Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([C:8]([NH2:10])=O)[CH2:4][CH:5]([CH3:7])[CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(O)C>[ClH:1].[ClH:1].[NH2:10][CH2:8][CH:3]([NH2:2])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)CC(N)C(N)=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)CC(N)CN
Yield: 149.1 %

Procedure:
To a stirred slurry of D,L-leucine amide hydrochloride (50.0 g, 0.300 mole) in anhydrous THF (500 ml) at room temperature under a dry argon atmosphere was added a solution of lithium aluminum hydride (1200 ml -1.0M in THF, 1.20 mole) over a 15 minute period. The mixture was refluxed for 8 h and then quenched by the dropwise addition of H2O (200 ml) while cooling in an ice bath. The mixture was filtered to remove solid and the filtrate was retained. The solid was washed with THF (100 ml) and slurried in hot THF (2×1.0 l). The THF filtrates and washings were combined and the solid was discarded. The THF solution was acidified to pH 1 with concentrated HCl. The solvent was removed in vacuo to give a pale yellow oil. The oil was dissolved in ethanol and the solvent was removed in vacuo to give an oil which crystallized. The crude material was purified by recrystallization from MeOH-ethyl ether to give 42.3 g (75% yield) of the product as a white crystalline solid: mp 228°-30° C.; 1H NMR (DMSO-d6) δ0.89 (d, J=6.5 Hz, 3 H), 0.90 (d, J=6.5 Hz, 3 H), 1.51 (t, J=7.2 Hz, 2 H), 1.75 (Sept, J=6.7 Hz, 1 H), 3.08 (m, 2 H), 3.49 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:18](=[O:20])[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:12](=[O:22])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O.CC1(C)[O:47][C@@H:46]([CH2:48][O:49]N)[CH2:45][O:44]1>CC(N(C)C)=O>[OH:47][C@H:46]([CH2:48][OH:49])[CH2:45][O:44][N:17]1[C:18](=[O:20])[C:19]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:11][C:12](=[O:22])[N:13]([CH3:21])[C:14]=2[N:15]=[CH:16]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc21
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(OC[C@H](O)CO)cnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 13.2 %

Procedure:
Compound 5F (1.31 g, 3.17 mmol), potassium carbonate (1.1 g, 7.92 mmol) and 1-chloro-2,4-dinitrobenzene (1.60 g, 7.92 mmol) were stirred in DMA at 80° C. for 2 hours. (R)-O-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (4.66 g, 31.7 mmol) was added at r.t and the reaction was stirred for 1 hour at 80° C. Purification by prep-HPLC gave 210 mg (13%) of the title compound as a clear yellow solid (Deprotection occurred while concentrating the purification fractions containing 0.5% of TFA). 1H NMR (400 MHz, DMSO-d6): 6 ppm 10.18 (s, 1H) 8.93 (s, 1H) 7.81 (dd, J=10.11, 1.77 Hz, 1H) 7.62 (dd, J=7.58, 1.01 Hz, 1H) 7.37 (t, J=8.46 Hz, 1H) 5.56 (s, 1H) 4.39 (dd, J=10.74, 3.16 Hz, 1H) 4.21 (dd, J=10.61, 7.33 Hz, 1H) 3.82-3.88 (m, 1H) 3.50 (s, 3H) 3.42-3.46 (m, 2H). MS (ES) [m+H] calc'd for C17H16FIN4O5, 503; found 503.
Reaction SMILES: [I-].C[O:3][CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5]1.[CH3:30][C:31](C)=[O:32].C(=O)=O.CC(C)([O-])C.[K+]>C1COCC1>[CH:31]([CH2:30][CH2:10][CH:7]1[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]1)=[O:32]
Reactant: CC(C)=O
Reactant: COC1CCC(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [I-]
Solvent: C1CCOC1
Product: O=CCCC1CCC(=O)CC1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
In a 1 l, three-necked flask equipped with a stirrer, a thermometer and a nitrogen gas-introducing tube, (4-methoxycyclohexyl)methyltriphenylphosphine iodide (175.6 g, 0.34 mol) was suspended in THF (500 ml) in a nitrogen gas atmosphere, followed by cooling the suspension down to -30° C. or lower by means of acetone-dry ice refrigerant carrier, adding potassium-t-butoxide (40.1 g, 0.36 mol), and agitating the mixture for 2 hours, while keeping the temperature at -30° C. or lower. A solution of 4-(2-formylethane-1-yl)cyclohexanone (41.2 g, 0.27 mol) obtained according to the above process, dissolved in THF (150 ml), was dropwise added over 40 minutes, while keeping the same temperature, followed by elevating the temperature up to room temperature over one hour, further agitating the mixture at room temperature for 4 hours, adding water (300 ml) to the reaction solution to complete the reaction, three times extracting with toluene (300 ml), three times washing the toluene layer with water (300 ml), drying the layer over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, for concentration, and purifying the concentrated residue according to silica gel chromatography using a mixed solvent of toluene/ethyl acetate (2:1) as a developing solvent, to obtain yellow-brown crystals (65.0 g). The crystals refer to (4-(trans-4-methoxycyclohexyl)-(E,Z)-3-butenyl)cyclohexanone.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=2[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:20][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[C:7]([C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: OCc1ccc(OCC2CC2)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(CCl)ccc1OCC1CC1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
To a solution of (4-(cyclopropylmethoxy)-3-(trifluoromethyl)phenyl)methanol (0.258 g, 1.454 mmol) in toluene (4 mL) was added thionyl chloride (0.637 mL, 8.72 mmol). The reaction was stirred at 75° C. for 1.5 h. The reaction mixture was poured into ice water and extracted with hexanes (twice). The combined extracts were washed with NaHCO3 (thrice), dried over MgSO4 and concentrated to give the title compound as a white solid (0.275 g). 1H NMR (400 MHz, CDCl3) δ ppm 0.36-0.43 (m, 2H), 0.59-0.67 (m, 2H), 1.21-1.34 (m, 1H), 3.95 (d, J=6.44 Hz, 2H), 4.56 (s, 2H), 6.95 (d, J=8.59 Hz, 1H), 7.48 (dd, J=8.53, 2.34 Hz, 1H), 7.58 (d, J=2.15 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.CCCCCCC.C(OCC)(=O)C>O1CCCC1.O>[F:15][C:14]1([F:16])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9][C@@:8]1([C:6]1[CH:7]=[C:2]([C:26]2[CH:27]=[N:22][CH:23]=[N:24][CH:25]=2)[CH:3]=[CH:4][C:5]=1[F:21])[CH3:20]
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Reactant: OB(O)c1cncnc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cncnc3)ccc2F)C1(F)F
Yield: 84.8 %

Procedure:
In analogy to the procedure described in Example 1 (method A), the reaction of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (311 mg, 849 μmol) and pyrimidin-5-boronic acid (116 mg, 934 μmol) in tetrahydrofuran (8 ml) and water (4 ml) with [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) dichloromethane complex (34.7 mg, 42.5 μmol) as the catalyst yielded, after chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 10:90 as the eluent, the (R)-6,6-difluoro-5-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-5,7,7-trimethyl-1,4-oxazepan-3-one (263 mg, 85% yield) as a white foam. MS (ISP): m/z=366.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:39]=[CH:38][C:12]([C:13]([NH:15][CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:37])[CH2:23][CH2:24][CH2:25][NH:26]C(=O)OCC2C=CC=CC=2)=[O:14])=[C:11]([NH:40][CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[N:10]=1)#[N:2].[Si](I)(C)(C)C>CC#N>[NH2:26][CH2:25][CH2:24][CH2:23][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@@H:17]1[CH2:16][NH:15][C:13](=[O:14])[C:12]1[CH:38]=[CH:39][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[N:10][C:11]=1[NH:40][CH2:41][CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1)=[O:37]
Reactant: N#Cc1ccccc1-c1ccc(C(=O)NC[C@H]2CCCN2C(=O)CCCNC(=O)OCc2ccccc2)c(NCCC2CCCCO2)n1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: N#Cc1ccccc1-c1ccc(C(=O)NC[C@H]2CCCN2C(=O)CCCN)c(NCCC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of benzyl 4-((R)-2-((6-(2-cyanophenyl)-2-(2-(tetrahydro-2H-pyran-2-yl)ethylamino)nicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (47 mg, 0.072 mmol) in MeCN (1 mL) at 0° C. was added TMSI (72 mg, 0.36 mmol). The mixture was stirred at room temperature for 2 hrs and purified on RP-HPLC using a mixture of acetonitrile and H2O to give N—(((R)-1-(4-aminobutanoyl)pyrrolidin-2-yl)methyl)-6-(2-cyanophenyl)-2-(2-(tetrahydro-2H-pyran-2-yl)ethylamino)nicotinamide (36 mg, 77%). LRMS (M+H+) m/z 519.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:16](Cl)([Cl:18])=[O:17].C1(C)C=CC=CC=1>C1COCC1.C(OCC)C>[O:7]=[S:4]1(=[O:8])[CH2:5][CH2:6][N:1]([C:16]([Cl:18])=[O:17])[CH2:2][CH2:3]1
Reactant: O=C(Cl)Cl
Reactant: O=S1(=O)CCNCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCS(=O)(=O)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Thiomorpholine 1,1-dioxide (3 g; 22.192 mmol) is dissolved in THF (70 mL) and cooled to 0° C. Triethylamine (3.708 mL; 26.6 mmol) is added, followed by 20% phosgene in toluene (35.229 mL; 66.6 mmol). The reaction mixture is stirred at room temperature for 18 hours. After this time, the reaction mixture is poured into ethyl ether (200 mL), then filtered through Celite®. The Celite® is washed with ethyl ether several times and the combined filtrates are concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, d-CDCl3): δ 3.1-3.2 (m; 4H), 4.1-4.3 (d, 4H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[C:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][C:8]2[O:13][CH:12]=[CH:11][C:10](=[O:14])[C:9]=2[CH:15]=1>C(O)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[C:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][C:8]2[O:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=2[CH:15]=1
Reactant: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccc(F)cc1F
Agent: [Pd]
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)C(=O)CCO2
Yield: 85.6 %

Procedure:
3.67 g of 6-(2,4-difluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one was suspended in 60 ml of acetic acid. Thereto was added 400 mg of 5% palladium-carbon. The mixture was subjected to hydrogenation at 40°-50° C. at atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration. The filtrate was concentrated. The resulting crystal was recrystallized from ethanol to obtain 3.16 g (yield: 85.6%) of 6-(2,4-difluorophenoxy)-2,3-dihydro-7-methylsulfonylamino-4H-1-benzopyran-4-one having a melting point of 163.5°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]=[O:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].Br[C:37]1[CH:42]=[CH:41][C:40]([CH:43]([F:45])[F:44])=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]([C:37]1[CH:42]=[CH:41][C:40]([CH:43]([F:45])[F:44])=[CH:39][CH:38]=1)[OH:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: FC(F)c1ccc(Br)cc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(C(F)F)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole-3-carboxaldehyde obtained in Example 29-(1) and 1-bromo-4-difluoromethylbenzene were treated in a manner similar to Example 25-(2) to give crude 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indol-3-yl 4-(difluoromethyl)phenyl methanol, which was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][N+:8]([O-:10])=[O:9])=[NH:6])[CH2:3][CH2:2]1.C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH:1]1([NH:4][C:5]([N:6]=[CH:14][N:15]([CH3:17])[CH3:16])=[N:7][N+:8]([O-:10])=[O:9])[CH2:3][CH2:2]1
Reactant: N=C(NC1CC1)N[N+](=O)[O-]
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=NC(=N[N+](=O)[O-])NC1CC1
Reaction time: 1.5 h

Procedure:
14.4 g of N-cyclopropyl-N'-nitroguanidine are added to 14.7 g of N,N-dimethylformamide-diethyl-acetal. After stirring at 70°-75° C. for 1.5 hours, the mixture is cooled and concentrated using a rotary evaporator. The crude product is stirred into diethyl ether, filtered off and washed with further diethyl ether, yielding N-cyclopropyl-N'-(N,N-dimethylaminomethylene)-N"-nitroguanidine (m.p.: 120°-122° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.C=O.[C:18](O)(=O)C.C(OCC)(=O)C>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@H:9]2[CH2:13][CH2:12][N:11]([CH3:18])[CH2:10]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CS[C@H]2CCNC2)cc1
Reactant: CC(=O)O
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1ccc(CS[C@H]2CCN(C)C2)cc1
Reaction time: 0.25 h

Procedure:
750 mg of (3S)-3-(4-methoxybenzylthio)pyrrolidine [which had been prepared by neutralization of 900 mg of (3S)-3-(4-methoxybenzylthio)pyrrolidine hydrochloride, prepared as described in step (3) above, with sodium bicarbonate] were dissolved in 15 ml of dry acetonitrile, and 1.44 ml of a 35% by volume solution of formaldehyde in water was added to the solution. The reaction mixture was then stirred for 15 minutes, after which it was neutralized by the addition of acetic acid; it was then again stirred for a further 2.5 hours. At the end of this time, the reaction mixture was poured into 200 ml of ethyl acetate, and the mixture was washed with a 2N aqueous solution of potassium hydroxide and an aqueous solution of sodium chloride. The organic layer was dried over potassium carbonate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 3:1 by volume mixture of ethyl acetate and methanol), to afford 349 mg of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[C:25]([F:28])([F:27])[F:26])=[O:5])[CH3:2].[CH3:37][NH:38][CH3:39]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:38]([CH3:39])[CH3:37])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[C:25]([F:27])([F:26])[F:28])=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2c(C(F)(F)F)cc(Cl)cc2c1Cc1ccccc1Cl
Product: CCOC(=O)c1c(N(C)C)nc2c(C(F)(F)F)cc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 29 step D from 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (80 mg, 0.14 mmol) and dimethylamine (3 ml, 2M solution in THF). Off white solid (45 mg, 69%). LC-MS (ESI): 471 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([Cl:18])=[CH:9][C:10]=1[O:11][CH2:12][C:13]([O:15]CC)=[O:14])=[O:5])C.Cl>[OH-].[Na+]>[C:4]([C:6]1[S:7][C:8]([Cl:18])=[CH:9][C:10]=1[O:11][CH2:12][C:13]([OH:15])=[O:14])([OH:5])=[O:3]
Reactant: CCOC(=O)COc1cc(Cl)sc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COc1cc(Cl)sc1C(=O)O
Temperature: 20 °C
Yield: 90.9 %

Procedure:
A mixture of 2.26 g of the product of Step B and 40 ml of 2N sodium hydroxide was refluxed under nitrogen for 45 minutes and the mixture was cooled to 20° C. 12 ml of 10N hydrochloric acid were added thereto and the mixture was vacuum filtered. The precipitate was washed twice with iced water to obtain 1.66 g of (2-carboxy-5-chloro-3-thienyl)oxyacetic acid melting at 214° C.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:45]=[CH:44][C:39]2[N:40]=[C:41]([CH3:43])[S:42][C:38]=2[CH:37]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:45]=[CH:44][C:39]5[N:40]=[C:41]([CH3:43])[S:42][C:38]=5[CH:37]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: Cc1nc2ccc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)cc2s1
Agent: Cl
Product: Cc1nc2ccc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5[nH]cnc45)c3F)cc2s1
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2-methylbenzo[d]thiazole-6-sulfonamide (21 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:8]=1>CO.C(#N)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:18])[F:19])[N:8]=1
Reactant: COCCN
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Solvent: CC#N
Solvent: CO
Product: COCCNc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 2-methoxyethanamine (59 μl, 0.69 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (66 mg, 0.25 mmol) in acetonitrile (2 mL). The reaction was stirred at rt over night. The reaction mixture was concentrated in vacuo and the crude was purified by preparative HPLC to give the title compound as a solid, 43 mg (57%).
Reaction SMILES: [P:1]([O:20][CH2:21][CH2:22][NH:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O:11][CH2:12][CH2:13][O:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])([O:3]CC1C=CC=CC=1)=[O:2].[I-].[Na+:44]>CC(C)=O>[P:1]([O-:3])([O:20][CH2:21][CH2:22][NH:23][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([O:11][CH2:12][CH2:13][O:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:2].[Na+:44]
Reactant: C=C(C)C(=O)OCCOP(=O)(OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCOP(=O)([O-])OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Specifically, the desired zwitterionic monomer represented by the Chemical Formula 16 can be obtained as follows. 2-Iodoethyl methacrylate and silver benzyl 2-(tritylamino)ethyl phosphate are refluxed in toluene, and thus benzyl 2-(methacryloyloxy)ethyl 2-(tritylamino)ethyl phosphate can be obtained. Next, benzyl 2-(methacryloyloxy)ethyl 2-(tritylamino)ethyl phosphate and sodium iodide are refluxed in acetone, and thus sodium 2-(methacryloyloxy)ethyl 2-(tritylamino)ethyl phosphate can be obtained. Next, sodium 2-(methacryloyloxy)ethyl 2-(tritylamino)ethyl phosphate is heated in 90% acetic acid under stirring, and thus the desired zwitterionic monomer represented by the Chemical Formula 16 can be obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2([CH:21]=[CH:20][NH:19][CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.[Pd]>[CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C2(C=CNCC2)N1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C2(CCNCC2)N1Cc1ccccc1

Procedure:
To a solution of 2-benzyl-2′,3′-dihydro-1′H-spiro[isoindole-1,4′-pyridin]-3(2H)-one (3.6 mmol) in HOAc (20 ml) is added 10% Pd on C (100 mg) and the mixture is hydrogenated at 50 psi overnight. The catalyst is filtered and washed with methanol (2×10 ml) and the combined filtrate is evaporated to dryness. The residue is partitioned between aqueous NaHCO3 solution (30 ml) and EtOAc (30 ml). The layers are separated and the aqueous layer is extracted with EtOAc (30 ml). The combined extracts are washed with brine (30 ml), dried over Na2SO4 and evaporated. The resulting title product as a light yellow solid is used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH:25]1[C:20]2[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[C:15](=[CH:14][CH2:13][CH2:12][N:9]3[CH2:8][CH2:7][C:6]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1(c2ccccc2)CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(c2ccccc2)CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 40 °C
Reaction time: 20 h
Yield: 47.9 %

Procedure:
The above ester (4.75 g, 10.5 mmol) was dissolved in ethanol (40 ml) and 5 N sodium hydroxide (5 ml) was added. The mixture was stirred at 40° C. for 20 h, ethanol was evaporated in vacuo and water (50 ml) followed by acetic acid (4 ml) were added. The mixture was extracted with dichloromethane (100 ml), the organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The residue was crystallised from diethyl ether to give 2.2 g (45%) of the title compound as a solvate with water and acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([CH2:21][CH3:22])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.[NH2:24][NH2:25].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:21][C:22]3[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[NH:25][N:24]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: CCC(C(=O)c1ccc(OC)cc1)C(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2n[nH]c(-c3ccc(OC)cc3)c2Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of the 1,3-diketone obtained in step 1 (1.0 equiv.), hydrazine (3.0 equiv.), conc. HCl aq. (catalytic amount) and ethanol was heated to reflux overnight. Cooled to rt and removed solvent in vacuo. Water and ethyl acetate were added. The organic layer was separated, washed with dil. HCI, brine, dried, filtered and the solvent was concentrated in vacuo to give the product 4-methoxy-1-[5-(4-methoxyphenyl)-4-benzylpyrazol-3-yl]benzene.