Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]([O:17]C)=[N:15][C:14]2[C:9]1=[N:10][C:11]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[N:12][C:13]=2[NH2:19].C(N(CC)C(C)C)(C)C.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl-]>CN(C=O)C>[NH2:19][C:13]1[N:12]=[C:11]([O:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[N:10]=[C:9]2[C:14]=1[NH:15][C:16](=[O:17])[N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1nc2c(N)nc(OC3CCCCC3)nc2n1CCCCCl
Reactant: C1CCNCC1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(OC2CCCCC2)nc2c1[nH]c(=O)n2CCCCN1CCCCC1
Yield: 14.1 %

Procedure:
Sodium iodide (0.006 g, 0.04 mmol) was added to a stirred mixture of 9-(4-chlorobutyl)-2-(cyclohexyloxy)-8-(methyloxy)-9H-purin-6-amine (0.103 g, 0.303 mmol), N,N-diisopropylethylamine (0.105 ml, 0.079 g, 0.609 mmol) and piperidine (0.120 ml, 0.103 g, 1.215 mmol) in DMF (1.5 ml). The resultant mixture was heated at 80° C. for 20 hours when LCMS showed the formation of two products, one corresponding to displacement of the chloride by piperidine and the second corresponding to concomitant hydrolysis of the 8-methoxy moiety. The reaction mixture was partitioned between dichloromethane (6 ml) and water (6 ml) and the phases separated using a hydrophobic frit. The solvent was removed from the organic phase under a stream of nitrogen in a blow-down unit and the residue was dissolved in 1:1 MeOH:DMSO (2 ml) and separated by mass directed autopreparation (Method A) to afford the title compound as a white solid (16.6 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[I:13])[CH3:4].C(N(CC)CC)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>CS(C)=O.O>[O:1]=[CH:2][CH:3]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[I:13])[CH3:4]
Reactant: CC(CO)NC(=O)c1ccccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C=O)NC(=O)c1ccccc1I
Reaction time: 0.17 h

Procedure:
A solution of 54.9 g (345 mmol) of sulfur trioxide-pyridine complex in 150 ml of DMSO is added dropwise at RT to 35 g (115 mmol) of rac. 2-iodo-benzoic acid-(1-hydroxy-prop-2-yl-amide) in 50 ml of DMSO and 48 ml (345 mmol) of triethylamine. After 10 min, the mixture is poured onto 0.4 l of EtOAc, 0.21 of sat. NaHCO3 solution and 0.2 l of water, the aqueous phase is separated and extracted 4 more times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation to form rac. 2-iodo-benzoic acid-(1-oxo-prop-2-yl-amide).
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:25]1([NH:15][N:14]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:26]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Brc1cccc2ccccc12
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(C(=NNc2cccc3ccccc23)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 52.6 %

Procedure:
Benzophenone hydrazone (1 equiv., 10 mmol, 2.04 g), 1-bromonaphthalene (1.0 equiv., 10 mmol, 1.39 mL), Pd(OAc)2 (0.01 equiv., 0.1 mmol, 23 mg), BINAP (0.01 equiv., 0.1 mmol, 63 mg), and toluene (10 mL) were added to an oven dried Schlenk flask and stirred at room temperature for 2 minutes, NaOtBu (1.4 equiv., 14 mmol, 1.345 g) and an additional 10 mL of toluene were then added. The flask was capped with a septum and purged briefly with argon (˜1 min.) and heated to 80° C. under argon for 4.5 hours. The reaction mixture was then cooled to room temperature, diluted with Et2O (10 mL), and concentrated under vacuum to give the crude product as a brown solid. Recrystallization of the crude product from hot ethanol (150 mL) gave the desired product as a red solid (1.6939 g, 5.26 mmol, 53% yield). The mother liquor was concentrated until the solution became cloudy, and then heated until the solution became clear, filtered and cooled to −4° C. for 12 hours. The resulting crystals were filtered to give an additional 1.062 g of the title product as an orange/red solid (3.3 mmol, 33% yield), to give a 85% overall yield of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>C(Cl)Cl.O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[N:19]([CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)=[O:18])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a mixture of 1-(4-benzyloxy-phenyl)-2-bromo-ethanone (28.55 g; 93.6 mmol) in CH2Cl2 (300 mL) and water (30 mL) was added nBu4NBr (1.51 g; 4.7 mmol) and NaN3 (6.69 g; 102.9 mmol) in one portion. After 4 h at RT, the layers were separated. The organic layer was washed water, dried (Na2SO4), filtered and concentrated in vacuo to afford 2-azido-1-(4-benzyloxy-phenyl)-ethanone (23.64 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([O:15]CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(OC2CCC(OCc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OC1CCC(Oc2ccc(F)cc2)CC1
Yield: 74.3 %

Procedure:
A mixture of 17.1 parts of 1-fluoro-4-[[4-(phenylmethoxy)cyclohexyl]oxy]benzene and 160 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo and the filtrate was evaporated, yielding 8.9 parts (74.3%) of 4-(4-fluorophenoxy)cyclohexanol as a residue (139).
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:17])[CH:8]=1)=O)[CH3:2].[NH2:21][NH:22][C:23]([NH2:25])=[S:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CI>C(O)C>[CH2:1]([O:3][CH:4]1[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:17])[CH:8]=2)=[N:21][NH:22][C:23](=[S:24])[NH:25]1)[CH3:2]
Reactant: NNC(N)=S
Reactant: CCOC(OCC)C(=O)c1ccc(C(=O)OC)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CI
Solvent: O
Solvent: CCO
Product: CCOC1NC(=S)NN=C1c1ccc(C(=O)OC)c(F)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
A mixture of methyl 4-(diethoxyacetyl)-2-fluorobenzoate (0.63 g, 0.0022 mol), thiosemicarbazide (0.24 g, 0.0026 mol), and p-toluenesulfonic acid monohydrate (20 mg) in ethanol (6 mL) was heated at 90° C. for 1.5 h. After cooling to RT, to the mixture was added methyl iodide (0.7 mL, 0.01 mol). The mixture was stirred at RT for 1 h. The mixture was concentrated. The residue was dissolved in acetic acid (4 mL), and heated at 60° C. for 2 h. After cooling, the reaction mixture was concentrated. The residue was treated with methanol. The formed precipitate was collected by filtration, and dried in-vacuo to afford the desired product (180 mg). Analytical LCMS: (M+H)+=280.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][S:4]([NH:7][CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])[CH2:12][CH2:11][N:10]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)(=[O:6])=[O:5].I[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.CNCCNC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu]I.O>[CH3:1][CH:2]([CH3:36])[CH2:3][S:4]([N:7]([C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:17])[CH2:12][CH2:11][N:10]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:35])([CH3:34])[C:30]([F:32])([F:31])[F:33])=[CH:25][CH:24]=1)(=[O:6])=[O:5]
Reactant: CC(C)CS(=O)(=O)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: Ic1cccnc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)c1cccnc1
Yield: 0 %

Procedure:
To a solution of 2-methyl-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-1-propanesulfonamide (0.130 g, 0.228 mmol, Example 210) in DMF (3.0 mL) was added 3-iodopyridine (0.094 g, 0.46 mmol, Aldrich, St. Louis, Mo.), N,N′-dimethylethylenediamine (0.020 mL, 0.18 mmol, Aldrich, St. Louis, Mo.), CuI (0.015 mg, 0.21 mmol, Aldrich, St. Louis, Mo.), cesium carbonate (0.22 g, 0.69 mmol), and water (0.30 mL). The resulting mixture was heated at 120° C. for 14 d, with additional aliquots of 3-iodopyridine (50 mg, 0.23 mmol) being added on 2nd and 5th day. The reaction mixture was then filtered and the filtrate was concentrated. The crude product was purified by column chromatography (24 g of silica gel, 1 to 5% 2M NH3 in MeOH in CH2Cl2) to afford 2-methyl-N-3-pyridinyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-1-propanesulfonamide (0.015 mg) as a mixture of two isomers.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:29])=[C:4]([N:10]2[CH2:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])[C@H:12]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(=O)=O.CO>>[NH2:1][C:2]1[C:3]([Cl:29])=[C:4]([N:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])[C@@H:12]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C=O
Solvent: CO
Product: COC(=O)N[C@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 43.8 %

Procedure:
(+/−)-methyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyl dimethylsilyl)oxy)piperidin-4-yl)carbamate (Example 171E, 927 mg, 2.112 mmol) was separated by chiral SFC (Berger SFC MGIII, Column: Lux Cel-425×3 cm ID, 5 μm; Flow rate: 85.0 mL/min; Mobile Phase: 85/15 CO2/methanol; Detector Wavelength: 220 nm). Methyl ((3S,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)carbamate (406 mg) was obtained as a white foaming solid. The enantiomeric purity of each fraction was estimated to be greater than 99.5%.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.[CH2:22]([SH:26])[CH2:23][CH2:24][SH:25]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]2[S:26][CH2:22][CH2:23][CH2:24][S:25]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: SCCCS
Reactant: COc1ccc(C=O)cc1OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C2SCCCS2)cc1OC

Procedure:
The first step in the process for making Justicidin P can be conducted by adding boron trifluoride etherate (BF3.Et2O) to a solution containing 3,4-dimethoxybenzaldehyde and 1,3-propanedithiol in methylene chloride. After a suitable reaction time, the mixture is washed with a NaOH solution and a saturated solution of NaCl. The product is dried and then recovered by evaporation under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:30])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.CO.C(=O)([O-])[OH:34].[Na+]>Cl.O1CCOCC1>[OH:1][CH2:2][C:3]1([CH3:30])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:29]=[CH:28][C:25]([C:26]([NH2:27])=[O:34])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1
Reactant: O=C([O-])O
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C#N)cn5)cc4)CC3)n2CCS1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(N)=O)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of the compound (9.14 g, 17.2 mmol) obtained in Example 60-5) in 2 N hydrochloric acid-1,4-dioxane (200 mL) was stirred at 50° C. for 2 h. The reaction mixture was cooled to room temperature, methanol (40 mL) was added to the reaction mixture, and insoluble substances were dissolved by sonication. Saturated aqueous sodium hydrogencarbonate (400 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane and purified by silica gel column chromatography (ethyl acetate:methanol=3:2) to obtain the title compound (2.74 g, 38%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([S:12](Cl)(=O)=O)[CH:11]=1)[O:8][CH:7]([C:16]([F:19])([F:18])[F:17])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2.II.[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.CI>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([S:12][CH3:27])[CH:11]=1)[O:8][CH:7]([C:16]([F:19])([F:18])[F:17])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(S(=O)(=O)Cl)c2OC1C(F)(F)F
Agent: II
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CI
Product: CCOC(=O)C1=Cc2cc(Cl)cc(SC)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To benzene (solvent) was added ethyl 6-chloro-8-(chlorosulfonyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Step 2, 0.68 g, 1.68 mmol), iodine (0.11 g, 0.84 mmol), and triphenyl phosphine (4.41 g, 16.8 mmol) amd the resulting mixture heated to reflux for 4 h and allowed to cool to RT and stand for 48 h. To this crude reaction was added Et3N (0.58 mL, 0.424 g, 4.20 mmol) and methyl iodide (0.06 mL, 0.13 g, 0.92 mmol). After extractive workup and silica chromatography the title compound was obtained as a yellow, crystalline mass (0.215 g, 36%). 1HNMR (CDCl3-d6/300 MHz) 7.59 (s, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 5.78 (q, 1H, J=6.8 Hz), 4.20-4.40 (m, 3H), 2.42 (s, 3H), 1.33 (t, 3H, J=7.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][C@H:11]([C:14](O)=[O:15])[CH2:10]2)=[N:6][CH:7]=1.[CH3:32][NH:33][CH3:34].C1COCC1.Cl.C(N=C=NCCCN(C)C)C.N1C2C(=NC=CC=2)N(O)N=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][C@H:11]([C:14]([N:33]([CH3:34])[CH3:32])=[O:15])[CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To (1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentanecarboxylic acid U-31332-EXP080 (10 mg, 0.023 mmol), 2M dimethyl amine in THF (0.011 ml, 0.023 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (8.70 mg, 0.045 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (4.32 mg, 0.032 mmol) were added then dimethylformamide (1 ml) and diisopropyl ethylamine (0.016 ml, 0.091 mmol) were added, and the reaction mixture was stirred at ambient temperature for 18 hr and the progress followed by LCMS. The crude reaction mixture was filtered and purified by preparative LC. The product fractions were combined, 50 mL of 1M NaOH and 50 mL of ethyl acetate were added. The organic layer was removed, washed with 50 mL 1M NaOH, 50 mL saturated salt solution, dried over sodium sulfate, and reduced to constant mass. 3 mg of the desired compound was obtained. LCMS (m/z): 468.1 (MH+), retention time=0.72 min., 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.77-2.16 (m, 6H) 2.96 (s, 3H) 3.07 (s, 3H) 3.10-3.25 (m, 1H) 4.29 (m, 1H) 4.56 (d, J=5.27 Hz, 2H) 5.12 (br. s., 1H) 5.87 (br. s., 1H) 6.38 (d, J=8.50 Hz, 1H) 6.58 (s, 1H) 6.91-7.01 (m, 1H) 7.06-7.20 (m, 1H) 7.26-7.37 (m, 2H) 7.44-7.53 (m, 1H) 8.09 (s, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH:16]=[O:17])[C:11](Cl)=[N:12]2)=[CH:7][CH:6]=1)(=O)C.CCN(CC)CC.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH:16]=[O:17])[CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc2cc(C=O)c(Cl)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cnc2cc(O)ccc2c1
Temperature: 110 °C
Yield: 59.8 %

Procedure:
To a solution of 2-chloro-3-formylquinolin-7-yl acetate (2.9 g, 14 mmol) and Pd(PPh3)4 (1.6 g, 1.4 mmol, 0.1 eq.), Et3N (17 g, 168 mmol, 16 eq.) in DMF (100 mL) was added formic to acid (3.48 g, 75.6 mmol, 5.4 eq.) dropwise over 5 min. The mixture was warmed to 110° C. over 2 h. Then, the reaction mixture was diluted (water), extracted (EA), washed (brine), dried (Na2SO4), filtered and evaporated to dryness to give the crude product, which was purified by silica gel column chromatography (PE-EA, 1:1) to give desired compound as yellow solid (1.45 g, yield 60%). ESI-MS: 216 (M+H)+. 1H NMR (300 MHz, CDCl3) δ: 7.26-7.32 (m, 2H), 8.04-8.07 (d, 1H), 8.78 (d, 1H), 9.13 (s, 1H), 10.13 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[O:7][N:6]=1.[ClH:15].Cl.[CH2:17]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[ClH:1].[ClH:15].[F:14][C:12]1[CH:11]=[CH:10][C:9]2[C:5]([CH2:4][CH2:3][CH2:2][N:24]3[CH2:25][CH2:26][N:21]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23]3)=[N:6][O:7][C:8]=2[CH:13]=1
Reactant: CCCCN1CCNCC1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCN1CCN(CCCc2noc3cc(F)ccc23)CC1
Yield: 17.5 %

Procedure:
A mixture of 12 g of 3-(-chloropropyl)-6-fluoro-1,2-benzisoxazole, 10 g of 1-n-butylpiperazine dihydrochloride, 21 g of potassium carbonate and a few crystals of potassium iodide in 80 ml of dimethylformamide was stirred at 70° C. for three hrs, cooled, filtered and concentrated to an oil. The oil was stirred with water and extracted with ether. The ether extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was converted to a salt by treatment with ethereal hydrogen chloride. Recrystallization from ethyl acetate/methanol gave 3.2 g (18%) of product, mp 260° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+].O>C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NCc1nccnc1Cl)[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CC[C@@H](c2ncc3c(Cl)nccn23)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
(R)-Benzyl 3-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (5.90 mmol, 2.21 g) was dissolved in ethyl acetate (20 ml) and N,N-dimethylformamide (1.538 ml). The stirred reaction mixture was cooled to 0° C. and phosphorous oxychloride (23.58 mmol, 2.198 mL) was added. After stirring at room temperature for 3 hours the reaction mixture was cooled to 0° C. and an excess of solid sodium hydrogencarbonate was added. The suspension was stirred at 0° C. for 10 minutes and 20 minutes at room temperature. Then it was cooled to 0° C. and water was added. The organic layer was separated and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated in vacuo to yield (R)-benzyl 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (2.11 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:6][CH2:5][O:4]1.[Cl:31][CH2:32][CH2:33][CH2:34][S:35](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:37])=[O:36]>>[Cl:31][CH2:32][CH2:33][CH2:34][S:35]([NH:1][CH2:2][C:3]1([CH2:8][O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:6][CH2:5][O:4]1)(=[O:37])=[O:36]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CN)CCCO1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CNS(=O)(=O)CCCCl)CCCO1

Procedure:
2-Aminomethyl-2-octadecylcarbamoyloxymethyltetrahydrofuran IVb2 is allowed to react and worked by the same procedure as described in (4). The summary of the experimental condition and the physical data of the prodcut are listed in the Table 7.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:20]Br>C(#N)C>[Br:20][C:9]1[C:8]2[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[NH:11][N:10]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc2c(Br)n[nH]c2c1
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
6-(1H)-indazole carboxylic acid methyl ester (1.5688 g, 8.90 mmol) and cesium carbonate (4.38 g, 13.44 mmol) were dissolved in acetonitrile (89 ml) at 25° C. Bromine (0.554 ml, 10.75 mmol) was added and the reaction mixture was allowed to stir for 20 min. The reaction was stopped, quenched by addition of saturated aqueous sodium hydrogen carbonate (30 mL) and 10% aqueous sodium thiosulfate (30 mL), and the mixture extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×50 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The title compound (2.241 g, 8.79 mmol, 99% yield) was recovered as a light orange/white solid. LC-MS: [M+1]=255.2.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[N:8]([CH2:9][C:10]([O:12]C)=[O:11])[C:7](=[O:14])[CH:6]1[CH2:15][CH3:16])[CH:2]=[CH2:3].[OH-].[K+].ClCCl>C(O)C.O>[CH2:1]([S:4][CH:5]1[N:8]([CH2:9][C:10]([OH:12])=[O:11])[C:7](=[O:14])[CH:6]1[CH2:15][CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCSC1C(CC)C(=O)N1CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: C=CCSC1C(CC)C(=O)N1CC(=O)O
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
To a stirred solution of 3 g of methyl 2-(4-allylthio-3-ethylazetidin-2-on-1-yl)acetate in 10 ml of absolute ethanol was added dropwise a solution of 0.9 g of potassium hydroxide in a mixture of 12 ml of ethanol and 1 ml of water. After 5 minutes, the mixture was poured into a mixture of 10 ml of dichloromethane and 20 ml of water. After acidification with 13 ml of 2M HCl, the mixture was extracted with further dichloromethane; the dichloromethane extracts were extracted with saturated sodium bicarbonate solution. These aqueous extracts were acidified to pH 1.5 with 5M HCl and then extracted with dichloromethane. These organic extracts were evaporated to dryness to afford the title compound as a white crystalline solid (2.56 g).