Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].C(N(CC)[P:13](Cl)([O-:15])=[O:14])C.[Cl-].[NH4+]>C(OCC)C>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([P:13]([C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)(=[O:14])[OH:15])[CH:3]=1
Reactant: Cc1cccc(Br)c1
Reactant: CCN(CC)P(=O)([O-])Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cccc(P(=O)(O)c2cccc(C)c2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 34.4 %

Procedure:
In 250 ml of dehydrated diethyl ether, 102.6 g (0.6 mole) of m-bromotoluene was reacted with 15.3 g (0.64 mole) of metallic magnesium to prepare a Grignard reagent. To the resulting Grignard reagent was added dropwise 57 g (0.3 mole) of N,N-diethylamidochlorophosphate at 37° to 38° C. over a period of 2 hours. After the reaction mixture was heated at reflux for 4.5. hours, 400 ml of ice-water and 150 ml of saturated aqueous ammonium chloride were added thereto to decompose the salt. After liquid separation, 400 ml of concentrated hydrochloric acid was added to the ether layer under ice-cooling, followed by heating to remove the ether by distillation. To the residue was further added 100 ml of concentrated hydrochloric acid, and a reaction was conducted at 100° to 110° C. for 5 hours. The formed oily substance was separated from the aqueous layer, and 50 ml of a 20% aqueous solution of sodium hydroxide was added thereto to form a uniform solution. The insoluble matter was removed by extraction with toluene, and 20% sulfuric acid was added to the solution to neutralize and further to make it acidic. The precipitate thus formed was collected by filtration, washed with water, and dried to obtain 27 g of a crude product. Recrystallization from methanol yielded 25.4 g (percent yield: 34%) of di-(m-tolyl)phosphinic acid as a colorless solid having a melting point of 171.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC#N>[C:12]1([NH:11][C:2]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: Nc1ccccc1
Solvent: CC#N
Product: O=C(O)c1cnccc1Nc1ccccc1
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 4-chloronicotinic acid (150 mg, 0.952 mmol) and aniline (177 mg, 1.90 mmol) in MeCN (2 mL) was stirred and heated in the microwave (80° C., 300 W) for 1 h. The solid material was filtered off and the solvent was removed in vacuo. The crude 4-(phenylamino)nicotinic acid (202 mg) obtained was dissolved in THF (25 mL). After dropwise addition of LiAlH4 (1 M solution in THF, 3.77 mL, 3.77 mmol) at 0° C., the reaction mixture was stirred for 30 min, allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (0.4 mL) at 0° C. and excess EtOAc was added. All solid material was filtered off and the solvent was removed in vacuo. Trituration with Et2O provided (4-(phenylamino)pyridin-3-yl)methanol (115 mg, 60% over 2 steps). ESI-MS [M+H]+=201.1.
Reaction SMILES: [CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21]C(C)(C)C)=[O:20])=[O:13])[C@H:6]([F:11])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4].Cl>O1CCOCC1>[CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([OH:21])=[O:20])=[O:13])[C@H:6]([F:11])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@H](F)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)O)[C@H](F)C(=O)OC
Reaction time: 2 h

Procedure:
To methyl 3-(S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)-2-(S)-fluoropropionate H-4 (4.3 mmol) was added 4 N HCl in dioxane (15 mL), the solution stirred for 2 h, then evaporated to dryness to afford 4.3 mmol of methyl 3-(S)-n-butyl-3-[2-(S)-carboxypyrrolidin-1-yl-carbonyl)-2-(S)-fluoropropionate H-5 (quant.). To H-5 (0.15 mmol) in dioxane (1 mL) was added an amine (0.15 mmol), DIEA (0.38 mmol), and HATU or similar coupling reagent (0.15 mmol) and the solution stirred for 8 h. The reaction was cooled to 0° C., aqueous 50% hydroxylamine was added (0.5 mL) and the reaction stirred for 4 h. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy-3-(S)-n-butyl-3-[2-(S)-aminocarbonylpyrrolidin-1-yl-carbonyl)-2-(S)-fluoropropionamide H-6.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:29](O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[CH:1]1([N:7]2[C:8]3[C:9]4[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:10]=4[N:11]=[CH:12][C:13]=3[CH2:14][O:15][CH2:29]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(CO)cnc21
Reactant: CC(=O)O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2c3c(cnc21)COCN3C1CCCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
[4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (38 mg, 0.10 mmol) and aqueous formaldehyde (35 wt %, 0.6 mL, 8 mmol) in ethanol (2 mL) were stirred at 75° C. for 1 hour. The reaction mixture was then stirred with acetic acid (1 mL) at 75° C. for 1 hour, allowed to cool to room temperature, and after addition of saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1 (v/v)) to give the title compound as a colorless oil (19.8 mg, yield 51%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([Cu]C(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)c1c(C)[nH]c2ccccc12
Reactant: OB(O)c1ccccc1
Agent: CC(=O)[Cu]C(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)n(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.7 %

Procedure:
A mixture of methyl 2-methyl-1H-indole-3-carboxylate (500 mg, 2.65 mmol), phenylboronic acid (384 mg, 3.17 mmol), diacetylcopper (453 mg, 3.98 mmol), triethylamine (0.44 ml, 3.98 mmol), N,N-dimethylpyridin-4-amine (486 ml, 3.98 mmol) and 4A molecular sieve (1.02 g) in dichloromethane (15 mL) was stirred at room temperature for 12 hours. After filtration, the mixture was concentrated and purified by chromatography (silica gel, petroleum: ethyl acetate=10:1) to afford methyl 2-methyl-1-phenyl-1H-indole-3-carboxylate as white solid (272 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=8.0 Hz, 1H), 7.66-7.51 (m, 3H), 7.36 (dd, J=5.3, 3.2 Hz, 2H), 7.30 (s, 1H), 7.21-7.14 (m, 1H), 7.04 (d, J=8.2 Hz, 1H), 4.00 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: C(O[C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18]C=1)C=C.[NH2:23][C:24]1[CH:44]=[CH:43][C:27]([C:28]([NH:30][CH:31]([CH3:42])[C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH:35]2C(O)=O)=[O:33])=[O:29])=[CH:26][C:25]=1[Cl:45].O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([CH:35]2[CH2:36][CH2:37][CH2:38][N:34]2[C:32](=[O:33])[CH:31]([NH:30][C:28](=[O:29])[C:27]2[CH:43]=[CH:44][C:24]([NH2:23])=[C:25]([Cl:45])[CH:26]=2)[CH3:42])=[O:22])[CH2:11][C:10](=[O:12])[O:9]1)[C:15]1[CH:16]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1

Procedure:
Was prepared from the syn diastereomer of (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester (40) and 97a following the method used for 98a. The title compound was isolated as a pale yellow solid (720 mg, 51% yield). 1H-NMR (500 MHz, CD3OD) δ 1.16 (d, 0.5H), 1.40 (d, 2.5H), 1.64-2.25 (m, 4H), 2.61 (dd, 1H), 2.79 (dd, 1H), 3.37-3.59 (m, 1H), 3.59-3.74 (m, 1H), 3.77-3.92 (m, 1H), 4.29-4.47 (m, 1H), 4.47-5.02 (m, 4H), 5.48 (s, 0.5H), 5.66 (d, 1H), 5.68 (d, 0.5H), 6.79 (d, 1H), 7.17-7.52 (m, 5H), 7.48-7.62 (m, 1H), 7.68-7.83 (m, 1H). Analytical HPLC 15.98 min. LC-MS (ES+) m/e=529.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][N:3]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.CC1(C)CCCC(C)(C)N1.C([Li])CCC>C1COCC1.O>[F:1][C:2]1[C:7]([B:18]([OH:23])[OH:19])=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)[CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccc(C(C)c2ccc(F)nc2)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(C(C)c2cnc(F)c(B(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
2-Fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridine (1.078 g, 4.359 mmol) and triisopropyl borate (2.50 mL, 10.9 mmol) were dissolved in THF (11.5 mL). In a separate flask, 2,2,6,6-tetramethylpiperidine (1.11 mL, 6.54 mmol) was dissolved in THF (12 mL) and the flask was cooled in an ice water bath. Then, n-butyllithium solution (1.6 M in hexanes, 3.8 mL, 6.1 mmol) was added via syringe, and the yellow solution was stirred under nitrogen for 15 min. Then, the contents were transferred via syringe to the other flask, which was pre-cooled in a dry ice/acetone bath. After completing the transfer, the reaction was stirred under nitrogen at −78° C. for 1 h. Then, the reaction was allowed to slowly warm up to room temperature while being stirred overnight. The reaction was treated with water (30 mL) and stirred for about 30 min. The layers were separated, and the organic phase was extracted with 1 N aqueous NaOH (15 mL). The organic phase was discarded, and the aqueous phase was treated with aqueous 5N HCl to lower the pH to around 5-6. The aqueous phase was extracted with 10:1 DCM/MeOH. The extracts were combined, concentrated, and dried under high vacuum to afford 2-fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-ylboronic acid (1.2342 g). 1H NMR (400 MHz, CDCl3) δ 8.17-8.05 (m, 2H), 7.25-7.19 (m, 2H), 7.15-7.10 (m, 2H), 4.16 (q, J=7.37 Hz, 1H), 2.47 (s, 3H), 1.66 (d, J=7.24 Hz, 3H). m/z (ESI, +ve ion) 292 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]=[N:11][C:12]1[C:13]([NH2:25])=[N:14][C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:16][C:17]=1[CH3:18].C1COCC1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CO>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:25][C:13]2[C:12]([N:11]=1)=[C:17]([CH3:18])[N:16]=[C:15]([N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[N:14]=2
Reactant: COc1nccc(I)c1C=Nc1c(C)nc(N2CCOCC2)nc1N
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1nccc(I)c1-c1nc2c(C)nc(N3CCOCC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.7 %

Procedure:
To a solution of N5-(4-Iodo-2-methoxy-pyridin-3ylmethylene)-6-methyl-2-morpholin-4-yl-pyrimidine-4,5-diamine (140 mg, 0.31 mmol) in a mixture of MeOH:THF (20 mL:10 mL) was added iodobenzene diacetate (198 mg, 0.62 mmol). After stirring at ambient temperature for 4 hours, the solvents were evaporated in vacuo and the crude was purified by preparative HPLC (see method below) to give the title compound as an amber solid (50 mg, 36%): IR (KBr, cm−1) 3420, 2853, 1618; 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 7.83 and 7.54 (d, J=5.3, 1H), 3.91 (s, 3H), 3.81-3.77 (m, 8H), 2.72 (s, 3H); LCMS (+ESI, M+H+) m/z 453; HPLC: 97% (220 nm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([O:13][CH3:14])=[O:12])=[C:6](B(O)O)[CH:7]=1.[C:15]1([S:21]N2C(=O)C3C(=CC=CC=3)C2=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.OC1C(C(C)C)=CC(C(C)C)=CC=1C(O[Cu])=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([O:13][CH3:14])=[O:12])=[C:6]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(F)cc1B(O)O
Reactant: O=C1c2ccccc2C(=O)N1Sc1ccccc1
Agent: CC(C)c1cc(C(=O)O[Cu])c(O)c(C(C)C)c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)cc1Sc1ccccc1

Procedure:
5-Fluoro-2-(methoxycarbonyl)phenylboronic acid (1.00 g), 2-(phenylthio)isoindoline-1,3-dione (0.86 g), and (2-hydroxy-3,5-diisopropylbenzoyloxy)copper (0.29 g) were stirred in dioxane (15 mL) at 50° C. for 24 hours. The reaction mixture was chromatographed on silica gel with 5% ethyl acetate/hexanes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([N:13]2[C:17]3=[CH:18][CH:19]=[CH:20][C:21](=[O:22])[N:16]3[C@H:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@@H:14]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:12])=[O:11])[CH:5]=1.C1C(=O)N([I:45])C(=O)C1>>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([N:13]2[C:17]3=[CH:18][CH:19]=[C:20]([I:45])[C:21](=[O:22])[N:16]3[C@H:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@@H:14]2[C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)(=[O:11])=[O:12])[CH:5]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cccc(S(=O)(=O)N2c3cccc(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1
Product: COC(=O)c1cccc(S(=O)(=O)N2c3ccc(I)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1

Procedure:
The titled compound was prepared according to general method B by reaction of rac-3-[cis-2,3-bis-(4-chloro-phenyl)-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzoic acid methyl ester with NIS.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][NH:24][OH:25])=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1>O1CCOCC1.O>[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][N:24]([OH:25])[C:3]([NH:2][CH3:1])=[S:4])=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CN=C=S
Solvent: C1COCCO1
Solvent: O
Product: CNC(=S)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A solution of methyl isothiocyanate (1.36 g, 18.56 mmol) in 2 ml of dioxane is added dropwise to a suspension of 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine (2.01 g, 5.84 mmol) in 60 ml of dioxane and 60 ml of H2O at 0° C. The ice bath is removed. After one hour 0.5 g (6.84 mmol) additional methyl isothiocyanate is added and the reaction mixture is stored in a freezer overnight. The solids are collected by filtration and recrystallized from THF/hexane, rinsed with ether, and dried under high vacuum over P2O5 to give pure 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(methylamino)thioxomethyl]-1H-indole-3-methanamine (1.32 g, 54%); mp 198°-198.5° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N+:10]([O-])=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:17][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=[N+]([O-])c1ccc2cc[n+]([O-])cc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2ccnc(Cl)c2c1
Temperature: 90 °C
Yield: 14 %

Procedure:
To a suspension of 7-nitroisoquinoline N-oxide obtained in Preparation Example 1-5, Step 3 in toluene (185 ml) was added phosphorus oxychloride (3.5 ml, 37 mmol), and the mixture was stirred under heating at 90° C. for 2 hr. The reaction mixture was cooled to room temperature and the reaction mixture was poured into an aqueous sodium hydrogencarbonate solution. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetone=30:1) to give 1-chloro-7-nitroisoquinoline (540 mg, 14%).
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cncc(CC2CCCN2)c1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ncoc1-c1ccccc1)N1CCCC1Cc1cccnc1
Temperature: 25 °C

Procedure:
5-Phenyl-1,3-oxazole-4-carboxylic acid (40 mg, 0.211 mmol), 3-(pyrrolidin-2-ylmethyl)pyridine (50.5 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H19N3O2: 333.1477, found 333.1484.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([N:17]([S:33]([CH3:32])(=[O:35])=[O:34])[S:33]([CH3:32])(=[O:35])=[O:34])=[N:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(-c2cnc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cc3ccccc3)n2)cc1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) (337 mg, 1.05 mmol) was dissolved in anhydrous dichloromethane (9 mL), and to this was added triethylamine (220 μL, 1.58 mmol) and stirred at room temperature. To this was added methanesulfonyl chloride (245 μL, 3.16 mmol) and stirred for 1.5 h at the same temperature. To this was added 2 M hydrochloric acid to stop the reaction and after separating the aqueous layer and organic layer, the organic layer was washed with saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by silica gel column chromatography (28 g, n-hexane/ethyl acetate=3/1→3/2) to give 5-(4-acetoxyphenyl)-3-benzyl-2-bis(methanesulfonyl)aminopyrazine (c-39) as a yellow amorphous (241 mg, 48.3%). Rf=0.32 (n-hexane/ethyl acetate=3/2). Mp. 165.5-167° C. UV (MeOH) λmax (log ε) 306 (4.29), 293 (4.25), 259 (4.21). UV (pH PB) λmax (log ε) 336.5 (4.19), 264 (4.09). 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.59 (s, 6H), 4.36 (s, 2H), 7.20-7.26 (m, 1H), 7.26-7.35 (m, 6H), 8.11-8.17 (AA′BB′, 2H), 9.14 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 20.9, 38.5, 43.1 (1C×2), 122.7 (2C), 126.6, 128.3 (2C), 128.6 (2C), 129.5 (2C), 132.1, 137.6, 139.2, 141.5, 151.4, 152.5, 155.6, 169.0. IR (KBr, cm−1) 509, 523, 706, 756, 766, 912, 974, 1015, 1163, 1200, 1321, 1368, 1418, 1435, 1528, 1603, 1755, 3032. HRMS (FAB+) m/z 476.0936 (M+H, C21H22N3O6S2 requires 476.0950).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCc1ccc(C#N)nc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCc1ccc(-c2nc(=O)c3ccccc3s2)nc1
Yield: 97.8 %

Procedure:
tert-Butyl 3-(6-cyano-3-pyridyl)propanoate (0.46 g, 1.97 mmol) and methyl thiosalicylate (0.50 g, 2.96 mmol) were dissolved in toluene (30 ml), and triethylamine (0.55 ml, 3.94 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.71 g, 98%) as white crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[C:46]4[C:50](=[CH:51][CH:52]=3)[NH:49][CH:48]=[CH:47]4)=[CH:40][CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[C:46]4[C:50](=[CH:51][CH:52]=3)[NH:49][CH:48]=[CH:47]4)=[CH:40][CH:39]=2)[C:35]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A solution of triphenylphosphine (71 mg, 0.27 mmol) in methylene chloride (1.5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (48 mg, 0.27 mmol). The reaction mixture was stirred at 0° C. for 25 min and then treated with 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid (75 mg, 0.23 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (50 mg, 0.50 mmol). The resulting reaction mixture was stirred at 25° C. for 5 d. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 chloroform/methanol) to afford impure 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-N-thiazol-2-yl-propionamide. Repurification by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded pure 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-N-thiazol-2-yl-propionamide (8 mg, 9%) as a white solid: mp 112-115° C.; EI-HRMS m/e calcd for C25H25N3OS (M+) 415.1718, found 415.1714.