Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35](Br)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1CCN(C)C1=O>[Cl-].[NH4+].[C-]#N.[Zn+2].[C-]#N.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>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([C:39]#[N:40])=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(C)C1=O
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C#N)cn2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 4-tert-butyl-N-{6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (1.00 g), zinc cyanide (784 mg), tetrakis(triphenylphosphine)palladium (250 mg) and 1,3-dimethyl-2-imidazolidinone (40 ml) is stirred at 80° C. for 6 hours under argon atmosphere. The mixture is cooled to room temperature, and diluted with saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate, and the organic layer is washed with water (twice) and brine, dried over sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=10:1) and recrystallized from tetrahydrofuran/ethyl acetate to give 4-tert-butyl-N-{6-[2-(5-cyanopyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (590 mg) as colorless crystalline powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:14][C:13]2[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=2[C:11]=1[O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30](=[O:32])[CH3:31])=[CH:24][CH:23]=1)([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[OH:19][C:16]1[CH:17]=[CH:18][C:12]2[C:11]([O:21][C:22]3[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30](=[O:32])[CH3:31])=[CH:26][CH:27]=3)=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:1]([CH3:2])[CH3:3])[S:14][C:13]=2[CH:15]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(C)=O)cc3)c(-c3ccccc3C(C)C)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(O)ccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
To a solution of (E)-4-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2-one (71.3 mg, 0.161 mmol) in DCM (2.5 mL) at 0° C. was added BBr3 (1.0 M in Heptane, 0.403 mL, 0.403 mmol) dropwise. The resulting mixture was stirred at 0° C. for 1 h after which time the reaction was quenched by addition of sat. aq. NaHCO3 solution and extracted with 10% i-PrOH/DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 45-70% CH3CN/H2O) to afford (E)-4-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2-one (11.1 mg, 0.026 mmol, 16%). 1H NMR (400 MHz, CD3OD) δ ppm=7.55 (d, J=16.3 Hz, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.37-7.19 (m, 5H), 7.14-7.08 (m, 1H), 6.86 (d, J=8.8 Hz, 3H), 6.63 (d, J=16.3 Hz, 1H), 3.23 (p, J=6.9 Hz, 1H), 2.33 (s, 3H), 1.16 (d, J=6.8 Hz, 6H). HRMS (m/z, MH+): 429.1509.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49]([C:51]1([NH2:60])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]>CO.C(Cl)Cl.C(Cl)Cl>[CH2:46]([O:48][C:49]([C:51]1([NH:60][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cc2ccccc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cc3ccccc3s2)Cc2ccccc2C1
Yield: 69.5 %

Procedure:
To a 40 mL vial containing a stirring bar, benzo[b]thiophene-2-carboxylic acid (518 g, 2.44 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol) and the DIPEA (0.95 mL, 8.0 mmol) are added. The 2-aminoindane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added. The reaction is allowed to stir for 110 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.54 g of an off white solid. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 20% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% over 10 column volumes and then 90% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 13 through 27 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.62 g.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:17])(=[NH:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>C1C=CC=CC=1.CCCCCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:16][C:7](=[NH:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[S:27])=[CH:21][CH:20]=1
Reactant: CCCCCCCCC(=N)N
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CCCCCCCCC(=N)NC(=S)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 1.9 g. sodium in 200 ml. dry acetone, 16 g. nonanamidine hydrochloride, and 14.2 g. 4-chlorophenyl isothiocyanate in 100 ml. dry acetone there was obtained 1-(4-chlorophenyl)-3-(nonanimidoyl)-2-thiourea, m.p. 102°-103° C. (from benzene-n-hexane); hydrochloride (16.2 g.); m.p. 172°-174° C. (from acetonitrile).
Reaction SMILES: [Cl-].[Li+].[Mg].[H-].C([Al+]CC(C)C)C(C)C.Br[C:15]1[C:16]([Cl:21])=[N:17][CH:18]=[CH:19][CH:20]=1.[CH3:22][O:23][C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1)=[O:25]>O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:22][O:23][C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([C:15]2[C:16]([Cl:21])=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:33])[CH2:28][CH2:27]1)=[O:25]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: Clc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)c2cccnc2Cl)CC1
Reaction time: 1 h

Procedure:
To a mixture of lithium chloride (0.55 g, 13 mmol) and magnesium turnings (0.63 g, 26 mmol) in dry tetrahydrofuran (34 ml) was added 1M diisobutyl aluminum hydride solution in tetrahydrofuran (0.10 ml, 0.10 mmol) at room temperature. After stirring for 5 minutes a solution of 3-bromo-2-chloro-pyridine (2.00 g, 10.4 mmol) in dry tetrahydrofuran (1 ml) was added at 0-5° C. Stirring for 1 h was followed by addition of a solution of zinc chloride (1.42 g, 10.4 mmol), which had previously been dried by melting in vacuo followed by cooling under argon, in dry tetrahydrofuran (10 ml). After stirring for 1 h the mixture was decanted into another flask by cannulation under argon. Addition of tetrakis(triphenylphosphine)palladium(0) (0.59 g, 0.51 mmol) and trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester (2.10 g, 10.3 mmol) was followed by stirring at room temperature for 18 h. The mixture was partitioned between ethyl acetate (150 ml) and 0.1M aqueous hydrogen chloride solution (100 ml). The layers were separated. The aqueous layer was extracted with two 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash-chromatography with n-heptane/tert-butyl methyl ether as eluent gave the title compound (1.3 g, 46%) as yellow solid. MS m/e: 282 ([M+H]+)
Reaction SMILES: [C:1]([C:3]1([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+]>C(O)C.C(O)C.O>[NH2:2][CH2:1][C:3]1([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CC2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CN)(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of the tert-butyl 4-cyano-4-cyclopropylmethylpiperidine-1-carboxylate (I-2) (1.00 g, 3.78 mmol) in ethanol (5 mL) was added to 1M sodium hydroxide in 95% ethanol-water (75 mL) and the solution degassed with nitrogen. Raney Nickel (50% slurry in water) (2.6 g) was added and the black suspension shaken under hydrogen pressure (40 psi) at room temperature for 12 h. The catalyst was filtered off and washed with 95% ethanol-water. The filtrate was evaporated in vacuo then partitioned between water and DCM. The organic phase was separated and the aqueous phase re-extracted with DCM twice. The combined organic phase was dried (MgSO4) and the solvent removed in vacuo to leave tert-butyl 4-aminomethyl-4-cyclopropylmethylpiperidine-1-carboxylate (I-3) that was used in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 3.44 (m, 2H), 3.32 (m, 2H), 2.71 (s, 2H), 1.41 (s, 9H), 1.46-1.38 (m, 4H), 1.28 (d, J=6.7, 2H), 1.46 (s, 9H), 0.60 (m, 1H), 0.46 (m, 2H), 0.05 (m, 2H).
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]1[CH2:18][CH2:17][N:16]2[N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=[C:15]2[CH2:14]1)(=O)=O)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C(#N)C>[N:19]1[N:16]2[CH2:17][CH2:18][NH:13][CH2:14][C:15]2=[CH:21][C:20]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1cc2n(n1)CCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2n(n1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a mixture of ethyl 5-[(2-nitrophenyl)sulfonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (0.216 g, 0.568 mmol) and cesium carbonate (0.35 g, 1.1 mmol) was added a solution of benzenethiol (0.11 mL, 1.1 mmol) in acetonitrile (1 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue applied directly to silica purification (5% MeOH/DCM with 1% Et3N) to afford Intermediate 17 as a white solid (0.093 g, 84%). LC-MS: (FA) ES+196; 1H NMR (400 MHz, CDCl3) δ 6.49 (s, 1H), 4.35 (q, J=7.1 Hz, 2H), 4.17-4.13 (m, 2H), 4.04 (s, 2H), 3.29-3.25 (m, 2H), 1.74 (s, 1H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:26][C:27](O)=[O:28])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1.CN.[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:26][C:27](=[O:28])[NH:35][CH3:34])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[O:9])=[CH:30][CH:31]=1
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CC(=O)O)Cc2ccc(Cl)cc2)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)CN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of ((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-acetic acid, compound 49 (1 eq.) in DMF were added methylamine (33% w/w in EtOH) (1 eq.), TEA (1 eq.) and TBTU (1 eq.). The reaction was stirred at 20° C. for 15 h. The reaction was carried on with addition of methylamine (33% w/w in EtOH), TEA (1 eq.) and TBTU (1 eq.), then stirring at 20° C. for 15 h. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The organic layer was washed twice with water, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by preparative LCMS to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-methylcarbamoylmethyl-amide.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:17]=[CH:18][CH:19]=1
Reactant: Clc1nccc2cccnc12
Reactant: Nc1cccc(Cl)c1
Product: Clc1cccc(Nc2nccc3cccnc23)c1

Procedure:
The title compound, MS: m/e=256.0 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-[1,7]naphthyridine and 3-chloroaniline.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH:12]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][CH:3]=[C:2]3[C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(C(c2ccc3nccc(Br)c3c2)c2nccs2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccnc3ccc(C(c4ccc(Cl)cc4)c4nccs4)cc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-((4-bromoquinolin-6-yl)(4-chlorophenyl)methyl)thiazole (28 mg, 0.0674 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (37.5 mg, 0.121 mmol), Pd(dppf)Cl2.CH2Cl2 (5.5 mg, 0.00674), Na2CO3 (14.3 mg, 0.135 mmol) in 1,4-dioxane (0.8 mL) and water (0.4 mL) was heated at 95° C. for 5 hr under argon. The reaction was cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc once. The combined organics were concentrated and purified by silica column chromatography (50% EtOAc/hexanes) to yield tert-butyl 4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:11][N:10]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.[ClH:36]>C(Cl)Cl>[ClH:36].[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:6]2[CH2:7][C@@H:2]([CH3:1])[N:3]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[N:11][N:10]=3)[CH2:4][C@@H:5]2[CH3:8])=[O:35])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: C[C@@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)[C@@H](C)CN1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)Nc2ccc(F)cc2)[C@@H](C)CN1c1nnc(-c2ccc(F)cc2)c2ccccc12
Yield: 43 %

Procedure:
Treat a solution of 1-(trans-2,5-dimethylpiperazin-1-yl)-4-(4-fluorophenyl)phthalazine (0.3 g, 0.89 mmol) in CH2Cl2 (5 mL) with 1-fluoro-4-isocyanatobenzene (0.17 g, 1.25 mmol). Stir the reaction at ambient temperature for 1 h. Purify the reaction mixture by flash silica gel chromatography (0-50% EtOAc in hexanes). Pool and concentrate the appropriate fractions. Dissolve the mixture of N-(4-fluorophenyl)-4-(4-(4-fluorophenyl) phthalazin-1-yl)-trans-2,5-dimethylpiperazine-1-carboxamide isomers (0.3 g, 0.59 mmol) in MeOH (2 mL). Separate the mixture of trans-isomers by chiral chromatography (Chiralcel OJ-H, flow rate 30 mL/min, detection 225 nm, 6:4 MeOH: acetonitrile). Collect first eluting peak as Isomer 1 and the second eluting peak as Isomer 2. Pool and concentrate appropriate fractions. Dissolve the separated isomers in MeOH (1 mL) and treat each solution with 1 equivalent of 1 N aqueous HCl. Concentrate to give the hydrochloride salts of Isomer 1 (0.131 g, 44%) and Isomer 2 (0.129 g, 43%). Isomer 1: ES/MS m/z 474.2 (M+1), 99% ee. Isomer 2: ES/MS m/z 474.2 (M+1), 99% ee.
Reaction SMILES: O1CCCC1.[C:6]12([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=O)[CH:25]=[CH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:20][CH2:19]3)=O)[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[C:6]12([CH2:16][N:18]3[CH2:19][CH2:20][N:21]([CH2:24][CH:25]=[CH:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:22][CH2:23]3)[CH2:13][CH:12]3[CH2:14][CH:8]([CH2:9][CH:10]([CH2:11]3)[CH2:15]1)[CH2:7]2
Reactant: O=C(C=Cc1ccccc1)N1CCN(C(=O)C23CC4CC(CC(C4)C2)C3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C(=Cc1ccccc1)CN1CCN(CC23CC4CC(CC(C4)C2)C3)CC1
Temperature: 0 °C
Yield: 20 %

Procedure:
To 20 ml of tetrahydrofuran, 1 g of N-(1-adamantane carbonyl)-N' -cinnamoyl piperazine which was obtained in Example 1 (II) was dissolved and to this 0.24 g of lithium aluminum hydride powder were added gradually at 0° C. After refluxing for 4 hrs., it was cooled to 0° C and water was added to this at 0° C carefully to separate an organic solvent layer, subsequently the solvent was distilled away. The residues were dissolved in chloroform which was washed with water, dehydrated and then was distilled away. The residues were subjected to silica gel column chromatography (eluant: mixture of chloroform and methanol) and N-(1-adamantyl methyl)-N'-cinnamyl piperazine was obtained. Melting point of the product was 85°-87° C and the yield was 20%.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O.[NH2:18][C:19]1[C:20](Cl)=[N:21][CH:22]=[CH:23][CH:24]=1>C(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[C:3]3[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=3[NH:1][C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2ccccc2N)cc1
Reactant: Nc1cccnc1Cl
Solvent: ClCCl
Product: COc1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Temperature: 180 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 20.0 g (0.088 mole) of 2-amino-4'-methoxybenzophenone and 13.0 g (0.097 mole) of 3-amino-2-chloropyridine (96%) was heated at 180° C. under a nitrogen atmosphere for 2.0 hr. The reaction mixture was cooled to approximately 70° C. and 100 ml of methylene chloride was added slowly. After the mixture had cooled to room temperature, another 50 ml of methylene chloride was added and the mixture was stirred overnight. The suspended solid was collected by filtration, air dried, dissolved in methanol and basified with 3N sodium hydroxide. The suspension was diluted with 500 ml water and extracted with three 250 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. Analysis by mass spectra (EI and CI) indicated the residue was a mixture of [2-[(3-amino-2-pyridyl)amino]phenyl](4-methoxyphenyl)methanone and the title compound. The residue-mixture was dissolved in 250 ml toluene with a catalytic amount of para toluene sulfonic acid and the solution was refluxed overnight under a nitrogen atmosphere while separating water in a Dean-Stark trap. The reaction mixture was filtered while hot. The product precipitated as the filtrate cooled to room temperature and was collected by filtration. After recrystallization from benzene the product weighed 1.8 g, m.p. 198.5°-200-5° C. (d).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:14](OC(C)(C)C)=[O:15]>CCO>[N:14]([C:10]1[CH:9]=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]=1[NH2:12])=[O:15]
Reactant: CC(C)(C)ON=O
Reactant: Nc1ccnn1-c1ccccc1
Agent: Cl
Solvent: CCO
Product: Nc1c(N=O)cnn1-c1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 2-phenyl-2H-pyrazol-3-ylamine (250 mg, 1.57 mmol) in EtOH (3 mL) is added HCl (4N in dioxane, 1.15 mL, 4.6 mmol). The mixture is then cooled down to −10° C., tert-butyl nitrite (178 mg, 1.73 mmol) is added drop wise. After addition, the mixture is stirred at 0° C. for 1 h. The precipitate is collected by filtration to provide 4-nitroso-2-phenyl-2H-pyrazol-3-ylamine (180 mg, 60%) as yellow solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17]([C:24]([CH3:25])=[O:26])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(C)=O)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Yield: 54 %

Procedure:
To a solution of trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine (605 mg, 1.89 mmol) in 5 mL of CH2Cl2 was added 4-dimethylaminopyridine (347 mg, 2.84 mmol), followed by 1 mL of acetic anhydride After 12 hr the reaction was diluted with CH2Cl2 and washed with 1M H3PO4. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (2:1, hexanes:ethyl acetate) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(methylcarbonyl)pyrrolidine as a viscous oil (370 mg, 54%). 1H-NMR (300 MHz) analysis indicates a 1:1 mixture of amide rotamers (δ 2.07 and 2.09 singlets). Anal. Calcd for C20H27NO5 : C, 66.46; H, 7.53; N, 3.88. Found: C, 66.19; H, 7.58; N, 3.82.