Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1([C:23]2[S:24][C:25]([C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=4)[N:29]=3)=[CH:26][N:27]=2)[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:19]([O:21]C)=[O:20])[CH:12]=[CH:11][C:10]1=2.[OH-].[Na+]>CCO>[NH2:8][C:9]1([C:23]2[S:24][C:25]([C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:43])([F:45])[F:44])[CH:39]=[CH:38][N:37]=4)[N:29]=3)=[CH:26][N:27]=2)[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:19]([OH:21])=[O:20])[CH:12]=[CH:11][C:10]1=2
Reactant: COC(=O)c1ccc2c(c1)CCCC2(N)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(N)CCCc4cc(C(=O)O)ccc43)s2)c1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 30.2 %

Procedure:
To a solution of the trifluoroacetate salt of methyl 5-amino-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (30 mg, 0.056 mmol) in EtOH (2 mL) was added sodium hydroxide (1 mL, 2.000 mmol) and the mixture was stirred at 70° C. for 45 min. The organic solvent was then removed under reduced pressure, and the residue was diluted with water, neutralized with 2N HCl (˜1 mL), then extracted with EtOAc, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, then purified by reverse phase chromatography using a C18 column with a mobile phase of MeCN and water modified with 0.1% TFA. The product containing fractions were combined and lyophilized the trifluoroacetate salt of 5-amino-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridine-2-yl)amino)pyridine-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid as white solid (8.9 mg, 25% yield). MS ESI calcd for C26H22F3N5O2S [M+H]+ 526, found 526. 1H NMR (600 MHz, cd3od) δ 8.47 (s, 1H), 8.40 (s, 1H), 8.34 (d, J=5.2, 1H), 8.02 (s, 1H), 7.94 (d, J=8.2, 1H), 7.55 (d, J=8.3, 1H), 7.32 (s, 1H), 7.03 (d, J=5.1, 1H), 6.90 (s, 1H), 3.06 (t, J=6.1, 2H), 2.72-2.59 (m, 1H), 2.46-2.38 (m, 1H), 2.34 (s, 3H), 2.07 (s, 1H), 2.01-1.90 (m, 1H).
Reaction SMILES: [CH2:1]1[CH2:4][CH:3]([CH2:5][N:6]2[C@@H:16]3[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]5[O:25][C@H:10]6[C:11]([CH2:13][CH2:14][C@:15]3([OH:26])[C@:9]6([C:19]=45)[CH2:8][CH2:7]2)=[O:12])[CH2:2]1.P(=O)(O)(O)O.[H][H]>CC(O)C.O.[Pt]>[CH:23]1[C:18]2[CH2:17][C@H:16]3[N:6]([CH2:5][CH:3]4[CH2:4][CH2:1][CH2:2]4)[CH2:7][CH2:8][C@:9]45[C@H:10]([C@@H:11]([OH:12])[CH2:13][CH2:14][C@@:15]34[OH:26])[O:25][C:20]([C:19]=25)=[C:21]([OH:24])[CH:22]=1
Reactant: [H][H]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CCC2)[C@H]1O5
Agent: [Pt]
Agent: O=P(O)(O)O
Solvent: CC(C)O
Solvent: O
Product: Oc1ccc2c3c1O[C@H]1[C@@H](O)CC[C@@]4(O)[C@@H](C2)N(CC2CCC2)CC[C@]314
Reaction time: 7 h
Yield: 97.5 %

Procedure:
6-ketonalbuphine (40 g, 112.8 mmoles) was dissolved in a mixture of IPA (200 mls) and water (200 mls) containing orthophosphoric acid (1.56 mls). The pH of the reaction mixture was 6.49. The reaction mixture was hydrogenated at 40 psi hydrogen gas and 50° C. in the presence of 10% Platinum on carbon catalyst (2.4 g, 0.56 mmoles Pt). After 7 hours, the pH of the reaction mixture is adjusted with orthophosphoric acid (6.25 mls) and filtered. Ammonia solution (25 mls) was added to bring the pH to 8.5-9.0 and the precipitate filtered, washed with 50% aqueous IPA (60 mls), and dried to provide 39.33 g (97% theory) of Nalbuphine alkaloid of purity 95.6% by HPLC.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH3:20])[C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>CN(C=O)C.O>[CH2:1]([N:8]([CH2:19][CH3:20])[C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(Cc1ccccc1)c1cccc(C(=O)O)c1C
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1)c1cccc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (3-[benzyl(ethyl)amino]-2-methylbenzoic acid (91% purity, 296 mg, 1.0 mmol) in DMF (10 ml) was added DIPEA (440 μl, 2.5 mmol) and HATU (570 mg, 1.5 mmol). The reaction was stirred at room temperature for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 222 mg, 1.3 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction mixture was then poured onto 150 ml of water and stirred for 20 min. The product was filtered, air dried under vacuum and then purified using RP-HPLC. The resulting solid was triturated with diethyl ether and isolated by filtration to afford the title compound as an off white solid (86 mg, 21%). LC-MS 99%, m/z=404.3, 1H NMR (500 MHz, Chloroform-d) δ 12.04 (s, 1H), 7.33-7.23 (m, 4H), 7.21 (t, J=6.8 Hz, 1H), 7.14-7.05 (m, 3H), 7.05-6.99 (m, 1H), 5.92 (s, 1H), 4.53 (d, J=5.9 Hz, 2H), 4.06 (s, 2H), 2.92 (q, J=6.9 Hz, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.16 (s, 3H), 0.92 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]([CH2:17][CH:18]([CH3:20])[CH3:19])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])(=[O:9])=[O:8].[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:7]([N:6]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5][C:4]1[CH:3]=[C:2]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:9])=[O:8]
Reactant: CC(C)CN(Cc1cccc(Br)c1)S(=O)(=O)c1ccccc1Cl
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CN(Cc1cccc(-c2cccc(S(C)(=O)=O)c2)c1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, N-(3-bromo-benzyl)-2-chloro-N-isobutyl-benzenesulfonamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-isobutyl-N-(3′-methanesulfonyl-biphenyl-3-ylmethyl)-benzenesulfonamide as a colorless solid. MS: 550.2 ([M+OAc]−)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(CC)CC>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:21]([NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2)c(Cl)c1
Reaction time: 15 h
Yield: 85.6 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.31 g, 6.56 mmol) and phenyl isocyanate (0.71 ml, 6.56 mmol) in THF (20 ml) was added Et3N (0.19 ml, 1.33 mmol) at room temperature. After 15 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-(N′-phenylureido)phenylacetate (1.79 g, 86%) as a pale brown solid. 1H-NMR (CDCl3) δ3.56 (s, 2H), 3.70 (s, 3H), 6.70 (m, 1H), 7.06 (s, 1H), 7.14-7.18 (m, 2H), 7.26 (dd, J=7.8, 1.9 Hz, 1H), 7.33-7.38 (m, 4H), 8.14 (dd, J=8.3, 3.0 Hz, 1H); MS (ESI) m/z 319 (M++1), 321 (M++3).
Reaction SMILES: Cl.C([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:24])[CH2:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][C:12]=1[F:25])(=O)C1C=CC=CC=1>>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:24])[CH2:18][NH:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:13][C:12]=1[F:25]
Reactant: CC(C)(C)NCC(O)c1ccc(NC(=O)c2ccccc2)c(F)c1
Agent: Cl
Product: CC(C)(C)NCC(O)c1ccc(N)c(F)c1

Procedure:
m.p. of the hydrochloride: 196°-197° C. (decomp.), was prepared from 1-(4'-benzoylamino-3'-fluoro-phenyl)-2-tert.butylamino-ethanol analogous to Example 4.
Reaction SMILES: [I:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7](O)[C:6]=1[O:14][CH2:15][CH2:16][I:17].[C:18]([O:26]CC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1CCCCC1.C(O)C>[I:17][CH2:16][CH2:15][O:14][C:6]1[CH:7]=[C:8]2[C:11](=[CH:12][C:5]=1[O:4][CH2:3][CH2:2][I:1])[O:26][C:18](=[O:25])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2
Reactant: O=Cc1ccc(OCCI)c(OCCI)c1O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc(OCCI)c(OCCI)cc2oc1=O

Procedure:
To 1.73 g (10.8 mmol) of the bis-iodoethoxyhydroxybenzaldehyde from Example 8 was added diethyl malonate, 2.1 g (4.6 mmol), and this mixture was heated on a steam bath. When the mixture had become homogeneous, two drops of piperidine were added. After the mixture had cooled, a precipitate formed. The solution was diluted with a few milliliters of ethanol and reheated to boiling on the steam bath. After the solution had cooled, it was filtered and the precipitate product retained. The product was a solid with a m.p. of 162°-165° C. Proton NMR confirmed the structure of the product.
Reaction SMILES: [OH:1][CH:2]([CH2:12][OH:13])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:3][CH:2]([OH:1])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of t-butyl N-(2,3-dihydroxypropyl)carbamate (9.0 g, 47 mmol) in CH2Cl2 (75 mL) was added t-butyldimethylsilyl chloride (7.80 g, 51.7 mmol), triethylamine (7.86 mL, 56.4 mmol) and DMAP (230 mg). The solution was stirred at rt overnight. After diluting with CH2Cl2 (50 mL), the solution was washed with water (2×100 mL), dried over MgSO4 and concentrated. The residual oil was distilled by Kugelrohr under vacuum to give the desired product (13.6 g, 95%). MS (DCI) m/z 306 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12](Cl)=[O:13])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[CH:4]=1)#[N:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOC(C)=O.C(Cl)Cl>C1COCC1.O>[C:18]1([NH:17][C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3]([C:1]#[N:2])=[CH:4][N:5]3[CH2:15][CH3:16])=[CH:10][CH:9]=2)=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: CCn1cc(C#N)c2ccc(C(=O)Cl)cc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1cc(C#N)c2ccc(C(=O)Nc3ccccc3)cc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
A suspension of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride (70 mg, 0.30 mmol) in THF (5 mL) is cooled to 0° C. and treated with aniline (0.08 mL, 0.90 mmol). After the addition, the reaction is warmed to ambient temperature and after stirring for an additional 16 hours, the reaction mixture is diluted with H2O and extracted with EtOAc (2×). The combined organic phases are washed with saturated NaCl and then dried and concentrated to afford the product. Chromatography (EtOAc/CH2Cl2, 2/98) over silica gel gives 44 mg (51%) of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid phenylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12]([NH2:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][C:12]([NH2:14])=[O:13]
Reactant: NC(=O)CBr
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(OCC(N)=O)c1
Temperature: 70 °C
Reaction time: 9 h
Yield: 82.8 %

Procedure:
A mixture of 3-methoxyphenol (2.48 g, 20.0 mmol), 2-bromoacetamide (3.31 g, 24.0 mmol) and K2CO3 (5.53 g, 40.0 mmol) in acetone (30 mL) was stirred at 70° C. for 9 h. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (3.0 g, 83%).
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:26])[CH:8]=[CH:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C(OCC)=O)=[C:14]([O:24][CH3:25])[CH:13]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([NH:6][C:7](=[O:26])[CH:8]=[CH:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:24][CH3:25])[CH:13]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)Oc1ccc(C=CC=CC(=O)NCC=C(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C=CC=CC(=O)NCC=C(C)C)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
To a solution of 1.34 g of 5-(4'-ethoxycarbonyloxy-3'-methoxyphenyl)pentadienoic acid prenylamide in 10 ml of methanol are added 2.8 ml of 2N aqueous solution of sodium hydroxide followed by stirring at room temperature for 15 min. The mixture is acidified with 1N hydrochloric acid and then extracted with chloroform. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with methylene chloride is obtained 0.77 g of 5-(4'-hydroxy-3'methoxyphenyl)pentadienoic acid prenylamide (11). Spectroscopic data of the product support the structure of the formula (11) below.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=O)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[NH:27][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Reactant: Nc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(Nc2ccccn2)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 5 h
Yield: 50.6 %

Procedure:
Para-toluenesulphonic acid (50 mg) is added to an agitated solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy1-isoindolinone (6 g) and 2-aminopyridine (2 g) in xylene (150 cc) at a temperature close to 20° C. in a Dean Stark apparatus. Agitation is continued for 5 hours at a temperature close to 135° C. After cooling to a temperature close to 20° C., the solution is washed with aqueous sodium bicarbonate solution (2×100 cc) then with distilled water (2×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 80° C. The precipitate is recrystallized from boiling acetonitrile (45 cc). 3.7 g of 3-(2-pyridylamino)-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone are obtained, melting at 153° C.
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=O)[C:2]1[C:3](=CC=CC=1)[OH:4].[CH2:19]([C:27](C1C=CC=CC=1)=[C:28](OC)C([O-])=O)[CH2:20][CH2:21][CH2:22]CCCC.O1[SiH2]O[SiH2]O[SiH2]O[SiH2]O[SiH2]1>>[CH3:28][CH2:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][CH2:1][CH2:2][CH2:3][OH:4]
Reactant: CCCCCCCCC(=C(OC)C(=O)[O-])c1ccccc1
Reactant: CCCCCCCCOC(=O)c1ccccc1O
Agent: O1[SiH2]O[SiH2]O[SiH2]O[SiH2]O[SiH2]1
Product: CCCCCCCCCCCCCCOCCCO

Procedure:
2% C12-C15 alkyl benzoate (Finsolv TN from Finetex); 5% octyl salicylate (Escalol 587 from ISP); 7.5% octylmethoxycinnamate (Escalol 557 from ISP); 8.2% phenyltrimethicone; 13.3% cyclopentasiloxane; 18% siliconized polyamide; and 1% fragrance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[CH:26][CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I46) (0.157 g, 0.264 mmol) in DMF (15 mL) was added to a solution of 10% Pd/C (95 mg) in DMF (5 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and washed through with EtOAc (100 mL). The solvent was removed in vacuo to afford a pale yellow oil which was purified by column chromatography on silica gel (0-20% EtOAc in petroleum benzine 40-60° C.) to yield the title compound (I47) (0.128 g, 81%) as a pale yellow viscous oil; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=0.4 Hz, 1H), 7.59-7.54 (m, 2H), 7.39 (s, 1H), 7.28-7.17 (m, peaks obscured by CDCl3), 4.25 (bs, 2H), 3.75 (s, 2H), 3.68 (s, 3H), 3.17-3.04 (m, 4H), 2.81 (t, J=12.1 Hz, 2H), 2.64 (tt, J=11.8, 3.4 Hz, 1H), 1.83 (d, J=13.0 Hz, 2H), 1.67-1.59 (m, 2H), 1.49 (s, 9H). LCMS Method C: rt 7.02 min; m/z 621 [M+Na]+, 599 [M+H]+, 543 [M−tButyl+2H]+, 499 [M-Boc+2H]+.
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C([Li])CCC.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH2:61][CH2:62][CH:63]=O)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[N:50]=[C:51]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:52][C:53]=1[CH3:54]>O1CCCC1>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH2:61][CH:62]=[CH:63][CH2:8][CH2:7][CH:3]2[O:2][CH2:6][CH2:5][O:4]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[N:50]=[C:51]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:52][C:53]=1[CH3:54]
Reactant: c1ccc([P+](CCC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(CCC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(CC=CCCC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 1 h

Procedure:
To a suspension of [2-(1,3-dioxolan-2-yl)ethyl] triphenylphosphonium bromide (6.7 g) in tetrahydrofuran (THF) (60 ml) was added dropwise, at -30° C. in nitrogen streams, a hexane solution of n-butyl lithium (1.6M, 9.4 ml). The mixture was stirred for one hour at the same temperature, to which was then added dropwise, at -30° C., a solution of 3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propionaldehyde (4.1 g) in tetrahydrofuran (THF) (10 ml). The cooling bath was removed, and the reaction mixture was stirred for further one hour at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), followed by distilling off the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:2), was obtained 2-[5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl]-3-pentenyl]-1,3-dioxolan as an oily product (4.5 g). This oily product was dissolved in methanol (50 ml)--tetrahydrofuran (THF) (30 ml). To the solution was added palladium-carbon (5%, 0.5 g), which was subjected to catalytic hydrogenation at room temperature under 1 atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 2-[5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl]-1,3-dioxolan (3.8 g, 75%), which was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.81-82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:7]([OH:9])[CH:8]=1.F[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:7]([CH:8]=1)[O:9][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(Cc2ccc(OC)cc2O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cc2ccc(OC)cc2Oc2ccc(C=O)cc2)cc1
Yield: 74.2 %

Procedure:
The title compound was synthesized by referring to Synthesis, 1991, (1), 63. To a solution of 5-methoxy-2-(4-methoxybenzyl)phenol (1.9 g) in N,N-dimethylacetamide (6 ml) was added 4-fluorobenzaldehyde (960 mg) and potassium carbonate (1.3 g), and the solution was refluxed for 1 hour and 10 minutes. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.0 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)[C@H](CO)C3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCN(C(=O)[C@H]4CCCN4)[C@H](CO)C3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-((S)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-2-(hydroxymethyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.075 g, 0.12 mmol) in dichloromethane (2 mL) and the resulting solution was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-20% methanol in dichloromethane) to give the title compound as a white solid (0.024 g, 0.048 mmol, 40%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1 H), 7.67 (d, J=8.8 Hz, 1 H), 7.45 (d, J=2.0 Hz, 1 H), 7.14 (dd, J=2.4, 8.4 Hz, 1 H), 6.94 (dd, J=2.4, 8.8 Hz, 1 H), 6.85 (d, J=8.4 Hz, 1 H), 6.55 (d, J=2.0 Hz, 1 H), 5.89 (q, J=6.8 Hz, 1 H), 4.76-4.72 (m, 1 H), 3.97-3.87 (m, 3 H), 3.80-3.77 (m, 1 H), 3.65-3.60 (m, 2 H), 3.44-3.41 (m, 1 H), 3.21-3.15 (m, 2 H), 2.89-2.82 (m, 2 H), 2.77-1.65 (m, 2 H), 1.96 (d, J=7.5 Hz, 3 H), 1.89-1.71 (m, 3 H); MS: (ES) m/z calculated for C25H30Cl2N5O2 [M+H]+ 502.2, found 502.4.