Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:20]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:20]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]([OH:11])=[O:23]
Reactant: COc1c(C)c(Cc2cccc(C=O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Reactant: OO
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
An aqueous solution (7 ml) of sodium dihydrogenphosphate (4.01 g, 33.42 mmol), an aqueous solution (7 ml) of sodium chlorite (1.74 g, 19.33 mmol) and aqueous hydrogen peroxide (1.89 ml, 30%) were added to an acetonitrile solution (12 ml) of 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (1.87 g, 4.28 mmol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (1.90 g, 4.20 mmol, 98%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH2:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>C(Cl)(Cl)(Cl)Cl>[CH2:10]([C:22]1[CH:23]=[CH:24][C:25]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:26][CH:27]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCc1ccccc1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCc1ccc(C(=O)CC)cc1

Procedure:
96.0 g (0.72 moles) of anhydrous aluminum chloride was added to a 1 L flask equipped with a stirrer, thermometer, and an addition funnel. 250 mL of carbon tetrachloride was added followed by 68.4 g (0.74 moles) of propionyl chloride from a pipette. This reaction mixture was cooled to 5°±3° C. and 153.9 g (0.625 mole) of "soft" dodecylbenzene (Dodane S, produced by Monsanto Chemical Co.) was then added over a 3 hour period while the temperature was maintained at 5°±3° C. The reaction was held at this temperature for an additional hour at which point approximately 500 mL of 10% HCl was slowly added with the temperature kept below 15° C. The reaction mixture was then washed 3 times with 5% HCL, once with water and the solvent stripped under vacuum. The residue was taken up in toluene and washed twice with 5% NaOH, once with water, once with dil. HCl, once with water and then stripped to give 192.0 g of a light brown, fluid oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=2)[N:19]=1>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:12])[CH2:7][CH2:8][N:9]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]([F:24])([F:26])[F:25])=[N:21][N:22]=3)[N:19]=2)[CH2:10][CH2:11]1
Reactant: OC1(c2nccs2)CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: OC1(c2nccs2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 65 %

Procedure:
A mixture of 4-(1,3-thiazol-2-yl)piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-(1,3-thiazol-2-yl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 65% yield.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([OH:9])[CH:5]=[C:4]([OH:10])[C:3]=1[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cl-].[NH4+]>[CH2:17]([C:7]1([OH:8])[C:6]([OH:9])=[C:5]([CH2:11][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:4]([OH:10])=[C:3]([C:11](=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:15])[C:2]1=[O:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)CC(=O)c1c(O)cc(O)c(O)c1O
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)CC(=O)C1=C(O)C(Cc2ccccc2)=C(O)C(O)(Cc2ccccc2)C1=O
Yield: 46.1 %

Procedure:
Under a stream of argon, 212 mg (5.31 mmol, 2.40 equivalents) of an oily dispersion of 60% sodium hydride was washed with hexane to remove the oil component. While the dispersion kept cooled with cold water, 11.0 ml of dry dimethyl sulfoxide was added and stirred. To this, was added 500 mg (2.21 mmol) of 2-methylpropyl-(2,3,4,6-tetrahydroxyphenyl) ketone (9) and stirred for 40 minutes. To the produced mixture, 0.525 ml (4.42 mmol, 2.00 equivalents) of benzyl bromide was added dropwise and stirred for four hours. The resultant mixture was combined with 10 ml of a saturated aqueous ammonium chloride solution and extracted by ether. The organic layer was washed with saturated brine, dried over sodium sulfate, concentrated under a reduced pressure, and subjected to silica gel chromatography (100 g of Wako Gel C-200, eluted with hexane:ethyl acetate=3:2) to obtain 207 mg (yield 23.1%) of the product (33) in the form of yellow powdery crystals.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:14][CH3:15])[CH:6]=1)C.[Li+].[OH-]>CO>[CH2:19]([O:18][C:16]([N:13]([CH2:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[Br:11])[C:4]([OH:26])=[O:3])[CH2:14][CH3:15])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccc(Br)c(CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCN(Cc1cc(C(=O)O)ccc1Br)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4-bromo-benzoic acid ethyl ester (3.62 g, 7.2 mmol) was dissolved in MeOH (40 mL) and cooled to 0° C. 1N Aqueous LiOH (22 mL, 22 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The mixture was quenched with 1N aqueous HCl (22 mL) and extracted three times with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to give the title compound, which was combined with the hydrolyzed product isolated in step 5.
Reaction SMILES: C[CH:2]1[C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5][CH2:4][C:3]1([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:12]=[O:13].[BH4-].[Na+]>CO>[CH2:10]1[CH2:9][O:8][C:7]2([CH2:6][CH2:5][CH2:4][C:3]([CH2:12][OH:13])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:2]2)[O:11]1
Reactant: CC1C2(CCCC1(C=O)c1ccccc1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1(c2ccccc2)CCCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of methyl 3,3-ethylenedioxy-1-phenylcyclohexanecarbaldehyde (1.43 g, 5.81 mmol) in methanol (25 mL) at 0° C. was added sodium borohydride (221 mg) in portions, and the resulting suspension was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate and methanol was removed under vacuum. The aqueous layer was extracted with dichloromethane 3 times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as clear colorless sticky oil (1.25 g, 87% yield). 1H NMR (400 MHz, CDCl3) δ 1.48-1.81 (7H, m), 1.88 (1H, d, J=16 Hz), 2.06 (1H, d, J=12 Hz), 2.22 (1H, d, J=12 Hz), 3.73-4.06 (5H, m), 7.15-7.25 (2H, m), 7.31-7.38 (3H, m). HPLC purity (retention time): 85% (1.44 min, method C). MS: 271.40 (M+Na+).
Reaction SMILES: P.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(CC)(C)C.CS(O[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:31]3[CH:36]=[C:35]([N:37]4[CH:42]=[CH:41][C:40](=[O:43])[NH:39][C:38]4=[O:44])[CH:34]=[C:33]([C:45]([CH3:48])([CH3:47])[CH3:46])[C:32]=3[O:49][CH3:50])[CH:27]=2)[CH:22]=1)(=O)=O.[CH3:51][S:52]([NH2:55])(=[O:54])=[O:53]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:45]([C:33]1[C:32]([O:49][CH3:50])=[C:31]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([NH:55][S:52]([CH3:51])(=[O:54])=[O:53])[CH:30]=[CH:29]3)[CH:36]=[C:35]([N:37]2[CH:42]=[CH:41][C:40](=[O:43])[NH:39][C:38]2=[O:44])[CH:34]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: COc1c(-c2ccc3cc(OS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCC(C)(C)O
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.0037 g, 4.04 mmol), di-tertbutyl 2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0047 g, 9.7 μmol) and milled potassium phosphate tribasic (0.094 g, 0.445 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. tert-Amyl alcohol (1.0 mL) was added, the contents were heated to 80 ° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl methanesulfonate (0.2 g, 0.404 mmol), methanesulfonamide (0.046 g, 0.485 mmol) and tert-amyl alcohol (1.5 mL) were added to a 40-mL reaction vial. The reaction temperature was raised to 110 ° C., and the contents were stirred for 14 hours. HPLC analysis of the reaction mixture showed that the titled compound was formed in 7 area % at 210 mn.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[N:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:19])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18]([C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:22][CH:21]=2)=[O:19])[CH2:16][CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Cl)ccc1N1CCN(C(=O)c2ccc(O)cn2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)N2CCN(c3ccc(Cl)cc3C(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of 6-{[4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl]carbonyl}pyridin-3-ol (Example 208, 0.26 g, 0.69 mmol), methyl bromoacetate (0.13 g, 0.82 mmol) and potassium carbonate (0.19 g, 1.38 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was filtered through NH-silica gel pad to give the title compound (0.27 g, 89%) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1ccc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
To 1-methyl-5-nitro-1H-indole (0.5 g, 2.84 mmol) in ethyl acetate (10 ml), tin (II) chloride hydrate (2.5 g, 11.4 mmol, 4 eq) was added and the reaction mixture stirred overnight at room temperature. The reaction mixture was basified with aqueous sodium hydroxide solution (pH 8) and the compound extracted using ethyl acetate. The crude compound obtained was purified by column chromatography over silica gel using ethyl acetate/hexane (1:1) as eluent to give 1-methyl-1H-indol-5-ylamine (120 mg, 27%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[S:20][C:21]([C:24]([OH:26])=O)=[CH:22][N:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:45]2C=CC=CC=2N=N1.CN.O1CCCC1>CN(C=O)C.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[S:20][C:21]([C:24]([NH:41][CH3:45])=[O:26])=[CH:22][N:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ncc(C(=O)O)s3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1cnc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1,3-thiazole-5-carboxylic acid (15.0 mg, 0.0322 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14.2 mg, 0.0322 mmol) and 2.0 M of methylamine in tetrahydrofuran (0.100 mL, 0.200 mmol) in DMF (1.0 mL) was stirred at r.t. for 2 h., and was diluted with methanol (0.8 mL). The resulting solution was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=479.1.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:5]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:4]=2[S:3]1.[Br:17]Br>O1CCOCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:5]2[CH:12]=[C:13]([Cl:16])[C:14]([Br:17])=[CH:15][C:4]=2[S:3]1
Reactant: COC(=O)Cn1c(=O)sc2ccc(Cl)cc21
Reactant: BrBr
Solvent: C1COCCO1
Product: COC(=O)Cn1c(=O)sc2cc(Br)c(Cl)cc21
Reaction time: 0.67 h

Procedure:
To a solution of methyl 2-oxo-5-chloro-3-benzothiazolineacetate (10 g) in dioxane (100 ml) was added dropwise bromine (2 ml) with stirring at 25°-30° C. during 40 minutes. After the stirring was continued at ambient temperature for 4 hours, precipitates in the resultant mixture were separated by filtration, washed with dioxane and diethylether and dried to give crystalline methyl 2-oxo-5-chloro-6-bromo-3-benzothiazolineacetate (8.38 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:22][CH:23]([CH3:39])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1)=[O:25].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C.O>[O:21]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[N:11]1[C@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:36]1[CH2:37][CH2:38][CH:33]([C:29]2[CH:28]=[C:27]([NH:26][C:24](=[O:25])[CH:23]([CH3:22])[CH3:39])[CH:32]=[CH:31][CH:30]=2)[CH2:34][CH2:35]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H](CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](c3ccccc3)N3C(=O)c4ccccc4C3=O)CC2)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
A mixture of 2-[(1S)-3-chloro-1-phenylpropyl]-1H-isoindole-1,3(2H)-dione (4.50 g, 15.0 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (4.26 g, 15.0 mmol), K2CO3 (4.16 g, 30.0 mmol), and NaI (3.40 g, 20.0 mmol) in DMF (40 mL) was stirred at 90° C. for 12 hrs. The reaction mixture was diluted with water (50 mL), extracted with CH2Cl2 (3×50 mL), and the combined organic extracts were washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product (5.10 g, 74%). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, 1H, J=5.5 Hz), 7.82 (d, 1H, J=5.5 Hz), 7.71 (d, 1H, J=5.5 Hz), 7.70 (d, 1H, J=5.4 Hz), 7.56 (d, 2H, J=7.1 Hz), 7.35-7.27 (m, 5H), 7.22 (t, 1H, J=7.5 Hz), 7.09 (s, 1H), 6.81 (d, 1H, J=7.8 Hz), 5.49 (dd, 1H, J=5.5, 9.6 Hz), 2.97 (d, 1H, J=10.1 Hz), 2.92-2.82 (m, 2H), 2.44 (sept, 1H, J=6.7 Hz), 2.40-2.29 (m, 3H), 2.00-1.83 (m, 2H), 1.79-1.39 (m, 5H), 1.26 (d, 6H, J=6.9 Hz); ESMS m/e: 510.4 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C([O:18][C:19]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][C:20]=1[C:21]([NH:23][C:24]1[CH:36]=[C:35](Br)[CH:34]=[CH:33][C:25]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:22])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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.C(OCC)(=O)C.COCCOC.O>[OH:18][C:19]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][C:20]=1[C:21]([NH:23][C:24]1[CH:36]=[C:35]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:34]=[CH:33][C:25]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:22]
Reactant: OB(O)c1cccs1
Reactant: CC(=O)Oc1ccc(N2CCCCC2)cc1C(=O)Nc1cc(Br)ccc1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1ccc(-c2cccs2)cc1NC(=O)c1cc(N2CCCCC2)ccc1O
Temperature: 25 °C
Yield: 36.5 %

Procedure:
Water (0.60 mL), thiophene-2-boronic acid (0.024 g), sodium carbonate (0.041 g), and bis(triphenylphosphine)palladium(II) dichloride (2.2 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) solution of tert-butyl 2-(2-acetoxy-5-(piperidin-1-yl)benzamido)-4-bromobenzoate (0.080 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-85% hexane/ethyl acetate] to obtain 0.027 g of tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(thiophen-2-yl)benzoate as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CN1CCC(=O)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C2CCN(C)CC2)C3)cc1

Procedure:
Compound eg was synthesized according to the procedure described in Example 8 reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 1-methylpiperidin-4-one. LC-MS: m/z=+494 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]#[CH:18])[N:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].O.C(Cl)(Cl)(Cl)[Cl:27]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]#[C:18][Cl:27])[N:12]=[CH:11][N:10]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C#CCOc1cc(-c2cccc(F)c2F)ncn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Product: Fc1cccc(-c2cc(OCC#CCl)ncn2)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In 5 ml of carbon tetrachloride was dissolved 241 mg of 4-(2,3-difluorophenyl)-6-(2-propynyloxy)pyrimidine, to which 136 mg of potassium carbonate and 136 mg of tetra-n-butylammonium chloride were added, followed by stirring at room temperature for 16 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 159 mg of 4-(2,3-difluorophenyl)-6-(3-chloro-2-propynyloxy)pyrimidine (the present compound (136)).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:15]=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[BH4-].[Na+].[Cl-].[NH4+]>CO.C1COCC1>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C=O)cc1OCCCCCCCCCC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCOc1ccc(CO)cc1OCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
3,4-Didecyloxybenzaldehyde (6.78 g., 16.2 mmol, 1 equiv.) is dissolved in 44 mL of methanol and 20 mL of THF. Sodium borohydride (0.613 g., 16.2 mmol, 1 equiv.) is added in portions. The mixture is stirred for 30 minutes at room temperature. The solution is poured into saturated ammonium chloride solution, and then extracted twice with EtOAc. The organic extracts are washed with brine, dried (MgSO4), and evaporated. Chromatography on silica gel using 10%-20% EtOAc/hexane affords 3,4-didecyloxybenzyl alcohol (12a) (5.71 g., 13.6 mmol, 84%) as a clear oil: mp=41°-42.5° C.; UVmax (EtOH) 206 nm (ε=19085), 232 nm (ε=5340), 280 nm (ε=2239); 1H NMR (300 MHz, CDCl3) δ 6.90 (s, 1H, ArH), 6.83 (s, 1H, ArH), 6.83 (s, 1H, ArH), 4.58 (d, J=6 Hz, 2H, ArCH2OH), 3.96 (m, 4H, RCH2O), 1.79 (m, 4H, RCH2CH2O), 1.58 (t, J=6 Hz, 1H, OH), 1.44 (m, 4H, decyl), 1.25 (m, 24H, decyl), 0.86 (m, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ 149.34, 148.72, 133.68, 119.58, 113.83, 112.95, 69.42, 69.21, 65.41, 31.92, 29.64, 29.59, 29.43, 29.36, 29.30, 26.04, 22.69, 14.12; IR (KBr) 3346, 2956, 2922, 2850, 1520, 1468, 1262, 1236, 1138 m-1 ; MS (DCI) m/e 421 (MH+), 403 (M--OH). Anal. Calcd for C27H48O3 : C, 77.09; H, 11.50. Found: C, 77.26; H, 11.61.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[CH2:11][N:12]([CH2:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:21]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[CH2:11][N:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]([CH3:34])([CH3:33])[C:26]([OH:28])=[O:27])=[CH:35][CH:36]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(NC(=O)CN(Cc2ccc(OC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)CN(Cc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccco2)c(C)c1
Yield: 82 %

Procedure:
7.09 g (14.00 mmol) of the compound from Example 3-1 and 35 ml of trifluoroacetic acid are stirred at room temperature in 35 ml of dichloromethane for 2 hours. The solvent is distilled off and the residue is then dissolved in ethyl acetate, washed with water, 20 per cent strength sodium acetate solution and saturated sodium chloride solution and then dried over magnesium sulphate. The solvent is removed and the residue is then purified by flash chromatography on silica gel (dichloromethane→dichloromethane/ethyl acetate 5:1→2:1→1:1). The gives the target compound in a yield of 82%.