Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.C(O)(=O)C.[CH3:11][C:12]1[C:13]([CH:19]([CH:22]2[CH2:24][CH2:23]2)[CH:20]=O)=[N:14][CH:15]=[CH:16][C:17]=1[Cl:18].[C:25](OC)(=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>C(O)C>[Cl:18][C:17]1[CH:16]=[CH:15][N:14]2[C:13]([C:12]=1[CH3:11])=[C:19]([CH:22]1[CH2:24][CH2:23]1)[CH:20]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[C:25]2=[O:31]
Reactant: Cc1c(Cl)ccnc1C(C=O)C1CC1
Reactant: COC(=O)CC(=O)OC
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Piperidine (7 mL, 70.9 mmol) and acetic acid (5.5 mL, 95 mmol) were added to a solution of 2-(3-methyl-4-chloro-pyridin-2-yl)-2-cyclopropyl-acetaldehyde (4.98 g, 23.75 mmol) in absolute ethanol (200 mL). Dimethyl malonate (16.44 mL, 144 mmol) was added and the reaction mixture was stirred at 100° C. for 5 h (the reaction mixture turned into a red solution). The solvent was evaporated under reduced pressure. The resulting mixture was diluted with ether (100 mL) and washed with water (100 mL) and brine (50 mL). The organic layer was separated and dried over sodium sulfate. The mixture was evaporated to dryness. Dowtherm A (110 mL) was added. This reaction mixture was heated to 240° C. under microwave irradiation and stirred at this temperature for 0.5 h during which the reaction mixture turned into a black solution. The residue was purified by reversed phase flash chromatography using a 5%-100% acetonitrile gradient in water with 1% TFA yielding the cyclized methyl ester (4 g, 51.4%). ESI-MS m/z: 292 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm: 9.34 (d, J=7.8 Hz, 1H), 8.42 (s, 1H), 7.13 (d, J=7.8 Hz, 1H), 3.95 (s, 1H), 3.01 (s, 1H), 2.35-2.27 (m, 1H), 1.03-1.08 (m, 2H), 0.72-0.76 (m, 2H); 13C NMR (100 MHz CDCl3) δ ppm 166.6, 155.4, 148.4, 145.5, 142.3, 130.7, 129.0, 117.6, 115.6, 105.4, 52.3, 19.6, 17.0, 9.9 (2CH2).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:29](O)[CH2:30][OH:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:31]1[C:2]2([CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]2)[O:1][CH2:29][CH2:30]1
Reactant: COC(=O)C1CCCC(=O)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCC2(C1)OCCO2
Temperature: 25 °C

Procedure:
Methyl 3-oxocyclohexanecarboxylate (930 mg) and pyridinium p-toluenesulfonate (299 mg) were combined in toluene (29.8 mL) to give a colorless solution. Ethylene glycol (0.996 mL) was added and the reaction was refluxed under Dean-Stark conditions for 2 days. The reaction was cooled to room temperature, triethylamine was added, and then the mixture was concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix 0-40% hexane/ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:17][OH:18])[N:13]=[CH:12][C:11]=2[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:17][O:18][S:29]([CH3:28])(=[O:31])=[O:30])[N:13]=[CH:12][C:11]=2[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(CO)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(COS(C)(=O)=O)cc21
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To 6-hydroxymethyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.268 g, 0.96 mmol) and triethylamine (0.417 mL, 3 mmol) in EtOAc (4.8 mL) was added methanesulfonyl chloride (0.224 mL, 2.9 mmol) at 0° C. The reaction was stirred at the same temperature for 1 h. Water (5 mL) was added and the aqueous mixture extracted with EtOAc (3×5.0 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo to give the title compound (0.279 g,) as a pale yellow oil. MS: [M+H]+=357.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[C:7]([C:8]([Cl:13])=[O:10])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(Cl)c1cnccc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-chloronicotinic acid (1.57 g, 10.0 mmol, 1.0 eq) in 25 mL of toluene was added thionyl chloride (1.8 mL, 25.0 mmol, 2.5 eq) at room temperature. The reaction mixture was stirred at 100° C. for 3 hours. The mixture was concentrated under reduced pressure, dissolved in 25 mL of toluene and concentrated again to give crude 4-chloronicotinoyl chloride hydrochloride salt, which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH:16]=1
Reactant: CC1(C)CCC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(c2cc(Br)ccc2N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
A mixture of 4-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (1.5 g, 3.32 mmol) produced in Example (3e), trifluoroacetic acid (3 mL, 38.7 mmol) and dichloromethane (6 mL) was stirred for 2 hours and 30 minutes at room temperature. Saturated aqueous solution of sodium carbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to give 1.21 g of a crude product of the title compound as a brown oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([N+:22]([O-:24])=[O:23])[C:6]2[S:10][C:9]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])=[N:8][C:7]=2[CH:21]=1.[BH4-].[Na+]>CS(C)=O.O.Cl>[C:13]1([CH3:20])[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:12]=1[NH:11][C:9]1[S:10][C:6]2[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][C:3]([CH3:2])=[CH:21][C:7]=2[N:8]=1
Reactant: Cc1cc(C)c(Nc2nc3cc(CCl)cc([N+](=O)[O-])c3s2)c(C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c(Nc2nc3cc(C)cc([N+](=O)[O-])c3s2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloromethyl-N-mesityl-7-nitro-1,3-benzothiazol-2-amine (120 mg, 0.332 mmol) in dimethyl sulfoxide (DMSO) (2 ml) was added sodium borohydride (25 mg, 0.663 mmol). The mixture was stirred at room temperature for 3 h and diluted with water and neutralized with 1N HCl solution. The aqueous solution was extracted with AcOEt.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[O:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[O:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]3=[N:29][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]3[CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 20.4 g) in THF (dry) (250 mL) was added 2-chloroethanesulfonyl chloride (32.2 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-phenoxyphenyl)pyridin-2-amine (29.09 g) in THF (dry) (150 mL) was dropwised at 0° C. and the mixture was stirred at room temperature under N2 for 2 days. The mixture was quenched with THF/water (v/v=5/1) at 0° C. under N2 carefully. Water (500 mL) and EtOAc (400 mL) were added to form precipitates (stirred for 30 min) which were washed with water and EtOAc, collected and crystallized from DMSO/EtOH (500 mL/1000 ml, at 90° C.) to give the title compound (36.0 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:5]([NH2:6])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.O1CCOCC1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:35][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:6][C:5]1[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)=[CH:8][C:2]([C:31]2[CH:32]=[N:33][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:35][CH:36]=2)=[CH:3][C:4]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)(O)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1c(C2CCCO2)cc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ncc(-c2cc(C3CCCO3)c(N)c([N+](=O)[O-])c2)cn1
Yield: 78.8 %

Procedure:
Mixed 4-bromo-2-nitro-6-tetrahydrofuran-2-yl-aniline (6a) (40.40 g, 92%, 129.5 mmol), 1,4-dioxane (260 mL, Sigma-Aldrich 360481), 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (7) (41.05 g, 155.4 mmol), and aqueous 2.7 M Na2CO3 (143.9 mL, 388.5 mmol). A stream of nitrogen was bubbled through the stirring mixture for 1 hr, followed by addition of tetrakis(triphenylphosphine)palladium (0) (7.48 g, 6.47 mmol, Strem 462150). The reaction mixture was stirred at reflux for 2 hrs (HPLC showed complete reaction), allowed to cool, diluted with EtOAc, washed with water, saturated aqueous NH4Cl, brine, dried over MgSO4, and filtered through a short plug of Florisil® eluting with EtOAc. The filtrate was concentrated under reduced pressure giving adark brown oil. Dissolved in CH2Cl2 and eluted through a short plug of silica gel with CH2Cl2 and then EtOAc. The desired fraction was concentrated on a rotary evaporator until a precipitate formed giving a thick brown slurry, which was triturated with MTBE. The solid was collected by filtration, washed with MTBE, and dried under high vacuum giving (8) as a yellow solid (35.14 g, 99+% HPLC purity,). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 345.00 (2.69 min). 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 2H), 8.36 (d, J=2.2 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.09 (s, 2H), 4.92 (t, J=7.2 Hz, 1H), 4.62 (s, 1H), 4.20-4.11 (m, 1H), 4.03-3.94 (m, 1H), 2.39-2.26 (m, 1H), 2.23-2.08 (m, 3H), 1.64 (s, 6H) ppm. The filtrate was further concentrated and purified by ISCO silica gel chromatography eluting with 0 to 80% EtOAc/hexane giving a second crop of product (8) as an amber solid (4.46 g, 88% overall yield; 88% HPLC purity.
Reaction SMILES: ClN1C(=O)CCC1=O.[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[N:21][OH:22])=[CH:12][CH:11]=1.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1.BrC(C(F)(F)F)=C.FF.C(N(CC)CC)C>CN(C)C=O.O>[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH2:31][C:30]([C:28]3[CH:27]=[C:26]([Cl:36])[CH:25]=[C:24]([Cl:23])[CH:29]=3)([C:32]([F:33])([F:35])[F:34])[O:22][N:21]=2)=[CH:12][CH:11]=1
Reactant: ON=Cc1ccc(Br)c2ccccc12
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: C=C(Br)C(F)(F)F
Agent: FF
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3ccccc23)=NO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Chlorosuccinimide (1.70 g, 12.7 mmol) was added to a solution of 4-bromo-1-naphthalenecarboxaldehyde oxime (i.e. the product of Step A, 2.33 g, 9.3 mmol) in N,N-dimethylformamide (6.0 mL). The reaction mixture was stirred for 1 h at room temperature, and then a solution of 1,3-dichloro-5-[1-(trifluoromethyl)ethenyl]benzene (2.70 g, 11.2 mmol, prepared from commercially available 2-bromo-3,3,3-trifluoropropene by the method described in J. Fluorine Chem. 1999, 95, 167-170) and triethylamine (4.5 mL, 32.0 mmol) in N,N-dimethylformamide (9.0 mL) was added. After stirring for an additional 2 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate/hexanes to afford the title compound as a white solid (2.9 g). 1H NMR (CDCl3): δ 8.87 (m, 1H), 8.32 (m, 1H), 7.77 (d, 1H), 7.66 (m, 2H), 7.55 (s, 1H), 7.46 (dd, 1H), 7.32 (d, 1H), 4.24 (d, 1H), 3.88 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CS(O[CH2:39][CH2:40][CH2:41][N:42]1[CH2:48][CH:47]([OH:49])[C:44]2([CH2:46][CH2:45]2)[CH2:43]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:49][CH:47]1[C:44]2([CH2:46][CH2:45]2)[CH2:43][N:42]([CH2:41][CH2:40][CH2:39][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:20]([C:22]5([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]5)=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:48]1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)cn2)CC1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)cn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
To a solution of N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide (110 mg, 0.25 mmol) in DMA (2 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (125 mg, 0.50 mmol) and Cs2CO3 (243 mg, 0.75 mmol). The reaction was then stirred at rt for 24 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (10 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v) EtOAc/CH3OH/Et3N) to afford the desired compound as a pale yellow solid (110 mg, 75%).
Reaction SMILES: N=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[NH:11])[NH:3]1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1>CO>[C:13]1([CH3:12])[CH:14]=[CH:15][C:16]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[NH:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH:10]=[C:2]2[N+:3]([CH3:4])=[CH:17][CH2:16][S:19]2)=[N:3]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C[N+]1=CCSC1=CC1=NC(=N)c2ccccc21
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Three grams of 1,3-diiminoisoindoline were dissolved in 25 ml of methanol. The solution was treated with 5.7 grams of 2,3-dimethyl thiazolinine p-toluenesulfonate which had been dissolved in 25 ml of methanol. The resulting mixture was heated at reflux for several hours. A yellow solid was obtained upon cooling and scratching the vessel. The solid was collected and washed free of the dark colored mother liquor with methanol and acetone. The dye was then dissolved in hot water from which it was recrystallized. The dye can be converted to other salts by adding an anion, such as iodide, to give a more insoluble salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=S)[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36](OCC)(=[O:39])[NH:37][NH2:38]>C1COCC1.C([O-])(=O)C.[Hg+]>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:38][NH:37][C:36](=[O:39])[N:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=S)NCC4)cc2)CCC1
Agent: CC(=O)[O-]
Agent: [Hg+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(=O)n3CC4)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of tert-butyl(1-(4-(3-phenyl-5-thioxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (55 mg, 0.113 mmol) in THF (7 mL) was added ethyl carbazate (23.6 mg, 0.226 mmol) and mercury acetate (54.1 mg, 0.17 mmol) under nitrogen. The resulting mixture was stirred at r.t. for 2 h. The mixture was concentrated to dryness under reduced pressure and partitioned between DCM (15 ml) and water (15 ml). The organic phase was separated and concentrated to dryness under reduced pressure. The resulting residue was suspended in toluene (7 ml). The resulting mixture was heated under reflux for 3 h. After cooled down to room temperature, the mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 4% MeOH in dichloromethane) to give tert-butyl(1-(4-(3-oxo-9-phenyl-2,3,5,6-tetrahydro-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-8-yl)phenyl)cyclobutyl)carbamate (32 mg, 56%). LCMS (Method A): RT=6.29 min, M+1=510. 1H NMR (500 MHz, CDCl3): 9.83 (1H,S), 8.10 (1H, s), 7.29 (2H, d), 7.22 (2H, d), 7.19-7.18 (3H, m), 7.13-7.11 (2H, m), 5.1 (1H, br), 4.01 (2H, t), 3.36 (2H, t), 2.43-2.28 (4H, m), 2.02-1.97 (1H, m), 1.76-1.70 (1H, m), 1.30-1.14 (9H, br).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:23]([O:26][CH:27]1[CH:39]=[CH:38][CH:37]([CH3:40])[CH:36]([C:41]([CH3:63])=[CH:42][CH:43]=[CH:44][CH:45]([CH3:62])[CH2:46][CH:47]2[O:61][CH:48]2[CH:49]([CH3:60])[CH:50]([O:53][C:54](=[O:59])[CH2:55][O:56][CH2:57][CH3:58])[CH2:51][CH3:52])[O:35][C:33](=[O:34])[CH2:32][CH:31]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:30][CH2:29][C:28]1([OH:73])[CH3:72])(=[O:25])[CH3:24]>ClCCl.C(OCC)(=O)C>[C:23]([O:26][CH:27]1[C:28]([O:73][CH:1]([O:3][CH2:4][CH3:5])[CH3:2])([CH3:72])[CH2:29][CH2:30][CH:31]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:66])[CH3:67])[CH2:32][C:33]([O:35][CH:36](/[C:41](/[CH3:63])=[CH:42]/[CH:43]=[CH:44]/[CH:45]([CH3:62])[CH2:46][CH:47]2[O:61][CH:48]2[CH:49]([CH3:60])[CH:50]([O:53][C:54](=[O:59])[CH2:55][O:56][CH2:57][CH3:58])[CH2:51][CH3:52])[CH:37]([CH3:40])[CH:38]=[CH:39]1)=[O:34])(=[O:25])[CH3:24]
Reactant: C=COCC
Reactant: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)C=CC=C(C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(O)C(OC(C)=O)C=CC1C
Agent: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOCC(=O)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC1C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Ethyl vinyl ether (82 mg, 1.1 mmol) and pyridinium p-toluenesulfonate (9.2 mg, 0.036 mmol) were added to a solution of 7-acetoxy-3-t-butyldimethylsiloxy-21-ethoxyacetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (27 mg, 0.036 mmol) in dichloromethane (1.5 mL) at room temperature. The mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crude product was purified by silica gel column chromatography (Kanto silica gel 60N, spherical, neutral, 40 to 100 μm, eluate; hexane:ethyl acetate=80:20) to obtain the title compound (16 mg, 54%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH2:43](O)[CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][OH:60]>>[ClH:1].[OH:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OCCOCCOCCOCCOCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: Cl

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 3,6,9,12,15-pentaoxaheptadecane-1,17-diol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[2-(2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethyl ester, hydrochloride. MS (ES+) m/z calcd. for C43H54Cl2F2N3O10: [(M+H)+]880. found: 880.
Reaction SMILES: C(O)(C)(C)C.Cl[S:7]([N:10]=C=O)(=[O:9])=[O:8].C(OC(NS(Cl)(=O)=O)=O)(C)(C)C.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[N:39]=[CH:40][C:41]([NH2:44])=[N:42][CH:43]=2)=[C:34]([F:45])[CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[NH:25][S:7]([NH2:10])(=[O:9])=[O:8])=[CH:33][C:34]=2[F:45])=[N:39][CH:40]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3N)cc2F)cn1
Reactant: O=C=NS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Nc1cnc(-c2ccc(-c3ccccc3NS(N)(=O)=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
To a solution of tert-butanol (13 mg, 0.18 mmol) in DCM (5 mL) was added chlorosulfonylisocyanate (25 mg, 0.18 mmol) at 0° Celsius. The resulting solution containing N-(tert-butoxycarbonyl)sulfamoyl chloride was added to a reaction flask containing 5-(2′-amino-3-fluorobiphenyl-4-yl)pyrazin-2-amine (50 mg, 0.18 mmol) and triethylamine (36 mg, 0.36 mmol) in anhydrous DCM (10 mL) at 0° Celsius. The mixture was warmed to rt, stirred 2 hours, then concentrated to dryness, re-dissolved in TFA/DCM (5 mL/5 mL), stirred at rt for 1 hour, and concentrated to dryness. The residue was diluted with water (10 mL) and saturated NaHCO3(aq) (10 mL), extracted with DCM (10 mL×3) and the combined organic extracts washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by HPLC to give the title compound (10 mg, 16%). MS (ESI): mass calcd. for C16H14FN5O2S, 359.09; m/z found, 360.0 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.33 (s, 1H), 8.04 (d, J=1.3, 1H), 7.91 (m, 1H), 7.63 (d, J=7.8, 1H), 7.44-7.22 (m, 4H), 7.24 (m, 1H), 7.05 (s, 2H), 6.70 (s, 2H).