Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH2:13])[CH2:7]1.N1C=CC=CC=1.[C:24](Cl)(=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7]1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of Intermediate 9 (0.028 g) in dichloromethane (2 ml) containing a suspension of polyvinyl pyridine (0.1 g) was treated with valeryl chloride (0.018 ml), and the mixture was shaken at 20° C. for 16 h. Tris (2-aminoethyl)amine polystyrene scavenger resin (Argonaut Technologies, 4.46 mmol/g; 0.067 g) was added, and the mixture was shaken at 20° C. for 2 h. The mixture was filtered and the filtrate applied directly to a silica gel cartridge (1 g Varian Bond Elut). Elution with chloroform, ether, and ethyl acetate gave the title compound (0.0225 g).
Reaction SMILES: [O:1]1[CH:5]([CH2:6]O)[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][C:14]=3[C:2]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[O:1]1[CH:5]([CH2:6][N:38]2[C:34](=[O:44])[C:35]3[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:37]2=[O:39])[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][C:14]=3[C:2]1=2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCC1Cc2ccc3c(c2O1)CCC3
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1Cc2ccc3c(c2O1)CCC3
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
To a solution of (±)-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethanol (0.500 g, 2.63 mmol) in tetrahydrofuran (25 mL) was added triphenylphoshine (1.03 g, 3.94 mmol), phthalimide (0.58 g, 3.94 mmol) followed by diethylazodicarboxylate (0.687 g, 3.94 mmol) and the reaction mixture was allowed to stir at room temperature for 12 h. The reaction was quenched by the addition of water (5 mL) and the solvent was removed in vacuo. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:3) provided 0.65 g of (±)-2-(3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethyl)-1H-isoindole-1,3(2H)-dione as a white solid (mp 131-135° C.). The solid was re-dissolved in methanol (10 mL) and hydrazine monohydrate (0.153 g, 3.06 mmol) was added to the reaction mixture. The reaction mixture was heated at reflux for 12 h, concentrated hydrogen chloride (12.1 M, 3 mL) was added and heating was continued for an additional 1 h. The reaction mixture was cooled to room temperature and diluted with water (150 mL) and aqueous sodium hydroxide (2.5 N, 10 mL). The reaction mixture was extracted with ethyl acetate (2×75 mL) and the combined organic layers were dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash column chromatography (silica, 10% aqueous ammonium hydroxide/methanol:ethyl acetate 1:19) provided a colorless oil. The oil was re-dissolved in isopropanol (1 mL) and hydrogen chloride (1.0 N in diethyl ether, 5 mL) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.42 g (71%) of (±)-1-(3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>230° C. (dec); Anal. calcd. for C12H15NOHCl: C, 63.85; H, 7.14; N, 6.21. Found: C, 63.64; H, 7.25; N, 6.02.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][C:27]=4[F:29])=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(F)cc1F
Product: COc1ccc(-c2nc3cc(-c4ccc(F)cc4F)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 2,4-difluorophenylboronic acid (136 mg, 0.86 mmol) the subtitle compound was obtained, (57 mg, 26%). 1H NMR (DMSO) δ 8.71(d, 1H), 8.53(dd, 1H), 8.01(s, 1H), 7.97(d, 1H), 7.70(m, 3H), 7.48(dt, 1H), 7.30(dt, 1H), 4.12(s, 3H). MS 383 m/z (M+H)+.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[O:22]([C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:38]2[CH2:39][CH2:40][N:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:30]=3)[CH2:36][CH2:37]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: c1ccc(Oc2cccc(N3CCNCC3)c2)cc1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(Oc4ccccc4)c3)CC2)c(OC)nc1C
Yield: 72 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-phenoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([S:17]([OH:20])(=[O:19])=[O:18])[CH:16]=1)[C:8]([O:10]C(C)C)=[O:9])([OH:4])(=[O:3])=[O:2].[CH2:21]([CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24]O)[CH3:22]>C(O)(C)C>[S:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([S:17]([OH:20])(=[O:18])=[O:19])[CH:16]=1)[C:8]([O:10][CH2:24][CH:23]([CH2:21][CH3:22])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:9])([OH:4])(=[O:2])=[O:3]
Reactant: CCCCC(CC)CO
Reactant: CC(C)OC(=O)c1cc(S(=O)(=O)O)cc(S(=O)(=O)O)c1
Solvent: CC(C)O
Product: CCCCC(CC)COC(=O)c1cc(S(=O)(=O)O)cc(S(=O)(=O)O)c1
Reaction time: 3 h

Procedure:
Into a one-liter, four-necked round bottom flask equipped with a thermometer, distillation head, and a glass stirrer with TEFLON paddle were charged 177 grams of 2-propyl 3,5-disulfobenzoate solution in isopropyl alcohol and 200 grams of 2-ethylhexanol. The solution was vacuum distilled to a pot temperature of 105° C. and then held at this temperature for an additional three hours. The resultant 2-ethylhexyl 3,5-disulfobenzoate was a brown viscous oil with an acid value of 165.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: Cc1cccc(OCC#N)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(C)cccc4OCC#N)n3)cc2CC1

Procedure:
(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-3-methyl-phenoxy)-acetonitrile was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-methyl-phenoxy]-acetonitrile in an analogous manner to Example 1221d. Title compound isolated as a white foam, (60 mg, 45%) LCMS 493.18 (M+H), HPLC purity 99%, 1H-NMR (CDCl3, 400 MHz) δ:8.04 (s, 1H), 7.32-7.28 (m, 1H), 7.11-7.08 (m, 2H), 7.03 (s, 1H), 6.96-6.93, (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 6.57 (s, 1H), 4.70 (s, 2H), 3.55 (dd, J=5.6 Hz, 2H), 3.38 (s, 3H), 2.85-2.81 (m, 2H), 2.75 (dd, J=5.6 Hz, 2H), 2.72-2.67 (m, 6H), 2.28 (s, 3H).
Reaction SMILES: F[C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=C\C1NC=CC=1OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[N:7]1[C:6](=[O:11])[CH:5]=[C:4]2[C:8]=1[CH:9]=[CH:10][CH:2]=[CH:3]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C=c2ccccc2=N1

Procedure:
Using Method C above, Ethyl-[(3R,4S,5R)-4-ethynyl-2,2,6-trimethyl-[1,3]-dioxan-5-yl]-carbamic acid tert-butyl ester (148.5 mg, 0.50 mmol) (Example 123C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (96 mg, 0.25 mmol) (Starting Material 6) using (Ph3P)4Pd (23.1 mg, 8 mol %) and CuI (5 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 5 h to give the coupling product (137.2 mg, 99.2% after flash column purification). This coupling product (125 mg) was then treated with 50% of trifluoroacetic acid/CH2Cl2 (5 mL) and 0.5 mL of water at r.t. for 1 h. The reaction mixture was concentrated to about 2 mL and diluted with AcOEt (50 mL) and then quenched with 2 N NaOH. The organic layer was washed with brine and dried with Na2SO4. After concentration, the crude product (113.6 mg) was triturated with AcOEt/hexanes and the precipitate was collected by filtration to offer (Z)-1,3-Dihydro-4-[(3R,4S,5R)-3,5-dihydroxy-4-ethylamino-1-hexynyl]-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (LLLLL) as a brown-orange solid. (Yield 29.5 mg, 31.6%). The filtrate was then purified via flash column chromatography (5%-10% MeOH in CH2Cl2) to give (R)-(Z)-1,3-Dihydro-4-[(5-ethylamino-6-methyl)-6H-pyran-2-yl]-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene)]-2H-indol-2-one (MMMMM). (Yield 33.6 mg, 37.6%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:33]Cl)=[C:24]([CH:32]=1)[O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:33][S:18][C:15]2[CH:16]=[CH:17][C:12]([C:3]3[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:9])[F:10])[N:5]([CH3:11])[N:4]=3)=[CH:13][CH:14]=2)=[C:24]([CH:32]=1)[O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Reactant: Cn1nc(-c2ccc(S)cc2)c(Cl)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(Cl)ccc1CSc1ccc(-c2nn(C)c(OC(F)F)c2Cl)cc1

Procedure:
This compound is prepared in a manner analogous to that of Step I of Example 1, using 0.58 gram (0.002 mole) of 4-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)thiophenol, 0.32 gram (0.002 mole) of methyl 2-(5-chloro-2-chloromethylphenoxy)propanoate (prepared as in Steps A through D of Example 2), and 0.41 gram (0.003 mole) of potassium carbonate in 60 mil of N,N-di-methylformamide, yielding the title compound.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:13]=[C:12](I)[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.C(N(CC)CC)C.[CH2:25]([NH:28][C:29](=[O:33])[CH:30]([Cl:32])[Cl:31])[C:26]#[CH:27]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C@@H:1]1([N:9]2[CH:13]=[C:12]([C:27]#[C:26][CH2:25][NH:28][C:29](=[O:33])[CH:30]([Cl:32])[Cl:31])[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: C#CCNC(=O)C(Cl)Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCC#Cc1cc([N+](=O)[O-])n([C@H]2C[C@H](O)[C@@H](CO)O2)c1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
1-(2-Deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (Compound 1) (354 mg, 1.0 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), CuI (30 mg, 0.16 mmol) and triethylamine (209 μl, 1.5 mmol) were dissolved in DMF (3.5 ml), followed by addition of a 1 M DMF solution of N-(2-propynyl)-dichloroacetamide (1.5 ml, 1.5 mmol). After stirring at room temperature for 12 hours, the reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed three times with water. After drying over anhydrous sodium sulfate, the organic layer was concentrated and purified on a silica gel column (CH2Cl2:MeOH, 20:1, v/v) and by HPLC (34%-35% CH3CN, 12 minutes) to give Compound 3 (317 mg, 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.ClCCl>N1C=CC=CC=1>[NH2:15][C:11]1[N:10]=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[CH:13][C:12]=1[NH:14][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.1 g, 0.36 mmol) in pyridine (2 mL), 4-methoxybenzoyl chloride (0.066 g, 0.39 mmol) was added. The mixture was stirred at room temperature overnight and the solvent was evaporated. Dichloromethane (1.6 mL) and tris-(2-aminoethyl)amine polystyrene (0.180 g, 0.72 mmol) were added and the mixture was stirred at room temperature for 1 h. The resin was filtrated and washed twice with dichloromethane. The filtrates were combined and the solvent was evaporated to give the title compound (0.172 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)O3)nc1

Procedure:
A solution of 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol (80 mg), 2-chloro-5-nitropyridine (56 mg) and potassium carbonate (52 mg) in dimethylformamide (1.0 ml) was stirred at 120° C. for 2 hrs. After cooling the mixture water (10 ml) was added and the precipitated product was filtered, washed with water and 2-propanol and dried under reduced pressure. Yield is 60 mg and mp 163-170° C. 1H NMR (DMSO-d6) δ=4.16 (dd, J=8.5, 11.6 Hz, 1H), 4.47 (dd, J=11.6, 2.6 Hz, 1H), 5.28 (dd, J=2.6, 8.5 Hz, 1H), 6.75 (dd, J=2.6, 8.8 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 7.21 (d, J=9.1 Hz, 1H), 7.39-7.52 (m, 5H), 8.60 (dd, J=2.8, 9.1 Hz, 1H), 9.05 (d, J=2.8 Hz, 1H).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][NH:4][C:5]1[N:15]=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10]C)=[O:8].C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:26])C>>[CH3:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][N:4]1[C:5]2[N:15]=[CH:14][CH:13]=[CH:12][C:6]=2[C:7](=[O:8])[O:9][C:10]1=[O:26]
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: CCOC(=O)c1cccnc1NC[C@@H](C)CC
Product: CC[C@H](C)Cn1c(=O)oc(=O)c2cccnc21

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 20A for the product of Example 3A (0.400 g, 68%). MS (DCI) m/z 252 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Reactant: C1COCCN1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Yield: 83.1 %

Procedure:
A mixture of 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid methyl ester (2 g, 5.594 mmol), morpholine (0.64 mL, 7.27 mmol) and diisopropylethylamine (1.46 mL, 8.392 mmol) in isopropanol (25 mL) was heated at reflux for 50 hours. After cooling to a temperature in the range of 15° C. to 40° C., the precipitated solid was filtered, washed with hexane and dried. The solid was dissolved in ethyl acetate, washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow solid (1.9 g, 83% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(N(CC)CC)C.[C:44]1([CH2:50][C:51](Cl)=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>ClCCl>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][C:51](=[O:52])[CH2:50][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)Cc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (220 mg, 0.45 mmol) in dichloromethane (10 ml) was treated with triethylamine (0.38 ml, 2.70 mmol) and phenylacetylchloride (280 mg, 1.80 mmol) at 0° C. and the resultant mixture stirred for 15 min. The mixture was then stirred at room temperature for 72 hr. The solvent was removed under reduced pressure and methanol (20 ml), saturated with ammonia gas, added. The resultant mixture was stirred at room temperature for 2 hr, treated with 2 molar aqueous sodium hydroxide (10 ml) and then left standing at room temperature for 24 hr. The methanol was removed under reduced pressure and the aqueous layer extracted with dichloromethane (×3). The combined organic layers were washed with water (×2), dried with anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was dissolved in 1,4-dioxan (6 ml), 0.88 aqueous ammonia solution (8 ml) added and the mixture stirred at room temperature for 10 days. The 1,4-dioxan was removed under reduced pressure and the aqueous layer extracted with dichloromethane (×3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>C(O)CC>[O:16]1[C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([CH3:19])=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]5)=[N:32][CH:31]=4)[N:7]=3)=[CH:18][C:13]=2[NH:14][C:15]1=[O:17]
Reactant: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Solvent: CCCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)nc2)nc1Nc1ccc2oc(=O)[nH]c2c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a vial with 5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (27.7 mg, 0.5 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4 mg, 1.0 mmol), PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vial was tightly closed, and the reaction mixture was stirred at 85° C. for 2 days. The solvents were removed in vacuo, and the crude product was purified by RP-HPLC. Purified compound (as a trifluoroacetate salt) was dissolved in MeOH—H2O (1:4, 2 mL) and was passed through a PL-HCO3-MP-SPE column, washing with same solvents (1 mL). The filtrate was collected and the solvent was removed by lyophilization. N4-(benzoxazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine was obtained as a purple solid, 23.1 mg (53% yield); 1H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.73 (s, 1H), 8.30-8.28 (m, 2H), 7.87-7.84 (m, 2H), 7.46-7.28 (m, 2H), 7.22 (d, J=8.5, 1H), 6.71 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H), 2.11 (s, 3H); LCMS (M+) m/z 433.52.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:9][CH2:8]1>[Cl-].[Zn+2].[Cl-].[Na].CO>[CH:1]1([N:7]2[CH2:8][CH2:9][CH:10]([O:13][C:14]3[N:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:11][CH2:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2cnc(OC3CCNCC3)nc2)cc1
Reactant: O=C1CCCC1
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Solvent: CO
Product: N#Cc1ccc(-c2cnc(OC3CCN(C4CCCC4)CC3)nc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.7 %

Procedure:
Cyclopentanone (0.022 mol) and 0.3 N zinc chloride-sodium borocyanide solution (0.55 ml) were added to a methanol solution (3.0 ml) of 2-(piperidin-4-yloxy)-5-(4-cyanophenyl)pyrimidine (46 mg, 0.16 mmol), and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with chloroform. The organic layer was washed with saturated saline solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified through partitioning thin-layer chromatography (chloroform:methanol=10:1) to obtain the entitled compound (50 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH:12][C:13]([C:15]1[N:16]=[C:17](Br)[S:18][CH:19]=1)=[O:14])(=[O:11])=[O:10].[CH3:21][O-:22].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH:12][C:13]([C:15]1[N:16]=[C:17]([O:22][CH3:21])[S:18][CH:19]=1)=[O:14])(=[O:11])=[O:10]
Reactant: C[O-]
Reactant: O=C(NS(=O)(=O)c1c(Cl)cccc1Cl)c1csc(Br)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(=O)NS(=O)(=O)c2c(Cl)cccc2Cl)cs1
Yield: 88.7 %

Procedure:
2.3 g of N-(2,6-dichlorophenylsulfonyl)-2-bromothiazole-4-carboxamide and 1.6 g of sodium methanolate in 45 ml of methanol are refluxed for 12 h. After cooling, the precipitate is filtered off with suction, washed with methanol and then dried under reduced pressure. 1.8 g of N-(2,6-dichlorophenylsulfonyl)-2-methoxythiazole-4-carboxamide with a melting point of 162°-165° C. are obtained. (Active ingredient Example No. 34).