Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].O=[C:16]1N(C(OCC2C=CC=CC=2)=O)[C@H](C(O)=O)CN1.CI.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:4]([CH3:16])[C:3]1=[O:14]
Reactant: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: CN1CC(C(=O)OC(C)(C)C)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CC(C(=O)OC(C)(C)C)N(C)C1=O
Temperature: -10 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A stirred solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (1.75 g, 8.74 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (22 ml) was cooled to −10° C. under argon, and then the methyl iodide (2.186 ml, 35.0 mmol) was added. Sodium hydride (60% dispersion in oil) (0.329 g, 8.22 mmol) was then added portion wise. The reaction mixture was allowed to warm to RT while stirring under argon overnight. The solvent was evaporated in vacuo and then the residue partitioned between ethyl acetate (40 ml) and brine (30 ml). The aqueous layer was re-extracted with ethyl acetate (×2) and then the combined organic extracts were washed with water (×2, 50 ml), brine (50 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo. The crude product was purified by flash-silica gel chromatography, eluting with 25-100% ethyl acetate/iso-hexane. The fractions containing product were combined and solvent evaporated in vacuo to give a yellow oil, 1,1-dimethylethyl 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylate (1.48 g, 79% yield). (ii) A solution of 1,1-dimethylethyl 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylate (1.92 g, 8.96 mmol) in dichloromethane (12 ml)/trifluoroacetic acid (6.00 ml) was stirred at room temperature for 24 hours. The solution was evaporated and the residue was co-evaporated with toluene (×3) and then dichloromethane (×2). The product was then dried to give crude 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylic acid (1.65 g) which was dissolved in dichloromethane (90 ml) to give a ˜0.1M solution in dichloromethane which was used in subsequent reactions. LC/MS [M+H]+=159.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CN(C)[CH:38]=[O:39]>O1CCCC1.O>[F:1][C:2]1[C:7]([CH:38]=[O:39])=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11]
Reactant: CCCS(=O)(=O)Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To propane-1-sulfonic acid (2,4-difluoro-phenyl)-amide (72, 1.5 g, 6.38 mmol) in tetrahydrofuran (10 mL) under an atmosphere of nitrogen, cooled in a −78° C. acetone/dry ice bath was added lithium diisopropylamide (0.80 M in tetrahydrofuran, 24 mL, freshly prepared from n-butyllithium and diisopropylamine). After 30 minutes, N,N-dimethyl-formamide (542 μL, 7.018 mmol) was added dropwise to the reaction. The reaction was stirred for 30 minutes at −78° C. and then allowed to warm to room temperature for 40 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a light yellow solid (73, 300 mg, 18%). MS (ESI) [M−H+]−=262.3.
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH:9]([S:35]CC1C=CC(OC)=CC=1)[CH2:10][NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:28]([O:30]C(C)(C)C)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.Cl>O>[NH2:7][CH:8]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH:9]([SH:35])[CH2:10][NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(CSC(CN[C@@H](Cc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(S)C(N)Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-[N-[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-[[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]-L-phenylalanyl]-L-leucine, 1,1-dimethylethyl ester (780 mg, 1.06 mmol), anisole (1.0 ml) and trifluoroacetic acid (14 ml) was stirred at room temperature under argon. After 1 hour, the reaction was cooled to 0° C. and mercuric trifluoroacetate (497 mg, 1.1 eq) was added. The reaction was stirred for 1 hour at 0° C. and then concentrated to a red oil. The oil was triturated with ether/hexane and a nearly colorless solid was collected and washed with hexane. The solid was dissolved in degassed 80% aqueous acetic acid (20 ml) and hydrogen sulfide was bubbled through the solution for 30 minutes. The black reaction mixture was filtered through a pad of Celite followed by a Millipore filter (Teflon). The filtrate was concentrated to an amber oil. The oil was diluted with degassed double distilled water (20 ml) and 1N hydrochloric acid (3.2 ml, 1.5 eq) and the mixture filtered (Millipore, Metricel). The clear, colorless filtrate was lyophilized and relyophilized twice from water to yield the title compound as a fluffy, colorless solid: 490 mg (0.87 mmol); Rf =0.70 (silica gel, N-butanol:water:acetic acid, 4:1:1); Rf =0.75 (silica gel, chloroform:methanol:acetic acid, 4:1:1); fast atom bombardment mass spectrum: (M+H)+ m/e=458, (M-H)- m/e=456; melting point 123°-160° C.; [α]D =-12.8° (c=1.23, methanol). Analysis: C25H35N3O3S.1.8 mole HCl.2.2 mole H2O: C, 53.34; H, 7.38; N, 7.46; S, 5.69; SH 5.87; Cl, 11.33. Found: C, 53.06; H, 7.15; N, 7.12; S, 5.39; SH, 5.86; Cl, 11.08.
Reaction SMILES: CC([N:5]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([F:29])[CH:22]=3)[N:18]=[C:17]([NH2:30])[N:16]=2)[CH2:10]1)C(=O)[O-])(C)C.[ClH:31].O1CCOCC1>>[ClH:31].[NH2:30][C:17]1[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([F:29])[CH:22]=2)[CH:20]=[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([NH2:5])[CH2:10]2)[N:16]=1
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H]1CCCN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCC[C@@H](N)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 1,1-dimethylethyl{(3R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinyl}carbamate (1.02 g, 2.473 mmol) was added 4M HCl in 1,4-dioxane (6.18 mL, 24.73 mmol), and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction was then concentrated to afford an HCl salt of the title compound (1.03 g) as a yellow solid. LC-MS (ES) m/z=313 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[N:4](C)[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:19][C:20]([F:40])([F:39])[O:21]C1C=CC(N2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:1][C:2]1[C:3](=[O:18])[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]([O:21][C:20]([F:40])([F:39])[F:19])=[CH:7][CH:6]=2
Reactant: O=C1C(=O)N(c2ccc(OC(F)(F)F)cc2)c2ccccc21
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Product: CCOC(=O)c1c(O)c(=O)[nH]c2ccc(OC(F)(F)F)cc12

Procedure:
Intermediate 23 was prepared as a white powder following the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 4-trifluoromethoxy-phenylindoline-2,3-dione. 1H NMR (400 MHz, chloroform-d) δ ppm 11.90 (1 H, br. s.), 11.28 (1 H, br. s.), 8.22 (1 H, br. s.), 7.36-7.53 (1 H, m), 7.43 (1 H, br. s.), 4.61 (2 H, d, J=7.1 Hz), 1.54 (3 H, t, J=6.9 Hz). LC-MS (ESI) m/z 317.9 (M+H), RT=2.00 min (Method B).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]Br.[OH-].[Na+]>C(O)(=O)C.CCOCC>[NH2:1][C:2]1[C:7]([Br:9])=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Cc1ccc(N)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cnc(N)c(Br)c1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-picoline (5 g) in acetic acid (40 mL) at r.t. was added bromine (2.6 mL) slowly. After 1 h, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0° C. The resulting orange precipitate was dissolved in ether and washed successively with saturated potassium carbonate, saturated Na2S2O3 and brine, dried and concentrated. Flash chromatography (eluting with hexane/ethyl acetate, 3:2 v/v) of the residual solid provided the title compound as a pale yellow solid (7.1 g).
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=1)([CH3:3])[CH3:2].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[CH3:24][N:25]([CH:27]=[C:17]([C:6]1[S:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:8][C:7]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:18]([O:20][CH3:21])=[O:19])[CH3:26]
Reactant: COC(=O)Cc1sc(C(C)C)nc1/C=C/c1ccccc1
Reactant: COC(OC)N(C)C
Product: COC(=O)C(=CN(C)C)c1sc(C(C)C)nc1/C=C/c1ccccc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 3.1 g of the product of Step E and 30 ml of dimethylformamide dimethyl acetal was heated to 50° C. and after 5 hours at this temperature, the mixture was allowed to return to 20° to 25° C. The mixture was stirred for 16 hours and then was brought to dryness. The residue was chromatographed on silica, eluting with a hexane--ethyl acetate mixture (8-2) to obtain after evaporation of the solvents, 2 g of the desired product. Thin layer chromatography; Rf=0.15 [eluant: hexane--ethyl acetate (8-2)].
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:13].CC1C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:13]
Reactant: O=C(COCCOC1CCCCO1)OCCOCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C(COCCO)OCCOCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of THP-protected hydroxy ester 5 (1 g, 2.53 mmol) in methanol (35 ml) was added p-TsOH (30 mg, 1 mg/ml). The reaction mixture was stirred at room temperature for 1 hr, concentrated and diluted with EtOAc. Organic layer was washed twice with NaHCO3 and water, dried over MgSO4, filtered and concentrated. The obtained oily residue (712 mg, 90%) was used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[F:13][C:14]([F:30])([F:29])[C:15]1([C:18]2[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=2)[C:23](O)=[O:24])[N:17]=[N:16]1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:23](=[O:24])[C:22]2[CH:26]=[C:18]([C:15]3([C:14]([F:30])([F:13])[F:29])[N:17]=[N:16]3)[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1ccc(C2(C(F)(F)F)N=N2)cc1C(=O)O
Product: COc1ccc(C2(C(F)(F)F)N=N2)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-[3-(trifluoromethyl)-3H-diazirin-3-yl]-2-methoxybenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH:6]2[CH2:13][CH2:14][CH3:15].[CH2:16]([C:18]1([CH2:23][CH:24]=O)[O:22][CH2:21][CH2:20][O:19]1)[CH3:17].[OH-].[K+].Cl>C(O)C.[Pd]>[CH2:16]([C:18]1([CH2:23][CH2:24][CH:7]2[CH:6]([CH2:13][CH2:14][CH3:15])[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:8]2=[O:12])[O:22][CH2:21][CH2:20][O:19]1)[CH3:17]
Reactant: CCCC1CC(=O)c2ccc(OC)cc21
Reactant: CCC1(CC=O)OCCO1
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCCC1c2cc(OC)ccc2C(=O)C1CCC1(CC)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
A mixture of 5-methoxy-3-propyl-1-indanone (184 mg, 0.90 mmol) and (2-ethyl-[1,3]dioxolan-2-yl)acetaldehyde (173 mg, 1.20 mmol) was treated with a solution of KOH (85% wt. pure, 20 mg, 0.30 mmol) in ethanol (1.0 mL). The resulting mixture was stirred at room temperature for 30 minutes, then treated with 10% Pd on carbon (9 mg), placed under a hydrogen atmosphere, and stirred vigorously at room temperature for 18 hours. The mixture was acidified with 2N HCl and partitioned between EtOAc (9 mL) and water (5 mL). The organic phase was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to an oil (316 mg). The crude product was purified by chromatography on a Biotage FLASH 12M column, eluting with 10% EtOAc in hexanes, to afford 2-[2-(2-ethyl-[1,3]dioxolan-2-yl)-ethyl]-5-methoxy-3-propyl-1-indanone (87 mg) as an oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH2:17][NH2:18].Cl[CH:23]([F:25])[F:24].Cl>CCCCCC.O1CCCC1>[F:24][CH:23]([F:25])[C:14]([NH2:13])([CH2:15][CH2:16][CH2:17][NH2:18])[C:19]([OH:21])=[O:20]
Reactant: FC(F)Cl
Reactant: NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: NCCCC(N)(C(=O)O)C(F)F
Temperature: 40 °C

Procedure:
Under nitrogen a solution (500 ml) of 2 M butyllithium in hexane is added to a stirred solution of 143.1 ml of diisopropylamine in 1.5 liters of tetrahydrofuran at -78° C. after which 261 g (0.81 mole) of ornithine dibenzaldimine methyl ester in 1.5 liters of tetrahydrofuran is added. Upon completion of the addition the reaction temperature is raised to 40° C. and maintained between 40° and 50° C. for 3 hours during which time chlorodifluoromethane gas is bubbled through the mixture with stirring. The reaction mixture is then treated with a saturated solution of sodium chloride. The organic material is extracted with ether, and the ether extract washed several times with sodium chloride solution, dried over magnesium sulfate and evaporated to give a viscous oil. The oil is stirred with 1 N HCl (1.5 l) for 3 hours, the mixture extracted several times with chloroform and the aqueous solution evaporated to dryness. The oily residue is refluxed with 12 N hydrochloric acid (1.5 l) for 16 hours, the cooled solution clarified by chloroform extraction before concentration, decolorization (charcoal), and further concentration to about 750 ml. The pH of the solution is adjusted to 3.5 by the addition of triethylamine, the solution treated again with charcoal before concentration to about 500 ml and dilution with 7-8 liters of acetone. The precipitated product is filtered off and washed with ethanol. The crude product is recrystallized by dissolving in about 150 ml hot water and treatment of the solution with hot ethanol (450 ml). On cooling crystals of 2-difluoromethyl-2,5-diaminopentanoic acid hydrochloride monohydrate separate 71 g (37%), m.p. 183° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].[OH-].[Na+].O.O1CCCC1>C(OCC)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CCCCc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CCCCc1cccs1
Yield: 90.3 %

Procedure:
A mixture of ethyl 5-(2-thienyl)pentanoate (15.40 g), sodium hydroxide (NaOH) (2.90 g), water (H2O) (18 ml), and tetrahydrofuran (THF) (100 ml) was stirred at reflux for 2.5 hours. The reaction mixture was poured into a mixture of water and diethyl ether (Et2O). The aqueous layer was separated, and acidified with 6 N hydrochloric acid (HCl), and extracted with ethyl acetate (AcOEt). The organic layer was washed with water and brine, and dried over magnesium sulfate (MgSO4), and evaporated to give 5-(2-thienyl)pentanoic acid (12.07 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5][C:6]=1[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)C(C)C)C>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:20][CH2:19]2)[S:5][C:6]=1[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc(NC2CCNCC2)sc1C(=O)c1c(F)cccc1F
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2nc(N)c(C(=O)c3c(F)cccc3F)s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with [4-amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(2,6-difluorophenyl)methanone (0.25 g, crude product from step D), anhydrous dichloromethane (1.5 mL) and methanesulfonyl chloride (3 eq, 155 uL). Then Diethylisopropyl amine (6 eq, 697 uL) was added to the above mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified through a silica gel column. 0.38 g of [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)thiazol-5-yl]-(2,6-difluorophenyl)methanone was obtained as a light brown solid. The overall yield for step D and E was 15%. 1H NMR (DMSO−d6, 400 MHz): δ1.45-1.57 (m, 2H, CH2), 1.95-2.05 (m, 2H, CH2), 2.82-2.90 (m, 5H, CH3, CH2,), 3.45-3.55 (m, 2H, CH2), 3.6-4.0 (broad, 1H, CH), 7.14-7.20 (m, 2H, Aromatic), 7.45-7.55 (m, 1H, Aromatic), 8.15-8.25 (broad, 1H, NH2), 8.7-8.9 (broad, 1H, NH). HR-MS (M+H)+: Observed: 417.0865: Calculated for 417.0861. Ki for CDK1 0.003 μM; CDK2 0.005 μM; CDK4 0.006 μM.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:34])[OH:33])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1.[CH2:39]([Sn:43]([CH2:57][CH2:58][CH2:59][CH3:60])([CH2:53][CH2:54][CH2:55][CH3:56])[C:44]1[N:45]=[N:46][N:47]([CH2:49][CH2:50][CH2:51]O)[CH:48]=1)[CH2:40][CH2:41][CH3:42].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:33])[O:34][CH2:51][CH2:50][CH2:49][N:47]4[CH:48]=[C:44]([Sn:43]([CH2:53][CH2:54][CH2:55][CH3:56])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:57][CH2:58][CH2:59][CH3:60])[N:45]=[N:46]4)=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCCO)nn1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(CCCO[PH](=O)CCCCc2ccc(Nc3ncc(C(F)(F)F)c(Nc4ccc(Br)nc4C(=O)NC)n3)c(OC)c2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A solution of (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propylphosphinic acid (Compound 74B, 0.370 g, 0.599 mmol), 3-[4-(tributylstannanyl)-1H-1,2,3-triazol-1-yl]propan-1-ol (Compound 64B, 0.299 g, 0.719 mmol) and DIPEA (0.313 mL, 1.80 mmol) in 1,2-dichloroethane (10.0 mL) was charged with (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (0.936 g, 1.80 mmol). The resulting mixture was stirred at rt for 16 hours. The reaction mixture was quenched with sat. aq. NaHCO3 (10 mL) and extracted with DCM (20 mL). The organic layer was washed with sat. aq. NaHCO3 (10 mL), washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a brown oil. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using 1:1 DCM-EtOAc/MeOH (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield an off-white solid (352.1 mg, 57.8%). MS (ESI): m/z 1016.90 [M+H]+. UPLC: tR=1.44 min (UPLC-SQD: analytical_non-polar 2 min).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C(N)(C)C.[Cl:18][C:19]1[CH:56]=[CH:55][C:22]([C:23]2[C:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:39]5N(CC)[C:42]6C=CC(C(O)=O)=[CH:49][C:41]=6[N:40]=5)[CH:35]=4)[N:30]=3)=[CH:27][C:26]([O:53][CH3:54])=[CH:25][CH:24]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:56]=[CH:55][C:22]([C:23]2[C:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:39]5[N:40]([CH:41]([CH3:49])[CH3:42])[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:35]=4)[N:30]=3)=[CH:27][C:26]([O:53][CH3:54])=[CH:25][CH:24]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Solvent: CC(C)N
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C(C)C)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and isopropylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [CH:1]1(Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[C:14]([O:18][C:19](=[O:44])[CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH:30][S:31]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:41][CH2:42][CH3:43])([CH3:17])([CH3:16])[CH3:15]>CC#N.CCOC(C)=O.O>[C:14]([O:18][C:19](=[O:44])[CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([N:30]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[S:31]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)(=[O:32])=[O:33])=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:41][CH2:42][CH3:43])([CH3:17])([CH3:16])[CH3:15]
Reactant: BrC1CCCCC1
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc2cc(N(C3CCCCC3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Cyclohexyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.