Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Yield: 68.2 %

Procedure:
1-[5-(3,4-Dimethylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.2423 mmol, HPLC purity 84.3%, 70.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.2423 mmol, 51.2 mg) were stirred with dimethylformamide (3 mL) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (72.3 mg, yield 68%).
Reaction SMILES: C(OCO[C@H:6]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:8]([C:9](=[O:35])[CH2:10][C@@H:11]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:12]3[CH2:13][C@@H:14]3[O:19][C@@:18]4([O:25][CH2:24][C@H:22]([CH3:23])[CH2:21][CH2:20]4)[C@@H:16]([CH3:17])[C@@H:15]32)[CH2:7]1)C.[OH-].[Na+]>Cl.CO.O1CCCC1>[CH3:17][C@@H:16]1[C@:18]2([O:25][CH2:24][CH:22]([CH3:23])[CH2:21][CH2:20]2)[O:19][C@H:14]2[CH2:13][C@@H:12]3[C@@:26]([CH3:34])([C@@H:15]12)[CH2:27][CH2:28][C@H:29]1[C@H:11]3[CH2:10][C:9](=[O:35])[CH:8]2[C@:30]1([CH3:33])[CH2:31][CH2:32][CH2:6][CH2:7]2
Reactant: CCOCO[C@H]1CC[C@@]2(C)[C@H](C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]3[C@H](C[C@@H]12)O[C@]1(CC[C@@H](C)CO1)[C@H]3C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC(=O)C5CCCC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 62 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Concentrated hydrochloric acid (2 drops) was added to a solution of (3β,5α,25R)-3-ethoxymethoxy-spirostan-6-one (0.70 g, 1.43 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). The mixture was stirred under nitrogen atmosphere and heated to 62° C. After 15 minutes, the reaction was cooled to 0° C. and neutralized with 15% sodium hydroxide solution. The mixture was concentrated in vacuo then diluted with ethyl acetate. The organic layer was washed with water (2×), brine (1×), dried (sodium sulfate), concentrated in vacuo and purified by flash chromatography (1:1 hexane/ethyl acetate) to afford 0.55 g (89.4%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:28])=O>C1COCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([Cl:28])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
2-Methoxy-4-(1-Boc-4-piperidyloxy)benzoic acid (3.2 g, 9.1 mmol) was dissolved in THF (35 ml). Thionyl chloride (1 ml, 1.63 g, 13.7 mmol) was added dropwise, followed by 2 drops of pyridine. The mixture was stirred at ambient temperature under nitrogen for 4.5 hours, then concentrated in vacuo. The residue was reconcentrated from ether to give 2-methoxy-4-(1-Boc-4-piperidyloxy)benzoyl chloride.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][CH2:13]Br)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:13][CH2:12][N:9]2[C:7](=[O:8])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[C:10]2=[O:11])=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCNc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask was added n-(2-bromoethyl)phthalimide, 95% (508 mg, 1999 μmol, Aldrich), 4-fluoroaniline (193 μL, 1999 μmol, Aldrich), DMF (2 mL), sodium carbonate (336 mg, 3999 μmol). The reaction mixture was stirred at 80° C. for overnight. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with water (20 mL), saturated NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give 2-(2-(4-fluorophenylamino)ethyl)iso-indoline-1,3-dione. MS (ESI pos. ion) m/z: 285 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[CH2:26]([O:28][C:29](=[O:43])[CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37](O)=[C:36]([F:41])[CH:35]=1)[CH3:27].C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:43])[CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([O:15][CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[C:2]([CH3:1])[CH:7]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:36]([F:41])[CH:35]=1)[CH3:27]
Reactant: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(O)c(F)c1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OCC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
Combine 1-(2-methyl-4′-trifluoromethyl-biphenyl-4-yl)-heptan-1-ol (0.090 g, 0.25 mmol) and 3-(3-fluoro-4-hydroxy-benzoylamino)-propionic acid ethyl ester (0.050 g, 0.20 mmol) in toluene (1.0 mL). Add 1,1′(diazocarbonyl)dipiperidine (0.076 g, 0.3 mmol) followed by tributyl-phosphane (0.074 mL, 0.3 mmol) under inert atmosphere. Stir at room temperature for 16 hours. Dilute reaction with ethyl acetate filter and remove solvent under reduced pressure. Purify on silica gel chromatography (0-50% Ethyl acetate/hexanes gradient) to provide 0.105 g of title compound (90%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:7]([OH:14])=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[H-].[Na+].I[CH:19]([CH3:21])[CH3:20].O>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:7]([O:14][CH:19]([CH3:21])[CH3:20])=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C=O
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)cc(C(C)(C)C)c(OC(C)C)c1C=O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
A stirred, cooled (ice bath) solution of 3-bromo-5-tert-butyl-6-hydroxy-2-methyl-benzaldehyde (Intermediate 140, 0.58 g, 2.14 mmol) in anhydrous N,N-dimethylformamide (10 mL) was treated with sodium hydride (0.34 g of 60% suspension in mineral oil, 8.56 mmol). After 30 minutes, 2-iodopropane (1.3 mL, 12.84 mmol) was added and the reaction mixture was heated at 75° C. overnight. The reaction mixture was then cooled and poured into iced water and extracted with diethyl ether. The organic extract was then washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography using 2-4% ethyl acetate in hexane as the eluent afforded the title product (0.43 g, 64%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:17][CH:18]=1)=[O:13])[CH3:10].C1(C)C=CC=CC=1>C(O)(=O)C>[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:17][C:18]=1[Br:1])=[O:13])[CH3:10]
Reactant: CCOC(=O)c1csc(-c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2)sc1Br
Reaction time: 8 h
Yield: 56.5 %

Procedure:
N-Bromosuccinimide (1.22 g, 6.83 mmol) was added to a solution of ethyl-2-phenylthiophen-4-carboxylate (6.83 mmol) in acetic acid (10 mL) and stirred overnight. Toluene was added and the solvent was removed under vacuum. The product was purified by flash chromatography on silica, eluting with 0%-10% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (1.2 g). LCMS m/z 312.52 [M+H]+ R.T.=4.55 mins (Analytical Method 5).
Reaction SMILES: [CH3:1][C:2]#[C:3][CH3:4].[N+](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9])=[N-]>FC1C(F)=C(F)C(F)=C(F)C=1F.[Hg]>[CH3:1][C:2]1[C:7]([C:12]([O:14][CH3:15])=[O:13])([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[CH3:4]
Reactant: CC#CC
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Hg]
Solvent: Fc1c(F)c(F)c(F)c(F)c1F
Product: COC(=O)C1(C(=O)OC)C(C)=C1C
Reaction time: 100 h
Yield: 46.2 %

Procedure:
A nitrogen-degassed solution of 33.5 grams (0.69 mole) of 2-butyne and 20.0 grams (0.13 mole) of dimethyl diazomalonate in approximately 325 grams of hexafluorobenzene was photolyzed for approximately 100 hours, at 0° C.-5° C., employing a 100-watt Hanovia mercury lamp in a manner similar to that described in Example XCVI Part A. Similar workup of the reaction mixture afforded 10.8 grams (0.06 mole) of dimethyl 2,3-dimethyl-2-cyclopropene-1,1-dicarboxylate. NMR analysis of the product indicated the following:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.P(Cl)(Cl)([Cl:14])=O.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:14][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2oc(S)nc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc2oc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methyl-benzooxazole-2-thiol (5.0 g, 30.2 mmol), phosphorus oxychloride (25.0 mL, 269.4 mmol), and phosphorus pentachloride (7.56 g, 36.3 mmol) were combined in CH2Cl2 (30 mL), and the reaction was stirred at room temperature overnight. The mixture was concentrated several times from fresh CH2Cl2 to remove traces of phosphorus oxychloride, and the residue was treated with saturated aqueous Na2CO3 to adjust to pH 8. The aqueous layer was extracted twice with CH2Cl2, and the combined organic layers were washed with H2O and brine, and then dried over Na2SO4, decanted, and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(=[O:17])[CH3:16]>S1(CCCC1)(=O)=O>[C:15]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[CH2:21][CH2:20]1)(=[O:17])[CH3:16]
Reactant: Cc1cccc(Cl)n1
Reactant: CC(=O)Nc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CC(=O)NC1CCN(c2cccc(C)n2)CC1
Reaction time: 24 h
Yield: 28 %

Procedure:
0.042 mole of 2-chloro-6-methylpyridine, 0.056 mole of anhydrous potassium carbonate and 0.052 mole of 4-acetamidopyridine in 75 ml of sulfolane are heated to 150° C. with stirring for 24 hours, then the sulfolane is concentrated up to 1.5 of its volume, the mixture is poured into 100 ml of water and extraction is effected four times with 150 ml of diethyl ether. The organic phase is washed with water, it is dried over anhydrous sodium sulfate, concentrated to dryness and the residue is crystallised in 40 m of ethyl acetate. Thus, the 4-acetamido-1-(6-methyl-2-pyridyl)piperidine is obtained; m.p. 145° to 147° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[CH:13][C:11]=1[NH2:12].[CH:26](=O)[CH3:27].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[C:14]1[CH:15]=[CH:16][C:10]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C:26]([CH3:27])=[N:12][C:11]=2[CH:13]=1
Reactant: CC=O
Reactant: COc1ccccc1Nc1ccc(-c2nc3ccccc3o2)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(C)nc2cc(-c3nc4ccccc4o3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
To a solution of 2-(2-(2-methoxyphenyl)aminoanilin-5-yl)benzoxazole (see Working Example 30-1) (48.0 mg, 0.135 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 20.5 μL, 0.405 mmol) and oxone (53.9 mg, 0.0878 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (18.2 mg, 38% yield) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13].[H][H]>[Pd].C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: Nc1c(CCO)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCO)c1N

Procedure:
A suspension of 10% palladium on carbon (66 mg) and 2-(2-amino-3-nitrophenyl)ethanol [See Seno, Kaoru; Hagishita, Sanji; Sato, Tomohiro; Kuriyama, Kaoru; J. Chem. Soc. Perkin Trans. 1; 2012 (1984) for the synthesis of this reagent] (531.5 mg, 2.92 mmol) in absolute ethanol (50 mL) was shaken under 40 psi hydrogen for 3 hours. After filtration and concentration, crude 2-(2,3-diaminophenyl)ethanol (474.4 mg) was obtained as a red oil, which crystallized on standing: Rf=0.08 (75% ethyl acetate in hexanes); 1H NMR (DMSO-d6) δ 2.58 (t, 2H, J=6.9 Hz), 3.53 (t, 2H, J=7.2 Hz), 4.32 (br s, 5H), 6.29 (m, 2H), 6.40 (dd, 1H, J=6.9, 2.1 Hz).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=1>ClCCCl>[Br:1][C:12]1[C:13](=[O:16])[CH2:14][CH2:15][C:11]=1[O:10][CH3:9]
Reactant: COC1=CC(=O)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: COC1=C(Br)C(=O)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-Bromosuccinimide (24.92 g, 0.140 mol) is added, portionwise, over 1 hour to a stirred solution of 3-methoxycyclopent-2-enone (14.95 g, 0.133 mol) in 1,2-dichloroethane (300 ml) at 0° C. in an amber flask. The reaction mixture is stirred at 0° C. for a further 90 minutes and then any remaining solid is removed by filtration. The filtrate is evaporated to dryness under reduced pressure, the resultant solid is dissolved in warm toluene (600 ml) and washed quickly with ice-cold water (2×100 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure until approximately 150 ml remains. The residue is cooled with an ice bath and left for 30 minutes. The resultant solid is removed by filtration, washed with hexane (50 ml) and air-dried to give 2-bromo-3-methoxycyclopent-2-enone.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([NH2:19])[C:16]([C:20]#[N:21])=[C:15](Cl)[N:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[NH2:19][C:17]1[C:16]([C:20]#[N:21])=[C:15]([NH:30][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[N:14]=[C:13]([C:11]([NH:10][CH2:9][C:8]2[CH:23]=[CH:24][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:12])[CH:18]=1
Reactant: CS(=O)(=O)c1ccc(CNC(=O)c2cc(N)c(C#N)c(Cl)n2)cc1
Reactant: NC1CCCC1
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cc(N)c(C#N)c(NC3CCCC3)n2)cc1
Temperature: 160 °C
Yield: 81 %

Procedure:
A mixture of Example 181F (36.5 mg, 0.1 mmol) and cyclopentylamine (25.5 mg, 0.3 mmol) in N,N-dimethylacetamide (1.5 ml) was stirred in a sealed tube. This reaction mixture was heated in a microwave reactor at 160° C. for 20 min. and purified on HPLC (10 mM ammonium acetate, 5% acetonitirle in H2O/CH3CN) to give titled compound (33.5 mg, 81%). 1H NMR (300 MHz, DMSO-d6) δ 8.97 (t, J=6.0 Hz, 1H), 7.88 (d, J=9.0 Hz, 2H), 7.53 (d, J=9.0 Hz, 2H), 6.89 (s, 2H), and 6.70 (s, 1H), 6.27 (d, J=6.0 Hz, 2H), 4.57 (d, J=6.0 Hz, 2H), 4.57 (m, 1H), 3.18 (s, 3H), 1.95 (m, 1H), 1.67 (m, 2H), 1.50 (m, 4H); MS (APCI) m/z 414 [M+H]+, 412 [M−H]−.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([CH:19]=O)=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24].CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]2[CH:19]=[C:23]([C:22]([O:26][CH3:27])=[O:25])[S:24][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(-c2ccccc2)n(Cc2ccccc2)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(-c3ccccc3)n(Cc3ccccc3)c2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
A solution (1.1 M) of 1-benzyl-2-chloro-5-phenyl-1H-pyrrole-3-carbaldehyde in THF at 0° C. was treated with methyl thioglycolate (1.5 eq.) and a solution (2 M) of potassium tert-butoxide (2.5 eq.) in THF. The mixture was stirred at 0° C. for 2 h then at RT for 40 h. The reaction was quenched with water and pH was turned to neutral value by addition of aqueous ammonium chloride (saturated solution). The mixture was extracted with AcOEt and the combined organic phase was washed with brine and dried. Evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (1:30 acetone/toluene) to afford the title compound (38%) as a solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([C:16](=O)[CH3:17])[CH:13]=[C:12]([C:19](=O)[CH3:20])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl>C(O)C>[ClH:27].[ClH:27].[C:22]([NH:25][N:26]=[C:16]([C:14]1[CH:13]=[C:12]([C:19](=[N:26][NH:25][C:22](=[NH:23])[NH2:24])[CH3:20])[CH:11]=[C:10]([CH:15]=1)[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:17])(=[NH:24])[NH2:23]
Reactant: CC(=O)c1cc(NC(=O)c2ccccc2)cc(C(C)=O)c1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: CC(=NNC(=N)N)c1cc(NC(=O)c2ccccc2)cc(C(C)=NNC(=N)N)c1
Yield: 97 %

Procedure:
Compound 26, FIG. 7E.26: A solution of 3,5-diacetylaniline (0.885 g) in tetrahydrofuran (10 mL) containing 0.45 mL pyridine was treated with 0.65 mL benzoyl chloride. The mixture was stirred 1 hr, then treated with 1 mL water and stirred 15 min. The mixture was then diluted with 40 mL water and stirred 30 min. Filtration and washing with water and isopropanol gave colorless needles of N-benzoyl-3,5-diacetylaniline, 1.36 g, mp 188°-189° C. A suspension of N-benzoyl-3,5-diacetylaniline (0.844 g) in aq. 87.5% ethanol (8 mL) containing 0.73 g aminoguanidine hydrochloride and a trace of HCl was heated at reflux for 18 hr. Cooling and filtration gave 1.357 g of N-benzoyl-3,5-diacetylaniline bis(amidinohydrazone) dihydrochloride (Compound 26), mp 268°-72° C.
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:6]1)([O:3][CH3:4])=[O:2].[CH3:12][O:13][CH2:14][CH2:15]Br.O>CS(C)=O>[C:1]([C:5]1([CH2:15][CH2:14][O:13][CH3:12])[C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1CSCCC1=O
Reactant: COCCBr
Solvent: O
Solvent: CS(C)=O
Product: COCCC1(C(=O)OC)CSCCC1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 5.3 g (25 mmol) of potassium enolate of 4H-2,3,5,6-tetrahydro-3-carbomethoxythiopyran-4-one in 50 ml DMSO, was added 3.47 g (25 mmol) of 2-bromoethyl methyl ether. The solution was stirred under N2 at room temperature for 4 days. The reaction mixture was poured into 500 ml H2O and extracted three times with ethyl acetate. The combined ethyl acetate solution was washed with water; 5% NaOH; H2O and brine; dried over magnesium sulfate, filtered and concentrated in vacuo to give about 5 g crude product. Chromatographed through a pressure column eluting with 10% ethyl acetate-n-hexane to give 2.49 g of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13]([NH2:15])=O)=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13]#[N:15])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C(N)=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C#N

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propoxy)6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide with triphosgen/triethylamine in THF. mp 105-107° C., 1H NMR(CDCl3) d 6.90(s,2H), 6.26(brs,1H), 6.05(s,1H), 4.24(m,1H), 2.28(s,3H), 2.25(s,3H), 2.17(s,6H), 1.72(m,4H), 0.97(t,6H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:8]2[CH:9]=[C:10]([C:21]([OH:23])=O)[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=2)[CH:5]=[CH:6][N:7]=1)[CH3:2].[N:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[CH:30]([NH2:32])[CH3:31]>>[N:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[CH:30]([NH:32][C:21]([C:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=[C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:3]2[CH2:1][CH3:2])[CH:9]=1)=[O:23])[CH3:31]
Reactant: CCc1nccn1-c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Reactant: CC(N)c1cnccn1
Product: CCc1nccn1-c1cc(C(=O)NC(C)c2cnccn2)cc(-c2ccc(C)cc2)c1

Procedure:
5-(2-Ethyl-imidazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid was subject to the amide coupling reaction described in step 3 of Example 3, but replacing C-(5-methyl-pyrazin-2-yl)-methylamine with 1-pyrazin-2-yl-ethylamine, to give 5-(2-ethyl-imidazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, MS (M+H)=412.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH:26]2[CH:24]([O:25]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].FC(F)(F)S([O-])(=O)=O.[Ca+2].FC(F)(F)S([O-])(=O)=O>C(#N)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][C@@H:24]([OH:25])[C@H:26]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: Clc1ccc(N2CCCNCC2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ca+2]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCCN(c3ccc(Cl)cc3)CC2)C1
Temperature: 80 °C
Reaction time: 17 h
Yield: 43.1 %

Procedure:
To a solution of 1-(4-Chloro-phenyl)-[1,4]diazepane (1.00 g, 4.80 mmol) in acetonitrile (10 mL) was added 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.925 g, 5.00 mmol) and Calcium(II) trifluoromethanesulfonate (0.676 g, 2.00 mmol). The solution was stirred at 80° C. for 17 hours under nitrogen atmosphere. The reaction was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over MgSO4, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate→87:10:3 ethyl acetate:methanol:triethylamine) to yield 0.819 g (41%) of the title compound. EST-MS m/z: 396 (M+1), FAS method rt: 1.25 min.