Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH3:33][C:34]([CH3:45])([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35](Cl)=[O:36]>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[C:34]([CH3:33])([CH3:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)C(C)(C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.250 g, 0.573 mmol) in pyridine (3 mL) at 0° C. was treated with 2,2-dimethyl-3-phenylpropanoyl chloride (0.304 g, 1.55 mmol). The reaction mixture was stirred for 10 min at 0° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 5 h. Solvent was removed under reduced pressure to dryness. Dichloromethane (15 mL) and saturated sodium bicarbonate solution (5 mL) were added to the solid. The layers were separated using an Empore extraction cartridge. The organic solvent was removed under reduced pressure. The crude solid was purified by flash chromatography using 10% methanol in dichloromethane, then 15% (methanol with 5% ammonium hydroxide) in dichloromethane as eluent. The crude solid from the previous purification was recrystallized using ethyl acetate and heptane. The precipitate was filtered to give 0.201 g (59%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide. A hot solution of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide (0.201, 0.337 mmol) in ethyl acetate was treated with a hot solution of maleic acid (0.117 g, 1.011 mmol) in ethyl acetate. The precipitate was filtered under nitrogen, and dried under high vacuum to give 0.265 g of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide tri-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 8.46 (s, 1H), 8.241 (s, 1H), 8.107-8.086 (d, 1H, J=8.4 Hz), 7.248-7.183 (m, 7H), 6.170 (s, 6H), 4.697 (m, 1H), 3.883 (s, 3H), 2.931 (s, 3H), 2.9-2.75 (br, s, 4H), 2.671 (s, 3H), 2.104-1.990 (m, 7H), 1.588-1.5632 (m, 2H), 1.226 (s, 7H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.413 min (95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:19][CH:18]([O:20][CH3:21])[CH2:17]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:22][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:33])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH:18]([O:20][CH3:21])[CH2:19]1
Reactant: COC1CN(CCOc2ccc(N)cc2-c2c(Br)cnn2C)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COC1CN(CCOc2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2-c2c(Br)cnn2C)C1
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy)benzenamine (39.2 mg, 0.103 mmol) in CH2Cl2 (4 mL) was added 4-chlorophenyl isocyanate (18.0 mg) and stirred for two hours. The resulting material was purified by HPLC. The product was dried in vacuo to afford the title compound as a white solid (50.7 mg, 92%). LCMS m/z (%)=534 (M+H 79Br, 74), 536 (M+H 81Br, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.79 (bs, 1H), 8.70 (bs, 1H), 7.60 (s, 11H), 7.52 (dd, J=8.95, 2.71 Hz, 1H), 7.47 (d, J=8.94 Hz, 2H), 7.35 (d, J=2.70 Hz, 1H), 7.31 (d, J=8.91 Hz, 2H), 7.09 (d, J=9.03 Hz, 1H), 4.02-3.86 (m, 2H), 3.83 (quint, J=5.80 Hz, 1H), 3.66 (s, 3H), 3.35-3.29 (m, 1H), 3.27-3.18 (m, 1H), 3.08 (s, 311), 2.74-2.56 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[S:10][CH:11]=[CH:12][C:13]=3[Cl:14])=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[S:10][CH:11]=[CH:12][C:13]=4[Cl:14])=[N:6][C:5]=13)=[O:19])[CH2:24]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3sccc3Cl)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cc(Cl)cc3oc(-c4sccc4Cl)nc13)C2
Temperature: 25 °C
Yield: 37 %

Procedure:
A mixture of 6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxylic acid (67 mg, 0.21 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (57 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42 mmol) and 1-hydroxybenzotriazole (57 mg, 0.42 mmol) in DMF (5 mL) was stirred at room temperature, then triethylamine (0.15 mL, 1.05 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (30 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallized from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-(3-chlorothiophen-2-yl)benzoxazole-4-carboxamide (35 mg, 37%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.01 (d, J=6.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.61 (d, J=5.5 Hz, 1H), 7.17 (d, J=5.0 Hz, 1H), 4.63-4.53 (m, 1H), 3.24-3.13 (m, 2H), 2.70-2.55 (m, 5H), 2.12-2.00 (m, 3H), 1.64-1.48 (m, 3H), 1.28-1.12 (m, 2H); MS (ESI+) m/z 450 (M+H); HPLC>99% (AUC), tR=13.32 min.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH:9]([OH:25])/[CH:10]=[CH:11]/[Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO[C:28](OC)([CH3:30])[CH3:29].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH3:29][C:28]1([CH3:30])[O:1][CH:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8][CH:9](/[CH:10]=[CH:11]/[Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH2:19][CH3:20])[O:25]1
Reactant: CCCC[Sn](/C=C/C(O)CC(O)CC(=O)OC)(CCCC)CCCC
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC[Sn](/C=C/C1CC(CC(=O)OC)OC(C)(C)O1)(CCCC)CCCC

Procedure:
A mixture of E-methyl 3,5-dihydroxy-7-tributylstannyl-6-heptenoate (4.18 g), 2,2-dimethoxypropane (18 ml) and pyridinium p-toluene sulfonate (0.227 g) is stirred in anhydrous methylene chloride (4.5 ml) at room temperature for about 20 hours, diluted with ether, washed with saturated sodium bicarbonate solution then saturated sodium chloride solution. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in 10% ether in hexane to give the desired product.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[Br:8][C:9]1[S:10][C:11]2[CH2:12][NH:13][CH2:14][CH2:15][C:16]=2[N:17]=1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C.C(N(CC)CC)C>[Br:8][C:9]1[S:10][C:11]2[CH2:12][N:13]([CH3:2])[CH2:14][CH2:15][C:16]=2[N:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1nc2c(s1)CNCC2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCc2nc(Br)sc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
2-Bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine trifluoroacetate (422 mg) was suspended in dichloromethane (10 ml), triethylamine (0.356 ml) was added, and the mixture was stirred at room temperature for 15 minutes. Acetic acid (0.216 ml) and an aqueous solution (35% solution, 0.202 ml) of formaldehyde were added to the reaction mixture, and the resultant mixture was stirred at room temperature for 2 minutes. Sodium triacetoxyborohydride (428 mg) was added to the reaction mixture, and the resultant mixture was stirred at room temperature for 1 hour. A 1N aqueous solution (10 ml) of sodium hydroxide was added to the reaction mixture and an organic layer was separated. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:1) to obtain the title compound (286 mg) as a pale brown oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[CH:7][N:6]=1)[C:2]#[CH:3].[OH-].[Na+].[I:20]I>C(O)C>[I:20][C:3]#[C:2][CH2:1][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: II
Reactant: C#CCOc1cc(Oc2ccccc2)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: IC#CCOc1cc(Oc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.7 %

Procedure:
To a solution of 0.3 g of 4-(2-propynyloxy)-6-phenoxypyrimidine dissolved in 3 ml of ethanol were added 1.87 ml of 10% sodium hydroxide and 0.51 g of iodine at 0° C. The mixture was stirred at room temperature for 5 hours, and the alcohol was distilled out under reduced pressure. A saturated sodium thiosulfate solution was added to the residue, which was extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of 4-(3-iodo-2-propynyloxy)-6-phenoxypyrimidine (the present compound (171)).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:23][CH3:24])=[O:6]
Reactant: Cc1c(F)cccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(F)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 10 g of 3-fluoro-2-methylbenzoic acid [J. Org. Chem., 26, 3208 (1961)]in 300 ml of dimethylformamide are added 30 g of potassium carbonate and 30 g of ethyl iodide and the mixture is stirred at room temperature for 8 hours. After adding 500 ml of toluene, washing with water and a saturated saline solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure to give 11 g of ethyl 3-fluoro-2-methylbenzoate (oil). Mass spectrum m/z: 182(M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([CH2:14][CH2:15][CH:16]=[CH2:17])[C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].C([N-]C(C)C)(C)C.[Li+].[I:27]I>C1COCC1.CCOCC.[Br-].[Zn+2].[Br-]>[CH3:1][O:2][C:3]([C@@H:4]1[C@H:16]([CH2:17][I:27])[CH2:15][CH2:14][N:5]1[C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])=[O:18]
Reactant: II
Reactant: C=CCCN(CC(=O)OC)[C@@H](C)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)[C@@H]1[C@H](CI)CCN1[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of [but-3-enyl-((S)-1-phenyl-ethyl)-amino]-acetic acid methyl ester [432555-77-6] (20.22 mmol) in THF (10 mL) was slowly added to a solution of lithium diisopropylamide (24.26 mmol) in 1:2 hexanes/THF (30 mL) at −78° C. The reaction mixture was warmed to 0° C., stirred for 1 h and then re-cooled to −78° C. A solution of zinc bromide (50.5 mmol) in Et2O (40 mL) was added and the reaction mixture was then warmed to rt. After stirring for 1 h, the mixture was cooled to 0° C. and iodine (22.24 mmol) was added in portions. The reaction mixture was stirred at 0° C. for 2 h and at rt for another 2 h, diluted with Et2O and then successively washed with a saturated solution of Na2S2O3 and a saturated solution of NH4Cl. The aqueous layers were each back-extracted with Et2O. The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a red oil. HPLC: tR=3.46 min (method G); ESI-MS: [M+H]+ 374.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[C:11]1([O:17][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1cccc(Cl)c1

Procedure:
Phenyl-3-chlorobenzoate is prepared by reacting 3-chlorobenzoyl chloride with phenol in toluene with some pyridine (1 mol equivalent per acid chloride) to trap the HCl that evolves. After aqueous extraction of the pyridinium salt and any excess starting materials, the product is crystallized from the toluene solution.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C1C(=O)N([I:19])C(=O)C1>C(#N)C.C(OCC)(=O)C>[I:19][C:6]1[N:2]([CH3:1])[C:3]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][CH:5]=1
Reactant: Cn1ccnc1-c1cccs1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1c(I)cnc1-c1cccs1
Temperature: 120 °C

Procedure:
To a solution of 1-methyl-2-(2-thienyl)-1H-imidazole (116 mg, 0.706 mmol) in acetonitrile (5 ml) was added NIS (159 mg, 0.706 mmol) at room temperature. The reaction mixture was heated in the Biotage Initiator Series microwave for 1 hour at 120° C. The reaction mixture was diluted in ethyl acetate, washed with 1N aqueous sodium hydroxide and brine then dried over sodium sulfate, filtered and concentrated to give 5-iodo-1-methyl-2-(2-thienyl)-1H-imidazole. The material was taken forward without any additional purification. LRMS (ESI) calculated for C8H8N2SI [M+H]+, 290.9; found 291.0.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]([O:28]CC)=[O:27])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a solution of ethyl 5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrole-2-carboxylate (1.5 g) in a mixed solvent of ethanol (15 mL) and tetrahydrofuran (15 ml) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 70° C. for 3 hr. After cooling to room temperature, the reaction mixture was concentrated, the residue was diluted with ethyl acetate, and 1N hydrochloric acid (10 mL) was added. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.3 g, yield 93%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 404 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17]I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][N:22]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ICCCc1ccc(OCc2ccccc2)cc1
Reactant: CCCNCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)CCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
To a solution of 3-(4-benzyloxyphenyl)propyl iodide (1.790 g) in DMF (20 ml) were added N,N-dipropylamine (1.3 ml) and potassium carbonate (1.391 g). The reaction mixture was stirred at room temperature for 29 hr, diluted with water, and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1) to obtain 3-(4-benzyloxyphenyl)propyl-N,N-dipropylamine (1.589 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:41]([O:44][CH2:45][CH2:46][CH2:47][NH2:48])([CH3:43])[CH3:42]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:48][CH2:47][CH2:46][CH2:45][O:44][CH:41]([CH3:43])[CH3:42])=[O:16])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: CC(C)OCCCN
Product: CC(C)OCCCNC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 3-isopropoxypropylamine (34 mg) according to Method B to give the title compound (34 mg). 1H-NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.28-7.17 (m, 5H), 7.03 (d, J=8.6 Hz, 1H), 4.80 (s, 2H), 4.50 (m, 1H), 4.24 (dd, J=5.1 Hz, J=9.3 Hz, 1H), 3.54 (t, J=6.1 Hz, 1H), 3.35 (m, 2H), 3.23 (m, 1H), 3.14 (m, 1H), 3.08-2.91 (m, 3H), 2.75 (dd, J=9.6 Hz, J=13.5 Hz, 1H), 1.63 (m, 2H), 1.35 (s, 9H), 1.12 (dd, J=2.0 Hz, J=6.1 Hz); IR (KBr) cm−1; HRMS m/z 629.2946 (calc. of monoisotopic mass for C32H43N3O10 gives 629.2948).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[C:5]([O:20][CH2:21][CH:22]2[CH2:24][O:23]2)[CH:4]=1>C(OCC)(=O)C>[Cl:1][CH2:24][CH:22]([OH:23])[CH2:21][O:20][C:5]1[CH:4]=[C:3]([OH:2])[C:16]2[C:15](=[O:17])[C:14]3[C:9]([O:8][C:7]=2[CH:6]=1)=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][CH:13]=3
Reactant: Cl
Reactant: COc1cccc2c(=O)c3c(O)cc(OCC4CO4)cc3oc12
Solvent: CCOC(C)=O
Product: COc1cccc2c(=O)c3c(O)cc(OCC(O)CCl)cc3oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Aqueous ethyl acetate 1M-HCl (3 mL) was added to 1-hydroxy-5-methoxy-3-(oxiran-2-ylmethoxy)-9H-xanthen-9-one (30 mg, 0.10 mmol) synthesized in Step 2 of Example 1, followed by stirring at room temperature for 30 minutes, and the reaction solvent was removed under reduced pressure. Ether was added to the residue, followed by sonication, and the solvent was removed to obtain the title compound (31 mg, 92%) as a light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10](=[O:27])[NH:11][C:12]2[CH:25]=[CH:24][C:15]([O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:26])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:36]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:27])[NH:11][C:12]2[CH:25]=[CH:24][C:15]([O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:26])=[O:8])=[CH:28][CH:29]=1)(=[S:36])[NH2:2]
Reactant: Cc1cc(OCC(=O)OC(C)C)ccc1NC(=O)NC(=O)c1ccc(C#N)cc1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(=O)OC(C)C)ccc1NC(=O)NC(=O)c1ccc(C(N)=S)cc1

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (11.36 g), pyridine (500 ml), triethylamine (70 ml) and H2S gas were reacted to give isopropyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-3-methylphenoxyacetate (12.23 g) as a yellow solid: NMR Spectrum (DMSO-d6) 1.24 (6H, d), 2.28 (3H, s), 4.69 (2H, s), 5.01 (1H, m), 6.78 (1H, dd), 6.85 (1H, d), 7.77 (1H, d), 7.96 (2H, d), 8.05 (2H, d), 9.65 (1H, br s), 10.04 (1H, br s), 10.56 (1H, s), 11.11 (1H, s); Mass Spectrum m/Z 452 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=O)OCC)=[CH:4][CH:3]=1.[C:25]1([NH:35][NH2:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:13]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[N:35]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[N:36]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=NC(=O)c1cccc2ccccc12)c1ccc(Br)cc1
Reactant: NNc1cccc2ccccc12
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1ccc(-c2nc(-c3cccc4ccccc34)n(-c3cccc4ccccc34)n2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The compound obtained in step A) (1.0 g, 0.026 mol) and 1-naphthyl hydrazine (0.45 g, 0.028 mol) is dissolved in CCl4 (15 ml) and stirred for 10 hours at 25° C. under a nitrogen atmosphere. The reaction mixture is stirred for 12 hours and filtered to remove traces of insoluble particles. The CCl4 solution is then concentrated and a few drops of methanol are added to the residue, wherein a brownish solid is obtained (Yield=0.7 g (56%)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH:11]([O-])([O-])OCC>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:3]=1[N:10]=[CH:11][NH:9]2
Reactant: CCOC([O-])[O-]
Reactant: Cc1nc(N)c(N)c(Cl)n1
Product: Cc1nc(Cl)c2nc[nH]c2n1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
6-Chloro-2-methylpyrimidine-4,5-diamine (8.89 g, 56.1 mmol, the material from Step 1) was suspended in ethyl orthoformate (100 mL, 601 mmol) in a flask fitted with a reflux condenser and placed in a preheated oil bath (100° C.) and stirred for 75 minutes. Then, the reaction was cooled to room temperature, concentrated, treated with hexanes and filtered. The solid washed with hexanes, collected, and taken on to Step 3. MS (ESI pos. ion) m/z: 169. Calculated exact mass for C6H5ClN4: 168.