Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:19](=O)[C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][CH2:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]1CCCC1.C([Li])C[CH2:28][CH3:29].ICC>C(#N)C>[CH2:28]([C:19]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:11][C:10]2=[O:21])[CH3:29]
Reactant: C1CCOC1
Reactant: O=c1c2c([nH]n1-c1ccccc1)CNc1ccccc1-2
Reactant: [Li]CCCC
Solvent: CC#N
Solvent: CCI
Product: CCc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, a mixture of 2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinoline-one (3.0 g, 11.5 mmol), N,N,N′-tetramethylethylenediamine (7.7 mL), and tetrahydrofuran (128 mL) was chilled to 0° C. A solution of n-butyllithium in hexanes (12.0 mL of 2.86 M) was added dropwise. After the addition was complete the reaction mixture was stirred for 5 minutes at 0° C. and then cooled to −78° C. To the cooled solution was added iodoethane (5.3 mL, 34 mmol). The reaction mixture was warmed to ambient temperature and stirred for 30 minutes before quenching with saturated aqueous ammonium chloride. The layers were separated and the organic layer was concentrated under reduced pressure to afford a yellow oil. The yellow oil was stirred in acetonitrile and filtered to provide material that was recrystallized from methanol to provide 100 mg of 1-ethyl-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as colorless needles., mp 331-334° C. MS (APCI) m/z 290 (M+H)+; Anal. calcd for C18H15N3O: C, 74.72; H, 5.23; N, 14.52. Found: C, 74.51; H, 4.96; N, 14.62.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]3[C:18](=[O:21])[NH:19][S:20][C:5]2=3)[CH2:3][CH2:2]1.Cl.Cl.[CH3:24][C:25]1([NH2:29])[CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][C:25]([NH2:29])([CH3:24])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]3[C:18](=[O:21])[NH:19][S:20][C:5]2=3)[CH2:2][CH2:3]1
Reactant: CC1(N)CNC1
Reactant: O=c1[nH]sc2c1c(=O)c1cc(F)c(F)c(F)c1n2C1CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(N)CN(c2c(F)cc3c(=O)c4c(=O)[nH]sc4n(C4CC4)c3c2F)C1
Yield: 74.3 %

Procedure:
A mixture of 250 mg (0.8 mmol) of 9-cyclopropyl-6,7,8-trifluoro-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, 255 mg (1.6 mmol) of 3-methyl-3-aminoazetidine dihydrochloride and 0.6 ml of triethylamine in 10 ml of pyridine is kept refluxing for 2 hours, the mixture is evaporated under vacuum, a mixture of ethanol with water is added, the resulting mixture is filtered and the product is washed. 0.225 g of 9-cyclopropyl-6,8-difluoro-7-(3-amino-3-methyl-1-azetidinyl)-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, melting point 294°-300° C., is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.[CH3:25][NH2:26]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[NH:26][CH3:25]
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Reaction time: 20 h

Procedure:
A mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg) and a solution of methylamine in THF (2.0M, 1.0 ml) was heated at 100° C. with stirring for 20 hours in a sealed tube. After cooling, the solvent was removed under reduced pressure and the residue was recrystallized from MeOH-IPE to give 5-[5-amino-6-(methylamino)-3-phenyl-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (13 mg). The filtrate was concentrated in vacuo, and the residue was rinsed with MeOH-IPE to give the desired product (60 mg).
Reaction SMILES: [Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C-:14]#[N:15].[Na+].C(O)(=O)C>C(O)C.O>[Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]([OH:9])[C:14]#[N:15]
Reactant: [C-]#N
Reactant: O=Cc1cccc(OC=C(Cl)Cl)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: N#CC(O)c1cccc(OC=C(Cl)Cl)c1
Yield: 91.9 %

Procedure:
To the combined solutions of 30 g of 3-(2,2-dichlorovinyloxy)benzaldehyde in 320 ml of ethanol and 15 g of NaCN in 30 ml water are added 39 ml of acetic acid dropwise at 0°-5° C. in the course of 1 hour. The resultant solution is stirred for 1 hour at 20°-25° C. and subsequently diluted with 1000 ml of H2O. The product is extracted with toluene, washed and evaporated, to yield 31 g of 3-(2,2-dichlorovinyloxy)mandelonitrile. The crude product can be processed without further purification.
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][CH:22]([C:24]2[O:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:27][N:28]=2)[CH3:23])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O.O>>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[O:25][C:24]([C@H:22]([NH:21][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([C@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[C:19]([F:20])=[CH:18][N:17]=3)[CH3:23])=[N:28][CH:27]=2)=[CH:30][CH:31]=1.[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[O:25][C:24]([C@@H:22]([NH:21][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([C@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[C:19]([F:20])=[CH:18][N:17]=3)[CH3:23])=[N:28][CH:27]=2)=[CH:30][CH:31]=1
Reactant: CC(Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1ncc(-c2ccc(Cl)cc2)o1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1ncc(-c2ccc(Cl)cc2)o1
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1ncc(-c2ccc(Cl)cc2)o1

Procedure:
(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one (124 mg, 0.246 mmol) was treated with 90% TFA/water for 2 hours. Concentrated in vacuo and neutralized by passing through a column of MP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded the diastereomeric mixture. Chiral SFC chromatography on an ID column (75 g/min, 120 bar, 21×250 mm) eluting 45% IPA/CO2 (v/v) to give (R)-3-(2-(((R)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.
Reaction SMILES: [OH:1][C@H:2]([CH:18]([CH3:20])[CH3:19])[C:3]([NH:5][C@H:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH3:7])=[O:4].CS(O[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)=O.[H-].[Na+]>C1COCC1>[CH3:19][CH:18]([CH3:20])[C@@H:2]([O:1][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3]([NH:5][C@H:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH3:7])=[O:4]
Reactant: CS(=O)(=O)OCCOc1ccccc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](O)C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](OCCOc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of methyl 4-[(1S)-1-[[(2R)-2-hydroxy-3-methyl-butanoyl]amino]ethyl]benzoate (3.0 g, 10.7 mmol) and 2-phenoxyethyl methanesulfonate (2.32 g, 10.7 mmol) in dry THF (25 mL) is added sodium hydride (440 mg, 10.7 mmol). The mixture is stirred at room temperature overnight and partitioned between 1N HCl and EtOAc. The aqueous layer is extracted with EtOAc. The combined EtOAc layers are washed with brine, dried with MgSO4, filtered, and concentrated. The crude material (4.7 g) is purified using silica gel column chromatography (120 g cartridge; 30 to 100% ethyl acetate in heptane) to provide the title compound as a white solid (1.41 g, 33%). MS (m/z): 400.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[NH:10]2)[CH3:4].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[N:10]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)[CH3:4]
Reactant: CCc1cc2[nH]c(=O)ccc2c(CC)n1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(ccc(=O)n2Cc2ccc(C(=O)OC)cc2)c(CC)n1
Yield: 72.1 %

Procedure:
Sodium hydride (50% dispersion in oil; 1.05 g) was added to a stirred solution of 5,7-diethyl-1,6-naphthyridin-2(1H)-one (4.0 g) in DMF (75 ml) and the mixture was stirred until effervescence ceased. Methyl 4-bromomethylbenzoate (4.58 g) was added and the mixture was stirred under argon for 4 hours. The mixture was then poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried (MgSO4) and solvent was removed by evaporation. The resultant solid was purified by flash chromatography, eluting with ethyl acetate/petroleum ether (3:1 v/v gradually increasing to 1.0 v/v) to give methyl 4-[(5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)-methyl]benzoate as a solid (5.0 g); m.p. 128°-130° C.; NMR (d6 -DMSO): 1.15(t, 3H), 1.25(t, 3H), 2.69(q, 2H), 3.06(q, 2H), 3.83(s, 3H), 5.56(s, 2H), 6.71(d, 1H), 7.04(s, 1H), 7.35(d, 2H), 7.91(d, 2H), 8.22(d, 1H); mass spectrum (+ve FAB, methanol/DMSO/NBA): 351 (M+H)+ ; microanalysis, found: C, 71.8; H, 6.3; N, 8.2%; C21H22N2O3 requires: C, 72.0; H, 6.3; N, 8.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1B(O)O.[NH2:12][C:13]1[C:14]([C:20]([O:22][CH3:23])=[O:21])=[N:15][C:16](Br)=[CH:17][N:18]=1.CCN(C(C)C)C(C)C>O1CCOCC1.O.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[NH2:12][C:13]1[C:14]([C:20]([O:22][CH3:23])=[O:21])=[N:15][C:16]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[CH:17][N:18]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(-c2c(F)cccc2F)cnc1N
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A solution of (2,6-difluorophenyl)boronic acid (270 mg, 1.7 mmol), methyl 3-amino-6-bromopyrazine-2-carboxylate (from Ark Pharm, 250 mg, 1.1 mmol), bis(tri-tert-butylphosphine) palladium (82 mg, 0.16 mmol), and DIPEA (370 μL, 2.1 mmol) in 1,4-dioxane (4 mL) and water (320 μL) in a vial was deoxygenated and purged with nitrogen several times. The vial was sealed and the reaction mixture was heated at 100° C. in the sealed vial for 14 h. The crude reaction mixture was filtered through a pad of diatomaceous earth and the inorganics were washed thoroughly with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (40 g silica gel column, eluting with 0-50% EtOAc in hexanes) to afford the sub-title compound (258 mg, 91% yield). LC/MS (ESI) calc. for C12H10F2N3O2(M+H)+: m/z=266.1. found: 266.0.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N-:14][C:15]2[N:20]=[C:19]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][OH:30])[C:16]=2[O:31][C:32]2[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Na+]>CC(C)=O>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][OH:30])[C:16]=2[O:31][C:32]2[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:1])[CH3:3].[OH2:12]
Reactant: COc1ccccc1Oc1c([N-]S(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Product: O
Temperature: 55 °C
Reaction time: 2 h
Yield: 198.4 %

Procedure:
40 g of Bosentan sodium salt were dissolved in acetone (353 g) and 8.48 g of hydrochloridric acid were added. Precipitated salts were filtered off and the clear solution was concentrated by distillation to a residual volume of 190 mL. The mixture was cooled to 55° C. and demineralized water (58 g) was slowly dropped keeping the temperature at 55° C. After 2 hours aging the temperature was decreased to 20° C. in 1 hour and stirred for additional 2 hours at that temperature. The precipitated solid was collected by filtration and the cake was washed with water-acetone 1:1 (38 g). 39.4 g of the desired product were obtained after drying in vacuo.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2]>ClCCl.C(O)(C(F)(F)F)=O>[CH2:31]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH2:23])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)[CH3:32]
Reactant: CCN(CC)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCc3ccccc3C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)c1ccc(NC(=O)C2(N)CCc3ccccc3C2)cc1
Yield: 97.3 %

Procedure:
(2-(4-Diethylamino-phenylcarbamoyl)-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester from Example 3 (320 mg) was dissolved in dichloromethane (10 mL) and TFA (5.0 mL). The volatiles were removed after 2 h. The amine-TFA salt was then dissolved in ethyl acetate (30 mL) and washed with 1 N NaOH. The organic phase was dried over MgSO4 and purified by column chromatography to provide the titled compound (240 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C(=CC=[C:40]([O:43]C)C=3)CC2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:43][CH3:40])[CH:18]=3)[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCc3ccc(OC)cc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCc3ccc(OC)cc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.27–1.31, 1.86, 2.58, 2.75, 2.83, 2.85, 2.97, 3.80, 4.54, 5.67, 6.83–6.88, 7.20; HRMS (FAB) calcd for C18H22BrN3O+H 376.1025, found 376.1020. Anal. Calcd for C18H22BrN3O: C, 57.45; H, 5.89; N, 11.17; Br, 21.23. Found: C, 56.15; H, 5.65; N, 10.83.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH:6][CH2:7][CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Product: O=C1CCC[C@H](/C=C/C(O)Cc2ccccc2)N1CC#CCOCCO
Yield: 69 %
Yield: 14 %

Procedure:
Sodium borohydride (24 mg, 0.63 mmol) followed by MeOH (1 mL) was added to a solution of {4-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester (82 mg, 0.21 mmol) in CH2Cl2 (2 mL) at 0° C. After 5 min at 0° C. the reaction was quenched with aqueous HCl (0.2 M, 10 mL). The reaction mixture was extracted with CH2Cl2 (3×10 mL), then the combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2) afforded 56.5 mg (69%) of {4-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester and 11 mg (14%) of (R)-1-[4-(2-hydroxy-ethoxy)-but-2-ynyl]-6-((E)-3-hydroxy-4-phenyl-but-1-enyl)-piperidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][C:4]=1[CH:16]=O.[C:18]1([C@H:24]2[C@@H:29]([NH2:30])[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][C:4]=1[CH2:16][NH:30][C@H:29]1[CH2:28][CH2:27][CH2:26][NH:25][C@H:24]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1cc2c(cc1C=O)C(C)(C)C(=O)N2C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)C(C)(C)C(=O)N2C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To 6-Methoxy-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5-carbaldehyde (936 mg, 4.0 mmol) in 50 mL of toluene was added (2S,3S)-2-Phenyl-piperidin-3-ylamine (1.0 g, 4.0 mmol) and 3 mL of methanol. The solution was heated to reflux with azeotropic water removal for 48 h. The solution was then concentrated and the residue was dissolved in CH2Cl2. Sodiumtriacetoxyborohydride (1.0 g, 4.7 mmol) was added and the mixture was stirred overnight. The mixture was then quenched with satd NaHCO3 and the layers were separated. The aqueous portion was extracted with CH2Cl2 (2×20 mL). The combined organic portions were washed successively with brine and water and concentrated. Silica gel chromatography (10:1 EtOAc/MeOH) gave 1.27 g (81%) of the title compound as an orange oil. Treatment of the oil with ethereal HCl gave 1.44 g of the dihydrochloride salt as an off-white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([NH2:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>C(O)C>[CH:21]1([CH2:20][NH:2][C@H:3]([C:11]([NH2:13])=[O:12])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:23][CH2:22]1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)[C@H](Cc1ccccc1)NCC1CC1
Yield: 39.1 %

Procedure:
To 100 ml. of anhydrous ethyl alcohol were added 8 grams (0.04 mole) of L-phenylalanine amide hydrochloride. To the mixture then were added 13.4 grams (0.16 mole) of solid anhydrous sodium bicarbonate and 6.44 grams (0.048 mole) of bromomethylcyclopropane. The mixture was refluxed for seven hours and then was evaporated in vacuo to an oil. The oil was dissolved in ethyl acetate, and the ethyl acetate solution was extracted with water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to an oil. The oil was applied to a 3×50 cm. column of Grace and Davison grade 62 silica gel in chloroform. The product was eluted with a gradient of chloroform containing up to 5 percent methanol. The product was isolated according to the thin-layer profile of the fractions collected to give 3.41 grams (39 percent) of the title compound.
Reaction SMILES: [N:1]1([CH:7]2[CH:16]3[N:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)[C:10](=[O:17])[CH:9]=[CH:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(OC([NH:25][CH2:26][CH2:27][CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[C:29](O)=[O:30])=O)(C)(C)C>>[ClH:38].[NH2:25][CH2:26][CH2:27][CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[C:29]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10](=[O:17])[N:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:2][CH2:3]1)=[O:30]
Reactant: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1C=CC(N2CCNCC2)C2C=CC=CN12
Product: Cl
Product: NCCC(C(=O)N1CCN(c2ccc(=O)n3ccccc23)CC1)c1ccc(Cl)c(Cl)c1

Procedure:
1-{4-[4-Amino-2-(3,4-dichlorophenyl)-butyryl]-piperazin-1-yl}-quinolizin-4-one hydrochloride was prepared by substituting 5-piperazin-1-yl-1H-indazole with 1-Piperazin-1-yl-1,9a-dihydro-quinolizin-4-one and substituting (D)-Boc-4-chlorophenylalanine with 4-tert-Butoxycarbonylamino-2-(3,4-dichlorophenyl)-butyric acid in Example 34, Step 2, then removing the Boc protecting group as described in Example 34, Step 3. 1H NMR (CD3OD, 400 MHz) δ 9.25 (d, J=7.2 Hz, 1H), 9.57 (d, J=8.8 Hz, 1H), 8.00 (m, 2H), 7.71 (d, J=7.2 Hz, 1H), 7.58 (m, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 4.31 (m, 1H), 3.82 (m, 5H), 3.65 (m, 2H), 3.34 (m, 1H), 2.98 (m, 1H), 2.86 (m, 1H), 2.36 (m, 1H), 2.03 (m, 1H). LCMS (APCI+) m/z 459, 461, 463 [M+H]+; Rt=2.02 min.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH2:6].[C:7]1(=[O:14])[CH:12]=CC(=O)C=C1.C.[OH:16]O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[C:7]([O:14][CH:2]1[CH2:3][CH2:4][C:5](=[CH2:6])[CH2:1]1)(=[O:16])[CH3:12]
Reactant: OO
Reactant: C=CCCC=C
Reactant: O=C1C=CC(=O)C=C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: C=C1CCC(OC(C)=O)C1
Reaction time: 2 h

Procedure:
Acetoxylation of l'hexa-1,5-diene ##STR3## A 500 ml three-neck flask is charged with 15 g of hexa-1,5-diene (0.18 moles), 150 g of acetic acid, 0.77 g of benzoquinone (7 mmoles), 1 g of charcoal and 80 mg of palladium acetate (0.35 mmoles). The temperature is taken to 50°, then 7 g (0.14 moles) of 70% by weight hydrogen peroxide are introduced in 8 h, and the reaction is allowed to proceed for a further 2 h while maintaining the temperature at 50°. The acetic acid is then distilled (35°, 20×102Pa). The residue is distilled under vacuum to provide 1-acetoxy-3-methylene-cyclopentane in 65% molar yield. 1-acetoxy-3-methylene-cyclopentane
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25]C)[CH:20]=3)[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:4][CH:3]=1.Br.O.[OH-].[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[C:11]([C:19]3[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=3)[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2CCO)ccn1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2CCO)cc[nH]1
Yield: 31 %

Procedure:
To a solution of 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol (0.28 g, 0.0006 mol) in 5 mL of acetic acid was added 3 mL of 48% hydrobromic acid. The reaction mixture was heated at reflux for 3 hour. The cooled mixture was then treated with water, basified with ammonium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (MeOH/CH2Cl2/NH4OH, 5:94:1) to give 0.07 g of product, 4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(1H)-pyridinone, as a yellow solid (32% yield), mp: 250-251° C.; 1H NMR (DMSO-d6): δ11.74 (s, 1H), 8.45 (d, J=5.0 Hz, 2H), 7.35 (m, 3H), 7.16 (m, 2H), 7.03 (d, J=5.0 Hz, 2H), 6.37 (s, 1H), 6.05 (d, J=5.2 Hz, 1H), 5.0 (m, 1H), 4.13 (m, 2H), 3.81 (m, 2H); Anal. Calc'd for C21H17FN4O2.0.2 H2): C, 66.06; H, 4.65; N, 14.67. Found: C, 66.31; H, 4.49; N, 14.27.