Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C@:40]12([CH2:50][S:51]([OH:54])(=[O:53])=[O:52])[C:47]([CH3:49])([CH3:48])[CH:44]([CH2:45][CH2:46]1)[CH2:43][C:41]2=[O:42]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]12([CH2:50][S:51]([O-:54])(=[O:52])=[O:53])[C:47]([CH3:49])([CH3:48])[CH:44]([CH2:45][CH2:46]1)[CH2:43][C:41]2=[O:42]
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of (S)-camphor-sulfonic acid (0.132 g, 0.57 mmol) in TFE (1 mL) at 40° C. The resulting solution was stirred for about 2 h and it was subsequently cooled to 5° C. No precipitation was observed upon cooling. The mixture was kept at 5° C. overnight while stirring and then a sample (1 ml) was taken from the mixture and evaporated to dryness under reduced pressure at 40° C. to give amorphous Nilotinib camphorsulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=3F)=[CH:11][N:10]([CH3:23])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:32][C:26]3[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=3[F:24])=[CH:11][N:10]([CH3:23])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1nc(Br)cc2c(-c3cc([N+](=O)[O-])ccc3F)cn(C)c12
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1nc(Br)cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 76.9 %

Procedure:
A mixture of Example 182A (367 mg, 0.965 mmol), 2,4-difluorophenol (111 μl, 1.158 mmol) and cesium carbonate (472 mg, 1.448 mmol) in 8 mL DMSO was heated under nitrogen at 90° C. for 1.5 hours. The mixture was partitioned between water and ethyl acetate (80 mL). The aqueous phase was extracted with ethyl acetate (2×60 mL). The combined organics were washed with water (2×), saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel with a gradient of 10-70% ethyl acetate in heptanes to give the title compound (331 mg, 0.742 mmol, 77% yield) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Ir:38].Cl>OCC(CO)O>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Ir+3:38]
Reactant: [Ir]
Agent: CC(=O)/C=C(/C)O
Agent: Cl
Agent: c1ccc(-c2nccc3ccccc23)cc1
Solvent: OCC(O)CO
Product: [Ir+3]
Temperature: 135 °C

Procedure:
50 ml of glycerol was introduced into a 100 ml-four-neck flask, and then stirred and heated at 130 to 140° C. for 2 hours while bubbling with nitrogen gas. The glycerol was left to cool to 100° C., and then 1.03 g (5.02 mmol) of 1-phenylisoquinoline and 0.50 g (1.02 mmol) of iridium (III) acetylacetonate were added. The reaction mixture was stirred and heated for 7 hours at around 210° C. under a nitrogen gas flow. After being left to cool to room temperature, the reaction product was added to 300 ml of 1N-hydrochloric acid, and the resulting precipitate was filtered and then washed with water. The precipitate was purified using silica gel column chromatography with chloroform used as an eluent, to yield 0.22 g of a red powder of iridium (III) tris(1-phenylisoquinoline) (26.8% yield). FIG. 1 illustrates the crystal structure of the iridium (III) tris(1-phenylisoquinoline) as obtained from single crystal structure analysis. As can be seen from FIG. 1, this crystal had pores with a diameter of about 0.8 nm.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:16]=[N:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH:23](O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[C:10]=1[C:11]#[N:12].C([SiH](CC)CC)C>ClCCl>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([C:13]2[CH:14]=[N:15][CH:16]=[C:9]([Cl:8])[C:10]=2[C:11]#[N:12])=[CH:22][CH:21]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N#Cc1c(Cl)cncc1-c1ccc(C(O)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(Cl)cncc1-c1ccc(Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Trifluoroacetic acid (5 mL, 64.9 mmol) was added to a solution of 3-chloro-5-(4-(hydroxy(phenyl)methyl)phenyl)isonicotinonitrile (327 mg, 0.816 mmol, 80% pure) and triethylsilane (5 mL, 31.3 mmol) in dichloromethane (10 mL). After 1 h at room temperature, the mixture was concentrated, quenched with saturated sodium bicarbonate (30 mL) and extracted with dichloromethane (3×15 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, loading with toluene and eluting with 10-30% ethyl acetate in hexanes, gave 3-(4-benzylphenyl)-5-chloroisonicotinonitrile as colorless liquid (195.2 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (1H, s), 8.68 (1H, s), 7.45-7.58 (2H, m), 7.28-7.43 (4H, m), 7.15-7.28 (3H, m), 4.07 (2H, s). MS (ES+) m/z: 305 (M−H2O+H); LC retention time: 4.391 min (analytical HPLC Method A).
Reaction SMILES: I[C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1.[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=CC=C[CH:17]=1.[F-].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C.C[Si](C)(C)C#CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:9]([C:6]1[C:7]([NH2:8])=[C:2]([C:17]#[C:16][CH3:21])[N:3]=[CH:4][N:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1c(I)ncnc1Oc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC#Cc1ncnc(Oc2ccccc2)c1N
Temperature: 60 °C
Reaction time: 16 h
Yield: 730 %

Procedure:
4-Iodo-6-phenoxypyrimidin-5-amine (5.00 g) was dissolved in a mixed solvent of N,N-dimethylformamide (100 mL)/triethylamine (50 mL), and 1-(trimethylsilyl)-1-propyne (3.3 mL), trans-dichlorobis(triphenylphosphine)palladium(II) (557.7 mg), triphenylphosphine (421.1 mg), copper(I) iodide (303.0 mg) and potassium fluoride (1.29 g) were sequentially added. The mixture was stirred at 60° C. under an argon stream for 16 hrs. The reaction mixture was treated with saturated aqueous sodium hydrogen carbonate solution and extracted with diethyl ether. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound (2.64 g) as a orange solid.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[NH:18][CH2:17][CH2:16]2.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[N:18]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1)[CH2:17][CH2:16]2
Reactant: C1CN2CCC(CC2)N1
Reactant: CNC(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(N2CCN3CCC2CC3)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 81.8 %

Procedure:
To a solution of 4-fluoro-N-methyl-2-nitrobenzamide (Intermediate 3L) (0.65 g, 3.3 mmol) in dimethylsulfoxide (50 mL) was added 1,4-diazabicyclo[3.2.2]nonane (0.62 g, 4.9 mmol) and potassium carbonate (1.36 g, 9.8 mmol). The resulting suspension was heated at 90° C. for 4 days. The mixture was filtered and the filtrate purified using a 20 g SCX cartridge to afford 4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methyl-2-nitrobenzamide (0.8 g, 2.7 mmol).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:6][C:5]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C(=O)(O)[O-].[Na+]>Cl>[O:2]=[C:3]1[CH2:6][C:5]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[CH2:4]1
Reactant: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(=O)C1
Yield: 72.4 %

Procedure:
A solution of dipropan-2-yl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (10.0 g, 34.6 mmol) in hydrochloric acid (3 N, 55 mL) was heated at 50° C. for 4 hours. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 6.073 g of dipropan-2-yl 3-oxocyclobutane-1,1-dicarboxylate as a light brown oil (yield was 72.3%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[SH:16][CH2:17][C:18]1[NH:19][C:20]([CH3:43])=[C:21]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[NH2:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][CH:46]=1>O1CCCC1>[NH2:44][C:45]1[CH:53]=[CH:52][C:48]([C:49]([S:16][CH2:17][C:18]2[NH:19][C:20]([CH3:43])=[C:21]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=3)[C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:50])=[CH:47][CH:46]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)NC(CSC(=O)c2ccc(N)cc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of dicyclohexylcarbodiimide (g 1.5) in tetrahydrofuran is added dropwise to a solution of 2-mercaptomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (g 2.7) and p-aminobenzoic acid (g 1.0) in tetrahydrofuran (20 ml) cooled to 0° C. in nitrogen atmosphere, the mixture is stirred at 0° C. for 15 minutes and then warmed to room temperature for 18 hours. The precipitate formed is filtered and the solvent is evaporated in vacuum. The residue is dissolved in ethyl acetate (150 ml) and washed with water (3×40 ml), with a sodium bicarbonate solution (3×30 ml) and then once again with water (3×20 ml). After drying on sodium sulphate and evaporation in vacuum of the solvent, the residue is purified by chromatography on silica gel (g 100) eluting with petroleum ether/ethyl acetate (8/2). The product is recrystallized from isopropyl ether. 3,2 g of 2-(p-aminobenzoylthio)methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine are obtained; m.p. 78°-80° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](I)[CH:7]=[C:6]([Br:11])[CH:5]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:7]=[C:6]([Br:11])[CH:5]=1
Reactant: O=C1CCCN1
Reactant: COC(=O)c1cc(Br)cc(I)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(Br)cc(N2CCCC2=O)c1
Temperature: 40 °C
Yield: 82.4 %

Procedure:
3-Bromo-5-iodobenzoic acid methyl ester (2.044 g, 5.996 mmol) in dioxane (25 ml) was treated with 2-pyrrolidinone (433 μl, 5.696 mmol), Cs2CO3 (2.93 g, 8.994 mmol), pd2(dba)3 (110 mg, 0.12 mmol) and Xantphos (208 mg, 0.36 mmol). The reaction mixture was heated to 40° C. for 3 days, then cooled to room temperature. The reaction mixture was filtered through celite and concentrated in vacuo. Column chromatography on silica gel (EtOAc) gave D9 (1.4 g) as a brown solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32]([C:33]([C@@H:35]3[CH2:38][C@H:37]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH2:36]3)=[O:34])[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:47][CH3:48])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>>[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32]([C:33]([C@@H:35]3[CH2:36][C@H:37]([CH2:39][C:40]([OH:42])=[O:41])[CH2:38]3)=[O:34])[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:47][CH3:48])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cooled TFA (2 mL) was added to tert-butyl 2-(cis-3-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate (100 mg, 0.17 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min. The pH of the reaction mixture was adjusted to 6 with cooled aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (67.0 mg, 0.126 mmol, 74.1%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9](SC(C)(C)C)=[C:8]2[CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:4][CH:3]=1.C(O)(=O)C1C(=CC=CC=1)S>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C(O)c1ccccc1S
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C)Cc1cc2cc(OC)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A mixture of the product from Step 1 (2.03 g, 4.29 mmol) and thiosalicylic acid (1.32 g, 8.58 mmol) in TFA (25 mL) was refluxed for 2.5 hours. The TFA was evaporated, the residue was diluted with EtOAc, washed twice with 1N aq NaOH, then 3× with H2O, dried and evaporated to afford the crude title product as a thick oil which was taken as such into the next step.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[C:17]3[O:18][C:19]4[C:24]([C:16]=3[CH:15]=[C:14]([CH3:26])[CH:13]=1)=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=4)=[N:7]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2N(C)C)CCCCC1.[I-].[F:59][C:60]([F:65])([F:64])[CH2:61][CH2:62][Zn+]>C1COCC1.C(O[Pd]OC(=O)C)(=O)C>[CH3:25][C:21]1[N:20]=[C:19]2[O:18][C:17]3[C:12]([C:6]4[CH:5]=[CH:4][C:3]5[C:8](=[CH:9][CH:10]=[CH:11][C:2]=5[CH2:62][CH2:61][C:60]([F:65])([F:64])[F:59])[N:7]=4)=[CH:13][C:14]([CH3:26])=[CH:15][C:16]=3[C:24]2=[CH:23][CH:22]=1
Reactant: FC(F)(F)CC[Zn+]
Reactant: Cc1cc(-c2ccc3c(Cl)cccc3n2)c2oc3nc(C)ccc3c2c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CN(C)c1cccc(N(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [I-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc3c(CCC(F)(F)F)cccc3n2)c2oc3nc(C)ccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
8-(5-chloroquinolin-2-yl)-2,6-dimethylbenzofuro[2,3-b]pyridine (3.40 g, 9.48 mmol), 2′-(dicyclohexylphosphino)-N2,N2,N6,N6-tetramethyl-[1,1′-biphenyl]-2,6-diamine (0.33 g, 0.76 mmol) and diacetoxypalladium (0.09 g, 0.38 mmol) were charged into a flask and diluted with THF (150 mL). This mixture was degassed by bubbling nitrogen followed by the addition of (3,3,3-trifluoropropyl)zinc(II) iodide (40 mL, 11.8 mmol) via syringe. This mixture was stirred at room temperature overnight. Upon completion of the reaction, it was quenched with aqueous ammonium chloride then was extracted two times with 200 mL ethyl acetate. These extracts were dried over magnesium sulfate then were filtered and concentrated under vacuum. The crude residue was purified by column chromatography using 20/80 Ethyl Acetate/Heptanes. The combined fractions were triturated in Heptanes to afford 2,6-dimethyl-8-(5-(3,3,3-trifluoropropyl)quinolin-2-yl)benzofuro[2,3-b]pyridine (2.55 g, 64% yield) as an off-white powder.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]5)[CH2:21]3)[CH2:27]4)=[CH:16][CH:15]=2)=[CH:6][CH:5]=1.Cl>O1CCOCC1.O>[C:20]12([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=4)=[O:30])=[CH:15][CH:16]=3)[CH2:27][CH:26]3[CH2:28][CH:22]([CH2:23][CH:24]([CH2:25]3)[CH2:29]1)[CH2:21]2
Reactant: COC(=O)c1ccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1ccc(C(=O)O)cc1
Yield: 62.7 %

Procedure:
A solution of 4-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid methyl ester (79.1 mg, 0.16 mmol) in 1,4-dioxane/H2O (3:1, 8 ml) was treated with LiOHH2O (15.9 mg, 0.38 mmol) at room temperature until the reaction was complete, as judged by TLC. The reaction mixture was then acidified with 10% HCl to PH 2, and then partitioned between ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:EtoAc:MeOH=6:3:1) to give 4-[2-(4-Adamantan-1-yl-phenoxy)acetylamino]-benzoic acid as a white solid (40.7 mg, 53.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:11]([O-])=O.[Na+].N>C(O)(=O)C.S(=O)(=O)(O)O.Cl>[Cl:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:11]
Reactant: CCc1ccc(N)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1ccc(NN)c(Cl)c1
Yield: 60.4 %

Procedure:
2-Chloro-4-ethylaniline [14.5 g.; described by K. Altau, J. Chem. Eng. Data, 8, 122 (1963)] was dissolved, with stirring, in glacial acetic acid (113 ml). A solution of sodium nitrite (7.0 g) in concentrated sulphuric acid (55 ml) was then added at 55°-60° C. The solution thus obtained was cooled to 0°-5° C. and a solution of stannous chloride (70 g) in concentrated hydrochloric acid (80 ml) was added with vigorous stirring. A cream-coloured solid precipitated. The mixture was filtered and the solid obtained was added to a mixture of aqueous ammonia and ice. The mixture thus obtained was extracted with diethyl ether (4×300 ml) and the combined ethereal extracts were dried over sodium sulphate, filtered and evaporated to dryness, to give 2-chloro-4-ethylphenylhydrazine (9.6 g), m.p. 55°-57° C., in the form of a cream-coloured solid. By proceeding in a similar manner, but replacing the 2-chloro-4-ethylaniline by the hereinafter indicated appropriately substituted aniline, there was prepared:
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:31])[CH:8]([O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C.Cl>O.O1CCCC1>[CH3:27][N:25]([CH3:26])[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH:8]([O:28][CH2:29][CH3:30])[C:7]([OH:31])=[O:6])=[CH:11][CH:12]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(N(C)C)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(N(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Lithium hydroxide hydrate (38 mg; 0.90 mmole) dissolved in water (2 ml) was added to a solution of 3-{4-[2-(4-dimethylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester (described in Example 99) (232 mg; 0.60 mmole) in tetrahydrofuran (6 ml). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with hydrochloric acid (2 M) to pH 5. Tetrahydrofuran was evaporated in vacuo, water (5 ml) was added and the mixture was extracted with ethyl acetate (10+5 ml), dried (sodium sulfate) and the solvent was evaporated in vacuo. Purification by filtration on silica gel gave 180 mg (yield 84%) of 3-{4-[2-(4-dimethylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([C:18]#[CH:19])[NH:12]4)[CH2:5][C@H:4]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:3]1.C(N(CC)CC)C.I[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1>CN(C)C=O.[Cu]I>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([C:18]#[C:19][C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[NH:12]4)[CH2:5][C@H:4]([NH:20][C:21](=[O:27])[N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[CH2:3]1
Reactant: C#Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1C
Reactant: Ic1cccs1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C#Cc5cccs5)c(c34)C[C@H]2N(C)C1

Procedure:
Under argon, 72 mg of 3-(6-methyl-2-ethynyl-8α-ergolinyl)-1,1-diethylurea is heated in 2 ml of dimethylformamide with 2 ml of triethylamine, 1.5 mg of copper(I) iodide, 0.069 ml of 2-iodothiophene, and 4.8 mg of palladium(O) tetrakis(triphenylphosphine) for 2 hours to 80° C. After evaporation, the mixture is taken up in ethyl acetate and washed in succession with dilute ammonia solution and saturated sodium chloride solution. After chromatography over silica gel with ethyl acetate:ethanol=1:1 and recrystallization from ethanol/hexane, 26 mg of 3-[6-methyl-2-(thien-2-ylethynyl)-8α-ergolinyl]-1,1diethylurea is obtained, mp 252°-256° C.