Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=[O:21])OC2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]1[CH2:56][CH2:55][N:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([N:60]3[CH2:59][CH2:58][CH:57]([N:54]4[CH2:53][CH2:52][N:51]([CH3:50])[CH2:56][CH2:55]4)[CH2:62][CH2:61]3)=[O:21])[CH:7]=2)[CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)=[O:49])[CH2:39][CH2:38]1)=[O:36]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.6 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) was added 1-methyl-4-(piperidin-4-yl)piperazine (68.7 mg), followed by stirring at room temperature for 12 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, ethyl acetate:methanol=20:1, then 10:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (34.6 mg, 72.8%).
Reaction SMILES: CS(OC[C@H]1OC1)(=O)=O.[CH3:10][O:11][C:12]1[C:21]2[N:20]=[C:19]([NH2:22])[N:18]3[CH2:23][CH2:24][N:25]=[C:17]3[C:16]=2[CH:15]=[CH:14][C:13]=1[O:26][CH2:27][C@H:28]1[CH2:30][O:29]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[S:37]1[C:41]([C:42](O)=[O:43])=[CH:40][N:39]=[CH:38]1>CO.C(Cl)Cl.CO>[OH:29][C@@H:28]([CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:27][O:26][C:13]1[CH:14]=[CH:15][C:16]2[C:17]3[N:18]([CH2:23][CH2:24][N:25]=3)[C:19]([NH:22][C:42]([C:41]3[S:37][CH:38]=[N:39][CH:40]=3)=[O:43])=[N:20][C:21]=2[C:12]=1[O:11][CH3:10]
Reactant: C1COCCN1
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Reactant: O=C(O)c1cncs1
Agent: CS(=O)(=O)OC[C@@H]1CO1
Solvent: ClCCl
Solvent: CO
Product: COc1c(OC[C@@H](O)CN2CCOCC2)ccc2c1N=C(NC(=O)c1cncs1)N1CCN=C21

Procedure:
Prepared using (S)-glycidyl methanesulfonate (Intermediate H, Step 1) in place of (R)-glycidyl methanesulfonate (Intermediate F, Step 1), and morpholine in place of piperidine in Step 1, and 1,3-thiazole-5-carboxylic acid in place of nicotinic acid in Step 2 (42.0 mg, 41%): TLC (9:1 CH2Cl2/MeOH+1% NH4OH in MeOH)Rf 0.43; HPLC ret. time 0.81 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 3.11-3.0 (m, 4H), 3.43-3.52 (m, 2H), 3.69 (app t, J=11.8 Hz, 1H), 3.78 (app t, J=11.6 Hz, 1H) 3.88-4.00 (m, 2H), 4.01 (s, 3H), 4.16-4.27 (m, 4H), 4.37-4.51 (m, 3H), 7.45 (d, J=9.1 Hz, 1H), 8.01 (d, J=9.1 Hz, 1H), 8.60 (s, 1H), 9.31 (s, 1H); mass spectrum m/z 487 ((M+1)+, 4.6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[CH:10]=[C:9]([C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:8]=[C:7](Br)[CH:6]=1.CC1(C)C(C)(C)OB([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][N:33]3[Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)C1C=CC=CC=1C1C=CC=CC=1N(C)C>[CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[CH:6]=[C:7]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][N:33]3[Si:38]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[CH:39]([CH3:40])[CH3:41])[CH:8]=[C:9]([C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:10]=1
Reactant: COC(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: CN(C)c1ccccc1-c1ccccc1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)Nc1cc(C(=O)c2cccnc2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Yield: 70.6 %

Procedure:
[3-Bromo-5-(pyridine-3-carbonyl)-phenyl]-carbamic acid methyl ester (316 mg, 0.94 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole (0.377 mg, 0.94 mmol) and chloro(di-2-norbornylphosphino)(2′dimethylamino-1,1′-biphenyl-2-yl)palladium (II) (53 mg, 0.094 mmol) were dissolved in dioxane (6 mL) under nitrogen. Aqueous 2M K3PO4 (1 mL, 1.2 mmol) was added and the mixture was heated at reflux overnight. The reaction mixture was filtered through Celite® and the solvent was removed. The product was chromatographed to give 0.350 g (70% yield) of [3-(pyridine-3-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-carbamic acid methyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:39][S:40]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In 4 ml of methylene chloride was dissolved 0.43 g of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. After 0.138 ml of triethylamine and 0.077 ml of methanesulfonyl chloride were added to the solution under ice cooling, the mixture was stirred for 3 days at room temperature. To the reaction solution were added 50 ml of ethyl acetate and 20 ml of 2N hydrochloride to fractionate the organic phase. The solvent was removed by distillation under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted by chloroform:methanol (9:1 v/v). The obtained crude crystals were recrystallized from chloroform-n-hexane to give 0.31 g of dimethyl 4-[2-[4-(methanesulfonylamino)butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. This compound has the following physicochemical properties.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=3[F:30])[CH2:16][CH2:15]2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CC(O)C.[Fe]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:32])[CH2:15][CH2:16]2)=[O:31])=[C:22]([F:30])[CH:23]=1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3F)CC2)c1
Agent: [Fe]
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3F)CC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.7 %

Procedure:
To a suspension of iron (O) powder (3.3 g, 58.76 mmol) and N-tert butyl-3-((4-(2-fluoro-4-nitrobenzoyl)piperazin-1-yl)methyl)benzamide (2.6 g, 5.88 mmol) in propan-2-ol (75 mL) was added 1M aqueous hydrochloric acid (8.8 mL, 8.1 mmol). The reaction was stirred at room temperature for 2.5 hours, filtered through dicalite and concentrated under vacuum. The residue was dissolved in methanol and purified by strong cation exchange chromatography, eluting macroporous polystyrene sulfonic acid with 2M ammonia in methanol. The resulting solution was concentrated under vacuum to afford the title compound as a viscous orange oil (2.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[CH3:18].CI.[CH3:21]C(C)([O-])C.[K+].O>[Cl-].[Na+].O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:21])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc2c(cc1Br)C(=O)C1(CCC(O)CC1)C2
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC1CCC2(CC1)Cc1cc(C)c(Br)cc1C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
6′-Bromo-4-hydroxy-5′-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 3, 1.72 g, 5.57 mmol) was dissolved in 2-Me THF (13 mL) under an inert atmosphere and the solution was cooled to 0° C. Methyl iodide (0.453 mL, 7.24 mmol) was added followed by portionwise addition of potassium tert-butoxide (0.875 g, 7.80 mmol). The resulting mixture was stirred at r.t. for 1 h. Potassium tert-butoxide (0.250 g, 2.23 mmol) was added and stirring continued. After another 30 min, potassium tert-butoxide (0.094 g, 0.84 mmol) was added and stirring continued. After a total of 4 h, full conversion was obtained and water (6 mL) and brine (3 mL) were added. The phases were separated and the organic layer was treated with charcoal and diatomaceous earth and then filtered through a plug of diatomaceous earth. The plug was rinsed with EtOAc and the organics were concentrated to yield 1.3 g (77% yield) of the title compound as a mixture of isomers with the methoxy group in either equatorial position (major) or axial position (minor). This mixture was used in the next step without further purification: MS (ES+) m/z 323, 325 [M+H]+.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=1.O.[ClH:20]>C(#N)C.[Cu](Cl)Cl.C(Cl)Cl>[Cl:20][C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1csc(Cl)n1
Temperature: 62.5 °C

Procedure:
To a mixture of copper (II) chloride (20 g, 0.15 mol) and 90% t-butyl nitrite (24 mL, 0.18 mol) in 500 mL acetonitrile at 60° C. was added in portions ethyl 2-amino-4-thiazolecarboxylate (21 g, 0.12 mol), maintaining the temperature at between 60-65° C. After the addition, the resulting reaction mixture was heated at 80° C. for 1 h, then cooled to RT and poured into a mixture of water, CH2Cl2 and 25 mL conc HCl. The aq layer was separated and extracted with CH2Cl2. The combined organic layers were washed with water, brine, dried and concentrated to give 21.5 g of ethyl 2-chloro-4-thiazolecarboxylate.
Reaction SMILES: [CH2:1]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(O)([C:16]#[N:17])C.CO.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([CH:7]1[CH:11]([C:16]#[N:17])[CH2:10][CH2:9][C:8]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(O)C#N
Reactant: CCCCCCC1=CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCC1C(=O)CCC1C#N

Procedure:
A mixture of 16,6 g of 2-n-hexyl-2-cyclopentenone (see foot note (1) under Table II) 12 g of acetone cyanhydrine (Org.Synth.Coll. Vol. 2, p. 7), 32 ml of methanol and 0,8 g of sodium carbonate in 12 ml of water, is heated at reflux temperature for 31/2 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[NH:14][N:13]=2)=[C:2]([CH:7]=1)[NH2:1]
Reactant: O=[N+]([O-])c1cc(CCl)n[nH]1
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ccc1SCc1cc([N+](=O)[O-])[nH]n1
Yield: 49 %

Procedure:
(5-Nitro-1H-pyrazol-3-yl)methanol (524 mg, 3.66 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (5 ml) at 35° C. for 2 hrs. The solvent was removed to get a crude 3-(chloromethyl)-5-nitro-1H-pyrazole. Then following General Procedure A, the title compound (515 mg, 49%) was prepared from 2-amino-4-chlorobenzenethiol (161 mg, 1.01 mmol), crude 3-(chloromethyl)-5-nitro-1H-pyrazole, K2CO3 (468 mg, 3.39 mmol) in DMF (3 ml).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[F:17][C:18]1[CH:25]=[C:24]([O:26][CH2:27][CH2:28]Br)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>>[C:20]([C:19]1[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:25][C:18]=1[F:17])#[N:21]
Reactant: N#Cc1ccc(OCCBr)cc1F
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCOc1ccc(C#N)c(F)c1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-fluoro-4-[(2-bromoethyl)oxy]benzonitrile: MS (ES) m/z 388 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]C(C)([O-])C.[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:23])[CH:12]=1)[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reaction time: 0.25 h

Procedure:
N-tert-Butoxycarbonyl-D-tryptophan (3.0 g) was dissolved in N,N-dimethylformaldehyde (30 mL) under argon, and potassium tert-butoxide (as 12% tetrahydrofuran solution) (17.7 g) was added dropwise thereto under cooling on ice, followed by stirring for 15 minutes. A solution of iodomethane (2.1 g) in N,N-dimethylformaldehyde (3.0 mL) was added to the mixture, and stirring was performed for 10 minutes. The resultant mixture was partitioned between 30% aqueous citric acid solution and ethyl acetate, and the organic layer was sequentially washed with 30% aqueous citric acid solution and saturated aqueous sodium chloride solution, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the thus-recovered residue. The precipitates were recovered through filtration, washed with diisopropyl ether, and dried under reduced pressure, whereby the title compound (1.89 g) was yielded.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)c(OC)c1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(NC(C)=O)cc2)c(OC)c1
Temperature: 130 °C

Procedure:
p-Acetylaminophenol (15.1 g, 0.1 M) in dimethyl formamide (30 ml) containing potassium carbonate (1.36 g, 0.1 M) is treated with 2,4-dimethoxybenzyl chloride (1.86 g, 0.1 M). The mixture is then heated at 130° C. for 3 hours, then the solvent removed by evaporation under reduced pressure. The residue is treated with water, and the precipitate filtered off and recrystallized from ethanol to afford p-(2,4-dimethoxybenzyloxy)acetanilide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2I.[CH3:13][O:14][CH2:15][C:16]#[CH:17]>CN(C)C=O.C(N(CC)CC)C.O.[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>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[C:17]#[C:16][CH2:15][O:14][CH3:13]
Reactant: C#CCOC
Reactant: Cn1nc(I)c2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1nn(C)c2ccc(Br)cc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 81.67 g of 5-bromo-3-iodo-1-methyl-1H-indazole in 750 ml of N,N-dimethylformamide and 335 ml of triethylamine is admixed at room temperature under argon with 25 ml of 3-methoxypropyne, 5.5 g of copper(I) iodide and 10 g of bis(triphenylphosphine)palladium(II) chloride, and subsequently heated to 60° C. After 1 hour, the reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate (4×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.67 (2:1 EtOAc-heptane). Rt=4.42 (gradient I).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[N:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1.[H-].[Na+]>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)=[N:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(OCCCOCc3ccccc3)cn2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(OCCCOCc3ccccc3)cn2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
A solution of 40 mg (0.09 mmol) of tert-butyl (3RS,4RS)-4-[5-(3-benzyloxy-propoxy)-pyrimidin-2-yl]-3-hydroxy-piperidine-1-carboxylate and 23 mg (0.1 mmol) of 2-bromomethyl-naphthalene in 5 ml of N,N-dimethylformamide was treated with 5 mg (0.1 mmol) of sodium hydride (50% dispersion in oil) and stirred at room temperature for 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure, the residue obtained was taken up in 3 ml of methylene chloride and the solution was chromatographed directly on silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 40 mg (76% of theory) of tert-butyl (3RS,4RS)-4-[5-(3-benzyloxy-propoxy)-pyrimidin-2-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as an oil; MS: 584 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:37][C:36]2[CH:39]=[CH:40][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCCCNC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 4-t-butyl-benzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0330 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (42.0 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:10])=[CH:5][C:4]=1[CH3:11].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl-:10].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P+:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][C:4]=1[CH3:11]
Reactant: COc1ccc(CCl)cc1C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1C
Product: [Cl-]
Temperature: 25 °C
Yield: 68.2 %

Procedure:
To a 250ml round-bottom flask equipped with a magnetic stir-bar and N2inlet was added 4-(Chloromethyl)-2-methylphenyl methyl ether (2.59g, 15.18mmoles, 1eq), dry toluene (50ml, 0.3M) and triphenylphosphine (3.98g, 15.18mmoles, 1eq). The reaction mixture was refluxed overnight. After cooling to room temperature the solvent was removed in vacuo, the residue washed with hexanes and the solid/liquid mixture was filtered to yield 4.48g (71%) of solid product.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[Br:12][C:13]1[CH:14]=[C:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][N:23]=2)[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1>CC#N>[Br:12][C:13]1[CH:14]=[C:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])[CH2:30][CH2:29]3)=[CH:24][N:23]=2)[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CC#N
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)cn2)c1=O
Reaction time: 72 h
Yield: 90.1 %

Procedure:
To a suspension of 123a (231 mg, 0.96 mmol) in MeCN (40 mL) at 70° C. was added 5-bromo-1-methyl-3-(5-(piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one 101j (350 mg, 0.96 mmol). The reaction mixture was stirred for 3 days. It was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (30:1) to afford 123b as yellow solid (452 mg, 90%). MS: [M+H]+ 524.7.