Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].BrCC(OC(C)(C)C)=O>>[CH2:15]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: CCCCCCCCCCCl
Agent: CC(C)(C)OC(=O)CBr
Product: CCCCCCCCCCOc1ccc(C=O)c2ccccc12

Procedure:
The desired product was prepared by substituting 4-hydroxy-1-naphthaldehyde and 1-chlorodecane for Example 20C and tert-butyl bromoacetate, respectively, in Example 20D.
Reaction SMILES: CO[C:3]([C:5]1([CH3:17])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH2:18]([N:20]([CH2:28][CH3:29])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH3:19].CC[Mg+].[Br-]>C1COCC1>[CH2:28]([N:20]([CH2:18][CH3:19])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:3]([C:5]2([CH3:17])[CH2:14][CH2:13][C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:4])=[CH:23][CH:22]=1)[CH3:29]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: COC(=O)C1(C)CCc2cccc(OC)c2C1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(NC(=O)C2(C)CCc3cccc(OC)c3C2)cc1
Yield: 11.2 %

Procedure:
The ester from Example 2A (170 mg, 0.73 mmol) was dissolved in THF (2.0 mL) and a solution (3.0 mL) of N,N-Diethyl-benzene-1,4-diamine (332 mg, 2 mmol) and EtMgBr (2.0 mmol) in THF was added at 0° C. The reaction mixture was quenched with aqueous NH4Cl after 3 hours. The mixture was extracted with ethyl acetate (3×15 mL) and the combined extracts were dried over MgSO4 and purified by column chromatography to provide the titled compound (30 mg, 8%). 1H NMR (400 MHz, DMSO-D6) δ 9.03 (s, 1H), 7.33 (d, J=9.2 Hz, 2H), 7.03 (t, J=8.0 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.58 (d, J=9.2 Hz, 2H), 3.77 (s, 3H), 3.27 (q, J=7.2 Hz, 4H), 3.11 (d, J=17.2 Hz, 1H), 2.74 (t, J=6.4 Hz, 2H), 2.43 (d, J=17.2 Hz, 2H), 2.15 (ddd, J=6.4, 6.4, 13.2 Hz, 1H), 1.73 (ddd, J=7.2, 7.2, 13.6 Hz, 1H), 1.26 (s, 3H), and 1.04 (t, J=7.2 Hz, 6H). MS (ESI) positive ion 367 (M+H)+; negative ion 365 (M−H)−.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[NH:16][N:15]=2)=[CH:10][CH:9]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CN(C=O)C>[I:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[N:16]([CH2:26][CH:28]3[CH2:29][O:30]3)[N:15]=2)=[CH:12][CH:13]=1
Reactant: ClCC1CO1
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(I)cc3)c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(c(-c3ccc(I)cc3)nn2CC2CO2)C1
Reaction time: 17 h
Yield: 57.6 %

Procedure:
Cs2CO3 (1.30 g, 4.01 mmol) was added to a solution of 1-[3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (1.34 g, 3.65 mmol) and epichlorohydrin (2.85 mL, 36.4 mmol) in DMF (10.0 mL). The mixture was stirred for 17 h then partitioned between EtOAc (400 mL) and saturated NaHCO3 (150 mL). The NaHCO3 layer was extracted with EtOAc (2×150 mL). The combined extracts were washed with H2O (2×150 mL), brine (150 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 10-25% acetone/CH2Cl2) to give 890 mg (58%) of the title compound. HPLC, tR=5.53 min. (Reverse phase conditions: HP 1100 LCMS, Phenomenex luna 2.1×150 mm column, 60% MeOH/H2O (0.5% AcOH) to 90% MeOH/H2O (0.5% AcOH), held at initial conditions for 2 min then ramped to final conditions over 5 min.) MS (electrospray), m/z calculated for C17H18lN3O2Na [M+Na]+445.04, found 445.95. 1H NMR (CDCl3, 500 MHz, a mixture of amide rotamers): 7.76 (d, J=8.3 Hz, 2H), 7.75 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 4.80 and 4.73 (A and B of AB quartet, Jab=15.6 Hz, 2H), 4.60 (s, 2H), 4.84 (dd, J=15.1, 2.1 Hz, 1H), 4.42 (dd, J=15.0, 2.1 Hz, 1H), 4.11 (t, J=5.0, Hz, 1H), 4.08 (t, J=5.0 Hz, 1H), 3.98-3.87 (m, 2H), 3.74 (m, 2H), 3.34 (m, 2H), 2.87-2.72 (m, 6H), 2.52 (dd, J=4.6, 2.6 Hz, 1H), 2.48 (dd, J=4.5, 2.6, 1H), 2.20 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]([CH3:16])([CH2:13][CH:14]=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][O:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CC(O)=O>[CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]([CH3:16])([CH2:13][CH2:14][N:22]([CH2:23][CH2:24][O:25][CH3:26])[CH2:21][CH2:20][O:19][CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCNCCOC
Reactant: CC(C)(CC=O)NC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COCCN(CCOC)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a 100-mL round-bottomed flask was added benzyl(2-methyl-4-oxobutan-2-yl)carbamate (1.04 g, 4.42 mmol) and bis(2-methoxyethyl)amine (0.776 mL, 5.30 mmol, Sigma-Aldrich) in 1,2-dichloroethane (20 mL) followed by AcOH (0.3 mL). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (1.124 g, 5.30 mmol, Sigma-Aldrich) was added portion wise. The reaction was stirred at RT for 1 h. Sat. NaHCO3 (20 mL) was added slowly and the mixture was extracted with EtOAc (40 mL×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified with silica gel chromatography (eluted with 10-90% EtOAc in Hex) to give benzyl(4-(bis(2-methoxyethyl)amino)-2-methylbutan-2-yl)carbamate (1.03 g, 2.92 mmol, 66% yield) as a colorless oil. MS (ESI, pos. ion) m/z: 353.1 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 7.27-7.40 (5H, m), 6.94 (1H, br. s.), 5.05 (2H, s), 3.45 (4H, t, J=5.8 Hz), 3.26 (6H, s), 2.64-2.73 (6H, m), 1.62 (2H, t, J=6.4 Hz), 1.36 (6H, s).
Reaction SMILES: [C:1]1([CH:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:18].[Na+].OO>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[C:1]1([CH:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:8]([NH2:9])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: Cc1ccc(CC(C#N)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: OO
Agent: [Br-]
Solvent: CO
Product: Cc1ccc(CC(C(N)=O)c2ccccc2)cc1
Yield: 98 %

Procedure:
221.3 Grams of 2-phenyl-3-(p-tolyl)-propionitrile (II-1), 40 g of a 25% aqueous sodium hydroxide solution, 291.5 g of a 35% aqueous hydrogen peroxide solution and 3.22 g of tetra-n-butylammoniumbromide were mixed at 50° C. for 4 hours in 663.9 g of methanol. After the reaction was completed, methanol was distilled off. The formed precipitates were filtered out, and washed with water to obtain 234.5 g of 2-phenyl-3-(p-tolyl)-propionamide (m.p.: 150°-151° C.) (I-I) in a yield of 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5 g (31.9 mmol) of 2-(4-Chloro-phenyl)-ethanol was dissolved in 100 ml of pyridine and the solution was cooled to 0° C. 6.09 g (31.9 mmol) of para-toluene sulfonyl chloride was added to this solution and the reaction was stirred at 0° C. for 2 h, then at room temperature for 16 h. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed once with saturated aqueous sodium bicarbonate, once with water, and once with saturated aqueous sodium chloride. The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The compound was recrystallised from n-heptane/ethyl acetate. Yield: 6.23 g MS (Cl+): m/e=311, chloro pattern.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:16])=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[CH3:18][Mg]Br.C(OCC)C.C(Cl)(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:16])=[CH:9][CH:10]=3)[C:5](=[CH2:18])[C:4]=2[CH:3]=1
Reactant: C[Mg]Br
Reactant: O=c1c2cc(Br)ccc2oc2ccc(Cl)nc12
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C=C1c2cc(Br)ccc2Oc2ccc(Cl)nc21
Temperature: 0 °C

Procedure:
To a suspension of 8-bromo-2-chloro-10H-chromeno[3,2-b]pyridin-10-one (20 g, 64.4 mmol) in 500 mL of THF at −78° C. was added dropwise methylmagnesium bromide 3.0 M in diethyl ether (13.82 mL, 116 mmol). The reaction was allowed to slowly warmed up to 0° C. in about 2 h. The reaction was quenched with NH4Cl solution, extracted with EtOAc, dried over Na2SO4, filtered and evaporated to give the corresponding crude tertiary alcohol. This solid residue was re-dissolved in 100 mL of THF and treated with mL of chloroform and the resulting solution was evaporated on a 75° C. water bath for 10 min to give crude 8-bromo-2-chloro-10-methylene-10H-chromeno[3,2-b]pyridine as a brownish solid.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10]P(=O)(OCC)OCC)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][O:22][CH2:23][O:24][C:25]1[C:29]([CH:30]=O)=[CH:28][N:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=1.O>O1CCCC1>[C:1]([C:5]1[S:6][CH:7]=[C:8](/[CH:10]=[CH:30]/[C:29]2[C:25]([O:24][CH2:23][O:22][CH3:21])=[N:26][N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(Cc1csc(C(C)(C)C)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C(C)(C)C)n1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of diethyl [(2-tert-butyl-1,3-thiazol-4-yl)methyl]phosphonate (2.2 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.3 g) was added to the reaction mixture, and the mixture was heated under reflux for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (4:1, v/v) to give 2-tert-butyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as pale-yellow crystals (2.6 g, yield 71%). melting point: 112-113° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][N:3]1[CH2:13][C:14]([O:16]C)=O.[CH3:18][C@H:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([CH3:25])[N:20]1[CH2:26][CH2:27][NH2:28]>>[CH3:18][C@H:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([CH3:25])[N:20]1[CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][N:3]1[CH2:4][CH:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][C:2]1=[O:1]
Reactant: COC(=O)CN1CC(c2ccccc2)CC1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CC(c2ccccc2)CC1=O

Procedure:
From 7.0 g. of methyl 2-oxo-4-phenyl-1-pyrrolidineacetate and 5.0 g. of cis-2-(2,6-dimethyl-1-piperidinyl)-ethylamine, following the procedure of Example 9, there is obtained cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-oxo-4-phenyl-1-pyrrolidineacetamide; m.p. 115°-116° C. after recrystallization from cyclohexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36](O)=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:41]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[C:36]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]1)(=[O:37])[NH2:41]
Reactant: CCN=C=NCCCN(C)C
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Yield: 50.1 %

Procedure:
A solution of (3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (540 mg), 1H-1,2,3-benzotriazol-1-01 ammonium salt (345 mg) and WSC.HCl (383 mg) in DMF (10 ml) was stirred at room temperature for 24 hr, and the mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object product (270 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]([CH2:22][CH:23]1C(=O)OC(C)(C)O[C:24]1=[O:32])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[C:24](=[O:32])[CH2:23][CH2:22][C@H:8]1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][CH:15]=1)=[O:33])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1C(=O)OC(C)(C)OC1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1

Procedure:
A solution of [(S)-2-Biphenyl-4-yl-1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)ethyl]-carbamic acid t-butyl ester (143 g, 320 mmol) in anhydrous toluene (1 L) was heated to reflux under nitrogen overnight. The solvent was removed under reduced pressure to give (S)-2-biphenyl-4-ylmethyl-5-oxopyrrolidine-1-carboxylic acid t-butyl ester, which was directly used without further purification and added to a solution of 3N HCl in EtOAc (1.2 L). The resulting mixture was stirred for 3 hours at room temperature. The solvent was removed in vacuo. The residue was re-crystallized in EtOAc (300 mL) to yield a first batch of the deprotected compound (56 g). The mother liquid was subject to chromatography column (eluted by EtOAc and hexanes from 1:1 to 100% EtOAc) to yield a second batch of the deprotected compound (8 g). To a suspension of the deprotected compound (64 g, 250 mmol) in anhydrous THF (500 mL) was added dropwise BuLi (100 mL, 2.5 M in hexanes) at −78° C. After stirring for 0.5 hour, pivaloyl chloride (34 g, 0.28 mol) was added dropwise. The mixture was stirred for 1 hour at −78° C. The reaction was then quenched with saturated aqueous NH4Cl, and the mixture extracted with EtOAc. The extract was dried over MgSO4 and concentrated to yield (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (85 g) as white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)=[O:32])=[N:28][CH:29]=1>O1CCCC1>[CH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[CH:42][C:33]=1[C:31]([NH:30][C:27]1[N:28]=[CH:29][C:24]([CH2:23][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]2)=[CH:25][CH:26]=1)=[O:32]
Reactant: CCOC(=O)Cc1n[nH]c2ccccc12
Reactant: O=C(Nc1ccc(CBr)cn1)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)nc2)c2ccccc12
Temperature: 25 °C
Yield: 21.3 %

Procedure:
Ethyl 2-(1H-indazol-3-yl)acetate (320 mg, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). Cesium carbonate (1.53 g, 4.70 mmol) was added, and stirred at room temperature for half an hour. Then N-[5-(bromomethyl)pyridin-2-yl]-2-naphthamide (532 mg, 1.56 mmol) was added. After reacted for 16 hours, the solid was filtered. The filtrate was concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a light yellow solid 154 mg, at a yield of 21.2%.
Reaction SMILES: [N:1]1([C:10]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=[C:12]([Cl:20])[CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2N=N1.C([O-])(O)=O.[Na+]>>[Cl:20][C:12]1[C:11]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[NH:1][C:10]=2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1
Reactant: COC(=O)c1cnc(Cl)cc1-n1nnc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1cnc(Cl)c2c1[nH]c1ccccc12
Temperature: 150 °C

Procedure:
A suspension of methyl 4-(1H-1,2,3-benzotriazol-1-yl)-6-chloronicotinate in PPA (1 M) was heated in a preheated oil bath at 150° C. for a period of 10-15 min. The reaction mixture was cooled to room temperature, poured slowly and carefully into an aqueous solution containing NaHCO3 solid. The aqueous phase was extracted with EtOAc, washed with brine, and the organic phase was separated, dried over MgSO4 and filtered. After evaporation of the organic solvent, the residue was purified by flash chromatography (10-70% EtOAc in hexanes) to provide the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc2C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)CC1(CC2)OCCO1
Yield: 91 %

Procedure:
A solution of 7-bromo-2-tetralone (1.1 g, 4.9 mmol), ethylene glycol (0.62 g, 10 mmol), and p-toluensulfonic acid (80 mg, 0.42 mmol) in benzene (20 ml) was stirred under N2 at reflux utilizing a Dean-Stark trap for 45 minutes. The cooled solution was diluted with diethyl ether (60 ml), washed with saturated NaHCO3 solution (2×10 ml), dried (MgSO4) and concentrated in vacuo to give 7'-bromo-3',4'-dihydrospiro[1,3-dioxolane-2,2'(1'H)-naphthalene] as an oil (1.2 g). 1H NMR (CDCl3, 200 MHz) δ: 1.95 (t, J=7 Hz, 2H, CH2), 2.91 (t, J=7 Hz, 2H, CH2), 2.95 (s, 2H, CH2), 4.01 (s, 4H, OCH2CH2O), 6.97 (d, J=8 Hz, 1H, Ar), 7.15-7.27 (m, 2H, Ar).
Reaction SMILES: C([O:3][C:4](=[O:9])[C:5](=O)[CH2:6]Br)C.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH2:21])=[S:20])=[CH:14][CH:13]=1>C(O)C>[F:23][C:11]([F:10])([F:22])[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]2[S:20][CH:6]=[C:5]([C:4]([OH:3])=[O:9])[N:21]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: O=C(O)c1csc(Nc2ccc(C(F)(F)F)cc2)n1
Temperature: 30 °C
Reaction time: 12 h

Procedure:
3-Bromo-2-oxo-propionic acid ethyl ester (0.59 mL) was added to a suspension of (4-trifluoromethyl-phenyl)-thiourea (1 grams), obtained in step (ii) of example-1, in ethanol (20 mL) and refluxed for about 12 hours. The reaction mixture was cooled and the solid obtained was filtered and dissolved in a minimum amount ethanol. 10% sodium hydroxide solution (10 mL) was added and stirred at about 25-35° C. for about 12 hours. The reaction mixture was then diluted with water and acidified with saturated citric acid solution. The solid that precipitated was filtered washed with water and dried to give the product (0.65 grams).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC(C)([O-])C.[Na+].C(=[NH:40])(C1C=CC=CC=1)C1C=CC=CC=1.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.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1COCC1>[NH2:40][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(N)cn2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
Bis(dibenzylideneacetone)palladium (0.17 g, 0.29 mmol) was added to a mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (6.15 g, 17.92 mmol, prepared as described in Patent Application WO 2001087870), sodium tert-butoxide (2.41 g, 25.09 mmol), benzophenone imine (3.61 g, 21.50 mmol), and BINAP (0.34 g, 21.5 mmol) in anhydrous toluene (150 mL). The mixture was heated to 80° C. and stirred for 16 h under an atmosphere of nitrogen. The mixture was diluted with EtOAc (100 mL) and filtered through diatomaceous earth then concentrated by evaporation to give an oil. This intermediate was stirred together with THF (150 mL) and 2N 1HCl (100 mL) for 2 h. The mixture was then neutralised by the addition of saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with EtOAc (3×100 mL). The organic extracts were dried, filtered, concentrated by evaporation and triturated with hexane to give the title compound as a solid (4.6 g, 92%); 1H NMR δ: 7.90 (2H, s), 4.61 (2H, s), 3.51-3.45 (4H, m), 3.40-3.30 (4H, m), 1.20 (9H, s); MS m/e MH+: 280.
Reaction SMILES: Br[C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Li])CCC.[B:38](OC(C)C)([O:43]C(C)C)[O:39]C(C)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:3]2[C:2]([B:38]([OH:43])[OH:39])=[CH:6][N:5]([C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:4]=2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
47.5 g 4-bromo-3-(4-fluorophenyl)-1-trityl-1H-pyrazole was dissolved in 400 mL anhydrous tetrahydrofuran, and then 40.7 mL solution of 1.6 M n-butyl lithium in hexane was added dropwise thereto at −70° C. The mixture was stirred for 30 minutes, 17.2 mL triisopropyl borate was added dropwise thereto, and the mixture was stirred at −70° C. for 1 hour and at −40° C. for 1 hour. The temperature was increased to 0° C., 50 mL aqueous saturated ammonium chloride solution was added thereto and stirred for 30 minutes, and water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was removed under reduced pressure, and upon addition of toluene to the resulting oil, colorless crystals were formed. The crystals were collected by filtration, to give 31 g of the title compound.