Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH2:30]([NH-:34])[CH2:31][CH2:32][CH3:33].CI>>[CH3:1][CH2:2][C:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])([CH3:30])[CH3:4].[CH2:30]([NH-:34])[CH2:31][CH2:32][CH3:33]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Agent: CCCC[NH-]
Solvent: CI
Product: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21

Procedure:
In U.S. Pat. No. 4,820,850 (89)/CA 1,287,063 (91, Merck), lovastatin is reacted with butylamine to produce lovastatin butylarnide. The two hydroxy groups in the butylamide are protected with tert-butyldimethylsilyl chloride to produce a disilylated lovastatin butylamide. The disilylated lovastatin butylamide is enolized with lithium pyrrolidide and the enolate is alkylated with methyl iodide to produce a disilylated simvastatin butylamide on aqueous workup. The silyl protecting groups are removed using hydrofluoric acid to produce simvastatin butylamide. The simvastatin butylamide is hydrolyzed using sodium hydroxide and, following acidification, the dihydroxy acid form of simvastatin is obtained. The dihydroxy acid compound is reacted with ammonium hydroxide to produce an ammonium salt which is then relactonized by heating to produce simvastatin.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[CH2:29][C@@H:28]([OH:30])[CH2:27][CH2:26][NH:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH:33]=[CH2:34].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>C(O)C>[CH2:34]([N:25]1[CH2:26][CH2:27][C@H:28]([OH:30])[CH2:29][C@@H:24]1[C:10]1[CH:11]=[CH:12][C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:33]=[CH2:32]
Reactant: C=CCBr
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: C=CCN1CC[C@H](O)C[C@@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 62.6 %

Procedure:
A mixture of 778 mg (1.90 mmole) of cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol, 160 microliters (1.84 mmole) of 1-bromo-2-propene and 300 mg (2.17 mmole) of potassium carbonate in 10 ml ethanol is stirred at 25° C. for 20.5 hours. An additional 4 microliters of 1-bromo-2-propene is added to the reaction and stirring continued for 7 hours. The reaction mixture is then added to 50 ml saturated sodium chloride and extracted with 250 ml ethyl ether. The ether extract is dried over magnesium sulfate and the solvent is evaporated. The resulting oil is purified via column chromatography on 28 g of silica gel eluted in 7 ml fractions with 1:3 methanol/ethyl ether to yield (fractions 10-35) 518 mg (61%) of the title compound as an oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]#[CH:9].[C:11]([O:15][C:16]([NH:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26]([C:35]2[N:36]=[CH:37][NH:38][CH:39]=2)([C:31]([O:33][CH3:34])=[O:32])[C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26]([C:35]2[N:36]=[CH:37][N:38]([CH2:9][C:8]#[CH:7])[CH:39]=2)([C:31]([O:33][CH3:34])=[O:32])[C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C#CCBr
Reactant: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1cnc(C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)(C(=O)OC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
322 mg (0.99 mmol) of cesium carbonate and sowie 20 μl (0.27 mmol, 80% pure in toluene) of propargyl bromide were successively added to a solution of 100 mg (0.25 mmol) of dimethyl 2-(6-tert-butoxycarbonylaminopyridin-3-ylmethyl)-2-(1H-imidazol-4-yl)malonate (example 12d) in 2 ml of DMF. The mixture was stirred at RT for 3 h and then poured into water and extracted with EA. Purification by chromatography on silica afforded 27 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[F:12].Cl.[CH3:14][NH:15][CH3:16].C(N(CC)CC)C>C(Cl)Cl>[F:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:15]([CH3:16])[CH3:14]
Reactant: O=[N+]([O-])c1cccc(CBr)c1F
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)Cc1cccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a stirred mixture of 1-(bromomethyl)-2-fluoro-3-nitrobenzene (0.70 g, 2.99 mmol) and dimethylamine hydrochloride (0.48 g, 5.98 mmol) in CH2Cl2 (10 mL) was added triethylamine (0.91 g, 8.97 mmol) dropwise. The mixture was stirred at room temperature for 3 h and evaporated to dryness under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The EtOAc solution was washed with water (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 1-(2-fluoro-3-nitrophenyl)-N,N-dimethylmethanamine (0.45 g, 76%) as a yellow viscous liquid. 1H NMR (400 MHz, CD3OD): δ 8.04-7.99 (m, 1H), 7.78-7.73 (m, 1H), 7.37 (td, 1H, J=8.0, 1.0 Hz), 3.64 (d, 2H, J=2.0 Hz), 2.29 (d, 6H, J=0.8 Hz).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][N:14]=[C:15]=[S:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:14]([CH2:13][C:12]2[CH:17]=[CH:18][C:9]([F:8])=[CH:10][CH:11]=2)[C:15]1=[S:16])[CH3:2]
Reactant: Fc1ccc(CN=C=S)cc1
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(Cc2ccc(F)cc2)C1=S
Yield: 38.3 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.4 g of 4-fluorobenzyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethyl acetate/hexane mixture. Title compound (4.85 g) was obtained as a white solid, m.p. 73°-76° C. Anal. Calcd. for. C12H13F N2O S: C, 57.12; H, 5.19; N, 11.10 Found: C, 56.97; H,5.15; N, 11.06. Mass spectrum (EI, M.+) m/z 252.
Reaction SMILES: [OH:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]([NH2:35])([CH3:34])[CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])[N:24]=1.Br>>[OH:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:18])[F:19])=[CH:8][C:9]([C:12]([NH:35][C:28]([CH3:34])([C:25]3[N:24]=[C:23]([CH3:22])[O:27][N:26]=3)[CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:14])=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(O)CCC1)C(F)(F)F
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Agent: Br
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(O)CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-hydroxycyclobutyl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (Example 126c) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer B) (example 125b) as starting materials and isolated (13 mg, 40%); MS (ESI, m/z): 507.5 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]3[O:35]C3)[C:28]([O:30]C)=[O:29])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]([OH:35])[CH2:1][NH:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:28]([OH:30])=[O:29])(=[O:24])=[O:25])=[CH:21][CH:22]=2)=[CH:15][CH:16]=1
Reactant: CNc1ccccc1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CNc3ccccc3)C(=O)O)cc2)cc1

Procedure:
Example 21 is prepared from N-methylaniline and 1d using the procedure described for compound 19.
Reaction SMILES: Cl.Br[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[CH2:11][NH:12][CH3:13])=[CH:5][CH:4]=1.C(N(CC)CC)C.[H][H].Cl>[Pd].C(O)C>[CH3:13][NH:12][CH2:11][C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[CH2:8][CH2:7][C:6]1[CH:18]=[CH:19][CH:3]=[CH:4][CH:5]=1
Reactant: CNCc1ccccc1CCc1ccc(Br)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CNCc1ccccc1CCc1ccccc1

Procedure:
A solution of 2.0 g. (0.00657 mole) of 2-(4-bromo-phenethyl)-N-methylbenzylamine hydrochloride in 200 ml. of absolute ethanol -- 1 ml. of triethylamine is shaken with hydrogen at atmospheric pressure and 25° C. over 400 mg. of 10% palladium on carbon until hydrogen uptake ceases. The catalyst is removed by filtration, the filtrate evaporated to dryness under reduced pressure, and the residue partitioned between aqueous sodium hydroxide and 1:1 ether-benzene. Evaporation of solvents from the washed and dried organic extract leaves the product as the residual oil. The oily base is converted to the hydrochloride salt by treating a solution in absolute ethanol with a slight excess of ethanolic hydrogen chloride. Dilution with absolute ether precipitates the hydrochloride as white crystals, m.p. 204°-206° C. After repeated recrystallizations from absolute ethanol-absolute ether, an analytical sample melts at 205°-206° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2]>[Ni].CO>[NH2:2][CH2:1][CH2:3][C:4]1([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)CC1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)CC1(CCN)CCN(C(=O)OC(C)(C)C)CC1
Yield: 44.5 %

Procedure:
The process is performed according to the procedure described in Example 12 (step 12.2.). Starting with 1.10 g (3.95 mmol) of tert-butyl 4-cyanomethyl-4-isobutylpiperidine-1-carboxylate and 1.16 g (19.75 mmol) of Raney nickel in 13 mL of methanol under a hydrogen atmosphere (70 psi), at 45° C. and after chromatography on a column of silica gel, eluting with a 96/4/0.4 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.50 g of expected product is obtained in the form of an oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:35])[CH2:21][C@@H:22]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46]Cl)=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])([CH3:39])([CH3:38])[CH3:37].O>CN(C=O)C>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][O:34][C:31]2[CH:32]=[CH:33][C:28]([C@@H:22]([C:23]3[CH:27]=[CH:26][O:25][N:24]=3)[CH2:21][C:20]([N:15]3[C@@H:14]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:18][O:17][C:16]3=[O:19])=[O:35])=[CH:29][CH:30]=2)=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)c1cc(CCl)ccc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 31 %

Procedure:
Cesium carbonate (360 mg, 1.1 mmol) was added to a mixture of 7.5 (40.0 mg, 0.10 mmol) and 26.5 (27.0 mg, 0.12 mmol) in DMF (2.0 mL). The resulting mixture was stirred at room temperature for 19 hours. The mixture was then treated with water (5 mL) and extracted with EtOAc (15 mL). The organic layer was separated, washed twice with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-30% EtOAc/hexane) to give (S)-3-((S)-3-(4-(4-tert-butyl-3-isopropylbenzyloxy)phenyl)-3-(isoxazol-3-yl)propanoyl)-4-benzyloxazolidin-2-one (18.0 mg, 30%) as a clear oil. The ester (18.0 mg, 0.031 mmol) was treated with THF/H2O (3/1, v/v, 2.0 mL) and hydrogen peroxide (30%, 0.021 mL, 0.19 mmol) and cooled to 0° C. LiOH (2.60 mg, 0.062 mmol) was added. The resulting mixture was stirred at 0° C. for 1 hour. A saturated solution of Na2SO3 was added to the mixture, and the reaction was stirred for 1 hour. The mixture was extracted with EtOAc (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-30% EtOAc/hexane) to give 26 (5.80 mg, 44%) as a colorless film. MS ESI (neg.) m/e: 420 (M−H). 1H NMR (500 MHz) (CDCl3) δ 8.28 (1H, s); 7.37-7.34 (2H, m); 7.20-7.17 (3H, m); 6.96-6.94 (2H, d, J=8.2 Hz); 6.07 (1H, s); 4.98 (2H, s); 4.56 (1H, dd, J=7.8, 7.4 Hz); 3.64 (1H, m), 2.36 (1H, dd, J=16.8, 7.8 Hz), 2.99 (1H, dd, J=16.8, 7.4 Hz), 1.43 (9H, s), 1.26 (6H, d, J=7.1 Hz).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][N:5]([C:17]2([CH2:21][C:22]#[N:23])[CH2:20][NH:19][CH2:18]2)[N:4]=1.Cl[C:25]1[N:26]=[CH:27][C:28]([C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[N:29][CH:30]=1.C(N(CC)C(C)C)(C)C.C(O)(C)(C)C>>[C:22]([CH2:21][C:17]1([N:5]2[CH:6]=[C:7]([B:8]3[O:9][C:10]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:14])[O:12]3)[C:3]([CH3:2])=[N:4]2)[CH2:18][N:19]([C:25]2[N:26]=[CH:27][C:28]([C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[N:29][CH:30]=2)[CH2:20]1)#[N:23]
Reactant: Cc1nn(C2(CC#N)CNC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)NC(=O)c1cnc(Cl)cn1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C2(CC#N)CN(c3cnc(C(=O)NC(C)C)cn3)C2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 100 °C

Procedure:
A mixture of {3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (0.43 g, 1.3 mmol), 5-chloro-N-isopropylpyrazine-2-carboxamide (0.24 g, 1.2 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.6 mmol) in tert-butyl alcohol (12 mL, 120 mmol) was heated at 100° C. for 4 h. After cooling, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-60%) to afford the desired product. LCMS cacld. for C23H33BN7O3 (M+1)+: m/z=466.3. Found: 466.2.
Reaction SMILES: C(OC([N:11]1[C@H:15]([CH3:16])[C@H:14]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:13]([NH:26][CH2:27][C:28]2[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=2[O:37][CH3:38])[C@@H:12]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[CH2:19]([O:18][CH2:17][C@@H:14]1[C@@H:15]([CH3:16])[NH:11][C@@H:12]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:13]1[NH:26][CH2:27][C:28]1[CH:33]=[C:32]([CH:34]([CH3:35])[CH3:36])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(C(C)C)cc1CN[C@H]1[C@@H](COCc2ccccc2)[C@@H](C)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(C)C)cc1CN[C@H]1[C@H](COCc2ccccc2)[C@@H](C)N[C@H]1c1ccccc1
Yield: 99.5 %

Procedure:
20% Pd(OH)2 --C (Pearlman's catalyst, Aldrich; 0.33 g) was added to a solution of (2S*,3S*,4R*,5R*)-1-benzyloxycarbonyl-4-benzyloxymethyl-3-[N-(5-isopropyl-2-methoxybenzyl)amino]-5-methyl-2-phenylpyrrolidine(0.61 g,1.03 mmol) and HCO2NH4 (0.39 g, 6.18 mmol) in MeOH (20 ml). The mixture was stirred and heated at a gentle reflux for 30 minutes. The catalysts were filtered off by the aid of a Celite pad, and washed with MeOH. The combined filtrate and washings were concentrated in vacuo. To the residue was added 1M NaOH aq. solution until the mixture became basic (pH 10-11). This was extracted with CH2Cl2 (×4). The combined CH2Cl2 extracts were washed with sat. NaCl aq. solution (×1), dried (K2CO3), and concentrated in vacuo to give a pale yellow oil (0.47 g). This was chromatographed over SiO2 (Merck Kieselgel 60, 7.0 g). Elution with CH2Cl2 --MeOH (300:1→200:1→100→60:1→50:1) gave title compound (0.40 g, 85%) as a pale yellow viscous oil: IRmax (film): 3340(w), 1610(m), 1498(s), 1250(s), 1110(s), 810(m), 738(s), 700(s) cm1 ; 1H-NMR δ: 7.43-7.20(m, 10H), 7.01(dd, J=8.4, 2.2 Hz, 1H), 6.82(d, J=2.2 Hz, 1H), 6.65(d, J=8.4 Hz, 1H), 4.56(s, 2H), 4.20(d, J=5.5 Hz, 1H), 3.67(d, J=13.6 Hz, 1H), 3.493(dd, J=9.3, 6.2 Hz, 1H), 3,489(s, 3H), 3.57(dd, J=9.3, 6.4 Hz, 1H), 3.42(d, J=13.6 Hz, 1H), 3.13(dd, J=5.5, 2.6 Hz, 1H), 3.06(dq, J=6.2, 6.2 Hz, 1H), 2.74(sep, J=7.0 Hz, 1H), 2.17-1.85(m, 3H), 1.42(d, J=6.2 Hz, 3H), 1.16(d, J=7.0 Hz, 6H) ppm.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)=[O:11])=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10]([CH:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[O:11])=[O:7])=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33]([F:32])([F:45])[F:44])[CH:24]=1
Reactant: CC(C)N(NC(=O)C1CCSCC1)C(=O)COc1ccc(F)cc1Br
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)C1CCSCC1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 45.1 %

Procedure:
A solution of tetrahydro-thiopyran-4-carboxylic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (116 mg, 0.27 mmol) in DME (2.5 ml)/2M Na2CO3 (0.468 ml, 0.94 mmol) was treated with 2-trifluoromethoxyphenylboronic acid (83 mg, 0.40 mmol) and Pd[PPh3]4 (62 mg, 0.053 mmol) in a microwave oven at 150° C., for 10 min. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexane gradient to afford the product as a solid (62.6 mg, 45%). MS m/e 515.48 (M+H+)
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCCCO)CC1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Product: O=C(OCc1ccccc1)N1CCC(CCCCCCBr)CC1

Procedure:
Prepared similarly to Intermediate 30 from phenylmethyl 4-(6-hydroxyhexyl)-1-piperidinecarboxylate.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(CO)cc2)CC1
Yield: 88.9 %

Procedure:
A solution of 4-(4-formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 4.47 mmol) in THF (50 mL) was mixed with LAH (0.7 g, 17.87 mmol) and stirred at reflux for 14 h. The reaction was quenched at room temperature by adding KOH aqueous (14 N, 20 mL). The supernatant was decanted and combined with DCM washings, then diluted with water (50 mL). The mixture was extracted with DCM (3×50 mL) followed by concentration using a rotary evaporator to give [4-(4-methyl-piperazin-1-yl)-phenyl]-methanol (0.82 g, 89%). To a solution of DMSO (0.56 mL, 7.96 mmol) in DCM (50 mL) at −78° C. was added oxalyl chloride (0.7 mL, 7.96 mmol) and the resulting mixture was stirred at −78° C. for 0.5 h. A solution of [4-(4-methyl-piperazin-1-yl)-phenyl]-methanol (0.82 g, 3.98 mmol) in DCM (20 mL) was slowly added. The reaction was stirred at −78° C. for 1.5 h. Triethylamine (1.7 mL, 11.94 mmol) was added and the reaction was allowed to gradually warm up to room temperature. After stirring for 4 h the reaction was quenched by adding sodium bicarbonate aqueous (1 N, 50 mL). The mixture was extracted with DCM (3×50 mL) followed by concentration to afford a residue, which was further purified by column chromatography to yield 4-(4-methyl-piperazin-1-yl)-benzaldehyde (0.5 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH:33]3[CH2:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:34]3)=[O:22])=[CH:17][C:9]1=2
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NC1Cc2ccccc2C1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z=562.95 (M+H+); retention time=0.98 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:23])[CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:23])[CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:33](=[O:37])[CH2:32]2)=[CH:38][CH:39]=1
Reactant: O=C1CN(CCc2ccc(F)cc2)CCN1
Reactant: CC1Cc2c(c3ccc(Br)cc3n2C)CN1C(=O)OC(C)(C)C
Product: CC1Cc2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc3n2C)CN1C(=O)OC(C)(C)C
Yield: 66.8 %

Procedure:
tert-Butyl 7-bromo-3,5-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (300 mg, 0.791 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (174 mg, 0.791 mmol) were reacted following the procedure for Example 2 (step f) to provide the title compound (275 mg, 67%) as a yellow oil: ESI MS m/z 521 [M+H]+.