Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH3:13][CH:14]1[O:18][C:17](=[O:19])[NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:13][CH:14]1[O:18][C:17](=[O:19])[N:16]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH2:15]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC1CNC(=O)O1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CN(c2ccc(C(=O)O)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-amino-2-propanol (1.4 g), diethyl carbonate (2.4 mL) and potassium carbonate (500 mg) was stirred at 150° C. for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 5-methyloxazolidin-2-one (1.9 g). To a mixture of ethyl 4-iodobenzoate (3.2 mL), 5-methyloxazolidin-2-one (1.9 g), potassium carbonate (8 g) and copper (I) iodide (720 mg) were added toluene (20 mL) and N,N′-dimethylethylenediamine (800 μL), and the mixture was refluxed for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was dissolved in methanol (20 mL) and 1,4-dioxane (20 mL), 1N aqueous sodium hydroxide solution (40 mL) was added, and the mixture was stirred at room temperature for 3 hr. 1N hydrochloric acid (40 mL) was added, and the mixture was extracted with chloroform. The solvent was evaporated to give the title compound (3.9 g).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-:20].[K+].[K+].OO>CS(C)=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]([NH2:13])=[O:20])=[CH:17][CH:18]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(COc2ccc(C=O)cc2)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cccc(COc2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-Formyl-phenoxymethyl)benzonitrile (1 equiv), in DMSO was added potassium carbonate (0.5 equiv), and hydrogen peroxide (4 equiv). The reaction mixture stirred at room temperature for 2 hours. The reaction was monitored by TLC. It was poured on water and extracted with ethyl acetate (×3). The organic phase was dried over magnesium sulphate, filtered and concentrated under vacuum to yield a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][OH:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:16][CH2:17][C:18](O)=[O:19].C1(C)C=CC(S([O-])(=O)=O)=CC=1.CN(C)C1C=C[NH+]=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[Br:16][CH2:17][C:18]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19]
Reactant: OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1cc[nH+]cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Product: O=C(CBr)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, 9-fluorenemethanol (99%, 0.694 g, 3.5 mmol), bromoacetic acid (99%, 0.406 g, 2.9 mmol), DPTS (0.130 g, 0.44 mmol) and DCC (99%, 0.729 g, 3.5 mmol) were combined in dichloromethane (9 mL), stirred at 0° C. for 1 h, and the precipitate of dicyclohexylurea was filtered off from the cold mixture. The filtrate was diluted with cold ethyl acetate (30 mL), washed twice with cold 5% aqueous solution of NaH2PO4 (60 mL, acidified with H3PO4 to pH=3), freed of water droplets, and the solvents were distilled off in vacuo. The residue was extracted with cold pentane to remove the excess of DCC, and purified by flash chromatography (silica-gel, hexane-CHCl3, 5:1 to 1:1) followed by crystallization from cold hexane. Yield of 8: 0.795 g (87%). The purity was confirmed by TLC (SiO2, heptane-ethyl acetate, 9:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)[CH:21]=1.C(N(C(C)C)C(C)C)C1C=CC=CC=1>ClCCl.C1COCC1>[NH2:33][C:17]1[N:18]=[CH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:21][C:16]=1[C:8]1[O:7][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: COCC(=O)Cl
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2o1
Agent: CC(C)N(Cc1ccccc1)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-methoxyacetyl chloride (0.033 ml) was added in one portion to a stirred ice-cooled suspension of 3-(1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (100 mg) and N-benzyl-N-isopropyl-propan-2-amine on polystyrene (185 mg, 3 mmol/g) in dichloromethane (5 ml) and THF (5 ml). The resulting suspension was stirred at room temperature for 2 hours. The resin was filtered, rinsed with dichloromethane/methanol. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in dichloromethane. After evaporation of the solvants, the resulting solid was triturated in acetonitrile to give the title compound (79 mg). NMR Spectrum: (CDCl3): 1.97-2.11 (m, 2H), 2.22-2.35 (m, 2H), 2.80-2.91 (m, 1H), 3.17-3.29 (m, 1H), 3.46 (s, 3H), 4.06-4.23 (m, 3H), 4.38-4.47 (m, 1H), 4.69-4.80 (m, 1H), 7.08 (bs, 2H), 7.35-7.42 (m, 2H), 7.58-7.63 (m, 1H), 7.69 (s, 1H), 7.73-7.78 (m, 1H), 7.80 (s, 1H), 8.35 (d, 1H), 8.41 (d, 1H); Mass spectrum: M+H+ 433.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][C:2]=1[C:15](O)=[O:16].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:30][C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH2:40][CH2:39]1>O1CCCC1>[Cl:30][C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[N:38]1[CH2:39][CH2:40][N:41]([CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:15]([C:2]2[CH:3]=[CH:4][C:5]3[C:14](=[CH:13][C:12]4[C:7]([CH:6]=3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:1]=2)=[O:16])[CH2:42][CH2:43]1
Reactant: O=C(O)c1ccc2cc3ccccc3cc2c1
Reactant: NCCCCN1CCN(c2cccc(Cl)c2Cl)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCCCCN1CCN(c2cccc(Cl)c2Cl)CC1)c1ccc2cc3ccccc3cc2c1
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 2-anthracenecarboxylic acid (100 mg, 0.45 mmol) and 1,1'-carbonyldiimidazole (82 mg, 0.5 mmol) in 10 mL of anhydrous tetrahydrofuran is stirred for 8 hours. A solution of 4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-1-aminobutane (150 mg, 0.5 mmol) in 1 mL of tetrahydrofuran is added and the resulting mixture is stirred for 30 minutes. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with aqueous Na2CO3, dried (Na2SO4) and concentrated in vacuo to give the title compound (183 mg, 80%). The hydrochloride salt is prepared by treating the free base with ethyl acetate-HCl. The hydrochloride salt of the title compound has a melting point of 245°-247° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[O:32][CH:33]=[CH:34][CH:35]=1.[C:36]([OH:44])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.CO>[C:36]([OH:44])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[O:32]1[CH:33]=[CH:34][CH:35]=[C:31]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: BrCCCCCCOCCCCCCc1ccco1
Agent: O=C(O)c1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(C(O)CNCCCCCCOCCCCCCc2ccco2)ccc1O
Yield: 70.5 %

Procedure:
A solution of N-[5-(2-amino-1-hydroxyethyl)-2-hydroxyphenyl]methanesulphonamide (0.95 g), 2-[6-[(6-bromohexyl)oxy]hexyl]furan (0.84 g) and DEA (0.54 ml) in DMF (20 ml) was heated at 90° for 5h, then evaporated in vacuo. The residue was purified by FCC with System A (39:10:1) eluant to afford a product which was dissolved in methanol (6 ml) and treated with benzoic acid (21 mg). The solvent was evaporated in vacuo and the residue triturated with dry ether to give the title compound as a beige solid (75 mg), t.l.c. (System A 39:10:1) Rf 0.15.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]([C:18]2[S:40][C:21]3[N:22]=[CH:23][N:24]=[C:25]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[O:34][C@H:35]4[CH2:39][CH2:38][O:37][CH2:36]4)[C:20]=3[C:19]=2[CH3:41])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH:8]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]([C:18]2[S:40][C:21]3[N:22]=[CH:23][N:24]=[C:25]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[O:34][C@H:35]4[CH2:39][CH2:38][O:37][CH2:36]4)[C:20]=3[C:19]=2[CH3:41])=[O:17])[CH2:10][CH2:9]1
Reactant: Cc1c(C(=O)NC2CCCN(C(=O)OC(C)(C)C)CC2)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)NC2CCCNCC2)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12
Temperature: 25 °C

Procedure:
A mixture of 380 mg (0.65 mmol) 4-[(4-{4-fluoro-2-[(S)-(tetrahydro-furan-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester and 0.15 ml trifluoroacetic acid and 10 ml dichloromethane was stirred at room temperature over night. The reaction mixture was concentrated in vacuo.
Reaction SMILES: CN1CCN(CC2CCCN(C3C=CC([N+]([O-])=O)=CC=3)C2)CC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=O)[CH2:36]2)[CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33]>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([CH2:41][N:43]3[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]3)[CH2:36]2)[CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33]
Reactant: COc1cc(N2CCC[C@@H](C(=O)N3CCN(C)CC3)C2)ccc1[N+](=O)[O-]
Agent: CN1CCN(CC2CCCN(c3ccc([N+](=O)[O-])cc3)C2)CC1
Product: COc1cc(N2CCC[C@@H](CN3CCN(C)CC3)C2)ccc1[N+](=O)[O-]

Procedure:
1-[(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-ylmethyl]-4-methyl-piperazine was prepared in an analogous fashion to 1-Methyl-4-[1-(4-nitro-phenyl)-piperidin-3-ylmethyl]-piperazine of Example 455a replacing (4-Methyl-piperazin-1-yl)-[1-(4-nitro-phenyl)-piperidin-3-yl]-methanone with [(R)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone. 1-[(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-ylmethyl]-4-methyl-piperazine was isolated as an orange oil (170 mg, 43%). LC/MS (E/I+) 349.24 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.CNC=O.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>CN(C)C=O.ClCCl.CO>[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]([CH2:24][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: c1c[nH]nn1
Reactant: COC(=O)c1cc(CCl)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CNC=O
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cn2ccnn2)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine triazole (0.72 g, 10.4 mmol) and methylformamide (6 mL). Cool in an ice bath and add sodium hydride (0.42 g, 60% i oil, 10.4 mmol). After 30 minutes, warm to ambient temperature. Add a solution of methyl 2-methoxy-5-chloromethylbenzoate (1.85 g, 6.74 mmol) in dimethylformamide (6 mL). Heat to 75° C. After 3 hours, partition the reaction mixture between water and ethyl acetate. Extract the organic layer with water, dry over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 95/5 dichloromethane/methanol containing 0.5% concentrated aqueous ammonia to give methyl 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoate: Rf=0.1 (silica gel, 1/1 hexane/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C@@H:9](N)[C:10]([OH:12])=[O:11])[CH:3]=1.Cl.C(O)(=[O:17])C.N([O-])=O.[Na+]>C([O-])(=O)C.[Na+].O>[OH:17][C@H:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(=O)O
Reactant: Cc1cccc(C[C@@H](N)C(=O)O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: Cc1cccc(C[C@@H](O)C(=O)O)c1
Reaction time: 0.5 h

Procedure:
To a solution of D-3-methylphenylalanine.HCl (5.5 g, 25.5 mmol) and acetic acid (13.0 mL) in 0.04 M aqueous sodium acetate (750 mL) is added a solution of sodium nitrite (5.28 g, 76.5 mmol) in water (12.5 mL) dropwise, over 30 min, and the solution is allowed to stir for 3 h. This solution is then saturated with NaCl, and extracted with EtOAc (3×150 mL). The combined organic layers are washed with brine (3×150 mL), dried (MgSO4) and evaporated to yield (R)-2-hydroxy-3-(3-methylphenyl)-propionic acid.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]=3)[CH:13]=2)=[CH:7][CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[CH2:23]([O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:30])=[O:3])=[CH:10][CH:9]=1)[CH:21]=[CH:20]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Oc2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
4-(6-Benzyloxy-2-naphthyloxy)benzoic acid ethyl ester (10.6 g, 26.2 mmol) was dissolved in a 2:1 mixture of THF and methanol (150 ml), added with 4N lithium hydroxide (33 ml) and stirred at room temperature. After completing the reaction, the reaction liquid was adjusted to pH 2 or thereabout with 1N hydrochloric acid, extracted with ethyl acetate, washed with water, dried with magnesium sulfate and concentrated to obtain the subject compound (8.70 g, 23.4 mmol). The result of 1H-NMR was consistent with the above structure.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:31]=[C:32]([F:40])[C:33]([C:36]([O:38]C)=[O:37])=[N:34][CH:35]=1)[CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1>[Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:31]=[C:32]([F:40])[C:33]([C:36]([OH:38])=[O:37])=[N:34][CH:35]=1)[CH3:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ncc(-c2ccccc2O[C@H](C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1cnc(C(=O)O)c(F)c1
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a tetrahydrofuran solution (96 ml) of methyl 5-(2-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}phenyl)-3-fluoropyridine-2-carboxylate (4.79 g) was added at room temperature an aqueous solution (48 ml) of lithium hydroxide monohydrate (192 mg), followed by stirring for 90 minutes. To the reaction solution was added 1 N hydrochloric acid for neutralization, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 5-(2-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}phenyl)-3-fluoropyridine-2-carboxylic acid (3.27 g).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:16][C:17]3[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(Cl)Cl>[C:1]1([C:7]2[C:12]([C:13]([O:15][C:33]3[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=3)=[O:14])=[C:11]([O:16][C:17]3[N:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[N:22]=3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(OC)nc(Oc2cccc(-c3ccccc3)c2C(=O)O)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClCCl
Product: COc1cc(OC)nc(Oc2cccc(-c3ccccc3)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step G, using equimolar amounts of 6-phenyl-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid, 4-nitrophenol, and dicyclohexylcarbiimide in methylene chloride, yielding 4-nitrophenyl 6-phenyl-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.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.O.C(#N)C>[C:9]1([C:2]2[CH:7]=[C:6]([C:17]3[C:18]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:14]=[CH:15][CH:16]=3)[N:5]=[CH:4][N:3]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1cccc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: c1ccc2c(-c3cc(-c4cccc5ccccc45)ncn3)cccc2c1
Yield: 41 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 5.00 g of 4,6-dichloropyrimidine, 11.56 g of 1-naphthaleneboronic acid, 7.12 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium (II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 2.91 g of 1-naphthaleneboronic acid, 1.82 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and was dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 2:1, so that a pyrimidine derivative Hd1npm, which was the objective substance, was obtained (yellow white powder, yield of 41%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (1-1) of Step 1 is shown below.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:30][CH2:31][C:32]1[N:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][C:36]=1[CH3:37])(=O)=O>CC#N.C(OCC)C>[C:15]([O:14][C:12]([CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:30][CH2:31][C:32]3[N:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:35][C:36]=3[CH3:37])=[CH:3][CH:4]=2)[O:9][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc2c(c1)OCC(C(=O)OC(C)(C)C)C2
Temperature: 25 °C

Procedure:
To a stirred solution of tert-butyl 7-hydroxychromane-3-carboxylate (2.5 g, 10 mmol) in CH3CN (20 ml), K2CO3 (4.1 g) and 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl methanesulfonate (3.7 g) were added and the reaction mixture was heated under reflux for overnight. The reaction mixture was cooled to room temperature and diluted with 100 ml of diethyl ether. The diluted solution was passed through a pad of silica and the silica was washed with more ether. The ether solution was evaporated to dryness and purified using silica chromatography. The product was isolated as a white sold (2.8 g, 64.3%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[N:17][CH:18]=[C:19]([CH:21]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[CH3:22])[CH:20]=3)[N:12]=[C:11]([CH3:42])[N:10]=2)=CC=1>FC(F)(F)C(O)=O>[CH3:41][O:40][C:37]1[N:36]=[CH:35][C:34]([NH:33][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:42])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH:21]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:24]=3)[CH3:22])=[CH:18][N:17]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(C)c3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (459.4 mg, 0.6277 mmol) was dissolved in trifluoroacetic acid (Aldrich, redistilled, 99+%, 7.5 mL) and the flask was fitted with a reflux condenser and put in a preheated oil bath (75° C.) and stirred overnight. Then, the reaction was cooled to room temperature, concentrated, diluted with DCM, and treated with saturated sodium bicarbonate and 5N NaOH to raise the pH of the aqueous phase to about 6. The layers were separated, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (25:1 DCM/MeOH to 20:1 DCM/MeOH). The fractions with product were collected, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH, but was still not 95% pure by HPLC. So, the filtrate and solid were combined, concentrated, treated with EtOAc and acetone (which in combination dissolved the compound), concentrated, and purified by HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min; total flow rate of 100 mL/min) to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (192.4 mg). 1H NMR (CDCl3, 400 MHz) δ 8.87 (s, 1H), 8.48 (s, 1H), 8.16 (d, J=1.57 Hz, 1H), 8.07 (d, J=8.02 Hz, 1H), 7.91 (d, J=8.22 Hz, 2H), 7.45 (d, J=8.22 Hz, 2H), 6.93 (d, J=9.00 Hz, 1H), 4.28 (q, J=7.56 Hz, 1H), 4.03 (s, 3H), 3.06 (s, 3H), 2.63 (s, 3H), 1.74 (d, J=7.04 Hz, 3H). m/z (ESI, pos. ion) 492 (M+H)+.