Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C1C(=O)N([O:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]2[S:27][CH2:26][CH:25]3[NH:28][C:29]([NH:31][CH:24]23)=[O:30])=O)C(=O)C1.CCOCC>CN(C=O)C>[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:17](=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]2[CH:24]3[CH:25]([NH:28][C:29](=[O:30])[NH:31]3)[CH2:26][S:27]2)[CH2:4][CH2:3]1
Reactant: NC1CCC(N)CC1
Reactant: O=C1NC2CSC(CCCCC(=O)ON3C(=O)CCC3=O)C2N1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: NC1CCC(NC(=O)CCCCC2SCC3NC(=O)NC32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,4-Diaminocyclohexane (37.6 mg, 0.33 mmol) was dissolved in dry DMF (3 mL) under nitrogen. Solution of NHS-Biotin (102.3 mg, 0.3 mmol) in dry DMF (3 mL) was added to stirred solution of diamine over a 15 min period. Reaction mixture was stirred for 16 h at ambient temperature. Dilution of reaction mixture with dry Et2O (50 mL) produced white precipitate. Precipitated 19b was filtered, washed with EtOAc (3×20 mL) for removing of NHS and dried in high vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]([NH:16][CH2:17][CH2:18]Br)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].CC#N>C(Cl)Cl>[C:12]([O:11][C:9](=[O:10])[NH:16][CH2:17][CH2:18][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCn1cc([N+](=O)[O-])cn1
Temperature: 80 °C

Procedure:
A flask was charged with 4-nitro-1H-pyrazole (3.5 g, 30.02 mmol), 2-(boc-amino)ethylbromide (6.9 g, 30.02 mmol), Cs2CO3 (1.07 g, 33.02 mmol) and MeCN (60 mL). The resulting reaction mixture was stirred at reflux (80° C.) for 1.5 h, then allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM. The filtrate was concentrated to yield tert-butyl(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate as a light orange oil, which was used in the next step without further purification. LC-MS conditions B: tR=0.63 min, [M+H]+=257.35.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[CH2:1]([N:8]([CH2:9][C:10]([F:12])([F:11])[F:13])[C:23]([C:19]1[CH:18]=[C:17]([Cl:16])[N:22]=[CH:21][N:20]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)CNCc1ccccc1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(c1cc(Cl)ncn1)N(Cc1ccccc1)CC(F)(F)F
Reaction time: 2 h

Procedure:
1.04 g (5.5 mmol) benzyl-(2,2,2-trifluoroethyl)-amine and 5.5 mL (5.5 mmol) of a 1M sodium hydroxide solution were added dropwise to 1.0 g (5.65 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane while cooling with a bath of ice and ethanol. The mixture was first stirred for 2 h with cooling and then for 1 h at RT. 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for 10 min. The organic phase was separated off, washed with water and 1M hydrochloric acid, dried on sodium sulphate, filtered and evaporated down i.vac.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#[N:2].[CH3:23][NH2:24]>C(O)C>[C:1]([N:3]=[C:4]([NH:24][CH3:23])[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#[N:2]
Reactant: CN
Reactant: CSC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Solvent: CCO
Product: CNC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
The mixture of trans-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.50 g) and 25% aqueous methylamine (10 ml) in ethanol (10 ml) was stirred under reflux for 1 hour and 10 minutes. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on silica gel (10 g) and eluted with chloroform and then a mixture of chloroform and methanol (20:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give trans-4-(2-cyano-3-methylguanidino)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[I:8].[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[I:8])[CH2:9][Br:10]
Reactant: Cc1ccc(I)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)ccc1I

Procedure:
A suspension of 40.4 g (160 mmol) of the compound from Example XXXI in 400 ml of carbon tetrachloride, 31.3 g of N-bromosuccinimide (176 mmol) and 2.63 g of azobisiso-butyronitrile (16 mmol) is heated under reflux overnight. After cooling, the precipitate is filtered off with suction and washed with carbon tetrachloride. The combined filtrates are concentrated and the residue is further reacted in the crude state.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.CN.Cl.[CH3:16][N:17](C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH2:9][C:10]([NH:17][CH3:16])=[O:12]
Reactant: O=C(O)CCCC1OCCCO1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CNC(=O)CCCC1OCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.9 %

Procedure:
To 4-[1,3]dioxan-2-yl-butyric acid (2.55 g, 0.015 mol) in dichloromethane (200 ml) was added methylamine (2M in THF, 8.1 ml, 0.016 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.09 g, 0.016 mol) and hydroxybenzotriazole (2.16 g, 0.016 mol) and the mixture stirred at room temperature overnight. The organic layer was washed with saturated sodium bicarbonate solution (200 ml) and the aqueous layer extracted with dichloromethane (4×50 ml). The combined organics were dried (Na2SO4) and evaporated to give a colourless oil (3.2 g)
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:27]([CH2:29][C@@H:30]([OH:37])[CH2:31][C:32](OCC)=[O:33])#[N:28].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:27]([CH2:29][C@@H:30]([OH:37])[CH2:31][C:32](=[O:33])[CH2:10][C:9]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:11])#[N:28]
Reactant: CCOC(=O)C[C@H](O)CC#N
Reactant: CC(=O)N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: N#CC[C@@H](O)CC(=O)CC(=O)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-bis(phenylmethyl)acetamide (prepared from N,N-bis(phenylmethyl)amine and acetyl chloride by refluxing for 2 hours in toluene) (120 g, 0.5 mol) in tetrahydrofuran (0.5 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.25 L of 2M) while maintaining the temperature between -30° C. to -45° C., and the mixture is stirred at -20° C. to -30° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (20 g, 0.125 mol) as a solution in 200 mL of tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -35° C. to -20° C. and transferred to a 2.2N aqueous hydrochloric acid solution (0.5 L). The aqueous layer is extracted with 300 mL of ethyl acetate, the aqueous layer is separated and reextracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6-cyano-5-hydroxy-3-oxo-N,N-bis(phenylmethyl)hexanamide as an oil. This oil, approximately 0.1 mol, is dissolved in tetrahydrofuran (200 mL) and methanol (100 mL) under a nitrogen atmosphere. The solution is cooled to -20° C., and a 50% solution of methoxydiethylborane in tetrahydrofuran (50 mL) is added. The reaction is cooled to -78° C., and sodium borohydride (12 g, 0.32 mol) is added over 30 minutes. The reaction is maintained at -78° C. for 5 hours and allowed to warm to room temperature and stand for 10 hours under a nitrogen atmosphere. The reaction is quenched by the addition of acetic acid (20 mL) and concentrated by vacuum distillation to an oil. The residue is dissolved with methanol (300 mL), concentrated by vacuum distillation, redissolved with methanol (300 mL), and reconcentrated by vacuum distillation to give a yellow oil. The oil is taken up in ethyl acetate (300 mL) and washed with deionized water (300 mL). The ethyl acetate solution is concentrated by vacuum distillation to give crude [R-(R*,R*)]-6-cyano-3,5-dihydroxy-N,N-bis(phenylmethyl)hexanamide as an oil which is used without further purification;
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][S:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[C:16]=1[CH2:17][C:18]1[C:19]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1.O.[OH-].[Li+]>C1COCC1.O>[CH3:27][C:26]1[C:19]2[C:18]([CH2:17][C:16]3[N:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]4=[N:9][C:8]=3[S:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[CH:22][S:21][C:20]=2[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCCSc1nc2ccccn2c1Cc1csc2cccc(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2scc(Cc3c(SCCCC(=O)O)nc4ccccn34)c12
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 100 mg (0.24 mmol) of 4-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridin-2-ylsulfanyl]-butyric acid methyl ester in 2 mL of THF is treated with a solution of 20 mg (0.48 mmol) of lithium hydroxide monohydrate in 1 mL of water at room temperature. The resulting mixture is heated to 40° C., and stirred at this temperature for 3 h. The reaction mixture is then cooled to room temperature and concentrated in vacuo. The residue is diluted with water and neutralized with 1N HCl solution. The product is extracted with ethyl acetate, and the organic layer is separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with 3˜10% methanol in dichloromethane solution to give the title compound. LCMS (ESMS): m/z 397 (M+H+)
Reaction SMILES: [C:1]([CH:4]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[CH:20][CH:19]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])=[O:8])([OH:3])=O.C(Cl)CCl.[NH2:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][CH:50]=1)[CH:47]=[N:46][CH:45]=[CH:44]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[O:12]=[C:11]1[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:8])[N:6]1[CH2:5][CH:4]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:27]([CH3:28])[CH3:29])[CH:30]([CH3:32])[CH3:31])=[CH:22][CH:23]=1)[C:1]([NH:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][CH:50]=1)[CH:47]=[N:46][CH:45]=[CH:44]2)=[O:3]
Reactant: Nc1ccc2cnccc2c1
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)c2ccccc2C(=O)O)C(=O)O)cc1)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)[Si](OCc1ccc(C(CN2C(=O)c3ccccc3C2=O)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
To 2-(2-carboxy-2-(4-((triisopropylsilyloxy)methyl)phenyl)ethylcarbamoyl)benzoic acid (E135) in pyridine was added EDC, DMAP and 6-aminoisoquinoline and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure 3-(1,3-dioxoisoindolin-2-yl)-N-(isoquinolin-6-yl)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanamide (E136).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15](O)[C:6]2=[N:5][N:4]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:30]>C(#N)C>[Cl:30][C:15]1[C:6]2[N:7]([C:3]([C:2]([F:18])([F:17])[F:1])=[N:4][N:5]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2ccccc2n2c(C(F)(F)F)nnc12
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: FC(F)(F)c1nnc2c(Cl)nc3ccccc3n12

Procedure:
To a suspension of 1-(trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxalin-4-ol (2.5 g; 0.01 mole) in 60 ml of acetonitrile, Et4N+Cl- (2.4 g) followed by N,N-dimethylaniline (1.7 ml) and POCl3 (3.75 ml) were added. Reaction mixture was refluxed for 20 hours. Volatiles were removed under reduced pressure, residue was dissolved in CHCl3 (100 ml) and added to the ice-water. Layers were separated, the aqueous layer was extracted with chloroform (2×200 ml). The combined extract was washed with 5% NaHCO3 (2×120 ml) followed by brine (2×50 ml). It was dried over MgSO4, filtered, and volatiles were removed. The residue was crystallized from chloroform-hexane affording 1.78 g of 4-chloro-1-(trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxaline; mass spectrum m/e, 272 (m+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.O.[CH:18]1[CH:23]=CC=C[CH:19]=1>C(O)(C)C>[CH:18]([O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([Br:1])[CH:10]=[C:9]([Br:11])[CH:8]=1)([CH3:23])[CH3:19]
Reactant: c1ccccc1
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC(=O)c1cc(Br)cc(Br)c1

Procedure:
A solution of 3,5-dibromobenzoic acid (Aldrich, 2.4 g, 8.6 mmol) in benzene (150 mL) and isopropanol (50 mL) was treated with concentrated sulfuric acid (2 mL) and heated to reflux overnight using a Dean-Stark water trap. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with water and saturated, aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a clear oil that was used as such for the next step (2.7 g, ˜100%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[C:13]([O:12][CH3:11])[C:18]=1[O:19][CH3:20]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Brc1cnc2[nH]ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cnc3[nH]ccc3n2)cc(OC)c1OC
Temperature: 110 °C
Yield: 88.5 %

Procedure:
A flask was charged with 2-bromo-5H-pyrrolo[2,3-b]pyrazine (9.5 g, 48 mmol), 3,4,5-trimethoxyphenylboronic acid (13.22, 62 mmol), and K2CO3 (19.9, 144 mmol). Dioxane (213 ml) and water (71 ml) were added, and the solution was vacuum degassed under argon. [1,1′-bis(Diphenylphosphino)ferrocene]dichloro-palladium(ll) (3.92 g, 4.8 mmol) was added, and the reaction mixture was refluxed (110° C.) overnight. The reaction mixture was filtered through a plug of celite using dichloromethane, and the filtrate was concentrated giving a black oil. The oil was purified by silica gel chromatography using 5%-60% EtOAc in hexanes as eluant to provide 12.12 g (89%) of 2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl:12][CH2:13][CH2:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:12][CH2:13][CH2:14][C@H:15]([N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@H](CCCl)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H](CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
Prepared according to the general procedure described in Srebnik, M.; Ramachandran, P. V.; Brown, H. C. J. Org. Chem. 1988, 53, 2916–2920. A mixture of phthalimide (0.147 g, 1.0 mmol), (R)-(+)-3-chloro-1-phenyl-1-propanol (0.171 g, 1.0 mmol), triphenylphosphine (0.262 g, 1.0 mmol) and diethyl azodicarboxylate (0.174 g, 1.0 mmol) in 5.0 mL of THF was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. The residue was washed with pentane (3×50 mL) and the combined pentane extracts were concentrated and chromatographed (silica, hexanes: EtOAc=8:1 as the eluent) to give the desired product (0.121 g, 50%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.82 (apparent dd, 2H, J=2.9 Hz), 7.70 (apparent dd, 2H, J=2.9 Hz), 7.56 (m, 2H), 7.39–7.27 (m, 3H), 5.64 (apparent dd, 1H, J=7.0, 9.2 Hz), 3.57 (m, 2H), 3.05 (m, 1H), 2.82 (septet, 1H, J=7.0 Hz); ESMS m/e: 300.1 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3)CC2)n(C(C)(C)C)n1

Procedure:
132 mg (73%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-phenylpiperazine (0.067 mL, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[N:6]=[C:7]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:8]2[C:9](=[O:11])[CH:10]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH:22]=O>CO>[CH3:16][C:15]1[C:7]2=[N:6][C:5]([CH:4]=[CH:22][C:21]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=3)=[CH:10][C:9](=[O:11])[N:8]2[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cc(=O)n2cccc(C)c2n1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=Cc2cc(=O)n3cccc(C)c3n2)cc(OC)c1OC
Yield: 21.5 %

Procedure:
To a solution of 2.2g of sodium methoxide in 100ml of absolute methanol is added 3.5g of 2,9-dimethyl-4H-pyrido-[1,2-a]pyrimidin-4-one, followed by 4.0g of 3,4,5-trimethoxybenzaldehyde. The mixture is stirred and heated under reflux for 28 hours. A crystalline solid separates and this is colled and filtered. The solid consists of a mixture of colorless and yellow crystals that are separated manually to give 1.52g of a pale yellow solid, melting point 208° - 210°C. The yellow solid is recrystallized from 35ml of methoxyethanol to yield 1.22g of the title compound, melting point 212°-214°C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:31])[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:31])[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(C2(O)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.6 %

Procedure:
10% Palladium on carbon (3.44 g, 3.23 mmol) was added to benzyl 4-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-1-carboxylate (13.49 g, 32.31 mmol) in MeOH (146 mL). The resulting mixture was stirred at room temperature for 20 hours under an atmosphere of hydrogen. The reaction mixture was filtered and evaporated to afford crude product. The crude material was triturated with DCM (100 mL) and MeOH (50 mL) to give a solid which was collected by filtration and dried under vacuum to give 4-(4-hydroxyphenyl)piperidin-4-ol (4.16 g, 66.6%).
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[F:38][C:39]([F:48])([F:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH2:16]([C@H:5]([CH2:4][C:1]([N:44]1[CH2:43][CH2:42][N:41]([CH2:40][C:39]([F:47])([F:48])[F:38])[CH2:46][CH2:45]1)=[O:3])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: FC(F)(F)CN1CCNCC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](CC(=O)N1CCN(CC(F)(F)F)CC1)Cc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
The resultant acid from Example 23 (0.500 g, 1.68 mmol) in CH2Cl2 (7 ml) at -10° C. was treated with N-methylmorpholine (0.20 ml, 1.82 mmol) and then isobutyl chloroformate (0.22 ml, 1.68 mmol). After 5 min 1-trifluoroethylpiperazine (0.30 g, 1.78 mmol) was added and the mixture was stirred at -10° C. for 15 min and then at room temperature for 2 h. The solvent was evaporated and the residue was taken up in ethyl acetate which was washed with saturated NaHCO3 solution, water and brine, and then dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel with 20-33% ethyl acetate in hexane provided 0.61 g (81%) of an oil. 1H NMR (CDCl3) δ7.10-7.40 (m,10H), 5.15 (d,1H), 5.05 (d,1H), 3.25-3.70 (m,5H), 3.04 (dd,1H), 2.97 (q,2H), 2.81 (dd,1H), 2.72 (dd,1H), 2.60 (m,4H), 2.32 (dd,1H).
Reaction SMILES: ClC(OC(Cl)C)=O.[F:8][C:9]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH:22]2[CH2:27][CH2:26][N:25](C)[CH2:24][CH2:23]2)=[O:21])[N:15]=1)=[O:12]>ClC(Cl)C>[F:34][C:29]1[CH:30]=[C:31]([F:33])[CH:32]=[C:9]([F:8])[C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)=[O:21])[N:15]=1)=[O:12]
Reactant: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: O=C(Nc1cccc(C(=O)C2CCNCC2)n1)c1c(F)cc(F)cc1F
Yield: 29.3 %

Procedure:
Add 1-chloroethyl chloroformate (0.8 g) into a solution of 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (0.216 g) in dichloroethane (10 mL) and heat at reflux for 1 hr. Then add more 1-chloroethyl chloroformate (1 mL) and heat at reflux overnight. Add methanol (10 mL) to the reaction mixture, concentrate to a small volume, dilute with methanol again, load onto an SCX column (10 g), wash with methanol, and elute with 2M NH3-methanol, evaporate and purify on a silica gel column (CH2Cl2 with 2 M NH3 in methanol) to obtain the title compound (61 mg). Mass spectrum (electric spray) m/z=364 (M+1); 1H NMR (CDCl3): 8.55 (d, J=8.1 Hz, 1H), 7.92 (dd, J=8.0, 8.0 Hz 1H), 7.84(1H, J=8.0 Hz, 1H), 6.81 (m, 3H), 3.89 (m, 1H), 3.12 (br d, 2H), 2.81 (m, 2H), 1.85 (m, 2H), 1.74 (br, 2H), 1.61 (m, 2H).