Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H:2]([CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9])[C:3]([OH:5])=[O:4].[OH:12]S(O)(=O)=O.N([O-])=O.[Na+]>O.CCOCC>[F:9][C:8]([F:11])([F:10])[CH2:7][CH2:6][C@@H:2]([OH:12])[C:3]([OH:5])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: N[C@H](CCC(F)(F)F)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)[C@H](O)CCC(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cool (0° C.), stirred solution of (2R)-2-amino-5,5,5-trifluoropentanoic acid (4.09 g, 23.90 mmol) (U.S. Publication No. 2009/0111858 A1) and H2SO4 (2.8 mL, 52.5 mmol) in water (95 mL) was added a solution of sodium nitrite (9.89 g, 143 mmol) in water (30 mL) dropwise via addition funnel over 60 min. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was diluted with Et2O, the aqueous phase was separated and extracted with Et2O (3×). The combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure to provide Preparation 4B (4.1551 g, >99%) as an amber oil. 1H NMR (400 MHz, CDCl3) δ 4.33 (1H, dd, J=8.03, 4.27 Hz), 2.09-2.42 (3H, m), 1.88-2.02 (1H, m).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[CH2:11][CH2:10][C:9]=2[N:8]=1>>[NH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:13]3[CH:18]=[CH:19][C:20]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:21][C:12]=3[CH2:11][CH2:10][C:9]=2[N:8]=1
Reactant: Nc1nc2c(c(=O)[nH]1)-c1ccccc1CC2
Reactant: O=S(=O)(O)Cl
Product: Nc1nc2c(c(=O)[nH]1)-c1ccc(S(=O)(=O)Cl)cc1CC2
Reaction time: 0.33 h

Procedure:
Chlorosulfonic acid(25 ml, Aldrich), cooled to 5° C. in ice, was stirred during its addition to 3-amino-1,2,5,6-tetrahydro-1-oxo-benzo[f]quinazoline (5 g, 0.025 mole) contained in a beaker immersed in an ice bath. The solution was removed from the ice bath, stirred for a further 20 min, then poured onto ice (1000 g). The solid product was removed by filtration, washed with water, and dried under high vacuum at room temperature. The sulfonyl chloride was used without further purification.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:15]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[NH:17][CH:18]=1.O>N1C=CC=CC=1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[NH:17][CH:18]=[C:14]([CH2:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[C:15]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: NCCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)NCCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
188 mg (1.08 mmol) of methanesulfonic anhydride were added to a solution of 290 mg (0.982 mmol) of 4-(3-aminopropyl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole (prepared as described in Example 1 above) in 5 ml of pyridine and the resulting mixture was allowed to stand overnight. At the end of this time, water was added to the reaction mixture, giving a precipitate which was collected by filtration and washed with ethyl acetate to give 208 mg (yield 57%) of the title compound as a pale brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH:11]([C:15](=O)[CH2:16][CH3:17])[C:10](=[O:19])[CH2:9]1.O.[NH2:21][NH2:22].O.NN>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[NH:22][N:21]=[C:15]([CH2:16][CH3:17])[C:11]=2[C:10](=[O:19])[CH2:9]1
Reactant: CCC(=O)C1C(=O)CC(c2ccccc2Cl)CC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 142.7 %

Procedure:
A solution of 5-(2-chlorophenyl)-2-propionylcyclohexane-1,3-dione (0.6 g) and hydrazine hydrate hydrazine hydrate (0.12 g) in ethanol (20 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(2-chlorophenyl)-3-ethyl-4,5,6,7-tetrahydroindazol-4-one (0.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:10]=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][N:12]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1cnc(-c2ccc(Cl)cc2)cn1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(OC)cc2)C1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)cn2)CCN(C(=O)c2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 5-(4-chloro-phenyl)-pyrazin-2-ol (Preparation 25) and 3-iodomethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 14) to afford the racemate as a white solid (44 mg, 22%)
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11]COCC.[N+](=C)=[N-]>O1CCCC1>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)cc1
Yield: 99.3 %

Procedure:
Fifty (50) mmol (12.4 g) of commercially available 4-iodobenzoic acid was dissolved in 200 ml of tetrahydrofuran and then added to an ether solution containing freshly prepared diazomethane. The excess diazomethane was subsequently consumed by addition of glacial acetic acid and the resultant solution was concentrated in vacuo. The residue thus obtained was partitioned between ethyl acetate and saturated NaHCO3. The layers were separated and the aqueous phase was extracted with 100 ml of ethyl acetate. The organic extracts were combined, dried over Na2SO4, and concentrated in vacuo, yielding 13.01 grams (99.3% yield) of a yellow solid which melted at 111° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:12]([O:14]C(=O)OCC)C.CC(C)([O-])C.[K+]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:12](=[O:14])[CH:9]=[C:8]2[OH:10]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CCOC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1cc(O)c2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.7 %

Procedure:
1-(5-Fluoro-2-hydroxy-phenyl)-ethanone (1.54 g, 10 mmol) and diethylcarbonate (2.42 mL, 20 mmol) were placed in a dry flask and dissolved in anhydrous tetrahydrofuran (30 mL.) The solution was then added drop-wise via cannula to a rapidly stirring solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 30 mL) The reaction was permitted to stir overnight (10 h) at room temperature under positive pressure of nitrogen. The crude reaction was concentrated under reduced pressure and partitioned between methyl tert-butyl ether and water. The layers were separated and the organic phase discarded. The aqueous phase was acidified to pH 5 and extracted three times with equal volumes of methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated to give the title compound (1.4 g, 78% yield.) MS ESI(−) m/e: 179.16 (M−1).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 0.42 h
Yield: 64.4 %

Procedure:
208 g of anthraquinone are introduced into 1145 g of 99% nitric acid (mole ratio 18:1) at 25° with cooling and the reaction mixture is stirred for 25 minutes. The reaction is then stopped by rapidly distilling off 693 g of 99% nitric acid and the product is precipitated by slowly cooling the reaction mixture to 0°. After washing with dilute nitric acid, the product is freed from nitric acid and distilled together with 800 g of paraffin oil at 30 Torr with a head temperature of between 250° and 300°. 1-Nitroanthraquinone which precipitates from the condensate is filtered off and freed from paraffin oil by washing with petroleum ether. 163 g of 98.9% pure 1-nitroanthraquinone are obtained (63.5% of the theoretical amount).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:25]1[NH:29][N:28]=[N:27][N:26]=1)[C:20]1[NH:24][N:23]=[N:22][N:21]=1.[OH-].[Na+]>CO.O.Cl>[NH:26]1[C:25]([CH:19]([C:20]2[NH:21][N:22]=[N:23][N:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[N:29][N:28]=[N:27]1
Reactant: COC(=O)CCCCCCCCCCCCCCCC(c1nnn[nH]1)c1nnn[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCCCCCCCCCC(c1nnn[nH]1)c1nnn[nH]1
Yield: 32.3 %

Procedure:
17,17-Bis(5-tetrazolyl)heptadecanoic acid methyl ester (1.70 g, 4.04 mmol) was dissolved in MeOH (40 ml), and a solution of NaOH (1.17 g, 29 mmol) in water (3 ml) was added. After stirring at room temperature for 19 h no more starting ester could be detected by 1H NMR, and the mixture was diluted with a mixture of water (130 ml) and 1N HCl (50 ml). The product was isolated by filtration, washed with water, and recrystallized from boiling MeCN (40 ml), to yield 0.53 g (32%) of the title compound as a solid. From the mother liquor more product (0.39 g) could be obtained. Total yield: 0.92 g, 56%.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)[CH2:2]1.[H-].[Na+].[CH2:12]([O:14][C:15](=O)[O:16]CC)[CH3:13]>CN(C)C=O>[O:9]=[C:6]1[CH2:7][CH2:8][C:3]2([CH2:2][CH2:1]2)[CH2:4][CH:5]1[C:15]([O:14][CH2:12][CH3:13])=[O:16]
Reactant: O=C1CCC2(CC1)CC2
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC2(CCC1=O)CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
To a stirred solution of spiro[2.5]octan-6-one (prepared according to the procedure reported in US2008176926) (0.900 g, 7.25 mmol) in dimethylformamide (10 ml) at 5° C. was added sodium hydride (0.580 g, 60%, 14.50 mmol) under a nitrogen atmosphere over a period of 10 min and the resulting mixture was stirred for an additional 20 min at the same temperature. To this reaction mixture, diethylcarbonate (1.72 g, 14.50 mmol) was added at 5° C. and stirred for 1 h and then allowed to stir at room temperature for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0° C. and quenched with saturated ammonium chloride (10 ml) and diluted with water (30 ml). The resulting mixture was extracted with diethyl ether (2×20 ml), and the combined organic layer was washed with water (2×20 ml), dried over anhydrous sodium sulphate, filtered, and the solvent was removed under reduced pressure to obtain a crude product which was purified by flash chromatography over silica gel (100-200 mesh) using 1% ethyl acetate in hexane as eluent to yield the title compound (0.510 g, 35.9%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH:19]([C:21]2[CH:26]=[C:25]([OH:27])[C:24]3[C:28]4[CH2:29][NH:30][CH2:31][CH2:32][C:33]=4[C:34]([CH3:37])([CH3:36])[O:35][C:23]=3[CH:22]=2)[CH3:20])=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH:19]([C:21]2[CH:26]=[C:25]([OH:27])[C:24]3[C:28]4[CH2:29][N:30]([CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4])[CH2:31][CH2:32][C:33]=4[C:34]([CH3:36])([CH3:37])[O:35][C:23]=3[CH:22]=2)[CH3:20])=[CH:12][CH:11]=1
Reactant: NC(=O)NC(=O)CCl
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 1.50 g. (0.011 mole) of chloroacetyl urea in 20 ml. of dimethylformamide was added dropwise to a stirred solution of 3.95 g. (0.01 mole) of 8-[5-(4-fluorophenyl)-2-pentyl]-10-hydroxy-5,5-dimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine in 25 ml. of dimethylformamide and 1.11 g. (0.011 mole) of triethylamine. After stirring at room temperature for 22 hours, the mixture was diluted with 45 ml. of water and extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was recrystallized from acetonitrile, m.p. 133°-134°.
Reaction SMILES: NC1C=CC2NC=C3C(=O)N(C4C=CC=CC=4)N=C3C=2C=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:44](=[O:45])[C:32]3=[CH:33][NH:34][C:35]4[CH:36]=[CH:37][C:38]([N+:41]([O-])=O)=[CH:39][C:40]=4[C:31]3=[N:30]2)=[CH:25][CH:24]=1>>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]=[C:32]3[C:44](=[O:45])[N:29]([C:26]4[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=4)[N:30]=[C:31]3[C:40]=2[CH:39]=1
Reactant: O=c1c2c[nH]c3ccc([N+](=O)[O-])cc3c-2nn1-c1ccc(Cl)cc1
Agent: Nc1ccc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1
Product: Nc1ccc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2c1

Procedure:
The title compound was prepared following the procedure described for 6a using 5b. 1H-NMR (DMSO-d6) δ (ppm): 7.19 (1H, tt, J=7.32, 1.22 Hz), 7.44 (4H, m), 8.22 (4H, m), 8.48 (1H, d, J=6.59 Hz). m/z 311.8 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:67]1[CH:72]=[CH:71][C:70]([N+:73]([O-:75])=[O:74])=[C:69]([N+:76]([O-:78])=[O:77])[CH:68]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[N+:73]([C:70]1[CH:71]=[C:72]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)[CH:67]=[CH:68][C:69]=1[N+:76]([O-:78])=[O:77])([O-:75])=[O:74]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 78 %

Procedure:
To an oven-dried flask, 1-boc-piperazine (1.59 g, 8.5 mmol), Cs2CO3 (2.91 g, 8.93 mmol), Pd2(dba)3 (0.72 g, 0.78 mmol), rac-2,2′bis(diphenylphosphino)-1,1′-binaphthyl (0.44 g, 0.71 mmol), toluene (6 mL) and compound 24 (1.76 g, 7.14 mmol) were added. While stirring the reaction mixture at room temperature, the air in the flask was removed and replaced by N2. This process was repeated three times. The reaction mixture was further stirred at room temperature for 0.5 h. Ethyl acetate (50 mL) was added to the mixture at room temperature, washed with H2O (15 mL) and brine (10 mL), dried over Na2SO4, and evaporated. The brown oily material was chromatographed on a silica column, eluting with hexanes:ethyl acetate (30:70), and then changing to (40:60), yielding compound 25. Yield: 78%, yellow solid. IR (KBr, cm−1) 3073 (Ar—H), 1683 (CO), 1528, 1432 (C═C), 1226 (C—N), 1151 (C-0); 1H NMR (500 MHz, CDCl3) δ 1.48 (9H, s, OC(CH3)3), 3.02 (m, 4H, 2CH2), 3.58 (m, 4H, 2CH2), 7.17 (dd, J=2.6, 8.8 Hz, 1H, H-6), 7.24 (d, J=2.5 Hz, 1H, H-2), 7.71 (d, J=8.5 Hz, 1H, H-4). 13C NMR (125.7 MHz, CDCl3) δ 28.30 (OC(CH3)3), 48.24 (CH2), 51.39 (CH2), 80.12 (OC(CH3)3), 124.23 (C-2), 124.92 (C-6), 127.49 (C-5), 128.17 (C-4), 141.62 (C-3), 146.94 (C-1), 154.60 (CO). Anal. Calcd for C15H20N4O6: C, 51.13; 11, 5.72; N, 15.90%. Found: C, 51.07; H, 5.78; N, 15.82%.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH3:28][CH:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=2)[C:11]([NH:35][CH:32]2[CH2:33][CH2:34][CH:29]([CH3:28])[CH2:30][CH2:31]2)=[O:12])=[CH:26][CH:27]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CC1CCC(N)CC1
Product: CC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 105.5 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.5 g (1.26 mmol) and 4-methylcyclohexylamine (0.143 g, 1.26 mmol) were used to afford 0.6 g of the required product. Percentage purity (LCMS): 84.6%, (M+1)=451.1+1.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:11]([CH2:14][CH2:15][CH2:16][N:17]=[N+]=[N-])(=[O:13])=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>CO>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:11]([CH2:14][CH2:15][CH2:16][NH2:17])(=[O:12])=[O:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCCN=[N+]=[N-])CC1
Solvent: CO
Product: CC(C)N1CCC(NS(=O)(=O)CCCN)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
250 mg (0.86 mmol) crude 3-azido-propane-1-sulfonic acid (1-isopropyl-piperidin-4-yl)-amide were dissolved in 10 ml MeOH. The solution was evacuated and rinsed with argon several times. 30 mg palladium on charcoal (10%) were added and again the mixture was evacuated and rinsed with argon several times. Finally argon was exchanged by hydrogen (balloon filled with hydrogen) and the mixture was stirred for 4 h at room temperature. The reaction mixture was filtered over “Celite” and the filter residue was washed with 10 ml MeOH. The filtrate was concentrated under vacuo to give crude 3-amino-propane-1-sulfonic acid (1-isopropyl-piperidin-4-yl)-amide as yellow oil. Yield: 200 mg MS (ES+): m/e=264.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:10])[CH:7]=1.C(OO)(=[O:23])C>C(O)(=O)C>[N+:18]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=1[CH2:8][S:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:17])(=[O:23])=[O:10])([O-:20])=[O:19]
Reactant: CC(=O)OO
Reactant: Cc1ccc([N+](=O)[O-])c(CS(=O)c2cccc[n+]2[O-])c1
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2cccc[n+]2[O-])c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Five grams [5.0 g (0.02 mole)] of 2-[[(5-Methyl-2-nitrophenyl) methyl]sulfinyl]pyridine-N-oxide, was slurried in 30 ml of glacial acetic acid. The slurry was stirred while 3.6 g of 40% peracetic acid (1.11 mole) was added dropwise. After addition, the mixture was heated to 60° C. for 4 hours, allowed to cool and stirred at room temperature overnight. Excess peracetic acid was destroyed using NaHSO3. The mixture was neutralized with K2CO3 solution, and the solid was filtered and washed with water. After drying, the solid melted at 178-183° C. and had an NMR consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]1([CH2:15][C:16]#[N:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+].CCOC(C)=O>CN1C(=O)CCC1.O>[Br:8][C:7]1[C:2]([CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]#[N:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccnc1Br
Reactant: N#CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#CC(c1ccccc1)c1ncccc1Br

Procedure:
2,3-Dibromo-pyridine (1 eq., 0.5 g) and Phenyl-acetonitrile (4 eq., 0.97 mL) were mixed in NMP (3 mL). Potassium tert-butoxide (1.3 eq, 0.3 g) was added to the solution. The resulting mixture was heated in microwave at 110° C. for 40 min EtOAc and water were added to the reaction mixture. The aqueous layer was separated and extracted with EtOAc (×3). The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid. It was used in the next step without further purification
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]([NH2:43])=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=3)[CH2:20][CH2:19]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:11]1[N:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[C:30]2[CH:31]=[C:32]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([NH2:43])[C:24]([N:21]2[CH2:20][CH2:19][O:18][CH2:23][CH2:22]2)=[CH:33]3)[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=12
Reactant: Cc1cccc(-c2nnc3ccccn23)c1Br
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cccc(-c2nnc3ccccn23)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A mixture of 3-(2-bromo-3-methylphenyl)-[1,2,4]triazolo[4,3-a]pyridine (0.32 g, 1.111 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.17 g, 0.479 mmol, prepared as in Example 2, Step 1-2), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.046 g, 0.096 mmol), potassium phosphate, anhydrous (0.198 mL, 2.393 mmol), and Pd2(dba)3 (0.044 g, 0.048 mmol) was purged with N2 followed by the addition of degassed dioxane (2 mL) and water (1.0 mL). The resulting mixture was heated in microwave at 140° C. for 12 min. The reaction was filtered, concentrated, and the resulting crude material was chromatographed on silica gel using gradient 2:1 hexanes/EtOAc and 0-5% 2M NH3 in MeOH/DCM to afford a light yellow solid. It was repurified by HPLC to afford 6-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as a white solid. MS (ESI, pos. ion) m/z: 437 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2].[CH3:15]C1C=CC(C)=CC=1O>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2]
Reactant: CCOC(=O)COc1ccccc1C
Reactant: Cc1ccc(C)c(O)c1
Product: CCOC(=O)COc1cc(C)ccc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 10.1, using 2,5-dimethylphenol as the starting material. 1H NMR (400 MHz) (CDCl3) δ 7.03 (1H, d, J=7.5 Hz); 6.72 (1H, d, J=7.5 Hz); 6.52 (1H, s); 4.62 (2H, s); 4.27 (2H, q, J=7.1 Hz); 2.30 (3H, s); 2.25 (3H,s); 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1>CN(C=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][NH:12][C:13](=[O:16])[NH:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2cnc(=O)[nH]c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2CNC(=O)NC2)cc1
Reaction time: 3 h
Yield: 54.5 %

Procedure:
To a solution of 4-(2-oxo-pyrimidin-5-yl)-benzoic acid methyl ester (761 mg, 3.3 mmol, reference example 19c) in DMF (20 mL) and methanol (5 mL) was added Pd on carbon (250 mg, 10% w/w). The resulting mixtured was stirred under an atmosphere of hydrogen gas for 3 h. This mixture is purged with nitrogen gas then filtered through celite. The filtrate is concentrated and the residue purified by flash chromatography (eluting with 5% methanol in dichloromethane) to give the title compound (421 mg) as a white solid. 1H NMR (CD3OD) ? 3.28 (m, 1H), 3.47 (d, J=7 Hz, 4H), 3.90 (s, 3H), 7.44 (d, J=8 Hz, 2H), 7.90 (d, J=8 Hz, 2H).