Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:11]=[C:10](Cl)[CH:9]=[CH:8][N:7]=1.[CH3:21][O:22][C:23]1[CH:60]=[CH:59][C:26]([CH2:27][N:28]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[C:29]2[N:34]=[CH:33][C:32]([C:35]3[C:36]4[CH2:49][CH2:48][NH:47][C:37]=4[N:38]=[C:39]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:40]=3)=[CH:31][N:30]=2)=[CH:25][CH:24]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:6]1[CH:11]=[C:10]([N:47]2[C:37]3[N:38]=[C:39]([N:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)[N:40]=[C:35]([C:32]4[CH:33]=[N:34][C:29]([N:28]([CH2:50][C:51]5[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=5)[CH2:27][C:26]5[CH:59]=[CH:60][C:23]([O:22][CH3:21])=[CH:24][CH:25]=5)=[N:30][CH:31]=4)[C:36]=3[CH2:49][CH2:48]2)[CH:9]=[CH:8][N:7]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1cc(Cl)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1cc(N2CCc3c(-c4cnc(N(Cc5ccc(OC)cc5)Cc5ccc(OC)cc5)nc4)nc(N4CCOCC4)nc32)ccn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A DMF solution (4 ml) of [tert-butoxycarbonyl-(4-chloro-pyridin-2-yl)-amino]-acetic acid methyl ester (200 mg, 0.667 mmol) obtained in Step A, bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (300 mg, 0.556 mmol), palladium acetate (12.5 mg, 0.0556 mmol), S-Phos (46 mg, 0.111 mmol) and potassium phosphate (354 mg, 1.67 mmol) was deaerated under irradiation of ultrasonic wave, followed by stirring at 100° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and diluted with water, followed by extraction with dichloromethane (30 ml×2). The organic layers were combined, and washed with saturated aqueous sodium chloride solution. After the organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure, followed by purification of the residue by silica gel column chromatography (dichloromethane/methanol=50:1), to obtain {[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-tert-butoxycarbonyl-amino}-acetic acid methyl ester as a yellow solid (400 mg, 90%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([N:5]1[CH2:6][CH2:7][CH:8]([CH2:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N1CCC(CC(=O)O)CC1
Reactant: Nc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)N1CCC(CC(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a mixture of (1-tert-butyl-piperidin-4-yl)-acetic acid (672 mg, 3.37 mmol), aniline (0.32 ml, 3.5 mmol), and HOBt (568 mg, 4.2 mmol) in DMF (20 ml), EDC (805 mg, 4.2 mmol) was added. It was stirred at r.t. for 2 hours and partitioned between water (200 ml) and ethyl acetate (200 ml). The organic phase was washed with 0.5 N aq. NaOH (2×50 ml) and brine (3×50 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on (SiO2, gradient heptane-ethyl acetate) to give 250 mg of the title compound. 1H NMR (500 MHz, DMSO-d6): 1.07 (s, 9H), 1.32 (br. m, 2H), 1.81 (br. d, 2H), 1.89 (m, 1H), 2.11 (br. t, 2H), 2.25 (d, 2H), 3.03 (br. d, 2H), 7.1 (t, 1H), 7.24 (br., 1H), 7.31 (t, 2H), 7.52 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and [4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine. LCMS (MH+): m/z=452.1, tR (minutes, Method F)=3.08
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[CH2:10][C:9]2([CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)[O:8][C:7]1=[O:18].[Br:19]N1C(=O)CCC1=O>CN(C)C=O.C(Cl)(Cl)Cl>[Br:19][C:5]1[S:1][C:2]([N:6]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:7]2=[O:18])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OC2(CN3CCC2CC3)CN1c1nccs1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1OC2(CN3CCC2CC3)CN1c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A solution containing 3′-(thiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one (2.80 g, 10.55 mmol) and N-bromosuccinimide (3.90 g, 21.86 mmole) in N,N-dimethylformamide (15 mL) were stirred at RT overnight. The mixture was diluted with chloroform, washed with saturated aqueous potassium carbonate and then with brine, dried through magnesium sulfate, and then the solvent was evaporated. The residue was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound as a pale solid (1.70 g), m/z 343, 345 (MH+).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6][C@@H:5]1[OH:27])[CH3:2].N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([O:27][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:36])[CH3:35]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(C)=O
Reaction time: 24 h

Procedure:
2β-Ethoxy-3α-hydroxy-5α-pregnane-11,20-dione (500 mg.) in dry methylene chloride (5 ml.) at 0° was treated with pyridine (2.0 ml.) and acetic anhydride (2.0 ml.). After 24 hours, methylene chloride was added, and the solution was washed with dilute hydrochloric acid and with water. It was then dried over sodium sulphate and evaporated to an oil. The title compound (350 mg.) was obtained as a colourless foam, [α]D + 132°.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[F:11][C:12]([F:19])([F:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:15]([NH2:16])=[CH:14][C:13]([C:12]([F:19])([F:18])[F:11])=[N:9]2)[CH:3]=1
Reactant: Cc1cccc(NN)c1
Reactant: N#CCC(=O)C(F)(F)F
Agent: Cl
Product: Cc1cccc(-n2nc(C(F)(F)F)cc2N)c1
Yield: 21.5 %

Procedure:
Following the procedure in Example 161A Step 3, m-tolylhydrazine hydrochloride (1.15 g, 7.30 mmol) and 4,4,4-trifluoro-3-oxobutanenitrile (1.0 g, 7.30 mmol) were reacted to give 1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (380 mg, 1.57 mmol, 22%). 1H NMR (300 MHz, DMSO-d6). δ 7.60-7.20 (m, 4H), 5.82-5.61 (m, 3H), 2.59 (s, 3H); LC-MS (ESI) m/z 242 (M+H)+.
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([CH2:9][C@H:10]([O:13][CH2:14][P:15]([OH:18])([OH:17])=[O:16])[CH2:11][OH:12])[CH:2]=1.[CH3:19][CH2:20][N:21]([CH:25]([CH3:27])C)[CH:22](C)[CH3:23]>CN(C=O)C>[CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([CH2:9][C@H:10]([O:13][CH2:14][P:15]([OH:18])([OH:17])=[O:16])[CH2:11][OH:12])[CH:2]=1.[CH3:19][CH2:20][N:21]([CH2:25][CH2:27][OH:5])[CH2:22][CH3:23]
Reactant: CCN(C(C)C)C(C)C
Agent: Nc1ccn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1
Solvent: CN(C)C=O
Product: CCN(CC)CCO

Procedure:
To prepare compound 5 of FIG. 2, 135 mg (0.428 mmol) cidofovir was exposed to 135 mg (1.04 mmol) DIEA and dissolved in 4 mL DMF. A HPMPC-DEEA salt was obtained after solvent was removed under vacuum. 650 mg (1.8 mmol) dipeptide (t-BOC-Val-Ser-t-butyl described above) was added to a reaction flask containing the HPMPC-DIEA salt and 4 mL dry DMF. 660 mg (1.27 mmol) PyBOP and 425 μL (2.44 mmol) DIEA were added, and the reaction took place stirring under N2 (g) at 40° C. for 1 h. An additional 330 mg (0.635 mmol) PyBOP was added and left for 3 additional hours. Solvents were removed under vacuum, and a silica gel column chromatography purification was performed [eluent; CH2Cl2:acetone:methanol, 20:10:1.]. Solvent was removed and deprotection of the t-BOC and t-butoxy groups was performed in 4 mL of CH2Cl2 in the presence of 2 mL of 99% TFA for 3 h at room temperature. Solvents were removed under vacuum and ether was added to precipitate the final compound, 5, which was filtered by methanol on a funnel containing a silica gel layer. Preparative HPLC purification on a C-18 column (5 μm, 100 Å, 21.4×250 mm by Varian) was obtained using a mobile phase containing 0.1 M TEA and 3.5% acetonitrile at pH 6.7 adjusted with acetic acid. A fraction of the sample was purified by preparative HPLC methods and evaluated by NMR and HR-MS techniques. 1H NMR (CD3OD): δ 0.94 (6H, m), 2.10 (1H, m), 2.94-5.73 (10H, m), 5.73 (1H, m), 7.40 (1H, m). 31P NMR (CD3OD): δ 14.3 and 15.6 (1P, 2s). Exact mass (C16H26N5O8P); 447.1519 m/z.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.[CH3:35][NH2:36]>C(#N)C.CO>[CH3:35][NH:36][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: CN
Reactant: CCOC(=O)c1cccc2nc(CCl)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)c1cccc2nc(CNC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 60 °C
Yield: 61 %

Procedure:
To a solution of ethyl 2-chloromethyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.2 g) in acetonitrile (5 ml) was added a solution of 40% methylamine in methanol (0.33 g) and the mixture was heated at 60° C. for 77 hours. The reaction solution was cooled to give pale yellow prisms (0.12 g, 61%), m.p. 248-250° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[NH3:16].C(OCC)(=O)C.CCCCCC>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH2:16])=[O:7])#[N:2]
Reactant: N
Reactant: N#Cc1cc(C(=O)Cl)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1cc(C(N)=O)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In 1-neck 250 mL round-bottomed flask, 3-cyano-5-(trifluoromethyl)benzoyl chloride (3.0 g, 1.0 eq.) was dissolved in THF (30 mL, 10 V) at 0° C. Ammonia gas was added and the reaction mixture was stirred for 1-2 h at 0° C. The progress of the reaction was followed by TLC analysis on silica gel with ethyl acetate:hexane (5:5) as mobile phase and visualization with UV, SM Rf=0.10 and Product Rf=0.25. Reaction mixture was quenched into the ice-water slurry (100 mL) and extracted in the ethyl acetate (100 mL×3). Organic layer was washed with brine solution (100 mL) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 2.5 g of crude compound as white solid, yield (88%). This crude 3-cyano-5-(trifluoromethyl)benzamide was directly used for next step without purification; Mass: (ES−) 212.95 (M−1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].[K+].[Br-]>ClCCl>[C:11]([C:2]([C:11](=[O:14])[CH:12]=[CH2:13])([CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10])[N:1]([C:11](=[O:14])[CH:12]=[CH2:13])[C:11](=[O:14])[CH:12]=[CH2:13])(=[O:14])[CH:12]=[CH2:13]
Reactant: NCCNCCNCCN
Reactant: C=CC(=O)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: C=CC(=O)N(C(=O)C=C)C(CNCCNCCN)(C(=O)C=C)C(=O)C=C
Temperature: 25 °C

Procedure:
Triethylene tetramine (2.93 g, 0.02 moles) in dichloromethane (100 ml) was added drop wise over 6 hrs to a solution of acryloyl chloride (7.24 g, 0.08 moles) in dichloromethane (40 ml), stirring vigorously at room temperature. The reaction was stirred at room temperature overnight and the suspension was filtered. The filtrate was extracted with NaOH(aq). The water was rotary evaporated and the residue was washed with acetone and filtered. The acetone washings were concentrated down and the yellow oil remaining was put through a silica gravity chromatography column with acetone as the elutant. A yellow solid was obtained and recrystallized with cold diethyl ether to give white crystals, m.p. 107-109.5° C. 1H n.m.r (D2)) δ6.60(4 H, m) CH═CH2;6.16 (6 H, m), CH═CH2; 5.79(2 H, m), CH═CH2;3.61 (6 H, m) N—CH2—CH2,3.52(6 H, m) N—CH2—CH2. 13C n.m.r (D2)) δ172.52, 172.39, 171.78, 171.70 (C═O); 132.70, 132.55, 132.14, 131.74 (CH═CH2), 130.52, 130.32, 129.93, 129.64 (CH═CH2), 50.35, 49.82, 49.35, 48.31, 47.33, 46.05 (NH—CH2—CH2). MS: mz: 363.2 (MH+, 100%), 291.2 (16), 238.1(6), 195.1(74); HRMS: found:363.20204; C18H26N4O4 requires: 362,4236Elemental analysis: found: C, 59.71; H, 7.22; N, 15.37; C18H26N4O4 requires C, 59.65; H, 7.23; N, 15.46. L.R. (KBr) (cm−1): 3283, 3423, 1672, 1642, 1552, 1278.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:16]C(=O)OCC3C4C=CC=CC=4C4C3=CC=CC=4)[CH:14]=2)[C:9](=[O:34])[N:8]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:7]=1[CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:2][CH2:3][CH3:4].N1CCCC1.O>CN(C)C=O>[C:44]([O:43][C:41](=[O:42])[NH:40][CH2:39][C:7]1[N:8]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:9](=[O:34])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)([CH3:47])([CH3:45])[CH3:46]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(NC(=O)OCC3c4ccccc4-c4ccccc43)cc12
Solvent: O
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(N)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 9H-fluoren-9-ylmethyl 4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinylcarbamate (0.45 g, 0.7 mmol) in N,N-dimethylformamide (10 ml) was added pyrrolidine (0.5 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.23 g, 79.3%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>CN(C=O)C.CC(=O)OCC.C(Cl)Cl.C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=2)=[O:12])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1
Reactant: COc1ccc(CC(=O)O)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cn2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 12.9 %

Procedure:
Prepared using General Procedures 6 and 9. To a stirred solution of 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (500 mg, 2.13 mmol) and methyl 6-aminonicotinate (325 mg, 2.13 mmol) in DMF (5 mL) were added HATU (852 mg, 2.24 mmol) and TEA (744 μL, 5.34 mmol). The reaction mixture was stirred at room temperature. After 1 h the reaction mixture was diluted with EA (30 mL) and washed with brine (2×30 mL). The organics were dried over MgSO4 and concentrated in vacuo to afford an orange oil which was dissolved in DCM (5 mL) and washed with 1 M HCl (5 mL). The mixture was passed through a phase separation cartridge and the organics concentrated in vacuo to afford an orange oil which was dissolved in THF (5 mL) and MeOH (3 mL). To the reaction mixture was added 1 M LiOH (4.27 mL, 4.27 mmol) and the reaction was stirred at room temperature for 1 h then concentrated in vacuo. The residue was suspended in water (15 mL), acidified to pH 1 using 1 M HCl and the mixture was filtered under vacuum. The crude product was triturated with MeOH (5 mL) and dried in vacuo to afford 97 mg (13%) of 6-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)nicotinic acid INT-80 as a white solid. LCMS-ESI (m/z) calculated for C16H13F3N2O4: 354; found 355 [M+H]+, tR=1.84 min (Method 10).
Reaction SMILES: ClCCl.[CH3:4][C:5]([NH:15][CH:16]([CH3:20])[C:17](=O)[CH3:18])([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:6][C:5]([N:15]1[CH:16]([CH3:20])[C:17]([CH3:18])=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[C:29]1=[O:30])([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)[CH3:4]
Reactant: CC(=O)C(C)NC(C)(C)c1cc(F)cc(Cl)c1
Reactant: O=C(Cl)Cc1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2cc(F)cc(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To 20 ml of dichloromethane were added 3.0 g of N-[1-methyl-1-(3-chloro-5-fluorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)amine and 3.5 g of pyridine, and 3.0 g of (2-fluorophenyl)acetyl chloride was then added dropwise thereto at 5° to 10° C. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with dichloromethane. After dried over anhydrous sodium sulfate, the solution was concentrated by evaporation, and the resulting oil was dissolved in 20 ml of ethyl acetate. Next, 10 ml of a 28% methanol solution of sodium methylate was added thereto, and after stirring under reflux for 15 minutes, the temperature of the solution was returned to room temperature and water was then added, followed by extraction with ethyl acetate. Afterward, the solution was washed with 12% hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate. Next, the solution was condensed by an evaporator, and then subjected to silica gel chromatography to obtain 2.2 g of 1-[1-methyl-1-(3-chloro-5-fluorophenyl)ethyl]-4,5-dimethyl-3-(2-fluorophenyl)-3-pyrroline-2-one.
Reaction SMILES: [C:1]([NH:3][CH2:4][CH2:5][N:6]([CH2:20][C@@H:21]1[CH2:25][C@@H:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][N:22]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8])#[N:2].O.O.C(O)(=O)C(O)=[O:48]>CC(C)=O.C(OCC)(=O)C>[CH3:30][S:27]([O:26][C@H:24]1[CH2:23][N:22]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])[C@H:21]([CH2:20][N:6]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[CH2:5][CH2:4][NH:3][C:1]([NH2:2])=[O:48])[CH2:25]1)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CN(CCNC#N)C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN(CCNC(N)=O)C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a solution of (2S, 4R)-2-[N-{2-(cyanoamino)ethyl}-N-(4-nitrobenzyloxycarbonyl)aminomethyl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.52 g) in acetone (30 ml) was added oxalic acid dihydrate (1.92 g) at ambient temperature. The mixture was stirred at the same temperature for 18 hours. Acetone was removed by evaporation to give a residue. A suspension of the syrup in ethyl acetate (100 ml) was washed in turn with 1N aqueous sodium hydroxide (50 ml×2), water (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98 v/v) to give (2S, 4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[N-(4-nitrobenzyloxycarbonyl)-N-(2-ureidoethyl)aminomethyl]pyrrolidine (1.43 g).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[C:8]([I:19])[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:28])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:28])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[C:8]([I:19])[C:7]2=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2c(C)c(I)c(=O)n(C3CCCC3)c2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: Cc1c(I)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Temperature: 25 °C
Yield: 73.9 %

Procedure:
8-Cyclopentyl-6-iodo-5-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.51 g, 3.76 mmol) and 2-benzenesulfonyl-3-phenyloxaziridine (0.98 g, 3.76 mmol) were combined in dichloromethane (14 mL) and stirred at room temperature until no starting material remained. The solvent was removed in vacuo and the residue was purified by chromatography (gradient 50% ethyl acetate in heptane to 100% ethyl acetate) to provide 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.16 g, 74%) as a white solid. MS (ESI); M++1: Calc'd, 418. Found 418. 1H NMR δ (300 MHz, CDCl3) 9.13 (s, 1H), 6.14-6.02 (m, 1H), 2.98 (s, 3H), 2.80 (s, 3H), 2.27-2.06 (m, 4H), 2.00-1.87 (m, 2H), 1.72-1.63 (m, 2H).