Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=O)([O-:3])=[O:2].P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][NH:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][N:35]([C@H:36]1[CH2:37][CH2:38][C@H:39]([CH3:42])[CH2:40][CH2:41]1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)C=Cc1cccc([N+](=O)[O-])c1)[C@H]1CC[C@H](C)CC1

Procedure:
Using 2.0 g of 3-nitrocinnamic acid, 1.9 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 60 ml of methylene chloride, 2.3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.04 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was conducted. As a result, 1.54 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-nitrocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17](OS(C)(=O)=O)[CH2:16][CH2:15]2)=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].[Cl:31]CCl>CN(C=O)C.C1(C)C=CC=CC=1>[ClH:31].[CH:17]12[N:13]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:14]([CH2:19][CH2:18]1)[CH2:15][CH2:16]2
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](Nc2ccc(C#N)c3ccccc23)CC1
Reactant: ClCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cl
Product: N#Cc1ccc(N2C3CCC2CC3)c2ccccc12
Reaction time: 0.5 h
Yield: 73 %

Procedure:
165RL97 (129 mg, 374 μmol) was stirred in DMF/toluene (1:1, 20 mL) at −40° C. and potassium tert-butoxide (42 mg, 374 μmol) was added. The stirring was continued for 30 min before the reaction mixture was brought to rt. After 2 hours, more potassium tert-butoxide (20 mg, 0.18 mol) was added and the reaction was stirred overnight. The mixture was diluted with dichloromethane (50 mL) and washed with water (3×30 mL). The organic layer was dried over sodium sulfate, filtered and evaporated and the residue purified by column chromatography on silica gel using dichloromethane as eluent, yielding the desired compound (67.8 mg, 73%).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>C(O)C>[N:12]1([CH2:2][C:3]2[NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: c1c[nH]cn1
Solvent: CCO
Product: c1ccc2[nH]c(Cn3ccnc3)nc2c1
Yield: 13.2 %

Procedure:
A solution of 2-chloromethyl-1H-benzimidazole (4.85 g) and imidazole (9.9 g) in ethanol (37 ml) was stirred at 70° C. for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (120 g) with a mixture of methanol and dichloromethane (5:95) as an eluent to afford an oil, which was crystallized from ethyl acetate. Recrystallization from a mixture of methanol and diethyl ether to give 2-(imidazol-1-yl)methyl-1H-benzimidazole (0.76 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[N:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1C.[C:14]1(C)C=CC=CC=1>>[Br-:1].[OH:5][CH2:4][CH2:3][CH2:2][N+:6]1[CH:7]=[CH:8][C:9]([CH3:14])=[CH:10][C:11]=1[CH3:12]
Reactant: OCCCBr
Reactant: Cc1ccccc1
Reactant: Cc1cccc(C)n1
Product: Cc1cc[n+](CCCO)c(C)c1
Product: [Br-]
Reaction time: 18 h

Procedure:
3-Bromopropanol (3,5 equivalents) was dissolved in some toluene in a round-bottomed flask flushed with nitrogen. Then, lutidine (1 equivalent) was added and the mixture was heated to reflux. After several hours, an off-white product appeared in the flask as a sticking solid. The reaction was stopped after 18 hours. The solvent was removed under the reduced pressure and ether was added to precipitate out the solids. After washing with ether, the product as off-white powders were dried. The yield of the reaction is 83%. The product is soluble in acetone, methanol and acetonitrile but not in diethyl ether. 1H NMR (CDCl3, 200 MHz): δ 2.24 (m, 2H), 2.61 (s, 3H), 3.03(s, 3H), 3.70 (t, 2H, J=4.86), 5.14 (t, 2H, J=7.26), 7.67 (s, 1H), 7.81(d, 1H, J=6.06), 9.65 (d, 1H, J=6.52); IR (CHCl3, cm−1): 1642 (C═C) (C═N), 3432 (O—H).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[N:25]1[CH:26]=[CH:27][C:22]([NH:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:23][CH:24]=1
Reactant: Nc1ccncc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccncc1
Yield: 71.7 %

Procedure:
Reaction of oleic acid (1.00 g, 3.54 mmol) with 4-aminopyridine (0.33 g, 3.54 mmol) was conducted according to the general amide coupling procedure using DCC to obtain the product as a colorless liquid (0.91 g, 72%). EIMS m/z: 359 ([M]+).
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH2:5][I:6].[CH3:11][P:12]([CH3:14])[CH3:13].C1COCC1>CC(=O)CC>[I-:6].[CH3:11][P+:12]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH2:3][C:2]([CH3:7])([N+:8]([O-:10])=[O:9])[CH3:1]
Reactant: CP(C)C
Reactant: CC(C)(CCCI)[N+](=O)[O-]
Solvent: CCC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CCC[P+](C)(C)C)[N+](=O)[O-]
Product: [I-]
Temperature: 100 °C
Yield: 93 %

Procedure:
To a 100 mL round bottomed flask was added 4-methyl-4-nitropentyl iodide (2.0 g, 7.78 mmol), 2-butanone (20 mL) and a 1 M solution of trimethylphosphine in THF (15.5 mL, 2 equiv, 15.5 mmol). This flask was placed into a stainless steel pressure vessel, sealed and heated at 100° C. for 4 days. The vessel was cooled and opened in a fumehood. The flask was removed and contained a white solid. The steel vessel contained solvent. The white solid was suspended in ethyl acetate (100 mL), filtered, rinsed with EA (2×50 mL) and dried under high vacuum to give a pale yellow solid (2.39 g, 93%). 1H NMR (D2O, 400 MHz): δ 1.62 (s, 6H), 1.84-1.88 (d, J=14.4, 9H), 2.10-2.14 (m, 2H), 2.20-2.28 (m, 2H). LRMS (ESI+) for C9H21NO2P+ (206.1); Found: 206 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH2:12]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](O)=[O:24])[CH2:19][CH2:18]1)[CH2:13][CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:10]([C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]2)=[O:24])=[CH:7][CH:6]=1)#[N:11]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: N#CC#Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C#CC#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A mixture of 143 mg of (p-hydroxyphenyl)propiolonitrile, 218 mg of trans-4-pentylcyclohexanecarboxylic acid, 227 mg of N,N'-dicyclohexylcarbodiimide and 12.2 mg of 4-(dimethylamino)pyridine in 15 ml of methylene chloride was stirred at room temperature for 105 minutes in a round flask under argon gasification. The yellow heterogeneous mixture was subsequently poured into 30 ml of water and extracted twice with 30 ml of methylene chloride each time. The organic phases were washed in sequence twice with 30 ml of water each time, twice with 30 ml of 5% acetic acid each time and twice with 30 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the residue (383 mg) on silica gel with 3% ethyl acetate/petroleum ether gave 270 mg (84%) of trans-4-pentylcyclohexanecarboxylic acid p-(2-cyanoethynyl)phenyl ester as colourless crystals. A single crystallization from hexane yielded 219 mg of the ester as colourless platelets (purity 99.7%); m.p. (C-N) 76.8° C., cl.p. (N-I) 153.2° C.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([CH:11]3[CH2:13][CH2:12]3)=[N:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(C)C)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C([O:54][CH2:55]C)C.[O:57]1CCCC1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:11]1([C:8]2[S:9][C:10]3[C:2]([C:55]([OH:54])=[O:57])=[CH:3][CH:4]=[C:5]([O:14][CH3:15])[C:6]=3[N:7]=2)[CH2:13][CH2:12]1
Reactant: C1CCOC1
Reactant: CCOCC
Reactant: COc1ccc(Br)c2sc(C3CC3)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)O)c2sc(C3CC3)nc12

Procedure:
Starting from 7-bromo-2-cyclopropyl-4-methoxybenzothiazole (515 mg), palladium (II) acetate (40 mg), bis-diphenylphosphinopropane (149 mg), and triethylamine (2.5 ml) in tetrahydrofuran (15 ml) and water (7 ml). Trituration of the residue with diethyl ether yielded the title compound as an off-white solid (360 mg). TLC Rf 0.49 (ethyl acetate).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+]>CO.O>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[S:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH2:14]1
Reactant: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CS3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CS3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
1-[(4-Methoxyphenyl)carbonylmethyl]-4-(4H,6H-1,3,4-thiadiazin-5-one-2-yl)pyridinium bromide (3.84 g, 9.09 mmol) was dissolved in methanol-water (1:1 v/v %) (50 ml), gradually added with sodium borohydride (3.43 g, 90.9 mmol) under ice cooling and then stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was added withdichloromethane, then washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain the titled compound (2.44 g) aswhite crystals.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:27])=[C:12]([NH:17][C@H:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH3:19])[CH:13]=[CH:14][C:15]=3[NH2:16])[CH:5]=2)[CH2:3][CH2:2]1.[C:28](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4[C:11]([F:27])=[C:12]([NH:17][C@H:18]([C:20]5[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=5)[CH3:19])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:28]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: C[C@H](Nc1ccc(N)c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](Nc1ccc2ncn(-c3cc(C4CC4)[nH]n3)c2c1F)c1ccc(F)cc1
Yield: 32.9 %

Procedure:
A mixture of (S)-N3-(5-cyclopropyl-1H-pyrazol-3-yl)-2-fluoro-N1-[1-(4-fluorophenyl)ethyl]benzene-1,3,4-triamine (Method 71; 0.370 g, 1.00 mmol) and formamidine acetate (0.209 g, 2.00 mmol) in EtOH (10 ml) was heated at reflux for 1 hour. After cooling, the reaction mixture was treated with saturated sodium bicarbonate solution (5 ml) and EtOAc (15 ml). The organic layer was separated, washed with brine (3 ml), and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as an off-white solid (0.125 g, 33%). NMR (400 MHz) 12.79 (s, 1H), 8.08 (s, 1H), 7.45 (m, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.09 (t, J=8.8 Hz, 2H), 6.60 (t, J=8.2 Hz, 1H), 6.19 (s, 1H), 5.68 (d, J=7.2 Hz, 1H), 4.65 (m, 1H), 1.98 (m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.01 (m, 2H), 0.77 (m, 2H). MS: Calcd.: 379; Found: [M+H]+ 380.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)(O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Product: CC(C)(O)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 300 mg, 50%). mp 181–181° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.04 (s, 6H), 1.72 (t, J=6 Hz, 2H), 4.43 (s, 1H), 4.53 (t, J=6 Hz, 2H), 7.49 (s, 2H), 7.53 (m, 1H), 7.63 (ddd, J=9 Hz, J=9 Hz, J=1.5 Hz, 1H), 7.79 (ddd, J=9 Hz, J=9 Hz, J=3 Hz, 1H), 7.83 (d, J=9 Hz, 1H), 7.95 (d, J=9 Hz, 2H), 8.19 (s, 1H); MS (DCI/NH3) m/z 466 (M+H)+. Anal. calcd. for C21H21F2N2O5S: C, 54.12; H, 4.66; N, 8.81. Found: C, 54.19; H, 4.55; N, 9.03.
Reaction SMILES: [Si:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].Br[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.CCN(CC)CC>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:2][Si:1]([C:5]#[C:6][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)([CH3:4])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1

Procedure:
TMS-acetylene (Aldrich) (5.0 mL, 35.5 mmol), ethyl 4-bromobenzoate (58 mL, 35.5 mmol) and Et3N (20 mL, 144 mmol) were combined in 50 mL CH3CN in a glass pressure tube. (Ph3P)2PdCl2 (198 mg, 0.28 mmol) and CuI (100 mg, 0.53 mmol) were added, and the reaction was sealed and heated at 100° for 18 h. Dilution with EtOAc, washing twice with water, then brine, drying and concentration provided 29-1 as a brown liquid.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.[CH3:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([CH2:29]C(O)=O)([CH2:22]3)[CH2:20]1)[CH2:26]2.[N:33]1[CH:38]=CC=CC=1>>[CH3:18][C:19]12[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][C:21]([CH2:29][N:33]=[C:38]=[O:8])([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: c1ccncc1
Reactant: CC12CC3CC(C1)CC(CC(=O)O)(C3)C2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: CC12CC3CC(C1)CC(CN=C=O)(C3)C2
Temperature: 100 °C
Reaction time: 0.67 h

Procedure:
Diphenylphosphoryl azide (6.41 g.) was added dropwise to a solution of 3-methyladamantan-1-ylacetic acid (4.85 g.) in dry pyridine (20 ml.) and stirred at 100° C. for 40 minutes to give 3-methyladamantan-1-ylmethyl isocyanate [I.R.: 2260 cm-1 ]. 5-Fluorouracil (2.52 g.) was added to the solution and stirred at 100° C. for 2 hours. The resultant mixture was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with dilute hydrochloric acid and water. Ethyl acetate layer was dried over magnesium sulfate, filtered and evaporated to give residue, which was recrystallized from ethanol to give colorless crystals of 1-[N-(3-methyladamantan-1-ylmethyl)carbamoyl]-5-fluorouracil. (984 mg.)
Reaction SMILES: [C:1]1([CH:7]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([N:19]3[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[N:20]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:27]2[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][OH:35])[C@@H:29]([OH:37])[C@H:28]2[OH:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>CO>[NH2:24][C:22]1[CH:21]=[N:20][N:19]([C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@@H:27]3[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][OH:35])[C@@H:29]([OH:37])[C@H:28]3[OH:38])=[C:10]([NH:9][CH2:8][CH:7]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:18]=2)[CH:23]=1
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc([N+](=O)[O-])cn4)nc32)[C@H](O)[C@@H]1O
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
The title compound is prepared by dissolving N-{(1S,2R,3S,4R)-4-[6-(2,2-Diphenyl-ethylamino)-2-(4-nitro-pyrazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP2) in methanol (˜1.0M), adding a 2:1 mixture by weight of activated carbon and ferric chloride and an excess of hydrazine monohydrate, and stirring the resulting mixture at 65° C. for four hours. Filtration through Celite™, removal of the volatile components under reduced pressure, and purification by column chromatography/crystallisation, affords the title compound.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH:32]1[CH:36]=[C:35]([CH:37]=O)[N:34]=[CH:33]1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:37][C:35]4[N:34]=[CH:33][NH:32][CH:36]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: O=Cc1c[nH]cn1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4c[nH]cn4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 1-H-imidazole-4-carboxaldehyde (8 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:6][CH:5]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(#N)C.C(N(C(C)C)CC)(C)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][CH2:11][NH:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:21]([F:20])([F:32])[F:33])=[CH:24][CH:25]=2)=[O:31])=[CH:19][CH:18]=1)[CH3:17]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCNC(=O)c1ccc(CNC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
Ethyl 3-(4-Aminomethylbenzoylamino)propanoate hydrochloride (0.25 g, 0.87 mmol) in acetonitrile (5 mL) and diisopropylethylamine (0.15 mL) was allowed to react with 4-trifluoromethoxyphenylisocyanate (0.37 g, 1.74 mmol) at 50° C. overnight. Upon cooling to 25° C. the product precipitated and was collected by filtration.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36](O)[CH2:35][CH2:34]1.N(C(OCC)=O)=N[C:46](OCC)=[O:47]>C1COCC1>[O:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]([C:46]([O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=2)=[O:47])[CH2:35][CH2:34]1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: OC1CCOc2ccccc21
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)C2CCOc3ccccc32)cc1OC
Temperature: 0 °C

Procedure:
To a stirred solution of methyl 4-hydroxy-2-methoxybenzoate (364 mg, 2.0 mmol) in dry THF (1.25 mL) was added triphenylphosphine (525 mg, 2.0 mmol) and the solution was cooled to 0° C. A 500 mL volume of 4-chromanol (200 mg, 1.33 mmol) and diethyl azodicarboxylate (315 mL, 2.0 mmol) in THF was added dropwise via syringe over 0.5 h. The reaction was filtered and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column packed in 92:8 hexanes:EtOAc and eluted with same. The appropriate fractions were combined and the solvent removed under reduced pressure to afford methyl 4-(4-chromanoyloxy)-2-methoxybenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[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](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[C:51]([O:52][CH3:53])=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([F:54])[CH:43]=1>C(Cl)Cl>[CH3:49][O:48][C:46](=[O:47])[C:45]1[CH:50]=[C:51]([O:52][CH3:53])[C:42]([NH:41][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:31])[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]2)=[O:29])=[CH:43][C:44]=1[F:54]
Reactant: COC(=O)c1cc(OC)c(N)cc1F
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 15 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (250 mg, 535 μmol, Eq: 1.00), was combined with CH2Cl2 (3 ml) to give a clear solution. DIPEA (242 mg, 327 μl, 1.87 mmol, Eq: 3.5) and diphenylphosphenic chloride (316 mg, 255 μl, 1.34 mmol, Eq: 2.5) were added and the reaction was stirred at RT for 5 minutes. Methyl 4-amino-2-fluoro-5-methoxybenzoate (107 mg, 535 μmol, Eq: 1.00) was added and the reaction mixture was stirred at RT overnight.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(C1C=CC(C2C=CC(C(C)(C)C)=CN=2)=NC=1)(C)(C)C.[CH3:35][C:36]1([CH3:43])[C:40]([CH3:42])([CH3:41])[O:39][BH:38][O:37]1>>[CH2:13]([O:12][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][C:8]=2[B:38]1[O:39][C:40]([CH3:42])([CH3:41])[C:36]([CH3:43])([CH3:35])[O:37]1)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CC1(C)OBOC1(C)C
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cn2)nc1
Product: CCOC(=O)c1cc2cccc(B3OC(C)(C)C(C)(C)O3)c2[nH]1
Temperature: 62 °C

Procedure:
A mixture of ethyl 1H-indole-2-carboxylate (1.89 g), 5,5′-di-tert-butyl-2,2′-bipyridine (0.081 g), and (Ir(OMe)(COD))2 (0.152 g) in hexanes (30 mL) was treated with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.66 g) via a syringe. The reaction mixture was degassed via vacuum/nitrogen cycle three times. The reaction mixture was heated at 62° C. for 12 hours. After this time, the solvent was removed and the residue was purified by flash chromatography on silica gel eluting with 1:9 ethyl acetate/hexane to give the title compound. 1H NMR (500 MHz, DMSO-d6): 9.75 (s, 1H), 7.87 (d, J=7.93 Hz, 1H), 7.64-7.65 (m, 1H), 7.24 (s, 1H), 7.16-7.17 (m, 1H), 4.36 (q, J=7.02 Hz, 2H), 1.38 (s, 12H), 1.35 (q, J=7.02 Hz, 3H).