Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:9]=[C:10]([OH:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].CS(O[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O>CC(N(C)C)=O>[CH3:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[O:17][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 85.6 %

Procedure:
Cesium carbonate (11.76 g, 26.11 mmoles, 2 equivalents) was added to a stirred solution of 3-methyl-4-nitrophenol (2.76 g, 18.05 mmoles, 1 equivalent) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (7.34 g, 19.96 mmoles, 1.1 equivalents) in anhydrous DMA (50 mls). The stirred reaction mixture was then heated to 90° C. (thermostatically controlled heating mantle) for 22 hours. The reaction mixture was then allowed to cool to room temperature and was filtered through a plug of Celite. The reaction flask and the Celite were then washed with ethyl acetate (250 ml). The organic solution was then transferred to a separatory funnel and extracted with additional ethyl acetate (3×200 ml). The combined ethyl acetate solution was then washed with water (2×100 ml), saturated sodium chloride (2×100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a product. This material was triturated with diethylether to give a crystalline solid which was filtered off, washed with diethylether and dried under reduced pressure to give 5.2 g of tert-butyl 4-(3-methyl-4-nitrophenoxy)piperidine-1-carboxylate (yield=82%). 1H-NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.89 (d, 1H), 7.74 (d, 1H), 3.82 (d, 2H), 3.65 (m, 2H), 2.40 (s, 3H), 1.76 (m, 1H), 1.54 (m, 2H), 1.38 (s, 9H), 0.98 (m, 2H). MS (EI): 351 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])OC2C=CC=CC=2)=[CH:11][N:10]=1.[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2>>[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:16](=[O:24])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][CH:11]=1)[CH2:30][CH2:29]2
Reactant: O=C(Nc1ccc(OCc2ccccn2)nc1)Oc1ccccc1
Reactant: Brc1ccc2c(c1)CCN2
Product: O=C(Nc1ccc(OCc2ccccn2)nc1)N1CCc2cc(Br)ccc21

Procedure:
Phenyl N-[2-(pyridin-2-ylmethyloxy)pyridin-5-yl]carbamate (D3) and 5-bromoindoline were converted into the title compound using a method similar to that of Example 1, m.p. 138-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[N:7][CH:8]=1.P(Cl)(Cl)([Cl:22])=O>C(Cl)(Cl)(Cl)Cl>[Cl:22][C:8]1[N:7]=[N:6][C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Oc2cc(C(F)(F)F)nn2C)nnc1Cl
Yield: 64 %

Procedure:
5-Methoxy-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine, 1-oxide (Compound No. 55, 1.0 g, 0.00344 mole) and phosphorus oxychloride (0.6 g, 0.00391 mole) were refluxed under N2 in carbon tetrachloride (40 mL) for 18 hours. The mixture was then partitioned between water and ethyl acetate. The aqueous layer was extracted again with ethyl acetate and the combined organic layers were washed with saturated sodium bicarbonate, brine, filtered through silica gel with ethyl acetate and evaporated in vacuo. The crude solid was recrystallized from ethyl acetate/cyclohexane to give 3-chloro-4-methoxy-6-[[1-methyl-3-(trifluoromethyl)- 1H-pyrazol-5-yl]oxy]pyridazine (0.681 g, 64% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cnn(-c3ccc(F)cc3)c2cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)c1cc2c(cnn2-c2ccc(F)cc2)cc1CC(C)(C)C(=O)O
Yield: 99.2 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yl)-2,2-dimethylpropanoate (87 mg, 0.236 mmol) was heated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, and concentrated in vacuo to give 83 mg (99% yield) of acid 3-(1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yl)-2,2-dimethylpropanoic acid. MS found: (M+H)+=355.
Reaction SMILES: [NH2:1][C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH:29]1([C:32]([NH:1][C:2]2[N:28]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]5[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=5)=[O:19])[CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)nn4c3)ccc2F)n(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2F)n(C)n1
Yield: 71 %

Procedure:
To a solution of N-{5-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (581 mg, 1.52 mmol) in N,N-dimethylacetamide (5 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (166 μL, 1.83 mmol), and the mixture was stirred at room temperature for 1 hr. Cyclopropanecarbonyl chloride (492 μL, 0.966 mmol) was further added and the mixture was stirred for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (485 mg, 71%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[C:19](F)[N:18]=[C:17]([C:22]#[N:23])[N:16]=2)=[CH:10][CH:9]=1>C(O)(C)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[CH:20]=[C:19]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:18]=[C:17]([C:22]#[N:23])[N:16]=2)=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: N#Cc1nc(F)cc(Nc2ccc(Cl)cc2)n1
Solvent: CC(C)O
Product: N#Cc1nc(Nc2ccc(Cl)cc2)cc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Morpholine (0.16 g) was added to a solution of the product from step (ii) (0.16 g) in iso-propylalcohol (4 ml) and stirred for 2 h at room temperature. The mixture was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution, the organics separated, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/ethyl acetate (1:1). Yield 0.09 g
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31]2[N:32]=[C:33]([NH:36]C(=O)C)[S:34][CH:35]=2)[C:14]1=[O:40])=[O:11].CO.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31]2[N:32]=[C:33]([NH2:36])[S:34][CH:35]=2)[C:14]1=[O:40])=[O:11]
Reactant: CC(=O)Nc1nc(CN2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)N=C(c3ccccc3)c3ccccc32)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(CN2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)N=C(c3ccccc3)c3ccccc32)cs1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A mixture of (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-1-[(2-acetamidothiazol-4-yl) methyl]-5-phenyl-2H-1,4-benzodiazepine-2-one, methanol (13 ml), tetrahydrofuran (8 ml) and conc. hydrochloric acid (0.8 ml) was stirred for 7.0 hours at 70° C., cooled and adjusted to pH 7.0 with 5% aqueous solution of sodium bicarbonate. To the mixture were added water (100 ml) and ethyl acetate (100 ml) under cooling. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with an eluent of a mixture of ethyl acetate and chloroform (2:1) to give (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-1-[(2-aminothiazol-4-yl)methyl]-5-phenyl-2H-1,4-benzodiazepine-2-one.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)=[CH:14][CH:15]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=Cc1ccc(N2CCC(N3CCCCC3)CC2)cc1
Reactant: C1CCNCC1
Product: c1cc(N2CCC(N3CCCCC3)CC2)ccc1CN1CCCCC1

Procedure:
Prepared from the product of Example 5 and piperidine.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C@@H:20]([O:23]C(=O)C)[C:19]2=[O:27])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].O>CO>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C@@H:20]([OH:23])[C:19]2=[O:27])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(N2CC[C@@H](OC(C)=O)C2=O)nc1Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCOc1ccc(N2CC[C@@H](O)C2=O)nc1Cc1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
453 mg of 2-benzyl-3-methoxymethyloxy-6-[(3R)-3-acetoxy-2-pyrrolidinone-1-yl]pyridine was dissolved in 5 ml of methanol, and two droplets of a 28% methanol solution of sodium methoxide was added thereto under stirring at room temperature, followed by stirring for 30 minutes. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to separation and purification using silica gel column chromatography using 66% ethyl acetate/hexane as an eluent, to give 371 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20](N)[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:26].[OH-].[NH4+]>O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([OH:26])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Oc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A solution of 1.2 g (0.00354 mol) of 9-chloro-7-(2-fluorophenyl)-2-amino-5H-pyrimido[5,4-d][2]benzazepine in 20 ml of concentration sulfuric acid and 20 ml of water was refluxed for 12 hr, and then cooled. After the addition of ice, the reaction mixture was basified with ammonium hydroxide and extracted with 100 ml of dichloromethane. The solids were collected by filtration and recrystallized from dichloromethane/methanol to give the end product as white prisms, mp 297°-299° dec. The dichloromethane extract was dried, evaporated and the residue crystallized from dichloromethane/methanol to give additional product.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH2:22])[C:16]([C:23]([NH2:25])=[O:24])=[CH:15]2>CCCCCC>[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[N:22]=[C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])[NH:25][C:23](=[O:24])[C:16]1=[CH:15]2
Reactant: NC(=O)c1cc2cc(F)ccc2nc1N
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)c1nc2nc3ccc(F)cc3cc2c(=O)[nH]1
Temperature: 160 °C

Procedure:
A mixture of diethyl oxalate (57.2 g., 0.392 mole) and 6-fluoro-2-aminoquinoline-3-carboxamide (5.34 g., 0.0261 mole) is heated for eighteen hours at 160° C. under a nitrogen atmosphere and then allowed to cool to room temperature. Hexane (300 ml.) is added, the mixture stirred and filtered to provide the desired product. It is washed with hexane and dried. Yield = 4.9 g. (71%); m.p. 272° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:17]([C:16](=[O:21])[CH3:15])[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
20 g (106 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 12 ml (116 mmol) of 2,4-pentanedione, 9.1 ml (159 mmol) of acetic acid and 0.21 ml (2.1 mmol) of piperidine in 400 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from isopropanol. 24.3 g (73% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([C:8]2[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=2[C:10]([N:12]([C:15]([CH3:29])([CH3:28])[CH2:16][NH:17]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH3:14])=O)=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](=[O:7])[C:8]2[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=2[C:10]2[N:12]([CH2:13][CH3:14])[C:15]([CH3:29])([CH3:28])[CH2:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: CCN(C(=O)c1ccccc1C(=O)c1ccc(Cl)cc1)C(C)(C)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Product: CCN1C(c2ccccc2C(=O)c2ccc(Cl)cc2)=NCC1(C)C
Reaction time: 21 h

Procedure:
One-hundred-ninety grams of 2-(p-chlorobenzoyl)-N-[1,1-dimethyl-2-(p-toluenesulfonamido)ethyl]-N-ethyl benzamide and 400 ml. of 90% (v/v) sulfuric acid were mixed together and heated in a steam bath for 45 minutes. The solution was left at room temperature for 21 hours, then quenched with 3 volumes of ice water. The mixture was extracted with dichloromethane. The aqueous portion was cooled and made basic with 50% sodium hydroxide solution. The mixture was extracted with dichloromethane. This solvent was removed in vacuo. The residue crystallized on standing overnight. A portion was recrystallized from diethyl ether-hexane to obtain 4'-chloro-2-(1-ethyl-5,5-dimethyl-2-imidazolin-2-yl)benzophenone, m.p. 85°-87°C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][CH2:20][CH3:21].[Cl-].[NH4+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:19][CH2:20][CH3:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
6.694 g of ethyl 4-nitrophenylacetate are dissolved in 30 ml of DMF, added dropwise to a suspension of 1.4 g of sodium hydride in 30 ml of DMF with ice-cooling and stirred for 30 min. 2.91 ml of 1-bromopropane in 20 ml of DMF are subsequently added, and the mixture is stirred at 23° C. for 12 h. The reaction mixture is subsequently stirred into 100 ml of saturated ammonium chloride solution. The mixture is washed four times with 100 ml of ethyl acetate each time, the combined organic phases with 100 ml of sodium chloride solution, dried over sodium sulfate and, after filtration, evaporated to dryness in vacuo. The residue is purified by column chromatography (reversed phase). Yield: 5.3 g (66%) of ethyl 2-(4-nitrophenyl)pentanoate; LC-MS retention time: 2.28 min (“nonpolar” gradient).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:40])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]2[NH:24][C:25](=[O:40])[CH2:26][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N:34]4[CH:38]=[N:37][CH:36]=[N:35]4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2
Yield: 88.1 %

Procedure:
Prepared from {5-(isobutyl-methyl-amino)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M122) (0.50 g, 0.87 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (350 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[F:11][C:12]([F:18])([F:17])[CH:13](OC)[OH:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][CH:13]([OH:14])[C:12]([F:18])([F:17])[F:11])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: COC(O)C(F)(F)F
Product: O=C(NC(O)C(F)(F)F)c1ccc(Br)cc1
Temperature: 100 °C

Procedure:
was prepared by use of 2,2,-trifluoro-1-methoxy-ethanol in place of chloral in the general method set forth above with the following procedural changes: A mixture of 4-bromobenzamide (0.78 g, 3.9 mmol) and 2,2,2-trifluoro-1-methoxy-ethanol (0.51 mL, 4.3 mmol) was heated at 100° C. for 18 hours. The mixture was evaporated and the residue was diluted with chloroform and concentrated onto silica gel. The product was purified on a SiO2 MPLC column with 1% MeOH:CH2Cl2 to yield the intermediate 4-bromo-N-(2,2,2-trifluoro-1-hydroxyethyl)benzamide, which was used in the general method set forth above to prepare Compound 13.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)=[CH:4][CH:3]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[C:22]1([NH:28][C:29]([NH:1][C:2]2[CH:21]=[CH:20][C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]=[CH:11][N:12]=3)=[CH:4][CH:3]=2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(Oc2cc(Nc3ccccc3)ncn2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Nc3ccccc3)ncn2)cc1
Yield: 87 %

Procedure:
N-(6-(4-Aminophenoxy)pyrimidin-4-yl)phenylamine (55.6 mg, 0.200 mmol) and phenyl isocyanate (26.1 mg, 0.220 mmol) were stirred together in dimethylformamide (1 ml) at room temperature for 12 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (69.0 mg, 0.174 mmol, 87%) as colorless crystals.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[N+:2]=[N-].C1(P(C2C=CC=CC=2)CCC(ON2C(=O)CCC2=O)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[N+:1](=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[N-:2]
Reactant: [N-]=[N+]=NCC(=O)c1ccccc1
Agent: O=C(CCP(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: [N-]=[N+]=CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
A solution of azide 2i (74 mg, 0.459 mmol) in anhydrous toluene (1.5 mL) was cooled to 0° C. A solution of phosphine 1e (171 mg, 0.482 mmol) in toluene (1.0 mL) was added dropwise. The resulting solution was maintained at 0° C. for 2 h and was then allowed to warm to room temperature. The mixture was then diluted with anhydrous CH2Cl2 (5 mL) and was stirred for an additional 30 min. The solution was then placed directly on a column of silica gel and eluted with 15% EtOAc/hexanes to give diazo-compound 5i as a yellow oil (33 mg, 0.226 mmol, 49% yield).
Reaction SMILES: [CH:1](C1C=C(C(C)C)C=CC=1C(C1C=CC=CC=1C(OC/C=C(/CCC=C(C)C)\C)=O)=O)(C)[CH3:2].C(C1C=CC=CC=1C(C1C=CC=CC=1C(OC/C=C(/CCC=C(C)C)\C)=O)=O)(C)C.[CH3:64][CH:65]([CH2:81][CH3:82])[C:66](=[O:80])[C:67]([O:69][CH2:70][CH2:71][CH:72]([CH3:79])[CH2:73][CH2:74][CH:75]=[C:76]([CH3:78])[CH3:77])=[O:68]>CCCCCC>[O:80]=[C:66]([C:65]1[CH:64]=[CH:2][CH:1]=[CH:82][CH:81]=1)[C:67]([O:69][CH2:70][CH2:71][CH:72]([CH3:79])[CH2:73][CH2:74][CH:75]=[C:76]([CH3:77])[CH3:78])=[O:68]
Reactant: CCC(C)C(=O)C(=O)OCCC(C)CCC=C(C)C
Reactant: CC(C)=CCC/C(C)=C/COC(=O)c1ccccc1C(=O)c1ccc(C(C)C)cc1C(C)C
Agent: CC(C)=CCC/C(C)=C/COC(=O)c1ccccc1C(=O)c1ccccc1C(C)C
Solvent: CCCCCC
Product: CC(C)=CCCC(C)CCOC(=O)C(=O)c1ccccc1

Procedure:
UV/Vis (hexane): 370 (sh, 30), 352 (40), 340 (sh, 40), 294 (sh, 1020), 252 (10350), 248 (10360). IR (neat): 3065w, 2962s, 2926s, 2872m, 2855m, 1738s, 1693s, 1597m, 1581m, 1451m, 1379m, 1322m, 1313m, 1300m, 1246w, 1198s, 1175s, 1122w, 1042w, 1030w, 1003m, 998m, 941w, 831w. 1H NMR (360 MHz, CDCl3): 8.04-7.97 (m, 2H); 7.69.7.62 (m, 1H); 7.55-7.45 (m, 2H); 5.12-5.03 (m, 1H); 4.50-4.36 (m, 2H); 2.15-1.90 (m, 2H); 1.90-1.75 (m, 1H); 1.75-1.50 (m, 2H); 1.66 (s, 3H); 1.59 (s, 3H); 1.45-1.32 (m, 1H); 1.32-1.15 (m, 1H); 0.96 (d, J=6.3, 3H). 13C NMR (90.6 MHz, CDCl3): 186.50 (s); 164.02 (s); 134.87 (d); 132.56 (s); 131.51 (s); 130.02 (d); 128.90 (d); 124.40 (d); 64.85 (t); 36.93 (t); 35.30 (t); 29.44 (d); 25.69 (q); 25.38 (t); 19.38 (q); 17.66 (q). MS (EI): 288 (M+, 1); 270 (4); 260 (1); 227 (1); 215 (1); 187 (1); 174 (1); 165 (1); 155 (4); 152 (3); 138 (9); 137 (10); 134 (2); 123 (11); 109 (8); 106 (10); 105 (100); 96 (3); 95 (20); 83 (3); 82 (12); 81 (24); 80 (2); 78 (3); 77 (36); 70 (3); 69 (26); 68 (5); 67 (10); 57 (3); 56 (3); 55 (11); 53 (3); 51 (10); 43 (4); 42 (3); 41 (28); 39 (5); 29 (4); 27 (4).