Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl.[N:12]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>O>[F:10][C:3]1[C:2]([NH:1][NH2:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: O=N[O-]
Reactant: N#Cc1cccc(N)c1F
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(NN)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Amino-2-fluoro-benzonitrile (100 mg, 0.735 mmol) was dissolved in water (0.94 mL), added with conc. hydrochloric acid (0.74 mL) at 0° C., and then further added with an aqueous solution (0.294 mL) of sodium nitrite (61 mg, 0.882 mmol). The resulting mixture was stirred at 0° C. for 1 hr. To the reaction mixture, conc. hydrochloric acid solution (0.94 mL) of tin chloride (321 mg, 1.69 mmol) was added and stirred at room temperature for 1 hr. Thereafter, the reaction solution was neutralized with aqueous solution of sodium hydroxide, and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the residues were obtained after concentration under reduced pressure to give the target compound as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])=[O:22])[C:11](=[O:30])[CH:10]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]3[NH:45][N:44]=[N:43][N:42]=3)[CH:36]=2)=[O:33])[N:9]=1.C(N(CC)CC)C.Cl[C:54]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])=[O:22])[C:11](=[O:30])[CH:10]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]3[N:45]([C:54]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[N:44]=[N:43][N:42]=3)[CH:36]=2)=[O:33])[N:9]=1
Reactant: Cc1cccc2c1N(CC(=O)c1ccccc1O)C(=O)C(NC(=O)Nc1cccc(-c3nnn[nH]3)c1)N=C2c1ccccc1F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc2c1N(CC(=O)c1ccccc1O)C(=O)C(NC(=O)Nc1cccc(-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)c1)N=C2c1ccccc1F
Reaction time: 8 h
Yield: 88.7 %

Procedure:
A mixture of N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-hydroxyphenacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea (150 mg), triethylamine (75 mg) and chlorotriphenylmethane (69 mg) in a mixture of N,N-dimethylformamide and tetrahydrofuran (1:3, 4 ml) was stirred overnight. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture. The separated organic layer was washed with water and brine, and then dried over sodium sulfate. The solvent was evaporated in vacuo to afford an amorphous mass, which was triturated in diisopropyl ether and collected by filtration to afford N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-hydroxyphenacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-{3-[1-(triphenylmethyl)tetrazol-5-yl]phenyl}urea (186.0 mg, 88.6% yield) as a crystalline powder.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:17](O)([CH:19]([CH3:21])[CH3:20])[CH3:18])[CH:14]=[CH:15][CH:16]=1)[CH3:9].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:1][C:2]([CH3:23])([CH3:24])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH:19]([CH3:20])[CH3:21])=[CH2:18])[CH:12]=1)[CH3:9]
Reactant: CC(C)C(C)(O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C=C(c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1)C(C)C
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Compound 20 (0.76 g; 2.32 mmol) was dissolved in pyridine (35 ml). While the solution was stirred at room temperature, phosphorus oxychloride (3.71 g; 24.2 mmol) was added dropwise. The mixture was heated for 3 hours at 100° C. while being stirred, and brought to room temperature. The mixture was poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.41 g of the target compound (yield: 56.9%).
Reaction SMILES: Cl[C:2]1(Cl)[C:7]([CH2:8][C@@H:9]([CH3:12])[CH2:10][CH3:11])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)[NH:3]1.C[C@@H](CC)CBr.C(OCC)(=O)CC(OCC)=O.C[O-].[Na+].Cl.C(OC1C=CC(C(N)=N)=CC=1)CCCCCC.OC1C(C[C@@H](C)CC)=C(O)N=C(C2C=CC(OCCCCCCC)=CC=2)N=1.CN(C)C1C=CC=CC=1.[H][H]>[Pd].C(N(CC)CC)C.CO>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[N:3]=[CH:2][C:7]([CH2:8][C@@H:9]([CH3:12])[CH2:10][CH3:11])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCOc1ccc(C2=NC=C(C[C@@H](C)CC)C(Cl)(Cl)N2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CCCCCCCOc1ccc(-c2nc(O)c(C[C@@H](C)CC)c(O)n2)cc1
Agent: CCCCCCCOc1ccc(C(=N)N)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(=O)CC(=O)OCC
Product: CCCCCCCOc1ccc(-c2ncc(C[C@@H](C)CC)cn2)cc1

Procedure:
A mixture of 40 g of (S)-4,4-dichloro-2-(p-heptyloxy-phenyl)-5-(2-methylbutyl)-pyrimidine [obtainable by reacting (S)-2-methylbutyl bromide with diethyl malonate in the presence of sodium methanolate, followed by condensation of the resultant diethyl (S)-2-methylbutyl malonate with p-heptyloxybenzamidine hydrochloride, and reacting the resultant (S)-4,6-dihydroxy-2-(p-heptyloxyphenyl)-5-(2-methylbutyl)-pyrimidine with phosphoroxy trichloride and dimethylaniline], 400 ml of methanol, 40 ml of triethylamine and 20 g of Pd-C (5%) is hydrogenated at room temperature under normal pressure until the theoretical amount of hydrogen has been taken up. After filtering off the catalyst and distilling off the solvent, the residue is recrystallized from ethanol. (S)-2-(p-Heptyloxyphenyl)-5-(2-methylbutyl)-pyrimidine is obtained.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)([O-:9])=[O:8].FC(F)(F)S(O[C:25]1[CH2:26][CH2:27][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:29]=1)(=O)=O.[Li+].[Cl-]>O1CCOCC1.CCOC(C)=O.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>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([C:26]2[CH2:25][CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:27]=2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1C=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C=C(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
A solution of 2 M aqueous Na2CO3 (5.70 mL, 9.09 mmol) was added to a degassed mixture of 4-nitrophenylboronic acid (0.909 g, 1.52 mmol, 1.2 eq), tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-pyrrole-1-carboxylate (I134 and I135) (1.44 g, 4.54 mmol), LiCl (0.385 g, 9.08 mmol) and Pd(PPh3)4 (1.57 g, 1.36 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 80-90° C. for 4 hours. The resulting mixture was dissolved in EtOAc (70 mL) and the organic layer was washed with H2O (50 mL), brine (50 mL) and dried over Na2SO4 to yield a dark red oil. The oil was purified by column chromatography on silica gel (0-20% EtOAc in petroleum benzine 40-60° C.) to give a mixture of the title compounds (I134 and I135) (0.442 g, 34%) as a light yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.41-8.32 (m, 2H), 8.24-8.19 (m, 2H), 7.81-7.73 (m, 2H), 7.52 (dd, J=8.8, 2.4 Hz), 6.43-6.33 (m, 1H), 4.58-4.48 (m, 4H), 4.42-4.31 (m, 4H), 1.52 (s, 9H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[S:16])[NH:11][CH2:12][C:13](N)=[O:14].[CH2:17](I)[CH3:18]>C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][N:11]=[C:10]1[S:16][CH2:17][CH3:18]
Reactant: Cc1cccc(C)c1NC(=S)NCC(N)=O
Reactant: CCI
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1c(C)cccc1C
Yield: 28.7 %

Procedure:
The title compound was prepared by the procedure described in Example 12 using 8.0 g of 2-[3-(2,6-dimethylphenyl)-thioureido]-acetamide, 25.0 g of ethyl iodide, and (200 mL) ethanol. Crystallization from hexane/diethyl ether mixture afforded the title compound as a light yellow solid (2.4 g), m.p. 86°-88° C. Anal. Calcd. for. C12H16N2O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.98; H, 6.57; N, 11.30. Mass spectrum (El, M.+) m/z 248 1H-NMR (DMSO-d6 ; 400 MHz) δ7.27-7.30 (m, 1H), 7.21 (m, 1H), 7.19 (m, 1H), 7.33 (d, 1H), 4.42 (s, 2H), 3.06 (q, 2H), 2.07 (s, 6H), and 1.26 ppm (t, 3H).
Reaction SMILES: F[O-].[C:3]([C:7]([O:10]C(C(Cl)(Cl)F)Cl)([F:9])[F:8])([F:6])([F:5])[F:4].C(C(OC(C(F)Cl)(Cl)Cl)(F)F)(F)(F)[F:18]>>[C:3]([C:7]([O:10][F:18])([F:9])[F:8])([F:6])([F:5])[F:4]
Reactant: FC(Cl)C(Cl)(Cl)OC(F)(F)C(F)(F)F
Reactant: FC(Cl)(Cl)C(Cl)OC(F)(F)C(F)(F)F
Agent: [O-]F
Product: FOC(F)(F)C(F)(F)F
Reaction time: 3 h

Procedure:
The reaction is carried out for 3 hours. The raw product (65.0 g) is analyzed by GLC/MS. The hypofluorite conversion is 100% and the selectivity in the two reaction products CF3CF2O—CHCl—CFCl2 and CF3CF2O—CCl2—CHClF is equal to 61%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
To a solution of 2-(4-chlorophenyl)ethanol (2.00 g, 12.77 mmol) in dichloromethane (100 ml) was added Dess-Martin periodinane (8.12 g, 19.16 mmol) and the mixture was stirred at room temperature over weekend. Then was added diethylether (150 ml) and the resulting mixture was washed with a 1:1 solution (150 ml) of sodium carbonate (aqueous saturated) and sodium thiosulfate (aqueous saturated) and then with sodium bicarbonate (aqueous saturated) and finally with brine. The organic phase was then dried over sodium sulfate and evaporated. Silica gel flash chromatography (pentan/ethylacetate:9/1) afforded the desired compound (0.834 g, 42%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([OH:19])[CH:3]=1.[OH-].[Li+].O>O1CCCC1>[Br:1][C:2]1[C:11]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:19])[CH:3]=1
Reactant: COC(=O)c1cc(CN2CCOCC2)c(Br)cc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(CN2CCOCC2)c(Br)cc1O
Temperature: 50 °C

Procedure:
Methyl 4-bromo-2-hydroxy-5-(4-morpholinylmethyl)benzoate (may be prepared as described in Description 17; 350 mg, 0.96 mmol) was redissolved in tetrahydrofuran (4 ml) and lithium hydroxide (69 mg, 2.87 mmol) was added followed by water (1 ml). The mixture was heated at 50° C. for 1 hour. The mixture was cooled and the solvent removed in vacuo to yield the title compound as a brown oil. 302 mg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH3:8].[C@H:10]12[CH2:16][C@H:13]([NH:14][CH2:15]1)[CH2:12][N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:14]2[CH2:15][C@@H:10]3[CH2:16][C@H:13]2[CH2:12][N:11]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Cc1cc(Cl)nnc1Cl
Product: Cc1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)nnc1Cl
Yield: 56 %

Procedure:
3,6-Dichloro-4-methylpyridazine (Aldrich Chemical Company) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), were processed as described in Example 2A to provide the title compound (56% yield). 1H NMR (CDCl3, 300 MHz) δ 1.41 (s, 4.5H), 1.43 (s, 4.5H), 1.90-2.09 (m, 2H), 2.31(s, 3H), 3.35-3.45 (m, 3H), 3.53-3.60(m, 1H), 4.56(s, 0.5H), 4.69(s, 0.5H), 4.90(s, 0.5H), 5.08(s, 0.5H), 6.48(s, 1H); MS (DCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]3[S:17][CH2:16][CH2:15][CH2:14][N:9]3[C:10](=[O:13])[C:11]=2[CH:12]=1.[OH:19]O>C(O)(=O)C>[CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]3[S:17](=[O:19])[CH2:16][CH2:15][CH2:14][N:9]3[C:10](=[O:13])[C:11]=2[CH:12]=1
Reactant: CN(C)c1ccc2cc3n(c(=O)c2c1)CCCS3
Reactant: OO
Solvent: CC(=O)O
Product: CN(C)c1ccc2cc3n(c(=O)c2c1)CCCS3=O
Reaction time: 1 h

Procedure:
A mixture of 550 mg. of 8-dimethylamino-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline, 10 ml. of acetic acid, and 0.41 ml. of a 35% aqueous hydrogen peroxide solution was stirred at 20°-30° C. After one hour, the reaction mixture was filtered and after adding 10 ml. of water to the filtrate, anhydrous sodium carbonate was added to it to make the filtrate basic. The precipitates formed were recovered by filtration and dried. By recrystallizing from benzene-hexane, 300 mg. of 8-dimethylamino-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline-1-oxide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:23]=2[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:29][C:27]2[CH:26]=[CH:25][C:24]3[O:20][CH2:21][CH2:22][C:23]=3[CH:28]=2)[CH2:16][CH2:15]1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Reactant: O=Cc1ccc2c(c1)CCO2
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)CCO4)CC2)c2cc(Cl)ccc2o1

Procedure:
Prepared from 6-Chloro-4-(piperidin-4-ylamino)-chromen-2-one and 2,3-dihydro-benzofuran-5-carbaldehyde in a manner analogous to that described above. 1H NMR (500 MHz, MeOD-d4) δ ppm 8.13 (s, 1H), 7.61 (d, 1H), 7.33-7.36 (m, 2H), 7.84 (d, 1H), 7.24 (s, 1H), 5.45 (s, 1H), 4.61 (t, 2H), 4.26 (s, 2H), 3.85 (br t, 1H), 3.58 (br d, 2H), 3.26 (t, 2H), 3.16(br t, 2H), 3.35 (br d, 2H), 1.93 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N:46]=[C:47]=[O:48])[CH:41]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:47]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=1)=[O:48])[CH:29]=3
Reactant: O=C=Nc1cccc(F)c1
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(F)c1)Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Yield: 49 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 1-fluoro-3-isocyanatobenzene as the starting materials in 49% yield. LCMS for C25H21ClFN6O (M+H)+: m/z=475.2. 1H NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H), 9.47 (s, 1H), 9.03 (m, 1H), 8.81 (m, 1H), 8.12 (s, 1H), 7.86 (m, 1H), 7.40 (m, 1H), 7.31 (m, 1H), 7.24 (m, 2H), 7.05 (m, 3H), 6.84 (m, 2H), 6.68 (m, 1H), 2.82 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[CH3:12][O:13][C:14]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1c(N)cccc1F
Product: COc1c(F)cccc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-methoxy-3-fluoroaniline to yield 2-[(2-methoxy-3-fluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=2)[C:10]([O:12][C:13](C)(C)C)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[Br-].[K+].Cl>CO>[N:1]1([C:7]2[CH:8]=[C:9]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 4.17 h

Procedure:
A mixture of 3-(4-morpholinyl)-5-nitro-benzoic acid, 1,1-dimethylethyl ester (Example 87b; 0.77 g, 2.5 mmol), 1,8-diazabicyclo[5,4,0]undec-7-ene (0.56 mL, 3.75 mL), and potassium bromide (1.09 g, 12.5 mmol) in methanol (25 mL) is stirred at 90° C. for 250 min. The cooled mixture is then added to hydrochloric acid (50 mL of 0.1 M) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed with saturated aqueous sodium hydro-carbonate (2×25 mL), water (2×25 mL) and brine (2×50 mL), dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ethyl acetate—hexane to afford the title compound as yellow crystalline solid.
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])(C)(C)C.FC(CC(O)=O)(F)F.C(OCC)(=O)C>ClCCl>[Cl:29][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:20])([F:19])[F:21])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[C:8]([CH3:30])[CH:9]=3)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Agent: O=C(O)CC(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (Example I19) (74.14 g) in dichloromethane (750 ml) was added trifluoromethyl acetic acid (“TFA”) (148 ml). The reaction mixture was stirred at ambient temperature for 16 hours. Ethyl acetate was added and the mixture was washed with water, dried over sodium sulfate and concentrated. The residue was crystallized from ethyl acetate and heptane to give 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (55.0 g). 1H-NMR (CDCl3, 400 MHz): 8.12 (d, 1H), 7.65-7.45 (m, 5H), 4.15 (d, 1H), 3.75 (d, 1H), 2.75 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](B(O)O)[CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:21]1[CH:30]=[CH:29][C:28]2[N:27]=[CH:26][C:25]3[N:31]([CH3:46])[C:32](=[O:45])[N:33]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])=[CH:36][CH:35]=4)[C:24]=3[C:23]=2[CH:22]=1>CN(C=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:44][C:40]([C:37]1[CH:36]=[CH:35][C:34]([N:33]2[C:24]3[C:23]4[CH:22]=[C:21]([C:3]5[CH:2]=[N:1][C:10]6[C:5]([CH:4]=5)=[CH:6][CH:7]=[CH:8][CH:9]=6)[CH:30]=[CH:29][C:28]=4[N:27]=[CH:26][C:25]=3[N:31]([CH3:46])[C:32]2=[O:45])=[CH:39][CH:38]=1)([CH3:43])[C:41]#[N:42]
Reactant: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21
Reactant: OB(O)c1cnc2ccccc2c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4cnc5ccccc5c4)ccc3ncc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
0.3 mmol of 3-quinoline boronic acid (Aldrich, Buchs, Switzerland), 8 mg of bis(triphenylphosphine)palladium (II) dichloride (Fluka, Buchs, Switzerland) and 0.5 ml of a 1 M solution of Na2CO3 are added to a solution of 84 mg (0.2 mmol) of 2-[4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile (Example 1i) in 2 ml of DMF. The mixture is stirred for 1 h. at 100° C. After this time, the mixture is quenched with sat. aqueous NaHCO3 and extracted with EtOAc (2×). The organic layer is washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue is loaded on silica gel and purified by flash chromatography to give the title compound. ES-MS: 470 (M+H)+; analytical HPLC: tret=2.90 min (Grad 1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH3:29][O:30][C:31](=[O:36])[CH2:32][CH2:33][C:34]#[CH:35]>C(N(CC)CC)C.[Cu]I>[CH3:29][O:30][C:31](=[O:36])[CH2:32][CH2:33][C:34]#[C:35][C:8]1[N:7]=[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:28])[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1
Reactant: C#CCCC(=O)OC
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(CCC(=O)OC)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.4 %

Procedure:
11 mg of bis-triphenylphosphine-palladium(II) chloride and 1.5 mg of copper(I) iodide are added to a solution of 300 mg of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester and 68 mg of 4-pentynoic acid methyl ester in 5 ml of triethylamine, and the mixture is stirred for 20 hours at room temperature. The reaction mixture is filtered, the filter residue is washed with ethyl acetate and the filtrate is concentrated by evaporation. The residue is taken up in water, shaken out with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. The crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate and for complete purification subjected to high-pressure liquid chromatography on reversed-phase silica gel (Nova-Pak HR C18) with acetonitrile/water=75/25. 280 mg of 5-{2-(2-methoxycarbonylethyl)-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-pyridyl}-4-pentynoic acid methyl ester is obtained as colorless oil.