Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C([Li])(C)(C)C.[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:29][CH3:30])=[C:20]([C:22]([CH3:28])([CH3:27])[CH2:23][C:24](=[O:26])[CH3:25])[CH:21]=1>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:29][CH3:30])=[C:20]([C:22]([CH3:27])([CH3:28])[CH2:23][C:24]([CH2:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)([OH:26])[CH3:25])[CH:21]=1
Reactant: Cc1cc(C)nc(C)c1
Reactant: COc1ccc(F)cc1C(C)(C)CC(C)=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(C)(O)Cc1cc(C)cc(C)n1
Temperature: -70 °C
Reaction time: 0.03 h
Yield: 56.1 %

Procedure:
To a solution of 2,4,6-trimethylpyridine (0.14 g) in THF (1 mL) stirred under argon and cooled to −70° C., tert-butyl lithium (1.7M in pentane, 0.75 mL) was added dropwise over 2 minutes. After stirring for an additional 2 minutes, 4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 17) (0.22 g) in THF (0.8 mL) was added all at once. After 5 minutes, the reaction was quenched with EtOH (0.2 mL) and allowed to warm to room temperature. The mixture was diluted with EtOAc, washed with water, dried, filtered, and evaporated. Chromatography of the residue over silica gel (eluent: EtOAc-methylene chloride (2:98 to 8:92 gradient)) gave the product as an oil (0.19 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.[CH3:12][C:13]([CH3:16])([O-:15])[CH3:14].[K+].C(O)(C)(C)C.Cl>C1COCC1>[C:13]([O:15][C:3](=[O:2])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1)([CH3:16])([CH3:14])[CH3:12]
Reactant: COC(=O)c1cncc(O)c1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cncc(O)c1
Yield: 34.2 %

Procedure:
5-Hydroxy-nicotinic acid methyl ester (1 g, 5.99 mmol) and potassium t-butoxide (4 g, 36 mmol) was stirred in THF (10 mL) and t-butanol (10 mL) at room temperature overnight. 1N HCl was added to adjust pH˜7 and the mixture was extracted with EtOAc (3×). The combined extracts were dried (Na2SO4), concentrated and purified by column chromatography to give the product (400 mg, 34%). MS (DCI) m/z 196 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH2:3][N:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[I:16].[CH2:17](OCC)C>C(#N)C>[I-:16].[CH2:13]([O:12][C:10]([NH+:2]1[CH2:1][C:9]2[CH:8]=[CH:7][N:6]([CH3:17])[CH2:5][C:4]=2[CH2:3]1)=[O:11])[CH3:14]
Reactant: CCOCC
Reactant: CI
Reactant: CCOC(=O)N1Cc2ccncc2C1
Solvent: CC#N
Product: CCOC(=O)[NH+]1CC2=C(CN(C)C=C2)C1
Product: [I-]

Procedure:
9.6 g (50 mmol) of ethyl 2,3-dihydro-1H-pyrrolo-[3,4-c]pyridine-2-carboxylate and 6.3 ml (100 mmol) of methyl iodide are refluxed for 15 hours in 50 ml of acetonitrile. The batch is poured into diethyl ether, and the salt which has precipitated is filtered off with suction and dried in the air.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][N:16](C=O)[CH2:15][CH2:14]2)[N:5]=1)[CH3:2]>[OH-].[K+].C(O)C>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc(OCC)nc(N2CCN(C=O)CC2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc(OCC)nc(N2CCNCC2)n1
Yield: 102.5 %

Procedure:
The product from (b) (3.25 g) in potassium hydroxide solution (1 N, 20 ml) and ethanol (30 ml) was left at room temperature for 3 hours. Then further potassium hydroxide solution (20 ml) was added. After 45 minutes the reaction mixture was extracted with chloroform (5×30 ml), and the combined chloroform extracts dried (Na2SO4) and evaporated in vacuo to give 4,6-diethoxy-2-piperazino-1,3,5-triazine (3.0 g) as an oil. The product was characterized spectroscopically and used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:20][CH2:19][C:14]3(OCCO3)[CH2:13][CH2:12]2)[CH:3]=1.[O:21]1C2(CCCC(C3C=C(O)N4N=CC=C4N=3)C2)[O:24][CH2:23][CH2:22]1.O1C2(CCC(C3C=C(O)N4N=CC=C4N=3)CC2)OCC1>>[Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:12][CH2:13][CH2:14][C:19]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:20]2)[CH:3]=1
Reactant: Oc1cc(C2CCCC3(C2)OCCO3)nc2ccnn12
Reactant: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Agent: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Product: Clc1cc(C2CCCC3(C2)OCCO3)nc2ccnn12

Procedure:
7-Chloro-5-(1,4-dioxaspiro[4.5]decan-7-yl)pyrazolo[1,5-a]pyrimidine is synthesized in a manner similar to the synthesis of 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine, but with 5-(1,4-dioxaspiro[4.5]decan-7-yl)pyrazolo[1,5-a]pyrimidin-7-ol substituted for 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.BrC1C=CC=CC=1C(Cl)=O.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23]O>C(Cl)Cl.S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:8][CH2:23][C:22]([CH3:26])([CH3:25])[N:21]=2)=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(N)CO
Agent: O=C(Cl)c1ccccc1Br
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(Br)cc2)=N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
4-Bromo benzoic acid (50 g, 0.25M) placed in a 500 mL round bottom flask fitted with a reflux condenser was added 150 mL of thionyl chloride and for 8 h. The excess of thionyl chloride was removed under vacuum and the white solid obtained was dissolved in 100 ml of dry CH2Cl2 and kept in an ice bath. To this ice cooled solution of bromo benzoylchloride was added drop wise 45 g of 2-amino-2-methylpropan-1-ol dissolved in another 100 mL of dry CH2Cl2 with stirring for the period of 1 h. The ice bath was removed and the reaction mixture was stirred at room temperature for over night. The precipitated white solid was filtered and washed several time with CH2Cl2 (4×100 mL). The combined CH2Cl2 was removed under rotaevoporator and the solid obtained was slowly dissolved in 150 mL of thionyl chloride and refluxed for 3 h. The excess of SOCl2 was evaporated to one-six volumes and poured in to 500 mL of dry ether cooled in ice bath and kept in the refrigerator overnight. The ether was removed and the precipitated hydrochloride was dissolved in 500 mL of cold water. The aqueous solution was carefully neutralized using 20% KOH solution on cold condition (ice bath) and the brown oily residue separated was extracted with CH2Cl2 (3×200 mL) and dried over anhydrous Na2SO4. Removal of the solvent gave 42 g (67%) of 2-(4-bromophenyl)-4,4-dimethyl-1,3-oxazoline as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ ppm: 1.36 (s, 6H), 4.08 (s, 2H), 7.52 (d, 2H), 7.79 (d, 2H). Mass: 254.3 (M+).
Reaction SMILES: [OH-].[Li+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[C:14]([C:18]1[CH:44]=[CH:43][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[CH:26][C:25]=2[CH:41]=O)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].Cl>O1CCCC1>[C:14]([C:18]1[CH:44]=[CH:43][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:34][CH:35]=3)=[CH:26][C:25]=2[CH:41]=[CH:5][C:3]#[N:4])=[CH:20][CH:19]=1)([CH3:16])([CH3:17])[CH3:15]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)c1ccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2C=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2C=CC#N)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A mixture of lithium hydroxide (101 mg, 2.40 mmol), diethyl cyanomethylphosphonate (390 mg, 2.20 mmol) and tetrahydrofuran (20 ml) was stirred at 70° C. for 30 minutes under argon atmosphere. After the reaction mixture was cooled to room temperature, 4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl-3-carbaldehyde (compound of Example 4 (2); 857 mg, 2.00 mmol) was added, and the mixture was stirred at room temperature for 4 hours. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (631 mg, 70.0%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:4](C=O)=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][C:7]#[N:8].[CH3:16][C:17]1[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=1.[OH-].[Na+].[C:25](O)(=O)C>O>[NH2:8][C:7]1[N:20]2[N:21]=[C:17]([CH3:16])[CH:18]=[C:19]2[N:22]=[CH:25][C:6]=1[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: N#CCc1cccc(C(F)(F)F)c1C=O
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2ncc(-c3cccc(C(F)(F)F)c3)c(N)n2n1

Procedure:
21.3 g of m-trifluoromethyl-2-formylbenzyl cyanide and 9.7 g of 3(5)-amino-5(3)-methylpyrazole in 100 ml of glacial acetic acid were refluxed for 4 hours. The mixture was cooled and was then diluted with 500 ml of water, the pH was brought to 5-6 with 2N NaOH solution, and the oily product which precipitated crystallized after trituration. The crystals were filtered off under suction and then washed several times with water and dried under reduced pressure at 50° C. 25.0 g of 7-amino-2-methyl-6-(3'-trifluoromethylphenyl)-pyrazolo[1,5-a]pyrimidine of melting point 176° C. were obtained (Compound 10).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[C:5](=[O:9])[CH:6]=[N+:7]=[N-:8].CC[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22].CCO[C:28]([CH3:30])=[O:29]>>[N+:7](=[CH:6][C:5](=[O:9])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH2:3][CH2:2][N:20]1[CH2:21][CH2:22][C:28]([OH:29])([C:30]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:24][CH2:23]1)=[N-:8]
Reactant: [N-]=[N+]=CC(=O)C(CCBr)c1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Product: [N-]=[N+]=CC(=O)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Dissolve the product of Step 4 (3.93 g, 11.7 mmoles) in 50 ml of dry EtOAc. Add 4-hydroxy-4-phenyl-1-piperidine (2.55 g, 14.4 mmoles), followed by dry Et3N (13.3 ml.). Heat under N2 at 60°-65° C. for 28 h. Cool to room temperature, filter the solid and wash with EtOAc. Apply the filtrate to a silica gel column and elute the column with 1.5% CH3OH(NH3)/ETOAc. Yield: 2.34 g; Cl-MS: m/e=432 (M+H+, 35C1 +37Cl isotope).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[NH:27][C@@H:26]([C@H:28]([OH:30])[CH3:29])[CH2:25][O:24][CH2:23]2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:50]([C:53]1[CH:61]=[CH:60][C:56]([C:57](O)=[O:58])=[CH:55][CH:54]=1)([O-:52])=[O:51]>C(OCC)(=O)C.O.O1CCCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]2[NH:27][C@@H:26]([C@@H:28]([O:30][C:57](=[O:58])[C:56]3[CH:55]=[CH:54][C:53]([N+:50]([O-:52])=[O:51])=[CH:61][CH:60]=3)[CH3:29])[CH2:25][O:24][CH2:23]2)=[CH:20][CH:21]=1
Reactant: C[C@@H](O)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Reaction time: 2 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere and under ice-cooling, diisopropylazodicarboxylate (1.36 mL) was added dropwise in a tetrahydrofuran solution containing (R)-1-[(3R,5R)-5-(4-chlorophenyl)morpholin-3-yl]ethanol (903 mg), triphenylphosphine (1.81 g), and 4-nitrobenzoic acid (1.16 g). Stirring was continued for 30 minutes at the same temperature and for 2 hours at room temperature. Water and ethyl acetate was added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with brine and was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate 9/1→8/2→7/3), and the title compound (1.46 g) was obtained. The physical property values are as follows.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[CH3:31])[O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[N:21]=2)[CH:18]=1>CN(C)C(=O)C>[CH:25]1([C:23]([NH:22][C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][C:13]([O:12][C:11]4[CH:28]=[CH:29][C:30]([CH3:31])=[C:9]([NH:8][C:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)=[O:6])[CH:10]=4)=[CH:18][N:17]3[N:19]=2)=[O:24])[CH2:26][CH2:27]1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)C1CCC1
Yield: 47.6 %

Procedure:
In the same manner as in Example 24 and using cyclobutanecarbonyl chloride (56.0 μL, 0.489 mmol), N,N-dimethylacetamide (5 mL) and N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (140 mg, 0.433 mmol) as starting materials, the title compound (83.5 mg, 45%) was obtained as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O.I[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1>CCOC(C)=O.O>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14]([C:39]3[CH:44]=[N:43][CH:42]=[CH:41][N:40]=3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:5]1
Reactant: CC1CN(c2c(C=O)cc(B3OC(C)(C)C(C)(C)O3)c(F)c2F)CC(C)O1
Reactant: Ic1cnccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC1CN(c2c(C=O)cc(-c3cnccn3)c(F)c2F)CC(C)O1
Temperature: 85 °C
Yield: 39.5 %

Procedure:
To a suspension of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (11.5 g, 29.1 mmol) and sodium carbonate (8.8 g, 83.1 mmol) in previously degassed acetonitrile/water (1/1) mixture (140 mL) was added iodopyrazine (5.7 g, 27.7 mmol) under nitrogen. Bis-(triphenylphosphine)-dichloro-palladium-(II) (758 mg, 1.08 mmol) was added at room temperature and the reaction was heated overnight at 85° C. The mixture was cooled to room temperature, diluted with EtOAc and water. The phases were separated and the aqueous phase was re-extracted with EtOAc (×2). The combined organic layers were dried over MgSO4 and concentrated to give a brown oil. Purification on silica gel (hexane/EtOAc 9/1, 8/2 then 7/3) yielded 3.65 g of an off-white solid. 1H-NMR (500 MHz, CDCl3) d 10.35 (s, 1H), 9.06 (t, 1H), 8.70 (dd, 1H), 8.57 (d, 1H) 8.32 (dd, 1H), 4.24 (m, 2H), 3.43 (dt, 2H), 3.05 (m, 2H), 1.32 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:20][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:21])[NH:4][CH2:3]1.[OH-].[Na+].C(O)(=O)C.O>C(O)C>[CH3:1][C:2]1([CH3:22])[CH2:20][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:21])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CC(C)(C)CNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n2C1
Temperature: 80 °C
Yield: 45 %

Procedure:
Ethyl 4,4-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (7.6 g, 25.3 mmol) is dissolved in ethanol (250 mL) and 1M NaOH solution (88.6 mL, 88.6 mmol) is added. The reaction mixture is heated at 80° C. for 2 h. Acetic acid (40 mL) and water (350 mL) are added and the resulting solid is filtered and rinsed with water to afford the title compound (3.1 g, 45%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:22])([O-:18])=[O:17]
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: O=C(Nc1cccc(OCc2ccccc2)c1)c1ccccc1[N+](=O)[O-]
Yield: 89 %

Procedure:
Using the procedure described in Example 93, Part A, 3-benzyloxyaniline (10 mmol) and 2-nitrobenzoyl chloride (11 mmol) yielded 3.1 g (89%) of the title compound,
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([C:12]1[N:17]=[C:16]([C:18](=O)[CH3:19])[CH:15]=[CH:14][CH:13]=1)[CH3:11].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([C:18](=[N:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:21]([CH3:23])[CH3:22])[CH3:19])[N:17]=1)[CH3:11]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C)n1
Reactant: CC(C)c1ccccc1N
Solvent: Cc1ccccc1
Product: CC(=Nc1ccccc1C(C)C)c1cccc(C(C)=Nc2c(C)cccc2C)n1

Procedure:
1-{6-[1-(2,6-Dimethyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 1 (5.0 g, 0.0188 mol), 3.30 g (0.0244 mol) of 2-isopropyl-phenylamine 9, 100 g of fresh molecular sieves, and 100 ml of toluene were kept at 100° C. for 3 days under a flow of nitrogen. The solvent was removed in a rotary evaporator and the residue was recrystallized from 20 ml of ethanol. The yield of (2,6-dimethyl-phenyl)-(1-{6-[1-(2-isopropyl-phenylimino)-ethyl]-pyridin-2-yl}-ethylidene)-amine 8 was 4.90 g (68%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]([CH3:43])[CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]([CH3:42])[CH3:43])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)c1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K39) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (250 mg, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:40]([O:41][CH3:42])=[O:43])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:24])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]2[CH3:20]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)s2)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 31.7 mg, 0.0705 mmol) was dissolved in anhydrous methylene dichloride (1 mL), triethylamine (30 μL, 0.22 mmol) and methyl chlorocarbonate (10 μL, 0.13 mmol) were added thereto, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (26.8 mg) as a pale yellow amorphous product. (Yield 79%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: C1CCNCC1
Product: CCOC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 12 step A from 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B) and piperidine.
Reaction SMILES: N(C(OCC)=O)=NC(O[CH2:6][CH3:7])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:18]=[CH:19][CH:20]=1.CC(O)[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:6][CH2:7][CH:37]2[CH2:36][CH2:35][CH2:34][N:33]2[CH3:32])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(CCc2ccccc2O)c1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CC(O)CN1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CCc2ccccc2OCCC2CCCN2C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.2 %

Procedure:
11.3 g of diethyl azodicarboxylate were added dropwise, whilst ice-cooling and stirring, to a solution of 10.6 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 8.4 g of 1-methyl-2-pyrrolidylethanol and 17 g of triphenylphosphine in 200 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 15 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 5.70 g (yield 36%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH2:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=O)[CH2:21]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2].Cl.[NH2:37][OH:38]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH2:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:37][OH:38])[CH2:21]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(NC(=O)NC[C@@H]2CCCN(CC(=O)c3ccc(F)cc3)C2)cc(-c2nnnn2C)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cc(NC(=O)NC[C@@H]2CCCN(CC(=NO)c3ccc(F)cc3)C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
A solution of (S)-1-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-{l-[2-(4-fluorophenyl)-2-oxo-ethyl]-piperidin-3-ylmethyl}-urea (20 mg, 42 μmol) in pyridine (0.5 mL) was treated with hydroxylamine hydrochloride (6 mg, 82 μmol) and stirred at room temperature for 16 hours. The solution was concentrated under vacuum, and the residue was purified by flash chromatography, eluting with 2.5% methanol in dichloromethane, containing 0.25% aqueous ammonia, to provide a white glassy solid (10 mg, 50%). 1H NMR (300 MHz, CDCl3) δ8.14 (s, 1H), 7.59 (s, 1H), 7.54 (m, 2H), 7.48 (s, 1H), 7.28 (s, 1H), 7.00 (t, J=9 Hz, 2H), 6.15 (bt, 1H), 4.16 (s, 3H), 3.78 (ab, J=15 Hz, 2H), 3.19 (m, 2H), 3.06 (m, 1H), 2.95 (m, 1H), 2.60 (q, J=8 Hz, 2H), 2.26 (m, 1H), 2.09 (m, 1H), 1.78 (m, 3H), 1.60 (m, 1H), 1.19 (t, J=8 Hz, 3H), 1.10 (m, 1H). Mass spec (ES+) m/z 495.4 (M+H+).