Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29](=O)[CH:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N:38]3[CH:42]=[CH:41][N:40]=[C:39]3[CH3:43])[CH:33]=2)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:30])[CH2:28][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[CH3:43])[CH:33]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1N
Reactant: Cc1nccn1-c1cccc(C2=CC(=O)OC(C)(C)O2)c1
Product: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccc(F)cc3F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G43) and 2,2-dimethyl-6-[3-(2-methyl-imidazol-1-yl)-phenyl]-[1,3]dioxin-4-one (Example J15) according to the general procedure K. Obtained as a yellow oil (145 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[P:11](Cl)([Cl:14])([Cl:13])=[O:12]>>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][P:11]([Cl:14])([Cl:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(NP(=O)(Cl)Cl)cc1

Procedure:
To 300 ml of phosphorous oxychloride was carefully added 69 g (0.5 m) of 4-nitroaniline. The mixture was heated at reflux for 3 hours, then chilled to 10°. The crude product was collected by filtration, washed with ether and air-dried to give 93.6 g, m.p. 156.5°-157.5°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]3[CH:13]=[N:14][N:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:25][C:24](=[O:26])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)[C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[N+:27]([CH3:30])([O-:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]3[CH:13]=[N:14][N:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:25][C:24]([CH2:30][N+:27]([O-:29])=[O:28])([OH:26])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)[C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: C[N+](=O)[O-]
Reactant: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CC(=O)C3)n2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CC(O)(C[N+](=O)[O-])C3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-one (1.1 g) in DCM (10 mL) at 20° C. was added nitromethane (1 mL) and triethylamine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. It was concentrated under reduced pressure to afford a white solid. The crude product (1.3 g), 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-3-(nitromethyl)azetidin-3-ol, was used for next step without further purification. MS (ESI) m/z: 407 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>ClCCl>[Br:18][C:15]1[O:14][C:13]([C:9]2[C:10]([CH:11]=[O:12])=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]3[N:8]=2)=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1c(-c2ccco2)nn2c(Cl)cccc12
Solvent: ClCCl
Product: O=Cc1c(-c2ccc(Br)o2)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (2.0 g, 8.06 mmol) in dichloromethane was added N-bromosuccinimide (2.01 g, 11.28 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine and dried over magnesium sulfate. Filtration and concentration followed by recrystallization with ethyl acetate gave 2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (2.1 g, 80%) as a white solid. 1H NMR (CDCl3): δ 10.50 (s, 1H), 8.37 (dd, 1H), 7.47 (t, 1H), 7.20–7.18 (m, 2H), 6.54 (d, 1H). MS m/z 325 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](I)[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[C-:25]#[N:26].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[CH:10]=[C:9]([C:25]#[N:26])[C:8]2[C:7](=[O:12])[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: [C-]#N
Reactant: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cc(F)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
A mixture of 5-fluoro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.22 mmol), Pd(PPh3)4 (0.022 g, 0.24 mmol), sodium cyanide (0.014 g, 0.285 mmol), and CuI (0.004 g, 0.022 mmol) in acetonitrile (5 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate afforded 6-fluoro-3-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4-carbonitrile (0.035 g, 45%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.80 (s, 2H), 7.20 (d, 2H), 7.37 (m, 3H), 7.49 (d, 1H). GC-MS: m/z 350 (M)+.
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[O:6])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([NH:13][NH2:14])=[O:12]>C1COCC1>[CH:1]1([NH:4][C:5]([NH:14][NH:13][C:11](=[O:12])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH3:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1ccccc1C(=O)NN
Reactant: O=C=NC1CC1
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)NNC(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg (3.01 mmol) of cyclopropyl isocyanate, dissolved in 3 ml THF, are added dropwise to 500 mg (3.01 mmol) of 2-methoxybenzoic acid hydrazide, dissolved in 7 ml THF, and the mixture stirred overnight at room temperature. The resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo. 709 mg (94% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[S:12]1[CH:16]=[CH:15][C:14]2[CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:13]1=2.Cl>C(Cl)Cl>[S:12]1[C:16]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:15][C:14]2[CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:13]1=2
Reactant: c1ccc2c(c1)CCc1sccc1C2
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1cc2c(s1)CCc1ccccc1C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
11.0 g of succinic acid anhydride are dissolved in 220 cc of anhydrous methylene chloride with heating, the resulting solution is cooled to 20° and 30 g of aluminium chloride are added portionwise. After stirring for 15 minutes at room temperature, a solution of 22.0 g of 9,10-dihydro-4H-benzo[4,5]-cyclohepta[1,2-b]thiophene in 100 cc of anhydrous methylene chloride is added dropwise within 30 minutes, the resulting mixture is stirred for a further 45 minutes at room temperature and is poured on a mixture of 200 cc of concentrated hydrochloric acid and 200 g of ice. After adding 300 cc of methylene chloride, the entire mixture is heated for 15 minutes on a water bath, is cooled, the methylene chloride is removed and the aqueous phase is further extracted with methylene chloride. The acidic portion is extracted from the combined methylene chloride solutions with 0.5 normal caustic soda, the basic extract is acidified with 5 N hydrochloric acid and extracted with chloroform. The chloroform solutions are washed with water, dried over magnesium sulphate, filtered through active charcoal and evaporated to dryness. The title compound, obtained as solid residue, is recrystallized from dimethyl formamide/acetone. M.P. 202° to 203°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14]Br.[OH-].[K+].O>CN(C)C=O>[N+:8]([C:7]1[C:2]2[NH:1][CH2:14][CH2:13][O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc2c1NCCO2
Temperature: 200 °C
Reaction time: 48 h
Yield: 14.3 %

Procedure:
To a solution of 2-amino-3-nitrophenol (15.0 g, 97 mmol) and 1,2-dibromoethane (29.1 g, 155 mmol) in dimethylformamide (80 mL) was added KOH (10.9 g, 194 mmol) at 180° C. After stirring at 200° C. for 2 days, the mixture was poured to 150 g water. The mixture was concentrated under reduced pressure. The crude product was purified using column chromatography to give the title compound (2.50 g) as a red solid. MS (ESI): m/z 181 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15](=[O:24])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15](=[O:24])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]1)=[O:5]
Reactant: COc1cccc2c(=O)[nH]nc(Cc3ccc(F)c(C(=O)O)c3)c12
Reactant: COC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)[nH]nc(Cc3ccc(F)c(C(=O)N4CCC(OC)CC4)c3)c12
Yield: 54 %

Procedure:
2-fluoro-5-((8-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (125) and 4-methoxypiperidine were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.163 mL, 0.91 mmol) and then HBTU (347 mg, 0.91 mmol). The solvent was removed and the residue was dissolved in acetonitrile. A white solid precipitated, which was filtered and dried to afford the desired material as a white crystalline solid (140 mg, 54.0% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.49-1.60 (1H, m), 1.62-1.83 (2H, m), 1.86-1.96 (1H, m), 3.07-3.19 (1H, m), 3.32-3.36 (3H, m), 3.41-3.62 (3H, m), 3.78-3.82 (3H, m), 3.94-4.04 (1H, m), 4.36-4.46 (2H, m), 6.93-7.00 (1H, m), 7.10-7.30 (3H, m), 7.64-7.72 (1H, m), 8.00-8.12 (1H, m), 9.98-10.07 (1H, m); m/z (ES+) (M+H)+=426.4; HPLC RT=1.71 min.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[CH3:26][C:27]1[C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[S:30][C:31]=1[CH:32]=O>>[Cl:25][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[N:9][C:8]([C:1]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[C:17]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]2[S:30][C:29]3[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=3[C:27]=2[CH3:26])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: Cc1c(C=O)sc2ccccc12
Product: Cc1c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)sc2ccccc12

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and 3-methyl-benzo[b]thiophene-2-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 492.2.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][N:26]=[C:21]3[CH:20]=2)=[CH:9]1)C1C=CC=CC=1.N.[Na].O>O1CCCC1>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH:9]=[C:10]2[C:19]1[NH:27][C:22]2=[N:23][CH:24]=[CH:25][N:26]=[C:21]2[CH:20]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2Cc1ccccc1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2[nH]cc(-c3cc4nccnc4[nH]3)c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
A cooled (−78° C.) solution of 6-(1-benzyl-5-methoxy-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine [50 mg, Example 1(m)] in tetrahydrofuran (20 mL) was treated with liquid ammonia (20 mL) then with sodium (100 mg). After stirring at −78° C. for 30 minutes the reaction mixture was allowed to warm slowly to ambient temperature, then treated with water (50 mL) and then extracted three times with ethyl acetate (50 mL). The combined extracts were dried over sodium sulfate and then evaporated. The residue was triturated with diethyl ether to give the title compound (14 mg) as a brown solid, m.p. 268-271° C. MS: 265.24 (MH+).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:30][CH2:29][C@@H:19]3[CH2:20][N:21]([C:23]4[CH2:27][CH2:26][C:25](=[O:28])[CH:24]=4)[CH2:22][C@H:18]3[C@@H:17]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].CC([N-]C(C)C)C.C1C[O:51]CC1>>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:30][CH2:29][C@@H:19]3[CH2:20][N:21]([C:23]4[CH2:27][CH:26]([OH:51])[C:25](=[O:28])[CH:24]=4)[CH2:22][C@H:18]3[C@@H:17]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C1CCOC1
Reactant: C[C@@H](O[C@H]1OC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C[C@@H](O[C@H]1OC[C@@H]2CN(C3=CC(=O)C(O)C3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 20 mg (0.0359 mmol) of 3-[(3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)hexahydropyrano[3,4-c]pyrrol-2(3H)-yl]cyclopent-2-en-1-one (example 3) and 19 mg (0.0430 mmol) MoOPH in 1.0 mL dry THF under nitrogen atmosphere at −78° C. was added 0.045 mL (0.15 mmol) of 2.0 M solution of LDA. The resulting mixture was stirred at −78° C. for 1 hr then quenched by the addition of sat. aq. Na2S2O3. The mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and filtered through a fritted funnel. The residue was purified by prep TLC eluting with 95/5 DCM/(10% NH4OH/methanol) to afford the title compound as a mixture of diastereomers. 1H-NMR (CD3OD): δ: 1.38 (d, 3H, J=6.5 Hz), 2.15-2.50 (m, 3H), 2.60-2.82 (m, 1H), 2.90-3.22 (m, 4H), 3.40-3.86 (m, 2H), 4.14-4.24 (m, 1H), 4.25-4.32 (m, 1H), 4.38-4.44 (m, 1H), 4.73-4.85 (m, 1H), 4.09 (q, 1H, J=6.5 Hz), 6.60-7.12 (m, 2H), 7.16-7.22 (m, 2H), 7.38 (s, 2H), 7.76 (s, 1H) ppm. MS: (MH)+574.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([CH3:30])=[CH:25][C:24]=1[C:31]1[CH:35]=[C:34]([O:36][CH:37]([F:39])[F:38])[N:33]([CH3:40])[N:32]=1.C(OC)(C)(C)C>C(#N)C>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([CH3:30])=[CH:25][C:24]=1[C:31]1[C:35]([F:21])=[C:34]([O:36][CH:37]([F:38])[F:39])[N:33]([CH3:40])[N:32]=1
Reactant: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(Cl)cc1Cl
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: COC(C)(C)C
Solvent: CC#N
Product: Cc1cc(-c2nn(C)c(OC(F)F)c2F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
46.3 g (131 mmol) of Selectfluor™ were added to a solution of 40.2 g (131 mmol) of 3-(2,4-dichloro-5-methylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 0.5 l of acetonitrile. After the mixture had been stirred for 12 hours at room temperature, it was heated for a further hour at reflux temperature. Thereafter, three batches of 6.9 g (20 mmol) of Selectfluor™ were added to the reaction mixture, a little at a time, and the mixture was heated in each case for one hour at reflux temperature. The resulting mixture was subsequently treated with 0.5 l of methyl tert-butyl ether. The organic phase was washed with water, saturated aqueous sodium hydrogen carbonate solution and again with water, then dried over magnesium sulfate and finally concentrated. The crude product was purified by means of silica gel chromatography (eluent:hexane/ethyl acetate=9:1). Yield: 20.3 g.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)[CH:18]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3cccc(C(F)(F)F)c3)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 3-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 488.5. HPLC (Condition A), Rt: 4.86 min (HPLC purity: 66.8%).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:10]([F:19])[C:9]([OH:20])=[C:8]([CH:21]=[O:22])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:10]([F:19])[C:9]([O:20][CH:2]([CH3:4])[CH3:3])=[C:8]([CH:21]=[O:22])[CH:7]=1
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
2-Iodopropane (21.7 g) was added to a mixture of 6-bromo-2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (26.7 g) and potassium carbonate (23.6 g) in DMF (250 mL) at room temperature. The mixture was stirred at 60° C. under nitrogen atmosphere for 3 hours. The mixture was quenched with water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (28.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:29].Cl.[NH2:31][OH:32].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)C>[ClH:28].[OH:32][NH:31][C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(OCc2cccc(C(=N)NO)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl) methoxy]-5-methylphenyl ester (207 mg, 0.5 mmol), as prepared in step (a) of the Example 6, in methylene chloride (10 mL) was added 37% HCl in ethanol (10 mL) at 0° C. The mixture was allowed to stand at 0° C. for 3 days. The solvent was removed in vacuo and the residue was co-evaporated with methylene chloride several times. The residue was dissolved in ethanol (10 mL) and then treated with hydroxylamine hydrochloride (140 mg, 2.0 mmol) and Na2CO3 (106 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 days. Methylene chloride (150 mL) was added to the mixture, washed with 10% K2CO3 (2×50 mL), and dried over K2CO3. The solvent was removed in vacuo, HCl in methanol (30 mL) added and the solvent removed in vacuo. The residue was purified by flash chromatography (1:1 ethyl acetate/methylene chloride) to give the title compound as a white foam (95 mg, 39%). 1H-NMR (300 MHz, CDCl3) δ 2.25 (s, 3 H), 4.89 (br s, 1 H), 4.98 (d, 2 H, J=10.7 Hz), 5.58 (br s, 1 H), 6.15 (br s, 1 H), 7.33-7.64 (m, 6 H), 7.76-7.83 (m, 1 H), and 7.92 (d, 1 H, J=4.0 Hz). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2O5SCl: 447.1 (M+H), 469.1 (M+Na). Found: 447.1, 469.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:6]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)N=Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
L-phenylalanine methyl ester hydrochloride (4.31 g), p-anisaldehyde (2.45 ml), anhydrous magnesium sulfate (5.19 g) and triethylamine (2.9 ml) were added to methylene chloride (200 ml), and the mixture was stirred overnight at room temperature. The solid was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. Then, ethyl acetate (150 ml) was added to the residue. The solid was separated again by filtration, and the solvent was distilled off under reduced pressure to quantitatively obtain desired N-(p-methoxyphenylmethylene)-L-phenylalanine methyl ester (5.94 g).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[CH:19]=[C:18]([CH3:21])[N:17]=[C:16]([NH2:22])[C:15]=2[N:14]=[C:13]1[CH2:23][O:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:22][C:16]1[C:15]2[N:14]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:20]=2[CH:19]=[C:18]([CH3:21])[N:17]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
Isobutyryl chloride (181 μL, 1.73 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine (0.435 g, 1.57 mmol), triethylamine (280 μL, 2.04 mmol) and chloroform (8 mL). The reaction mixture was allowed to stir at ambient temperature for 4 hours then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate solution (10 mL). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (30 g of silica gel eluting with 1 L of 2% methanol in chloroform containing 0.5% triethylamine) to provide 0.225 g of N-{4-[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}-2-methylpropanamide as a white powder, m.p. 170.5–172.5° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:8][C:9](=[CH2:11])[CH3:10]>C(OC)(C)(C)C>[C:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1])([CH3:11])([CH3:10])[CH3:8]
Reactant: C=C(C)C
Reactant: C=CCCCCO
Solvent: COC(C)(C)C
Product: C=CCCCCOC(C)(C)C
Reaction time: 4 h
Yield: 75 %

Procedure:
200 g of hex-1-en-6-ol are dissolved in 250 ml of methyl tert-butyl ether, and 100 g of acidic ion exchanger (SPC 118H+) are added. Isobutylene is then passed in until the solution is saturated, and the reaction is monitored by thin layer chromatography, After 4 hours, the reaction is complete. Fractional distillation gives 243 g of 6-tert-butoxyhex-1-ene having a gas chromatographic purity of 98.5%; bp.: 66-67° C./32 mbar. Yield: 75% of theory.