Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4CCCC[O:25]4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[O:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)=[CH:4][CH:3]=1>C(O)=O.[Zn]>[CH:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]1[C:17](=[O:19])[C:18]2[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:10]([O:32][C:33]3[CH:34]=[N:35][CH:36]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:38]=3)[CH:11]=[N:12][C:13]=2[N:14]([CH3:31])[C:15]1=[O:30])=[O:25]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cncc(C(F)(F)F)c3)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(C(F)(F)F)c3)cnc21
Temperature: 50 °C
Yield: 29.8 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (172 mg, 0.277 mmol) in HCOOH (5 mL) was added Zn dust (88.5 mg, 1.385 mmol) at 20° C. The reaction was heated at 50° C. for 2 h, cooled to RT and filtered. The filtrate was concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) to give 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (45.3 mg, 29.8% yield) as an oil. LCMS: MH+ 549 and TR=1.471 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[N:26]1[CH2:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32].C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN1C(=O)CCC1>[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[N:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[C:27]1=[O:32]
Reactant: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Reactant: O=C1NCCCN1C1Cc2ccccc2C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1N(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CCCN1C1Cc2ccccc2C1
Yield: 14.7 %

Procedure:
Synthesized according to general procedure 43. The reaction was set up with 4-iodo-N-(thiazol-2-yl)benzenesulfonamide (250 mg, 0.68 mmol), 1-(2,3-dihydro-1H-inden-2-yl)tetrahydropyrimidin-2(1H)-one (138 mg, 0.68 mmol), copper(I) iodide (267 mg, 1.4 mmol), potassium carbonate (282 mg, 2.0 mmol), and NMP (1.7 mL). The dark mixture was purified via silica gel chromatography using 10% MeOH in CH2Cl2 to obtain the desired urea as a white solid (45 mg, 0.10 mmol, 15% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 7.71 (dd, J=1.9, 6.9 Hz, 2H), 7.45 (dd, J=1.9, 6.9 Hz, 2H), 7.26-7.21 (m, 3H), 7.23-7.11 (m, 2H), 6.83 (d, J=4.5 Hz, 1H), 5.25-5.19 (m, 1H), 3.68-3.65 (m, 2H), 3.20 (t, J=5.9 Hz, 2H), 3.09-2.98 (m, 4H), 2.01-1.91 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=455.3; tR=2.98 min.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].O=[C:8]1[N:12]([C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:11][C@@H:10]([C:21](OC)=[O:22])[CH2:9]1.O.[OH-].[Na+]>C1COCC1>[C:15]1([C@@H:13]([N:12]2[CH2:8][CH2:9][C@H:10]([CH2:21][OH:22])[CH2:11]2)[CH3:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1ccccc1)N1CC[C@H](CO)C1
Temperature: 0 °C

Procedure:
To a suspension of LAH (20 g, 0.526 mol) in dried THF (400 mL) was added dropwise a solution of (S)-methyl 5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylate (50 g, 0.202 mol) in dried THF (50 mL) at 0° C. The mixture was heated to reflux overnight. The reaction mixture was cooled to 0° C. and treated with water (20 mL) and aqueous NaOH (10%, 20 mL). The slurry formed was filtered off and washed with THF. The combined filtrate was evaporated to give compound ((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)methanol, which was used directly in the next step.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C@:8]1([OH:30])[CH2:25][C:24]2[C:23]([OH:26])=[C:22]3[C:13]([C:14](=[O:28])[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:21]3=[O:27])=[C:12]([OH:29])[C:11]=2[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[Br:31]Br.C12OC1CCCC2.Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:31][CH:10]1[CH2:9][C@@:8]([C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])([OH:30])[CH2:25][C:24]2[C:23]([OH:26])=[C:22]3[C:13]([C:14](=[O:28])[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:21]3=[O:27])=[C:12]([OH:29])[C:11]1=2
Reactant: CC(=O)OCC(=O)[C@@]1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Reactant: BrBr
Agent: Br
Agent: C1CCC2OC2C1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2C(Br)C1)C(=O)c1ccccc1C3=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Treatment of 9(R)-acetoxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (3.5 g) with bromine (3.41 g) was effected in a refluxing mixture of chloroform (875 ml) and carbon tetrachloride (1750 ml) with heating for 3 hours, while the reaction mixture was irradiated with 500 W lamp as radical reaction initiator in the presence of cyclohexene oxide (2.51 g) as a scavenger of the generated HBr. The solvent was removed under reduced pressure and ether (52.5 ml) was added to the residue. The resultant mixture was stirred at room temperature for 1.5 hours and precipitated crystals were filtered to give reddish orange powders of 7-bromo-9(S)-acetoxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 173°-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[C:22]=[O:23])[CH:16]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:23])[NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=2[S:10]([OH:13])(=[O:12])=[O:11])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(S(=O)(=O)O)c(N)cc1Cl
Reactant: O=C=Nc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(S(=O)(=O)O)c(NC(=O)Nc2cccc(Br)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
2-Amino-4-chloro-5-methyl-benzenesulfonic acid (665 mg, 3.0 mmol) was suspended in 30 ml dry THF and 1-bromo-3-isocyanato-benzene (624 mg, 3.15 mmol) was added. Upon addition of triethylamine (354 mg, 3.15 mmol) the suspension cleared and became a solution. The solution was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with diluted aqueous hydrochloric acid. The organic phase was dried over sodium sulphate and reduced to dryness under vacuum. The title compound was recrystallised from ethyl acetate/heptane to give 820 mg (65%) of white crystals (m.p. 275° C.; decomposition).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[OH:28][CH2:29][CH:30]([CH2:32]O)[OH:31].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:32][CH:30]([OH:31])[CH2:29][OH:28])=[O:24])=[CH:26][CH:27]=1
Reactant: OCC(O)CO
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
A solution of 11.8 g. of 4-(16-bromohexadecylamino)benzoic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2,3-dihydroxypropyl 4-(16-bromohexadecylamino)benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.[N+]([O-])([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[SH:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Sc1ncccn1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Product: Clc1cccc(Sc2ncccn2)c1
Reaction time: 8 h

Procedure:
A solution of 3-chloroaniline (5.0 g) in 1.5 M hydrochloric acid (100 ml) was diazotised by the gradual addition of a solution of sodium nitrate (3.0 g) in water (6 ml) at 0° C. Sodium bicarbonate (7.5 g) was then added to the solution and the whole reaction mixture was added rapidly with stirring to a solution of 2-mercaptopyrimidine (4.5 g) in water (3 l). When the addition of the diazonium salt solution was completed, 10 ml of a 15% solution of sodium carbonate was added causing precipitation of a colourless solid. The solid was collected by filtration and allowed to stand overnight during which time it decomposed to an oil which was purified by chromatography (70 g silica, chloroform elution). The title compound was obtained as a red oil (2.5 g, 29%) and identified by its pmr spectrum.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=[O:20])[C:14](=[N+:18]=[N-:19])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:21][OH:22].C(Cl)(Cl)Cl.O>C(N(CC)CC)C>[N+:18](=[C:14]([C:15](=[O:17])[CH3:16])[C:13](=[O:20])[CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([O:22][CH3:21])(=[O:4])=[O:3])=[CH:6][CH:7]=1)=[N-:19]
Reactant: CO
Reactant: CC(=O)C(=[N+]=[N-])C(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COS(=O)(=O)c1ccc(CCC(=O)C(=[N+]=[N-])C(C)=O)cc1

Procedure:
6-(4-Chlorosulfonylphenyl)-3-diazo-2,4-hexanedione (2.0 g, 6.4 mmol) obtained in Example 3, (3) was stirred in triethylamine (1.5 ml), methanol (2.5 ml) and chloroform (8 ml) for 6 h at 10°-15° C., then the mixture was poured into H2O and extracted thrice with chloroform. The organic extract was washed with H2O, dried over anhydrous MgSO4 and evaporated under reduced pressure. The residue was chromatographed on silica gel (Wako Gel C-200, manufactured by Wako Pure Chemical Industries, Ltd.) with chloroform as eluent to give the title compound as a pale yellow viscous oil; yield: 730 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1.[CH3:22][O-:23].[Na+].O.Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:23][CH3:22])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1
Reactant: Oc1cc(C(F)(F)F)nc(SCc2c(Cl)cncc2Cl)n1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cncc(Cl)c1CSc1nc(O)cc(C(F)(F)F)n1
Yield: 93 %

Procedure:
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)-pyrimidin-4-ol (see, e.g., Example 120; 1.0 g, 2.8 mmol) and a sodium methoxide solution (25% wt., 2.6 mL) in dimethyl sulfoxide (10 mL) was stirred at 70° C. overnight. Water (100 mL) was added, and the pH of the mixture was adjusted to around 6 with 2N HCl. The mixture was extracted with EtOAc (3×75 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo to afford 2-{[(3-chloro-5-methoxypyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (912 mg. 93%); 1H NMR (500 MHz, DMSO-d6): δ 3.97 (s, 3H), 4.59 (s, 2H), 6.68 (s (br), 1H), 8.32 (s, 1H), 8.39 (s, 1H); M+ 352.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 125.5 %

Procedure:
To the product from step 3 (0.36 g, 0.89 mmol) was added 4 M HCl in dioxane (5 mL). The resulting mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo. The crude product was triturated with ether and dried under reduced pressure to afford the title compound (0.19 g, 70%) as a light yellow solid; 1H NMR (400 MHz, DMSO-d6) 1.75 (m, 1H), 1.87-2.01 (m, 2H), 2.12 (m, 1H), 3.21 (m, 2H), 3.89 (m, 1H), 4.17 (m, 1H), 4.24 (dd, J1=4.0 Hz, J2=10.8 Hz, 1H), 6.94 (d, J=9.2 Hz, 2H), 7.05 (s, 4H), 7.40 (d, J=8.8 Hz, 2H); MS (m/z) 304.2 (M+1); LC (97.1%);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:4][C:3]=1[F:9]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)c(F)c1
Yield: 79 %

Procedure:
In a manner similar to the method described in example 132a, 4-bromo-3-fluoro-phenol (12 g, 62.3 mmol) was reacted with K2CO3 (26 g, 188 mmol) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (18.0 g, 75.3 mmol) to give [2-(4-bromo-3-fluoro-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane as yellow oil (17.2 g, 77%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1>CN(C=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:1]2[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]2)=[CH:14][CH:13]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=S1(=O)CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A mixture of thiomorpholine 1,1-dioxide (270 mg, 2.0 mmol) in DMF (10 ml) was prepared at room temperature and sodium hydride (60 wt % in oil, 96 mg, 2.40 mmol) added in one portion and the mixture stirred at room temperature for 1 h. 1-Bromo-4-(bromomethyl)benzene was then added in one portion and the mixture stirred overnight for 17.5 h under argon. The mixture was then quenched with saturated aqueous ammonium chloride solution (10 ml) and diluted with ethyl acetate (30 ml). The mixture was partitioned and the aqueous layer removed. The organic layers were then washed with 5% aqueous lithium chloride solution (2×10 ml), brine (10 ml), dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was then purified by column (0-5% methanol/dichloromethane) to afford 4-(4-bromobenzyl)thiomorpholine 1,1-dioxide as a colourless solid (283 mg, 0.93 mmol, 47%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:23])[CH2:19][CH2:20]2)=[CH:16][C:15]=1[C:24]([OH:26])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:2][N:3]([CH3:4])[C:24]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:14]=1[O:13][CH3:12])[CH2:20][CH2:19][C:18]2=[O:23])=[O:26]
Reactant: CNC
Reactant: COc1cc2c(cc1C(=O)O)C(=O)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1C(=O)N(C)C)C(=O)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of Dimethylamine hydrochloride (2.22 g, 27.24 mmol) and triethylamine (7 ml, 54.48 mmol) in CH2Cl2 (30 ml) was added 6-Methoxy-3-oxo-indan-5-carboxylic acid (2 g, 9.08 mmol), HOBt (2.45 g, 18.18 mmol), EDCI (3.48 g, 18.18 mmol) at 0° C. in order. The mixture was stirred at room temperature for 3 hrs and washed with 8% NaOH, water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product (1.69 g, 80% yield). LC-MS: m/e 234 (MH+)
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](Cl)=[CH:44][C:43]=1[F:49].[CH2:51]([C:53]([C:72]1[CH:77]=[CH:76][C:75]([CH2:78][CH2:79][C:80]2([OH:85])[CH2:84][CH2:83][CH2:82][CH2:81]2)=[C:74]([CH3:86])[CH:73]=1)([C:56]1[CH:61]=[CH:60][C:59](B2OC(C)(C)C(C)(C)O2)=[C:58]([CH3:71])[CH:57]=1)[CH2:54][CH3:55])[CH3:52]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:59]2[CH:60]=[CH:61][C:56]([C:53]([CH2:54][CH3:55])([C:72]3[CH:77]=[CH:76][C:75]([CH2:78][CH2:79][C:80]4([OH:85])[CH2:81][CH2:82][CH2:83][CH2:84]4)=[C:74]([CH3:86])[CH:73]=3)[CH2:51][CH3:52])=[CH:57][C:58]=2[CH3:71])=[CH:44][C:43]=1[F:49]
Reactant: CCC(CC)(c1ccc(CCC2(O)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(CCC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
A solution of palladium acetate (2.6 mg, 0.0114 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (9.4 mg, 0.0228 mmol) and potassium phosphate (48.4 mg, 0.22 mmol) in water (0.040 mL) and toluene (0.200 mL) was stirred for three minutes. A solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 24.7 mg, 0.12 mmol) and 1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-ethyl]-cyclopentanol (Example 40; 40.0 mg, 0.0815 mmol) in toluene (0.200 mL) was added, and the mixture was stirred in a nitrogen atmosphere at 100° C. for three hours. After filtration through cotton plug, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (17% ethyl acetate/hexane) to give the title compound (30.9 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]CC)=[O:27])[CH:20]=2)[NH:15]1)=[O:6].O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=2)[NH:15]1)=[O:6]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NC(=O)c1cccc(F)c1)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2ccccc2NC(=O)c2cccc(F)c2)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 2-(2-(3-fluorobenzamido)phenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous Sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-[2-(3-fluoro-benzoylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI−) [(M−H)−] 417.30.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH3:14])=[CH:4][CH:3]=1.[H][H]>CO.[C].[Pd]>[C:5]1([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH3:14])[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: CC1CNCCN1c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1CNCCN1c1ccccc1
Yield: 100 %

Procedure:
1-(4-chlorophenyl)-2-methylpiperazine (300 mg, 1.4 mmol) was dissolved in methanol (3 ml), and the resulting solution was mixed with palladium carbon (150 mg) and stirred at a room temperature for 21 hours in an atmosphere of hydrogen. The reaction solution was filtered, and the thus obtained residue was thoroughly washed with ethanol. The washed solution and filtrate were combined, and the solvent was evaporated therefrom under a reduced pressure to obtain 260 mg of the title compound (1.4 mmol, 100% in yield).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[CH:22]=2)[C:9]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:7])C>C(O)CO>[C:27]([C:23]1[CH:22]=[C:21]([N:10]2[C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:8]([C:6]([OH:7])=[O:5])=[C:9]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)([OH:29])=[O:28]
Reactant: CCOC(=O)c1cc(CCc2ccccc2)n(-c2cccc(C(=O)O)c2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: O=C(O)c1cccc(-n2c(CCc3ccccc3)cc(C(=O)O)c2-c2ccccc2)c1
Reaction time: 1.6 h

Procedure:
Solid NaOH (90 mg; 2.3 mmol) was added to a soln of 1-(3-carboxy-phenyl)-5-phenethyl-2-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (157 mg; 0.357 mmol) in ethylene glycol (2.0 mL) at 160° C. After 1.6 h, the rxn was cooled then quenched with 1 M HCl (5 mL). The product was extracted into EtOAc (3×3 mL) and this soln was washed with water (3×3 mL) and satd NaCl (2×3 mL). After drying over MgSO4, filtration through silica with an EtOAc wash and concd, crude product was obtained. LC-MS 412 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:26][CH2:27][N:28]([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21

Procedure:
To a solution of 320 mg (1 mmol) of 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester in 5 ml of DMF were added 218 mg (1.5 mmol, 1.5 eq.) of (2-chloro-ethyl)-dimethyl-amine hydrochloride and 418 mg (3 mmol, 3 eq.) of K2CO3. Stirring was continued at 60° C. over night. The mixture was poured on water and the product extracted with EtOAc. The organic phases were dried over Na2SO4 and concentration in vacuo afforded crude 4-[3-(2-dimethylamino-ethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid. This crude material was then dissolved in 5 ml of CH2Cl2 and 1 ml of TFA was added. After 2 hours at RT, the reaction was quenched by addition of aq. NaHCO3 (pH=9), and the product extracted with CH2Cl2. Concentration in vacuo afforded 200 mg (61%) of the title compound as a white solid.