Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](O)[C:7]2[S:12][CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:3])[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:18]>C(Cl)(Cl)Cl>[Cl:18][C:6]1[C:7]2[S:12][CH:11]=[CH:10][C:8]=2[N:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: CC(C)c1nc(O)c2sccc2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(Cl)c2sccc2n1
Yield: 99 %

Procedure:
A suspension of 2-isopropylthieno[3,2-d]pyrimidine-4-ol (1.66 g, 8.56 mmol) in POCl3 (30 mL) was refluxed for 1 h, cooled, diluted with chloroform (100 mL) and poured into a mixture of ice and NH4OH (150 mL). The organic phase was separated, washed with saturated NaHCO3 (20 mL), water and brine, dried (MgSO4) and concentrated in vacuo to give the title compound (2.01 g, 99%) as a pale yellow solid: IR νmax (Nujol)/cm−1 3065, 2960, 2926, 2855, 1561, 1513, 1457, 803; NMR δH (400 MHz, CDCl3) 1.40 (6H, d J 6.5 Hz), 3.38 (1H, heptet, J 6.5 Hz), 7.60 (1H, d J 5.0 Hz), 8.05 (1H, d, J 5.0 Hz).
Reaction SMILES: C(OC([N:7]1[CH2:11][CH:10]=[C:9]([C:12]2[N:13]=[C:14]([S:17][C:18]3[C@H:24]([CH3:25])[C@H:23]4[N:20]([C:21](=[O:29])[C@@H:22]4[C@H:26]([OH:28])[CH3:27])[C:19]=3[C:30]([O:32]CC=C)=[O:31])[S:15][CH:16]=2)[C@H:8]1[CH2:36][OH:37])=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>ClCCl.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>[OH:28][C@@H:26]([C@H:22]1[C:21](=[O:29])[N:20]2[C@@H:23]1[C@@H:24]([CH3:25])[C:18]([S:17][C:14]1[S:15][CH:16]=[C:12]([C:9]3[C@@H:8]([CH2:36][OH:37])[NH:7][CH2:11][CH:10]=3)[N:13]=1)=[C:19]2[C:30]([OH:32])=[O:31])[CH3:27]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@@H]3CO)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(Sc3nc(C4=CCN[C@@H]4CO)cs3)[C@H](C)[C@H]12
Reaction time: 0.05 h
Yield: 48.4 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-({4-[(2S)-1-[(allyloxy)carbonyl]-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1,3-thiazol-2-yl}sulfanyl)-6-[(1R)-1-hydoxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (33 mg, 0.06 mmol) in dicloromethane (3 ml) were added at 0° C. acetic acid (8.6 μl, 0.15 mmol), tributyltin hydride (165 ml, 0.61 mmol) and bis(triphenylphosphine)palladium chloride (4.2 mg, 0.006 mmol), and the mixture was stirred at the same temperature for 3 minutes. To the reaction mixture were added phosphate buffer (50 mM, pH7, 25 ml) and dichloromethane (5 ml). After separation of the aqueous layer, the dichloromethane layer was extracted twice with water and the aqueous layer was washed twice with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with 1–3% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-({4-[(2S)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1,3-thiazol-2-yl}sulfanyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (12.3 mg, 48%) as a white amorphous.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:18][CH:19]([CH2:23][NH:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])[C:20]([OH:22])=O)=[O:17])(=[O:13])=[O:12].[CH3:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[CH3:39][CH:40]1[CH2:45][CH2:44][N:43]([C:20]([CH:19]([NH:18][C:16](=[O:17])[CH2:15][NH:14][S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:12])=[O:13])[CH2:23][NH:24][C:25]([CH:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[CH2:31][CH2:32]2)=[O:26])=[O:22])[CH2:42][CH2:41]1
Reactant: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)O
Reactant: CC1CCNCC1
Product: CC1CCN(C(=O)C(CNC(=O)C2CCN(c3ccncc3)CC2)NC(=O)CNS(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 22 %

Procedure:
Using an analogous procedure to that described in Example 20, 2-[2-(2-naphthalenesulphonamido)acetamido]-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionic acid was reacted with 4-methylpiperidine to give N-{1-(4-methylpiperidin-1-ylcarbonyl)-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}-2-(2-naphthalenesulphonamido)acetamide in 22% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([OH:33])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1.[CH2:38]1CCN2C(=NCCC2)CC1.IC>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([O:33][CH3:38])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(C(=O)O)C2c1ccc2c(c1)OCO2
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CI
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.9 %

Procedure:
To a solution of (1RS,2SR,3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (1.98 g, 3.91 mmol) in acetonitrile (15 ml) was added DBU (0.655 g, 4.3 mmol) followed by iodomethane (2.77 g, 19.5 mmol). The reaction mixture was stirred at room temperature 3.5 h then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo to provide the title compound (1.79 g, 88%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH:16]1[CH2:19][CH2:18][CH2:17]1>CS(C)=O>[N:16]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: C1CNC1
Reactant: Brc1cccc(Br)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Brc1cccc(N2CCC2)n1
Temperature: 80 °C
Yield: 33.2 %

Procedure:
To a solution of 2,6-dibromopyridine (100 mg, 0.424 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (175.4 mg, 1.27 mmol) and azetidine hydrogen chloride (24.2 mg, 0.424 mmol) at room temperature. The reaction mixture was heated to 80° C. for 16 h, then was poured into ice cold water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and concentrated under reduced pressure to afford 2-(azetidin-1-yl)-6-bromopyridine (30 mg)
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]([C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH:39]=[CH:40][CH:41]=2)[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35](=[O:38])(=[O:37])[NH2:36])=[O:27])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C)C1C=CN=CC=1>[C:13]([C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH:39]=[CH:40][CH:41]=2)[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH:36][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:37])=[O:38])=[O:27])=[CH:19][CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Agent: CN(C)c1ccncc1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
In a stream of nitrogen and at 0° C., 0.24 ml (1.10 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuan (10 ml) solution containing 438 mg (1.00 mmol) of 3-(4-t-butylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 2 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 535 mg (yield: 99.0%) of the title compound.
Reaction SMILES: Cl.[Sn].[N+:3]([C:6]1[CH:7]=[C:8]([S:13](Cl)(=O)=O)[CH:9]=[CH:10][C:11]=1[Cl:12])([O-])=O>>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([SH:13])=[CH:7][C:6]=1[NH2:3]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Agent: [Sn]
Product: Nc1cc(S)ccc1Cl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a mixture of 100 g of chipped ice and 120 g of concentrated hydrochloric acid (35%), 120 g of metallic tin was added and then 25.4 g of 3-nitro-4-chlorobenzenesulfonyl chloride was added thereto. The mixture was stirred for one and a half hours while maintaining the temperature at 0° C. Then, the temperature was increased to 80° C. to 90° C. and the mixture was stirred with heating at the same temperature for 2 hours. After the completion of the reaction, the reaction solution was kept for one day in a cold place (at about -5° C. to about 10° C.). The crystals formed were collected and thoroughly washed with water. From the water used for the washing and the filtrate, newly formed crystals were also recovered and were added to the first crystals obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:11]([C:9]2[CH:10]=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1cc(F)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2cc(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
66 mg (0.33 mol) of 5-fluoro-1H-indol-7-carboxylic acid, 91 mg (0.30 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine and 63 mg (0.33 mmol) of EDC.HCl were dissolved in 3 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 7:3) to yield 100 mg (72%) product as a light yellow viscous oil. MS (ISP) 463.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]([CH3:15])[CH2:11][C@@H:12](O)[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:12]([CH3:13])[CH2:11][N:10]([CH3:15])[CH3:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C[C@H](O)CN(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](CN(C)C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromophenol (0.2 g, 1.16 mmol) and (S)-(+)-1-dimethylamino-2-propanol (0.14 ml, 1.16 mmol) were dissolved in dichloromethane (10 ml). PS-Triphenylphospine (1.74 g, 1.74 mmol) was added, followed by di-tert-butyl azodicarboxylate (0.4 g, 1.74 mmol). The mixture was stirred overnight at room temperature, then filtered and the filtrate washed with sodium hydrogenocarbonate then brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield: 0.3 g, 100%. LCMS method: 2, RT: 2.62 min; MI: 258-260 [M+1].
Reaction SMILES: [CH2:1]([CH:8]([O:10][P:11]([CH2:14][C:15]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1)([OH:13])=[O:12])C)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:8]([O:10][P:11]([CH2:14][C:15]1([C:20]([OH:22])=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]1)([OH:13])=[O:12])[CH3:1]
Reactant: CC(Cc1ccccc1)OP(=O)(O)CC1(C(=O)O)CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(O)CC1(C(=O)O)CCCC1
Yield: 102.6 %

Procedure:
3.5 g of 1-benzylethylphosphonomethyl-1-cyclopentanecarboxylic acid (preparation see Example 3E)) were dissolved in 150 ml of ethanol and treated with 1.0 g of 5% strength Pd catalyst on active carbon. The mixture was then hydrogenated at a hydrogen pressure of 2.1 bar for 4 hours. The catalyst was filtered out twice, the filtrate was evaporated in vacuo, and the residue was dried in a high vacuum. 2.60 g of oily 1-ethylphosphonomethyl-1-cyclopentanecarboxylic acid were obtained, which was reacted without further purification.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][O:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36]([OH:38])=O)=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][O:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:38])=[CH:25][C:24]=3[CH:39]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccoc2)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccoc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (155 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (115 mg) and triethylamine (526 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 4.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 62) (125 mg) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a stirred solution of (1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methanol (4.02 g, 20.0 mmol), methyl 4-hydroxybenzoate (3.04 g, 20.0 mmol) and Ph3P (6.28 g, 24.0 mmol) in THF (50 ml) was added DIAD (4.85 g, 24.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give methyl 4-(1-tert-butoxycarbonyl(2S)-pyrrolidinyl)methoxybenzoate (5.4 g, 81%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.47 (s, 9H), 1.88-2.04 (m, 4H), 3.41 (m, 2H), 3.91 (s, 3H), 3.90-3.92 (m, 1H), 4.11-4.16 (m, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.94 (d, J=8.3 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>CN(C=O)C>[CH3:19][C:10]1[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:1]=[C:24]=[S:25])[CH:3]=2)[C:9]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N=C=S)c1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyrazinedicarboxylic acid, dimethyl ester (3.8 mmol) in 16 mL of DMF was slowly added into a DMF solution (20 mL) of 1,1′-thiocarbonyldiimidazole (5.2 mmol) and the reaction went to completion in 0.5 hours. After DMF was removed in vacuo, the residue was purified by chromatography on silica gel eluted with 50% (v/v) ethyl acetate in hexanes to give the title compound as a yellow powder (1.19 g, 87%); 1H-NMR (CDCl3) δ 7.09 (t, 1H, J=8.1 Hz), 6.73 (dd, 1H, J=7.8, 1.9 Hz), 6.59 (dd, 1H, J=8.3, 2.4 Hz), 6.47 (t, 1H, J=2.1 Hz), 6.06 (s, 1H), 3.79 (s, 6H), and 2.43 (s, 6H); 13C-NMR (CDCl3) δ 166.0, 151.7, 149.1, 131.3, 129.6, 117.7, 112.6, 110.3, 108.9, 52.0, and 18.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19]Cl)=[CH:7]2.C(N(CC)C(C)C)(C)C.[I-].[Li+].[NH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[CH:7]2
Reactant: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: NN1CCOCC1
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccccc1-c1nc2c(Cl)cccc2cc1CNN1CCOCC1
Temperature: 50 °C
Reaction time: 19 h

Procedure:
To a mixture of 8-chloro-3-(chloromethyl)-2-(2-chlorophenyl)quinoline (Prepared in Example 2), N,N-diisopropylethylamine (0.584 mL, 3.35 mmol), and lithium iodide (0.00566 mL, 0.148 mmol) in 7 mL of DMF was added 4-aminomorpholine (0.0647 mL, 0.670 mmol) and the mixture was stirred at 50° C. After 19 h, the mixture was concentrated under reduced pressure to give an yellow oil. The crude mixture was purified by column chromatography on a 40 g of Redi-Sep™ column using 0-100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 10 min as eluent to give N-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)morpholin-4-amine as a light yellow foam (syrup): 1H NMR (400 MHz, choroform-d) δ ppm 8.39 (1H, s), 7.73-7.88 (2H, m), 7.37-7.53 (5H, m), 3.78-4.07 (2H, m), 3.64 (4H, t, J=4.7 Hz), 2.53 (4H, s); LC-MS (ESI) m/z 388.0 and 390.1 [M+H]+.
Reaction SMILES: [C:1](C(N)CN)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C([N:24](CC)CC)C>CN(C=O)C>[C:1]([NH2:24])([O:3][CH2:4][CH:5]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CCN(CC)CC
Reactant: NCC(N)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.17 h

Procedure:
To a solution of Fmoc-1,2-diaminoethane (0.06 mmol) in 0.4 mL DMF at 0° C., is added triethylamine (0.12 mmol) followed by dropwise addition of DOTA(OtBu)3 NHS ester (0.05 mmol) in 0.5 mL DMF for 10 min with stirring. After 10 min, the ice bath is removed and stirring is continued at room temperature (RT) for 6 h. The reaction mixture is poured over 2 mL ice-cold water and purified by preparative HPLC. After concentration and lyophilization, Fmoc amine monomer 23 is obtained which is further treated with 1 mL 20% piperidine in DMF, and the solution is stirred at RT for 30 min. The reaction mixture is poured over 2 mL ice-cold water and purified by preparative HPLC. After lyophilization, DOTA(OtBu)3-aminoethane 24 is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:28]=[CH:27][S:26][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:28]=[CH:27][S:26][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:29][C:30]4[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=4)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(N3CCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.2 %

Procedure:
A mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxylic acid (95 mg, 0.236 mmol), tert-butyl 4-aminobenzoate (59 mg, 0.306 mmol), HATU (116 mg, 0.306 mmol) and DIEA (91 mg, 0.708 mmol) in 10 mL of DMF was stirred at room temperature for 72 hours. The solvent was evaporated at 80° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:1)) to give tert-butyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxamido)benzoate (105 mg, 77%) as a solid. LC-MS: 577.2 [M+H]+, tR=1.69 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[C:4]([OH:9])[CH:3]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(Cl)c(Cl)cc1O
Temperature: 20 °C
Reaction time: 8 h
Yield: 1029.6 %

Procedure:
A solution of 3,4-dichlorophenol [AK Scientific] (30 g, 18 mmol) in acetyl chloride (19 mL, 270 mmol) was stirred at 60° C. for 2 hours. The reaction mixture was cooled to 20° C., treated with aluminum trichloride (37 g, 280 mmol) portionwise, and heated at 180° C. for 30 minutes. The reaction mixture was cooled to 20° C. and the solution hardened into a solid block that was not easy to break apart. This material was cooled to 0° C. and quenched slowly with 1 M HCl in portions. The solid block of material slowly broke apart with enough HCl and this heterogenous mixture was stirred at 20° C. overnight to ensure uniformity. The solid was filtered, washed with copious amounts of water, and dried under vacuum to give the desired product (38 g, quantitative) as a tan solid.