Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[CH:22]=[C:21]([NH:23][CH:24]([CH3:27])[CH2:25][NH2:26])[CH:20]=[C:19]([CH3:28])[N:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[CH3:16][C:17]1[CH:22]=[C:21]([NH:23][CH:24]([CH3:27])[CH2:25][NH:26][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH:20]=[C:19]([CH3:28])[N:18]=1
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1cc(NC(C)CN)cc(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(NC(C)CNC(=O)/C=C/C(F)(F)F)cc(C)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (15.4 mg, 0.11 mmol) was dissolved in DCM (0.75 ml containing one drop of dimethyl formamide), oxalyl chloride was added (14 mg, 0.11 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N2-(2,6-dimethyl-4-pyridyl)propane-1,2-diamine (21.6 mg, 0.1 mmol) and diisopropylethylamine (44 μl, 0.25 mmol) dissolved in dimethylformamide (1 ml) and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 10.7 mg (0.035 mmol, 35%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16](CO)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C(OCC)(=[O:30])C>C(Cl)Cl>[CH3:1][S:2]([O:4][CH:16]1[CH2:17][CH2:18][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:14][CH2:15]1)(=[O:30])=[O:3]
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (4.10 mL, 6.07 g, 52.9 mmol) was added dropwise to a solution of 1-(t-butoxycarbonyl)-4-(hydroxymethyl)piperidine from Step A (10.0 g, 46.4 mmol) and triethylamine (9.80 mL, 7.11 g, 70.3 mmol) in methylene chloride (140 mL) at 5-8° C. After 1 h, the mixture was diluted with ethyl acetate (400 mL) and washed with water (200 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL) and the combined organic layers were washed with 1 N aq. HCl (200 mL), saturated aq. sodium bicarbonate (200 mL), and saturated aq. brine (200 mL). The organic layer was dried (sodium sulfate), decanted, and evaporated to give 13.58 g of 1-(t-butoxycarbonyl)piperidin-4-yl methanesulfonate as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 1 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.39–7.31 (m, 3H), 7.29–7.21 (m, 5H), 7.02–6.96 (m, 4H), 4.80 (s, 1H), 3.40 (q, 2H, J=4.5 Hz), 2.94 (d, 2H, J=10.2 Hz), 2.51–2.38 (m, 4H), 1.97 (dt, 2H, J=1.8, 10.4 Hz), 1.81 (m, 2H), 1.68 (quintet, 2H, J=6.8 Hz,), 1.59 (m, 3H), 1.23 (d, 6H, J=6.9 Hz); ESMS m/e: 534.3 (M+H)+; Anal. Calc. For (HCl salt) C32H37F2N3O2.HCl.0.20 CHCl3: C, 65.11; H, 6.48; N, 7.07. Found: C, 65.30; H, 6.50; N, 6.96.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[CH2:22]([N:24]([CH2:39][CH3:40])[S:25]([CH2:28][CH:29]1[CH2:33][CH:32]([C:34](O)=[O:35])[CH:31]([CH2:37][CH3:38])[CH2:30]1)(=[O:27])=[O:26])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:39]([N:24]([CH2:22][CH3:23])[S:25]([CH2:28][CH:29]1[CH2:33][CH:32]([C:34]([NH:2][NH:1][C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]([S:12]([C:15]4[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=4)(=[O:13])=[O:14])[C:6]3=[N:7][CH:8]=2)=[O:35])[CH:31]([CH2:37][CH3:38])[CH2:30]1)(=[O:27])=[O:26])[CH3:40]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CCC1CC(CS(=O)(=O)N(CC)CC)CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCC1CC(CS(=O)(=O)N(CC)CC)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a suspension of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.390 g, 1.287 mmol, Example #1 Step D), 4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylic acid (0.375 g, 1.287 mmol), and HATU (0.538 g, 1.416 mmol) in DCM (6.4 mL) was added TEA (0.538 mL, 3.86 mmol). The reaction mixture was stirred at ambient temperature for about 1 h. The reaction mixture was partitioned between water (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (2×50 mL). The organic layers were combined and concd under reduced pressure. The material was purified by silica gel (120 g) chromatography eluting with a gradient of 20-100% EtOAc in DCM to provide N,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)methanesulfonamide (0.730 g, 98%) as a brown solid: LC/MS (Table 1, Method b) Rt=2.39 min; MS m/z: 577 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([C:24](O)=[O:25])=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:14]([F:27])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:42]C=2C=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:24]([C:23]1[CH:22]=[N:21][CH:20]=[CH:19][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:13][C:14]=1[F:27])(=[O:25])[NH2:42]
Reactant: CC(C)C[C@@H](COc1ccc(-c2ccncc2C(=O)O)c(F)c1)NC(=O)OC(C)(C)C
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](COc1ccc(-c2ccncc2C(N)=O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56.6 %

Procedure:
(S)-4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)-2-fluorophenyl)nicotinic acid (75 mg, 0.173 mmol) was taken in DMF (2 mL) and cooled to 0° C. To the solution was added EDC (49.9 mg, 0.260 mmol) and HOBT (53.1 mg, 0.347 mmol). After stirring the reaction mixture for 5 min, ammonium chloride (55.7 mg, 1.040 mmol) was added and the resultant mixture was stirred for 5 min. Diisopropylethylamine (0.121 mL, 0.694 mmol) was added and the mixture was allowed to stir at room temperature for an additional 12 h. The mixture was then quenched with ice and the residue was filtered and dried under vacuum to afford (S)-tert-butyl (1-(4-(3-carbamoylpyridin-4-yl)-3-fluorophenoxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.098 mmol, 57% yield) as a light yellow solid. LC/MS (ESI) m/e 432.2 [(M+H)+, calcd for C23H31FN3O4 432.2]; LC/MS retention time (method C): tR=1.83 min.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[Si]([N:36]=[C:37]=[O:38])(C)(C)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([C:37]([NH2:36])=[O:38])[CH2:27][CH2:28]4)[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C(CC1CCNCC1)N1CCC(=C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Solvent: ClCCl
Solvent: O
Product: NC(=O)N1CCC(CC(=O)N2CCC(=C3c4ccc(Cl)cc4SCc4cccnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared by a similar procedure from 4-[2-[4-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]-piperidine (120 mg, 0.265 mmol) in CH2Cl2 (3 ml), to which TMSNCO (200 μl, 170 mmol) was added at 0° C. After 5 minutes at 0° C., the mixture was stirred 3.5 hours at room temperature. The reaction mixture was diluted with water and extracted with CH2Cl2 ; the organic phase was washed with NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was chromatographed on silica in 5%MeOH/CH2Cl2 and eluted with 10%MeOH/CH2Cl2 to afford a white solid (103 mg); HRMS: calc.: 497.1778; found: 497.1766.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1.[CH:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=O>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH2:25][C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=2)[CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NCCc1ccc(Cl)cc1
Product: COC(=O)c1ccc(CN(CCc2ccc(Cl)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
The title compound was prepared according to Procedure 1B starting from N-Boc-piperid-4-one, 2-(4-chlorophenyl)ethylamine, and methyl 4-formylbenzoate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C(O[CH:22](OCC)[CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])C>C(#N)C.C(O)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOC(CCNC(=O)OC(C)(C)C)OCC
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOCc1nc2cnc3ccccc3c2n1N=CCCNC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
A solution of 2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.00 g, 4.13 mmol) in 20 mL of acetonitrile and 5 mL of glacial acetic acid was treated with tert-butyl (3,3-diethoxypropyl)carbamate (2.55 g, 10.3 mmol) and heated to reflux under an atmosphere of nitrogen. After 15 h, the reaction mixture was concentrated under reduced pressure to yield a brown oil. The oil was partitioned between CHCl3 and saturated NaHCO3 solution and the phases were separated. The organic portion was washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl {3-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)imino]propyl}carbamate (1.64 g) as a dark red/orange oil.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1)[CH3:3].Br[C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31]([NH2:33])=[O:32])[CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:34]1[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH2:43]([S:40]([N:37]1[CH2:36][CH2:35][CH:34]([C:25]2[C:24]3[C:28](=[C:29]([C:31]([NH2:33])=[O:32])[CH:30]=[C:22]([C:10]4[CH:9]=[N:8][CH:7]=[C:6]([CH2:5][NH:4][CH:2]([CH3:1])[CH3:3])[CH:11]=4)[CH:23]=3)[NH:27][CH:26]=2)[CH2:39][CH2:38]1)(=[O:42])=[O:41])[CH3:44]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC(C)NCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNC(C)C)c4)cc23)CC1
Temperature: 150 °C
Reaction time: 0.13 h
Yield: 70.3 %

Procedure:
To a CEM microwave tube containing (1-methylethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (22 mg, 0.080 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (50 mg, 0.121 mmol), K2CO3 (100 mg, 0.724 mmol), dioxane (1.5 mL), H2O (0.5 mL), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (7.3 mg, 0.012 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 50° C. and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×100 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 50° C. to give 27.2 mg of the title compound (70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH:18][CH3:19]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH:17]=[CH:18][CH3:19])=[C:4]([I:9])[CH:3]=1
Reactant: CC=CCBr
Reactant: Oc1ccc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCOc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a mixture of 4-chloro-2-iodo phenol (5.11 mmol, 1.3 g) in DMF (40 mL) and potassium carbonate (10 mmol, 1.4 g) was added crotyl bromide (10.2 mmol, 1.6 g) and the reaction mixture was stirred at room temperature for one hour. The reaction was quenched with H2O (100 mL) and extracted with EtOAc (2×50 mL). The EtOAc layer was collected, dried, filtered and the filtrate was evaporated to obtain 4-chloro-2-iodo O-crotyl phenol (94%, 1.5 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:44][CH2:45][O:46][C:47]([F:50])([F:49])[F:48])(=O)=O>C(Cl)(Cl)Cl>[Cl:21][C:20]1[C:15]([C:13]2[C:12]([Cl:30])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:44][CH2:45][O:46][C:47]([F:50])([F:49])[F:48])[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][CH:19]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)(F)OCCN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (45 mg, 0.10 mmol) and triethylamine (0.028 mL, 0.20 mmol) in chloroform (0.4 ml) was added 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (39 mg, 0.15 mmol). The mixture was stirred at ambient temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, purified by reverse phase HPLC, and lyophilized to give 29 mg of 3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(2-(trifluoromethoxy)ethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 562.4 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.32 (m, 4H) 1.36-1.52 (m, 2H) 1.58 (d, J=12.91 Hz, 2H) 1.65-1.84 (m, 1H) 2.07 (d, J=10.56 Hz, 4H) 2.99-3.17 (m, 3H) 3.23 (t, J=10.76 Hz, 2H) 3.35 (br. s., 2H) 3.64 (br. s., 1H) 3.72-3.89 (m, 2H) 4.34 (t, J=4.89 Hz, 2H) 6.32-6.47 (m, 1H) 6.49-6.65 (m, 1H) 6.67-7.10 (m, 2H) 7.49 (d, J=9.00 Hz, 1H) 8.03 (s, 1H) 8.75 (d, J=3.91 Hz, 1H)
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]([Cl:17])([Cl:16])[CH:13](O)[OH:14]>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH:13]([OH:14])[C:12]([Cl:17])([Cl:16])[Cl:11])=[O:8])=[CH:3][CH:2]=1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Cc1ccc(C(N)=O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)NC(O)C(Cl)(Cl)Cl)cc1
Reaction time: 12 h
Yield: 87.9 %

Procedure:
A mixture of p-toluamide (11.0 g, 81.3 mmol) and 2,2,2-trichloro-1,1-ethanediol (16.6 g, 100 mmol) in benzene (175 mL) was stirred at reflux in a Soxhlet extraction device charged with molecular sieves (20 g). After 12 hours, the extraction thimble of molecular sieves was replaced with a fresh portion of molecular sieves (20 g), and the reaction was allowed to heat at reflux for an additional 12 hours. Concentration in vacuo provided a heavy syrup which was dissolved in ethyl acetate (15 mL) and diluted with hexanes (175 mL). Refrigeration at 8° C. facilitated precipitation of a white solid that was collected by filtration and washed with hexanes to provide 20.2 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:3]([C:8]([N:13]([O:14][CH3:15])[CH3:12])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CNOC
Reactant: O=C(O)c1nccnc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a suspension of 3-chloropyrazine-2-carboxylic acid (5.46 g) in THF (100 mL) was added CDT (6.14 g) at room temperature, and the mixture was stirred at room temperature for 30 min and heated to 50° C. After stirring at 50° C. for 1 h, the mixture was cooled to room temperature. To the mixture were added N,O-dimethylhydroxylamine hydrochloride (5.04 g) and DIPEA (9.02 mL) at room temperature, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (3.05 g).
Reaction SMILES: [C:1]1([C:7]2[N:16]([CH3:17])[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13](=[O:24])[C:8]=2[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+]>[C:1]1([C:7]2[N:16]([CH3:17])[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13](=[O:24])[C:8]=2[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(-c2ccccc2)n(C)c(-c2ccccc2)cc1=O
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(-c2ccccc2)cc(=O)c(C(=O)O)c1-c1ccccc1

Procedure:
2.5 gms of methyl 2,6-diphenyl-1-methyl-4-oxonicotinate was suspended in 28 mls of 5% aqueous sodium hydroxide 8 hours, cooled, and filtered to remove residual insolubles. The clear basic solution was then acidified with dilute HCl to provide a white precipitate of 2,6-diphenyl-1-methyl-4-oxonicotinic acid. Recrystallization from methylene chloride/ether provided 2.4 gms of product. mp=209°-11° (dec).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH2:19])[CH3:15]>>[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH:19][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13])[CH3:15]
Reactant: CCOC(=O)CN1CCC(O)C1=O
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)CN1CCC(O)C1=O

Procedure:
3.0 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate and 3.7 g of 2-(diethylamino)ethylamine are heated to 95°-100° for 3.5 hours under nitrogen. The mixture is chromatographed on 45 g of aluminum oxide (neutral,activity grade III). The crude (R/S)-N-[2-(diethylamino)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with methylene chloride and ethyl acetate is again chromatographed on 25 g of aluminum oxide (neutral, activity grade III). The product which is eluted with ethyl acetate and ethanol is distilled in a bulb-tube at about 250°/0.03 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH3:27]CN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][O:14][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1

Procedure:
The product (0.867 g) obtained in the above (2) is dissolved in dichloromethane (15 ml), and thereto are added methanol (1.5 ml), 4-dimethylaminopyridine (34 mg) and WSC.HCl (0.633 g) under ice-cooling. The mixture is stirred under ice-cooling for two hours, and then stirred at room temperature for 12 hours. The mixture is concentrated under reduced pressure to the volume of about 5 ml, and the residue is poured into water. The mixture is extracted three time with ethyl acetate, and the organic layer is washed 1N HCl (twice), a saturated aqueous sodium hydrogen carbonate solution (twice), and with a saturated brine (twice), and then dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (0.875 g).
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]([CH2:22][O:23][P:24]([O:27][CH2:28][CH2:29][N+:30]([CH3:33])([CH3:32])[CH3:31])([OH:26])=[O:25])[OH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:34]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36][CH2:35]1.C(Cl)(Cl)Cl.CO>CN(C1C=CN=CC=1)C.ClCCl>[CH3:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:18][CH2:19][C@@H:20]([O:21][C:34]([CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:41])[CH2:22][O:23][P:24]([O:27][CH2:28][CH2:29][N+:30]([CH3:32])([CH3:31])[CH3:33])([O-:26])=[O:25])=[O:17]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(=O)(O)OCC[N+](C)(C)C
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)([O-])OCC[N+](C)(C)C)OC(=O)CCCC(=O)O
Yield: 42 %

Procedure:
PGPC (FIG. 1A, 1) was synthesized according to a modified version of the procedure by Watson et al. (J. Biol. Chem. 272, 13597-13607, 1997) and Subbanagounder et al. (Free Radic. Biol. Med. 28, 1751-1761, 2000). A solution of dry 1-palmitoyl-sn-glycero-3-phosphocholine (62 mg, 125 μmol), dry glutaric anhydride (70 mg, 613 μmol, 5 eq) and DMAP (p-(N,N′-dimethylamino)pyridine, 75 mg, 614 μmol, 5 eq) in 6 ml of anhydrous dichloromethane was magnetically stirred over night at 35° C. The reaction was monitored by TLC with CHCl3/MeOH/25% NH3 (65:35:5, v/v/v) as a developing system, and quenched by addition of 3 ml of MeOH. The resulting mixture was washed once with 1.8 ml of MeOH/H2O (1:1, v/v). After evaporation of the organic phase, excess DMAP was removed by trituration with 4 ml of diethylether. Removal of the supernatant afforded 32 mg of PGPC (42%, Rf=0.05).