Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:23][C:24]1[N:25]=[CH:26][C:27]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([C:47]([CH3:52])([CH3:51])[C:48]([OH:50])=O)[CH:42]=2)=[N:28][C:29]=1[C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=1.C(N(C(C)C)CC)(C)C.[NH2:62][CH2:63][CH2:64][OH:65]>ClCCl.C(OCC)(=O)C.[Cl-].[Na+].O>[NH2:23][C:24]1[N:25]=[CH:26][C:27]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([C:47]([CH3:52])([CH3:51])[C:48]([NH:62][CH2:63][CH2:64][OH:65])=[O:50])[CH:42]=2)=[N:28][C:29]=1[C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:31]=1
Reactant: NCCO
Reactant: CC(C)(C(=O)O)c1cc(-c2cnc(N)c(-c3cc(-c4ccccc4)no3)n2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)NCCO)c1cc(-c2cnc(N)c(-c3cc(-c4ccccc4)no3)n2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(benzotriazol-1-yloxy-dimethylamino-methylene)-dimethyl-ammonium tetrafluoroborate (10.40 mg, 0.03239 mmol) was added to a stirred solution of 2-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]-2-methyl-propanoic acid (13 mg, 0.03239 mmol), diisopropyl ethyl amine (5.442 mg, 7.334 μL, 0.04211 mmol) and 2-aminoethanol (9.895 mg, 9.778 μL, 0.1620 mmol) in dichloromethane (15 mL) and the reaction allowed to stir at ambient temperature for 1 hour. The reaction was diluted with ethyl acetate/brine. The aqueous layer was extracted with ethyl acetate (×1) and the combined organic extracts washed with brine (×1). The organic extracts were then dried over MgSO4, filtered and concentrated in vacuo. Compound was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% trifluoroacetic acid in water; solvent B: acetonitrile) over 16 minutes at 25 mL/minutes], combined fractions were then freeze-dried to give 2-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]-N-(2-hydroxyethyl)-2-methyl-pro panamide Compound I-46 as a yellow solid (4 mg, 21.67%). 1H NMR (400.0 MHz, MeOD) δ 1.8 (s, 6H), 3.4 (t, 2H), 3.7 (t, 2H), 7.53-7.57 (m, 3H), 7.62 (s, 1H), 8.0-8.05 (m, 2H), 8.42 (d, 1H), 8.48 (s, 1H), 8.7 (d, 1H), 9.03 (s, 1H); LC/MS m/z 445.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:19](Cl)(Cl)=[S:20]>>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:12][N:13]=2)=[CH:6][CH:7]=1)=[C:19]=[S:20]
Reactant: CCCCCc1cnc(-c2ccc(N)cc2)nc1
Reactant: S=C(Cl)Cl
Product: CCCCCc1cnc(-c2ccc(N=C=S)cc2)nc1

Procedure:
2-(4-Aminophenyl)-5-pentylpyrimidine (prepared from 4-aminophenylamidine and 2-pentylpropane-1,3-diol) is reacted with thiophosgene as described in Example 3, affording 2-(4-isothiocyanatophenyl)-5-pentylpyrimidine; m.p. 46°, c.p. 85.5°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](OS(C)(=O)=O)[CH:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:24]>CO>[NH2:24][CH:11]1[CH:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12]1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC(OCC(F)(F)F)C(OS(C)(=O)=O)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)C(OCC(F)(F)F)C1
Temperature: 140 °C
Reaction time: 10 h

Procedure:
A mixture of 3.95 g (0.011 mole) of 1-t-butoxycarbonyl-3-(2,2,2-trifluoroethoxy)-4-methylsulfonyloxypyrrolidine [prepared as described in step (a) above] and 100 ml of methanol containing 20% w/v ammonia was transferred to an autoclave and then stirred at 140° C. for 10 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 1:9 by volume mixture of ethanol and ethyl acetate as the eluent, to give 1.61 g of 3-amino-1-t-butoxycarbonyl-4-(2,2,2-trifluoroethoxy)pyrrolidine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:27]4[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)cn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.4) (322 mg, 1.0 mmol) and 2-amino-5-bromopyridine (173 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (71 mg, 17%). MS (ISP) 414.3 [(M+H)+].
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:46])(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].[Na+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:46][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 57.1 %

Procedure:
To 150 ml of acetone-water (2:1) are added 1.3 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 1.0 g of sodium stearate and the mixture is refluxed for 4 hours and allowed to stand at room temperature (15°-25° C.) overnight. The solvent is then distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the residue is dissolved in 100 ml of ethanol. To the solution is added 0.3 g of activated carbon and the insoluble material is filtered off. The solvent is distilled off to give a colorless viscous oil, which is allowed to stand at room temperature (15°-25° C.) to give 1.1 g of the above-identified compound as a solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.[CH3:10][S:11]([NH2:14])(=[O:13])=[O:12].N12CCCN=C1CCCCC2>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1nc(Br)cs1
Reactant: CS(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1nc(Br)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Bromo-1,3-thiazole-2-carboxylic acid (1.0 g, 4.8 mmol) were initially charged in tetrahydrofuran (10 ml). N,N′-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added and the reaction mixture was heated under reflux for 1 h. Methanesulphonamide (0.69 g, 7.2 mmol) was added and, after 10 min, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.10 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The residue was taken up in water and acidified with hydrochloric acid. The precipitated product was filtered off with suction. This gave 1.18 g (84% of theory) of 4-bromo-N-(methylsulphonyl)-1,3-thiazole-2-carboxamide.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][C:8]1[C:13]([O:14]C(=O)C)=[C:12]([CH3:18])[C:11]([CH3:19])=[C:10]([O:20]C(=O)C)[C:9]=1[CH3:24])[CH2:3][C:4]#[N:5].C[O-].[Na+].O.CCOCC>CO>[OH:20][C:10]1[C:11]([CH3:19])=[C:12]([CH3:18])[C:13]2[O:14][C:2]([CH3:1])([CH2:3][C:4]#[N:5])[CH2:6][CH2:7][C:8]=2[C:9]=1[CH3:24]
Reactant: C=C(CC#N)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC#N)O2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
A slurry of 500 mg (1.52 mmoles) of the mixture of E- and Z-3-methyl-5-(2,4,5-trimethyl-3,6-diacetyloxyphenyl)-3-pentenenitrile and 3-methylene-5-(2,4,5-trimethyl-3,6-diacetyloxy-phenyl)pentanenitrile in 5 ml of methanol was treated with 0.71 ml (3.34 mmoles) of a 4.7 M methanolic sodium methoxide solutiion. The resulting mixture was stirred at room temperature for 4.5 hr, then poured into 20 ml of water and worked-up with ether in the usual manner affording 345 mg (93%) of rac. 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetonitrile as a tan solid.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[Br:19][C:20]1[S:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=1>>[Br:19][C:20]1[S:21][CH:22]=[C:23]([C:25]([NH:1][C@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:26])[N:24]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(Br)n1
Yield: 55.8 %

Procedure:
(R)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg, 0.384 mmol) and 2-bromo-1,3-thiazole-4-carboxylic acid (96 mg, 0.460 mmol). The product was triturated using diethyl ether. Yield 55.8%. 1H-NMR (400 MHz; CDCl3): δ 1.12 (d, 3H), 4.27-4.52 (m, 3H), 6.97 (d, 1H), 7.85 (d, 1H), 8.00 (s, 2H), 8.07 (s, 1H), 8.23 (s, 1H), 8.64 (d, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:14])([O:9][Si](C)(C)C)[CH3:8].Cl>CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:14])([OH:9])[CH3:8]
Reactant: CC(C)(CCCCCBr)O[Si](C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(O)CCCCCBr

Procedure:
To a solution of 7-bromo-2-methyl-2-trimethylsilyloxyheptane (10) (14.0 g) in methanol (55 ml) at room temperature was added ethanolic hydrogen chloride (ca. 1M, 0.2 ml). After 10 minutes the solution was concentrated in vacuo (at room temperature) to constant weight. The residue was taken up in chloroform and reconcentrated to constant weight to give 7-bromo-2-methyl-2-heptanol (H, n=4, R1 =R2 =Me) as a chromatographically homogenous oil. The product was dissolved in THF (10 ml) and added to a premixed, stirred solution of potassium tert-butoxide (6.7 g) and thiophenol (3.6 ml) in N,N-dimethylformamide (50 ml) at room temperature. After a few minutes a precipitate started forming, and after 30 minutes the mixture was partitioned between ethyl acetate (300 ml) and water (200 ml). The organic layer was washed consecutively with 2N sodium hydroxide solution, water and brine. Drying and concentration in vacuo gave 6-hydroxy-6-methylheptyl phenyl sulphide as a chromatographically homogenous oil. This was dissolved in methanol (60 ml), and to the stirred solution was added sodium hydrogen carbonate (4.7 g), aqueous sodium tungstate solution (2%, 5 ml) and hydrogen peroxide (100 vol, 11.8 ml). The initial exothermic reaction which ensued was checked by momentary ice-cooling. The reaction mixture was then stirred at 50° C. for 1 hour. After cooling, the mixture was partitioned between dichloromethane (200 ml) and water. The aqueous layer was extracted with more dichloromethane, and the combined dichloromethane layers were washed with water, brine, and dried. Concentration in vacuo gave a crude product which was purified by chromatography (150 g silica gel; ether as eluant) to give the sulphone (13) as a viscous oil, δ (300 MHz) 1.18 (6H, s), 1.4 (7H, m), 1.75 (2H, m), 3.09 (2H, m), 7.5-7.75 (3H, m), 7.90 (2H, m).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[CH:8]=1.CCN(CC)CC.CS(Cl)(=O)=O.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36][CH2:2][C:3]2[CH:4]=[N:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[CH:8]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)n1ncc(CO)cc1=O
Reactant: Sc1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc(CSc2ccc(Cl)cc2)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)-6-oxopyridazine-1(6H)-carboxylate Part B (185 mg, 0.82 mmol) and Et3N (0.34 mL, 2.45 mmol) in CH2Cl2 (5 mL) under nitrogen at −10° C. was added a solution of methanesulfonyl chloride (0.076 mL, 0.98 mmol) in CH2Cl2 (2 mL). After stirring at RT for 15 min, 4-chlorobenzenethiol (355 mg, 2.45 mmol) was added to the reaction and the stirring at RT continued for 3 days. Following removal of the volatiles under vacuum, the crude product was purified by flash chromatography (silica gel/hexane-EtOAc 100:0 to 50:50 gradient, using LC-MS to identify fractions containing the desired product) to afford tert-butyl 4-((4-chlorophenylthio)methyl)-6-oxopyridazine-1(6H)-carboxylate 7C (137 mg, 47% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:7]([CH2:14][OH:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Na+]>Cl.O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:7]([CH2:14][OH:15])=[C:8]([C:10]([F:12])([F:11])[F:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(F)(F)F)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(C(F)(F)F)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 76.9 %

Procedure:
A solution of 4.06 g of 2-butyl-5-hydroxymethyl-4-trifluoromethyl-1-[(2'-(triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]imidazole in 40 mL of 10% hydrochloric acid and 80 mL of tetrahydrofuran was stirred at 25° for 2 hours and then poured into water containing an excess of sodium hydroxide. The aqueous solution was washed with diethyl ether, adjusted to pH 3 with 10% hydrochloric acid, and then extracted with chloroform. The combined chloroform extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (elution: 10% methanol/chloroform) furnished 2.04 g of 2-butyl-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-4-trifluoromethylimidazole as an amrphous solid.
Reaction SMILES: C([O:8][C:9](=[O:25])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.[OH-].[Na+]>CO>[CH2:18]([O:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[C:9]([OH:25])=[O:8])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)c1c(F)cccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c(F)cccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 7.3 g (21.7 mmol) of 2-benzyloxy-6-fluorobenzoic acid benzyl ester in 75 mL of methanol is added 20 mL of 1.0N NaOH. The mixture is stirred at 50° C. for 24 h. Another 10 mL of 1.0N NaOH is added and the mixture is stirred at RT for 18 h. The solvent is removed under reduced pressure and water is added to the residue. The solution is washed with MTBE and the aqueous phase is acidified with 1N HCl. The mixture is extracted with ethyl acetate (2×) and the organic solution is dried over sodium sulfate. The solvent is removed under reduced pressure to give the product as an oil: 1H NMR (CDCl3) δ 7.44-7.31 (m, 6H), 6.84-6.79 (m, 2H), 5.22 (s, 2H).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]([O:28][C:29]([NH:31][C@@H:32]([C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:33])=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([NH:31][C@@H:32]([C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:36][CH:35]=1)[CH3:33])=[O:30])([CH3:25])([CH3:26])[CH3:27]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and (R)-4-(1-tert.butoxycarbonylamino-ethyl)-aniline in DMF.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:38]([C:40]([C:59]1[CH:64]=[CH:63][C:62](/[CH:65]=[CH:66]/[C:67]([C:73]([F:76])([F:75])[F:74])([OH:72])[C:68]([F:71])([F:70])[F:69])=[C:61]([CH3:77])[CH:60]=1)([C:43]1[CH:48]=[CH:47][C:46](B2OC(C)(C)C(C)(C)O2)=[C:45]([CH3:58])[CH:44]=1)[CH2:41][CH3:42])[CH3:39].[CH3:78][O:79][C:80](=[O:89])[CH2:81][C:82]1[CH:87]=[CH:86][C:85](Br)=[CH:84][CH:83]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:78][O:79][C:80](=[O:89])[CH2:81][C:82]1[CH:87]=[CH:86][C:85]([C:46]2[CH:47]=[CH:48][C:43]([C:40]([CH2:41][CH3:42])([C:59]3[CH:64]=[CH:63][C:62](/[CH:65]=[CH:66]/[C:67]([OH:72])([C:73]([F:75])([F:76])[F:74])[C:68]([F:71])([F:70])[F:69])=[C:61]([CH3:77])[CH:60]=3)[CH2:38][CH3:39])=[CH:44][C:45]=2[CH3:58])=[CH:84][CH:83]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
Palladium acetate (3.6 mg, 0.016 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (13.1 mg, 0.032 mmol), potassium phosphate (51 mg, 0.24 mmol) and water (0.04 mL) were added to a solution of (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 40 mg, 0.070 mmol) and (4-bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 28 mg, 0.122 mmol) in toluene (0.4 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. Thereafter, the solution was filtered through amino silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (14.1 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([CH2:20][C:21]#[N:22])=[C:15]([Cl:23])[CH:14]=1.CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:12][C:13]1[CH:14]=[C:15]([Cl:23])[C:16]([CH:20]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH:8]([CH3:10])[CH3:9])[CH:6]=2)[C:21]#[N:22])=[C:17]([Cl:19])[CH:18]=1
Reactant: N#CCc1c(Cl)cc(N)cc1Cl
Reactant: CC(C)c1cc(Cl)nnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C#N)c2c(Cl)cc(N)cc2Cl)nnc1Cl
Temperature: 60 °C
Yield: 76.6 %

Procedure:
A solution of 3,6-dichloro-4-isopropyl pyridazine (7) (5.54 g, 29.0 mmol) in tetrahydrofuran (116 mL) in a 500 mL round bottom flask (caution: use an extra large flask) was treated with (4-amino-2,6-dichloro-phenyl)-acetonitrile (44) (5.81 g, 28.9 mmol). The reaction mixture was equipped with a cold water condenser and heated to 60° C. The flask was then raised out of the oil bath and potassium tert-butoxide (6.85 g, 57.99 mmol) was added. The mixture was heated to 60° C. for 45 min. The reaction was cooled to room temperature, transferred to a separatory funnel, diluted with ethyl acetate (500 mL) and was washed with a saturated aqueous sodium chloride solution (2×250 mL). The organic layer was separated, dried with magnesium sulfate, and was filtered. Silica gel 60 (70-230 mesh) was added to the filtrate and the solvent was concentrated under vacuum. The resulting mixture was purified by flash chromatography (Biotage 75 L) using silica gel eluted with 15%-30% ethyl acetate in hexanes. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford (4-amino-2,6-dichloro-phenyl)-(6-chloro-5-isopropyl-pyridazin-3-yl)-acetonitrile (45) (7.87 g, 77%) as an orange foam; LRMS for C15H13Cl3N4 (M+H) m/z=355. This compound was used without further purification. Molecular Weight=355.6567; Exact Mass=354.0206
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].IC.[C:12](=O)([O-])[O-].[K+].[K+].[H-].[Na+]>CC#N.O>[CH3:12][O:6][CH2:5][C:4]1[CH:3]=[C:2]([I:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: OCc1cccc(I)c1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CC#N
Product: COCc1cccc(I)c1
Temperature: 30 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a solution of 508 μl (4.0 mmol) of 3-iodobenzylalcohol and 1.25 ml (20.0 mmol) of iodomethane in MeCN (20 ml) there were added 829 mg (6.0 mmol) of potassium carbonate. After stirring 3 h at 30° C., 320 mg (8.00 mmol) of NaH were added and stirring was continued a further 3 h at RT. Water was then added to the reaction mixture, which was extracted with chloroform. The organic phase was successively washed with water and a satd aq. NaCl soln and dried over MgSO4. Following filtration and removal of the solvent in vacuo there were obtained 863 mg (3.5 mmol, 87%) of 3-methoxymethyliodobenzene.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][O:43][CH3:44]>>[CH3:36][O:37][CH2:38][CH2:39][N:40]([CH2:24][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[O:23][N:22]=1)[CH2:41][CH2:42][O:43][CH3:44]
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: COCCNCCOC
Product: COCCN(CCOC)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and bis-(2-methoxyethyl)amine (280 μl, 1.98 mmol) as starting materials.