Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[CH:13]2)[CH3:7].[I:17]I>O.C(O)C>[CH2:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[C:13]2[I:17])[CH3:7]
Reactant: CCc1cccc2cn[nH]c12
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1cccc2c(I)n[nH]c12
Yield: 48.2 %

Procedure:
To a stirred solution of sodium bicarbonate (1.67 g, 19.8 mmol) in water (4.65 mL) and ethanol (9.3 mL) was added 7-ethyl-1H-indazole (771 mg, 5.27 mmol) followed by iodine (1.87 g, 7.38 mmol). After 16 h the reaction mixture was quenched with sodium thiosulfate, diluted with ethyl acetate and washed with water. The organic layer was collected and dried (MgSO4). Purification by chromatography (silica, 5-25% ethyl acetate/hexanes) gave 7-ethyl-3-iodo-1H-indazole (690 mg, 2.54 mmol, 48%) as an off-white solid. MS (M+H)+=272.9; 1H NMR (CDCl3) δ: 7.39 (d, J=8.1 Hz, 1H), 7.30 (d, J=7.1 Hz, 1H), 7.22 (t, J=7.1 Hz, 1H), 2.95 (q, J=7.5 Hz, 2H), 1.41 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1.[Cl:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30]>C1(C)C=CC=CC=1.CC(C)=O>[Cl:25][CH2:26][CH2:27][NH:28][C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1)=[O:30]
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: O=C=NCCCl
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCn1c(C#Cc2ccc(NC(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 100 °C
Yield: 54.2 %

Procedure:
2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, was suspended in toluene (600 μL). 2-Chloroethyl isocyanate (32 μL, 0.37 mmol) was added, and the mixture was heated at 100° C. for 5 h. The reaction mixture was then cooled, diluted in acetone, and absorbed onto silica. Purification by column chromatography (5-10% EtOAc in CH2Cl2) yielded 1-(2-chloro-ethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl] urea (73 mg, 54%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cu](C#N)[C:14]#[N:15]>CN(C=O)C>[C:14]([C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:15]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)ccc1O
Temperature: 140 °C
Reaction time: 20 h

Procedure:
A suspension of methyl 5-bromo-2-hydroxybenzoate (2 g, 8.66 mmol) and copper cyanide (1.861 g, 20.78 mmol) in DMF (30 ml) was stirred under nitrogen at 140° C. for 20 h. The reaction mixture was then cooled, quenched with water (120 ml) and extracted with ethyl acetate (3×80 ml). The organic phase was washed with saturated brine (50 ml), dried over sodium sulphate and evaporated in vacuo to yield the title compound as a white solid. 1 g.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]2[C:13]=1[CH3:14].[F:15][C:16]([F:33])([F:32])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:20]4[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:32])[F:33])=[CH:18][CH:19]=4)=[CH:28][CH:27]=3)=[O:30])=[CH:6][N:5]2[C:13]=1[CH3:14]
Reactant: Cc1nc2ccc([N+](=O)[O-])cn2c1C
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: Cc1nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cn2c1C

Procedure:
Conducting the operations similar to those of Example 1 using 2,3-dimethyl-6-nitroimidazo[1,2-a]pyridine and 4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:8]([C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3C(OC(C)(C)C)=O)=[N:9][CH:10]=[N:11][CH:12]=2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:8]([C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[N:9][CH:10]=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ncncc1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(Cc2cncnc2[C@H]2CCCN2)cc1

Procedure:
(R)-tert-butyl 2-(5-(4-chlorobenzyl)pyrimidine-4-yl)pyrrolidine-1-carboxylate from step C was treated with 4M HCl in dioxane (10 mL) for 2 h. Removal of the solvent in vacuo gave the product in quantitative yield as an oil, which was used in the next step without purification. MS: calculated: 273.1 found (MH+): 274.3.
Reaction SMILES: C[O:2][B:3]([O:6]C)OC.[Cl-].[Mg+2].[Cl:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1.[Cl-]>C(OCC)(=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([B:3]([OH:6])[OH:2])[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccccc1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: OB(O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of trimethylborate in 200 mL of ethyl acetate was cooled to -65° C. 3-Chlorobenzene magnesium chloride (0.8M, 60 mL), i.e., a grignard reagent, was added to the solution in a dropwise manner over 20 minutes. The mixture was kept in the temperature range of -60° C. to -70° C. and stirred. After 30 minutes, the mixture was allowed to warm to 0° C. and stirred for 1 hour. The mixture was quenched with H2O (25 mL) and stirred at room temperature for 1 hour. The solvent was removed and the remaining mass was extracted ethyl ether (3×100 mL). The organic layers were combined and washed with H2O (2×50 mL), dilute HCl (2×100 mL), H2O (2×50 mL) and brine (1×50 mL). The organic layer was dried with MgSO4, concentrated and allowed to stand. 100 mL of hexanes was added and the solution was stirred for 1 hour. The solution was filtered and allowed to air dry yielding 4.6 g of 3-chlorobenzene boronic acid as a white solid.
Reaction SMILES: P(O[CH2:14][C@H:15]1O[C@@H:18](N2C3N=CN=C(N)C=3N=C2)[C@H:17](O)[C@@H:16]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.N[C@@H:33]([CH2:37][CH2:38][C:39](N[C@H](C(NCC(O)=O)=O)CS)=[O:40])[C:34]([OH:36])=[O:35].[Cl-].[Ca+2].[Cl-]>P([O-])([O-])([O-])=O>[OH:40][C:39]([CH:14]=[CH:15][CH:16]=[CH:17][CH2:18][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:38][CH:37]=[CH:33][C:34]([OH:36])=[O:35]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Product: CCCCCCCCCCCC=CC=CC(O)=CC=CC(=O)O

Procedure:
5-Lipoxygenase activity was determined according to the method described by Ochi et al., J. Biol. Chem.,258, p. 5754, 1983 using a crude enzyme fraction prepared from peritoneal exudated cells of guinea pigs which were induced by intraperitoneal injection of 2% case in solution. A solution of a test drug was mixed with a reaction solution (2mM ATP, 1 mM glutathione, and the enzyme fraction in 50 mM phosphate buffer, PH 7.4) and the mixture was pre-incubated at 37° C. for 5 minutes. Calcium chloride (1 mM) and 20 μM14C-arachidonic acid were added to the mixture, and then the mixture was subjected to a reaction at 37° C. for 10 minutes. After the completion of the reaction, the product was immediately extracted, dissolved in chloroform/methanol (2:1), and developed by thin-layer chromatography. Radioactivity of the 5-hydroxyeicosatetraenoic acid (5-HETE) fraction was measured using a liquid scintillation counter. Inhibitory rate of each drug-treated group against 5-HETE generation was obtained in comparison with the solvent-treated control, and IC50 was calculated according to the probit method. The results obtained are shown in Table 2 below.
Reaction SMILES: [CH2:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[O:10][CH2:9]1)[CH:2]=[CH2:3].[NH2:15][CH2:16][CH2:17][C:18]1[NH:19][C:20]2[CH:26]=[C:25]([C:27]3[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=3)[CH:24]=[CH:23][C:21]=2[N:22]=1>>[CH2:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:10])[CH2:9][NH:15][CH2:16][CH2:17][C:18]1[NH:19][C:20]2[CH:26]=[C:25]([C:27]3[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=3)[CH:24]=[CH:23][C:21]=2[N:22]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1OCC1CO1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(CCN)[nH]c2c1
Product: C=CCc1ccccc1OCC(O)CNCCc1nc2ccc(C3=NNC(=O)CC3C)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 1-(2-allylphenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)- pyridazinone.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)[CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:60]=[CH:59]C(C=CCN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC4OCCC=4C=3)=N2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:60]=[CH:59][C:3]([CH:2]=[CH:1][CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)=[CH:32][CH:31]=1
Reactant: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC3CC3)c2=O)CC1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CC=Cc2ccc(Cl)cc2)c1=O
Product: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC=Cc3ccc(Cl)cc3)c2=O)CC1
Yield: 45.8 %

Procedure:
The general procedure of Example 1 (6) was carried out by use of 2-(4-chlorocinnamyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one, to thereby yield the title compound as a faint brown powder (yield: 45.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=O)[CH:7]=[CH:6]2.[ClH:18].Cl.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:18].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:24]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:31][CH2:30]1)=[O:17])[CH:7]=[CH:6]2
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: COc1cc2ccc(C(=O)O)cc2cc1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2ccc(C(=O)N3CCN(Cc4cc(OC)c(OC)c(OC)c4)CC3)cc2cc1OC
Yield: 80.2 %

Procedure:
Using 6,7-dimethoxy-2-naphthoic acid (0.7 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.1 g), triethylamine (1.25 g), N,N-dimethylformamide (20 ml) and diethyl phosphorocyanidate (1 ml), an amidation as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=2:3) and converted to the hydrochloride in ethyl acetate to give 1-(6,7-dimethoxy-2-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (1.25 g) as colorless crystals, m.p. 235°-240° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=O.Cl.[CH3:11][NH:12][CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:9]=[C:6]([CH2:7][N:12]([CH3:13])[CH3:11])[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 5-bromonicotinaldehyde (XXV) (5.0 g, 26.9 mmol) in DCE (108 mL) was added dimethylamine-HCl (4.39 g, 53.8 mmol) and TEA (7.5 g, 53.8 mmol). The reaction was stirred at room temperature for 1 h. NaBH(OAc)3 was added and the reaction was stirred overnight at room temperature. The reaction was diluted with DCM and sat. aq. NaHCO3. The organic layer was separated, washed with water, brine, dried and concentrated under vacuum to produce 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XXVI) as a brown liquid (92.6% yield). 1H NMR (CDCl3) δ ppm 2.15 (s, 6H), 3.43 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2 Hz, 1H), 8.59 (d, J=3 Hz, 1H); ESIMS found for C8H11BrN2 m/z 215 (MBr79+H) and 217 (MBr81+H).
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([Cl:20])[C:6]([Cl:19])=[C:7]([O:17][CH3:18])[CH:8]=2)[C:3]1=[O:21].[CH3:22]I.C[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1([CH3:22])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([Cl:20])[C:6]([Cl:19])=[C:7]([O:17][CH3:18])[CH:8]=2)[C:3]1=[O:21]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2c1ccccc1
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2c1ccccc1

Procedure:
2-Methyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone (9.63 g., 0.03 mole) and methyl iodide (18.7 ml., 0.3 mole) dissolved in dimethylformamide (100 ml.) at 25° C. under nitrogen are treated portionwise with sodium methoxide (4.2 g., 0.036 mole) over a 45 minute period. Sodium iodide is filtered off, and the yellow filtrate is added to water (500 ml.) to precipitate 6.57 g. of 2,2-dimethyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone which melts at 146°-148° C. after crystallization from cyclohexane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[C:4]([F:13])[CH:3]=1.[BH4-].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:12])[CH2:9][OH:10])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)(C=O)c1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(CO)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionaldehyde (1.37 g, 5.58 mmol) in MeOH (18 ml) at 0° C. was added NaBH4 (0.21 g, 5.58 mmol). After being stirred for 2 hours at 0° C., the mixture was allowed to warm to room temperature. The reaction mixture was diluted with water (20 ml) and extracted with ether (3×75 ml). The combined organic layers were dried over MgSO4. The solvent was removed, and the residue was purified by flash column chromatography (15-35% EtOAc in Hexane) to give the product (1.10 g, 80.0% yield). 1H NMR (CDCl3) δ: 1.23 (s, 1H) 1.35 (s, 3H) 1.35 (s, 3H) 3.75 (d, J=1.26 Hz, 2H) 7.17 (d, J=2.27 Hz, 1H) 7.20 (d, J=3.03 Hz, 1H) 7.22 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2].[O:31]=[C:32]1[N:36]([CH2:37][C:38]#[CH:39])[CH:35]=[CH:34][O:33]1.O.C([O-])(O)=O.[Na+]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:39]#[C:38][CH2:37][N:36]3[CH:35]=[CH:34][O:33][C:32]3=[O:31])[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(I)cc2C(F)(F)F
Reactant: C#CCn1ccoc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(C#CCn1ccoc1=O)cc2C(F)(F)F
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 935.3 %

Procedure:
A mixture of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-chlorophenyl)oxindole (796 mg, 0.144 mmol), 3-(2-oxo-1,3-oxazolin-3-yl)-1-propyne (464 mg, 0.371 mmol), CuI (10.8 mg, 0.0567 mmol), and (PPh3)2PdCl2 (18.6 mg, 0.0265 mmol) in triethylamine (1 mL) was stirred for 4.5 h at 50° C. Water and sat. aqueous NaHCO3 were added and the mixture was extracted with ethyl acetate. The extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 80:1 to 50:1 chloroform/methanol to give the title compound (738 mg). The compound was dissolved in dioxane (2 mL) and 4 N HCl in dioxane (1 mL) was added. The solvent was evaporated azeotropically with toluene. The residual solid was washed with ether and dried in vacuo to give the hydrochloride (528 mg, 63%).
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:13])[N:11]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:12]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc(Cl)nn1CC1CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Cyclopropylmethyl bromide (0.82 mL) was added to a mixture of 6-chloro-2H-pyridazin-3-one (1.0 g) and K2CO3 (2.10 g) in N,N-dimethylformamide (10 mL). The resulting mixture was stirred at 60° C. overnight. Then, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 99:1:0.1) to afford the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C1C[CH2:18][N:17]2[C:12](=[N:13][CH2:14][CH2:15][CH2:16]2)CC1.CN(C)CCCN>>[CH3:12][N:17]([CH3:18])[CH2:16][CH2:15][CH2:14][NH:13][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Nc1ccnc(Cl)n1
Agent: CN(C)CCCN
Product: CN(C)CCCNc1nccc(N)n1
Temperature: 220 °C
Yield: 56.6 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol), DBU (419 μl, 2.78 mmol) and N,N-dimethyl-1,3-propanediamine (437 μl, 3.47 mmol) was heated to 220° C. via a microwave reactor for 30 min. The reaction mixture was purified by RP-HPLC to yield N2-[3-(dimethylamino) propyl]-2,4-pyrimidinediamine (256 mg, 1.311 mmol, 57% yield). MS (ES+) m/z 196.2 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([CH2:16][CH3:17])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:21][CH:18]2[CH2:20][CH2:19]2)[C:10]([CH2:16][CH3:17])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC1(C)CN(Cc2ccccc2)CCC1NC1CC1
Reaction time: 6 h

Procedure:
1-Benzyl-3-ethyl-3-methyl-4-piperidinone (4.2 g, 18.18 mmol) was added to the stirred solution cyclopropylamine (6.5 g, 115 mmol) in methanol (100 ml) and stirred for 6 hr. Sodium cyanoborohydride (1.14 g, 18.18 mmol) was added to it and reaction mixture was stirred for 15 hr. The reaction mixture was concentrated to dryness, triturated with water, extracted with chloroform, dried (Na2SO4) and concentrated to furnish crude 1-benzyl-4-cyclopropylamino-3-ethyl-3-methylpiperidine. Yield 4 g (88%), C18H28N2, m/z 273 (M+1).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:11]([OH:12])[C@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Thus, the mixture of D-glucose and D-mannose obtained in the above is subjected to the catalytic hydrogenation, thereby is formed D-mannitol at a high ratio such as 30-36% based on the initial D-glucose, which results in such a high yield of crystalline D-mannitol as 25-30%.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][C:23]=3[F:31])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:32][O:33][CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:29])[NH:36][CH2:35][CH2:34][O:33][CH3:32])=[CH:24][C:23]=3[F:31])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: Cc1c(Oc2ccc(C(=O)O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: COCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNC(=O)c1ccc(Oc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2C)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[6-(4-Carboxy-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (150 mg, 0.346 mmol), 2-Methoxy-ethylamine (31 mg, 0.41 mmol), HATU (157 mg, 0.42 mmol) and triethyl amine (70 mg, 0.7 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The mixture was purified through HPLC to provide Compound C122 (115 mg, 68%) as a solid. 1H NMR (MeOH-d4, 400 MHz) δ 1.22 (d, J=6.82 Hz, 6H), 1.71-1.74 (m, 2H), 1.97-2.00 (m, 2H), 2.16 (s, 3H), 3.34 (s, 3H), 3.35-3.39 (m, 2H), 3.53 (s, 4H), 3.71-3.74 (m, 2H), 4.81-4.84 (m, 1H), 5.33-5.36 (m, 1H), 7.30 (t, J=8.1 Hz, 1H), 7.66-7.69 (m, 2H), 8.09 (s, 1H). Exact mass calculated for C24H31FN4O6490.2, found 491.4 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([C:30]([O:1][CH2:2][CH2:3][C:4]3[C:5]4[N:6]([N:17]=[CH:18][N:19]=4)[C:7]([NH2:16])=[N:8][C:9]=3[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:31])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: Nc1nc(-c2ccccc2)c(CCO)c2ncnn12
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: Nc1nc(-c2ccccc2)c(CCOC(=O)C23CC4CC(CC(C4)C2)C3)c2ncnn12

Procedure:
The title compound was prepared by the method of Example 2 using 2.5 g (0.01 mole) of the product compound of Example 1 and 2.0 g (0.01 mole) of 1-adamantanecarbonyl chloride, except that the solution was not divided before purification.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].[C:29]1(C)[CH:34]=[CH:33][C:32](S(OCCCCCC)(=O)=O)=[CH:31][CH:30]=1>O>[CH2:33]([O:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][N:11]=2)=[CH:8][CH:9]=1)[CH3:3])[CH2:34][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OCCCCCC)cc2)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Into 20 ml of anhydrous dlmethylformamide were dissolved 1.78 g (5 millimole) of the (+)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine obtained in Preparation Example [starting material compound (VI)] 70, and then 0.24 g (6 millimole) of 60% sodium hydride was added thereto, followed by stirring at 40° C. for 1 hour. Subsequently, 1.79 g (7 millimole) of hexyl p-toluenesulfonate were added thereto, to subject to reaction at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water, extracted with 200 ml of toluene, followed by separation thereof, and the organic phase was washed with water sufficiently, followed by drying over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent; toluene: ethyl acetate) to obtain 1.81 g (yield: 82%) of (+)-2-{4-(1-hexyloxyethyl)phenyl}-5-decyloxypyrimidine.