stirred at room temperature for 1.5 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.13 g (54.5%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11](Cl)(=[O:13])=[O:12])=[CH:3]1.[NH3:15]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11]([NH2:15])(=[O:13])=[O:12])=[CH:3]1
Reactant: Cn1cc(S(=O)(=O)Cl)c2ccccc21
Reactant: N
Solvent: C1CCOC1
Product: Cn1cc(S(N)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-methyl-1H-indole-3-sulfonyl chloride (0.86 g, 3.75 mmol) in THF (40 mL) was added ammonia gas until saturation at ca. 10° C., then the flask was stoppered, and the reaction mixture was stirred at rt for 4 h. The reaction mixture was then quenched with water; the organic solvent was slowly evaporated under vacuum. The precipitate formed was filtered off, washed with water and dried over P2O5 under high vacuum to obtain 1-methyl-1H-indole-3-sulfonic acid amide (0.64 g) as a yellowish solid. MS (ISN): m/e 209.4 (M−H)−
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:40](=[O:41])[N:13]3[C:14]([C:37]([OH:39])=[O:38])=[C:15]([CH2:18]OC(=O)C4C=CC=CC=4S(=O)(=O)NC(OCC)=O)[CH2:16][S:17][C@H:12]23)=[O:9])=[CH:4][S:3]1.[SH:42][C:43]1[N:47]([CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[N:46]=[N:45][N:44]=1.C(=O)([O-])O.[Na+]>O>[NH:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:40](=[O:41])[N:13]3[C:14]([C:37]([OH:39])=[O:38])=[C:15]([CH2:18][S:42][C:43]4[N:47]([CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[N:46]=[N:45][N:44]=4)[CH2:16][S:17][C@H:12]23)=[O:9])=[CH:4][S:3]1
Reactant: CN(C)CCn1nnnc1S
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(=N)[nH]3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(=N)[nH]3)[C@H]2SC1

Procedure:
In water (5 ml) are dissolved 7β-(2-imino-4-thiazolin-4-yl)acetamido-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (313 mg), 5-mercapto-1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazole (113 mg) and sodium hydrogen carbonate (42 mg) and the resultant solution is heated at 55° C. for 60 minutes. The reaction solution is adjusted its pH to 5.8 and purified by column chromatography on Amberlite XAD-2 and the fractions rich in the desired product are pooled and lyophilized. The procedure provides 7β-(2-imino-4-thiazolin-4-yl)acetamido-3-{1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazol-5-yl}thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1

Procedure:
76 mg of solid yellow 3-{4-[3-(2-chloro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 2-chloro-5-trifluoromethylphenyl isocyanate.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[C:14]1([C:20]2(CCC)C=CC=C(SSCCC)[CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.BrC1C(C2C=NC=CC=2)=NNC=1>C(OCC)(=O)C>[C:14]1([CH2:20][CH2:21][CH2:1][S:2][C:3]2[C:4]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[N:5][NH:6][CH:7]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: CCCSSC1=CC=CC(CCC)(c2ccccc2)C1
Agent: Brc1c[nH]nc1-c1cccnc1
Solvent: CCOC(C)=O
Product: c1ccc(CCCSc2c[nH]nc2-c2cccnc2)cc1
Yield: 22 %

Procedure:
Compound 21I was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using 3-phenyl-propyldisulfanyl-3-propylbenzene as the disulfide (prepared according to the methodology described in Tetrahedron Letters, 42, 2001, 6741-6743) and 3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A). (conditions flash chromatography (ethyl acetate)) Yield: 22% (oil). 1H-NMR (400 MHz, CDCl3): δ 9.18 (d, J=2 Hz, 1H), 8.62 (dd, J=5 Hz, 2 Hz, 1H), 8.31 (dt, J=8 Hz, 2 Hz, 1H), 7.69 (s, 1H), 7.40-7.36 (m, 1H), 7.24 (bt, J=7 Hz, 2H), 7.17 (bt, J=7 Hz, 1H), 7.04 (bd, J=7 Hz, 2H), 2.65-2.57 (m, 4H), 1.84-1.75 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:15]
Reactant: Cn1cc(N)cn1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)c2cc(Br)ccc2OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat 1-methyl-1H-pyrazol-4-amine (61.7 mg, 0.64 mmol) was added in one charge to a stirred suspension of 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5; 150 mg, 0.49 mmol), EDC (281 mg, 1.47 mmol) and HOBT (224 mg, 1.47 mmol) in N,N-dimethylformamide (3 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. 20 ml of water was added and the mixture was extracted with ethyl acetate (20 ml×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give crude product, which was purified by prep-HPLC (Gilson GX-281; waters X-Bridge 5 μm 30*100 mm; A: 0.1NH3*H2O/Water; B: CH3CN) twice to yield the title compound as a white solid. 70 mg.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:7][CH:8]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:4]=[CH:5][C:6]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)=[N:7][CH:8]=4)[CH2:23][CH2:22]3)=[CH:8][N:7]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2ccc(CCl)cn2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2ccc(CN3CCN(Cc4ccc(-c5cc(OC)c(OC)c(OC)c5)nc4)CC3)cn2)cc(OC)c1OC

Procedure:
5-Chloromethyl-2-(3,4,5-Trimethoxyphenyl)pyridine (294 mg) and piperazine (43 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.