Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:13]([Mg]Cl)=[CH2:14].[Cl-].[NH4+]>C(OCC)C.[Cu]I>[CH2:1]([O:8][CH2:9][C@H:10]([OH:11])[CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Mg]Cl
Reactant: c1ccc(COC[C@H]2CO2)cc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CC[C@@H](O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A mixture of (2R)-2-[(benzyloxy)methyl]oxirane (9.8 g, 60 mmol) and copper(I) iodide (648 mg, 3.40 mmol) in diethyl ether (150 mL) was cooled to −78° C. Vinylmagnesium chloride (1.6 M solution in tetrahydrofuran; 41.0 mL, 65.6 mmol) was added drop-wise, and the reaction mixture was allowed to warm slowly to room temperature and stir for 18 hours. Ice and saturated aqueous ammonium chloride solution were added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with aqueous ammonium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. This material was used in the following step without further purification. 1H NMR (400 MHz, CDCl3), product peaks only: δ 2.25-2.31 (m, 2H), 3.39 (dd, J=9.4, 7.4 Hz, 1H), 3.53 (dd, J=9.5, 3.4 Hz, 1H), 3.87-3.93 (m, 1H), 4.57 (s, 2H), 5.09-5.16 (m, 2H), 5.78-5.89 (m, 1H), 7.3-7.4 (m, 5H).
Reaction SMILES: C([O:5][C:6](=[O:51])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=2[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:10]=[C:9]([C:42]2[CH:50]=[CH:49][C:45]3[O:46][CH2:47][O:48][C:44]=3[CH:43]=2)[CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[O:46]1[C:45]2[CH:49]=[CH:50][C:42]([C:9]3[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=4[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:10]=3)[C:6]([OH:51])=[O:5])=[CH:43][C:44]=2[O:48][CH2:47]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
3-Benzo[1,3]dioxol-5-yl-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid tert-butyl ester (6.9 g) was dissolved in a mixture of TFA and dichloromethane (1:1, 50 mL) and stirred at room temperature overnight. The solvents were removed under reduced pressure and the crude material was purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (6.3 g, 99% yield).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.C1N(CCCS(O)(=O)=O)CC[O:13]C1>>[CH3:1][C:2]1[C:7](=[O:13])[CH2:6][CH:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Reactant: O=S(=O)(O)CCCN1CCOCC1
Product: C=C(C)C1CC=C(C)C(=O)C1
Reaction time: 1 h

Procedure:
For transformation of limonene 50 mg Pleurotus sapidus mycel was placed in 1.5 mL MOPS buffer (0.1 M; pH 7.0) and the dried cell mass was rehydrated for one hour at 200 rpm and 24° C. For producing carvone 41 mM limonene were directly applied to the rehydrated culture. The reaction took place for 24 h at 150 rpm and 24° C. After addition of the internal standard (for example camphor for limonene transformation) samples were extracted with 2 mL azeotropic pentane/ether mixture, centrifuged and dried over night with Na2SO4.
Reaction SMILES: COC(OC)[CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([N:24]([CH3:32])C(=O)OC(C)(C)C)[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2.[Si]([C:39]#[N:40])(C)(C)C.B(F)(F)F.C[CH2:46][O:47][CH2:48]C>C(Cl)Cl>[CH3:46][O:47][CH:48]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][CH3:32])[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)[C:39]#[N:40]
Reactant: CCOCC
Reactant: COC(C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21)OC
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(C#N)OC)CC4)CC1
Reaction time: 3 h
Yield: 979.2 %

Procedure:
Into a 100-mL 3-necked round-bottom flask was placed a solution of tert-butyl N-(4-[[(3R)-3-(2,2-dimethoxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (470 mg, 0.96 mmol, 1.00 equiv) in distilled DCM (15 mL). TMSCN (474 mg) and BF3.Et2O (15 mg) were added via syringe under nitrogen at 0° C. The resulting solution was stirred for 3 hr in a water/ice bath. After completion, the reaction was quenched with saturated aqueous NaHCO3 and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the desired 2-methoxy-3-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (400 mg, crude) as a yellow oil. MS (ES): m/z 387 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])S[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:14][C:5]1=2)[CH3:2].Cl.OO[S:22]([O-:24])=[O:23].[K+]>CO.O>[CH2:1]([NH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:22](=[O:24])(=[O:23])[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:14][C:5]1=2)[CH3:2]
Reactant: O=S([O-])OO
Reactant: CCNC1CC(C)(C)Sc2sc(S(N)(=O)=O)cc21
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCNC1CC(C)(C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21

Procedure:
A solution of 5,6-dihydro-4-ethylamino-6,6-dimethyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide (3.95 g, 0.013 mol) in methanol (85 ml) was acidified with 6.25 N methanolic hydrogen chloride (2.1 ml). With stirring, a solution of `OXONE` (11.68 g, 0.019 mol) in water (65 ml) was added over 15 minutes. After stirring at ambient temperature for 17.5 hours, the mixture was filtered and the solid was washed with methanol. The combined filtrate and washings were concentrated in vacuo below 55° C. to remove methanol and the cloudy aqueous solution was basified with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (150 ml and 2×100 ml), and the combined extracts were washed twice with water, dried over sodium sulfate and evaporated in vacuo. The amorphous residue was converted to the crystalline hydrochloride salt using ethanolic hydrogen chloride to yield 2.16 g (44%) of analytically pure product melting at 255°-255.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1.[I-].[Na+].[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>CC(C)=O>[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][N:19]([CH2:2][CH2:3][CH2:4][C:5]2[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=2)[CH2:18]1
Reactant: N#CCc1ccc(CCCCl)cc1
Reactant: CC1CNCC(C)C1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1CC(C)CN(CCCc2ccc(CC#N)cc2)C1
Reaction time: 1 h

Procedure:
In a 250 ml round bottom flask 5.3 g of 4-(3-chloropropyl)benzylcyanide, 4.4 g of sodium iodide, 62.2 g of 3,5-dimethylpiperidine and 32.9 ml of acetone are mixed together and boiled for 1 hour at reflux.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[OH:13][C:14]([C:17]1[CH:18]=[C:19]([CH:23]=O)[CH:20]=[N:21][CH:22]=1)([CH3:16])[CH3:15].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH:1]1([N:4]2[C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=3[N:12]=[C:23]2[C:19]2[CH:18]=[C:17]([C:14]([OH:13])([CH3:15])[CH3:16])[CH:22]=[N:21][CH:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)c1cncc(C=O)c1
Reactant: Nc1ccc(F)cc1NC1CC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1cncc(-c2nc3ccc(F)cc3n2C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.479 g, 2.88 mmol) in DMF (6.97 mL) and water (0.23 mL) were added the title compound from Step C (0.302 g, 1.83 mmol) and OXONE® (0.729 g, 1.19 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and water. Solid potassium carbonate was added until the aqueous layer was basic (pH ˜9). Ethyl acetate was added, and the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (100% ethyl acetate) provided a product that was further purified by reverse phase HPLC(C18 OBD column, 20 to 90% acetonitrile/water, both 0.1% v/v trifluoroacetitic acid). Fractions containing the desired product were combined, washed sequentially with aqueous 1 N sodium hydroxide solution and brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound: LCMS m/z 312.01 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (d, J=1.7 Hz, 1 H), 9.85 (d, J=1.9 Hz, 1 H), 8.40 (s, 1 H), 7.73 (dd, J=8.8, 4.8 Hz, 1 H), 7.29 (dd, J=8.7, 2.2 Hz, 1 H), 7.08-7.04 (m, 1 H), 3.57-3.55 (m, 1 H), 2.21 (br s, 1 H), 1.69 (s, 6 H), 1.20-1.16 (m, 2 H), 0.79-0.75 (m, 2 H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(Cl)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light brown solid (72 mg, 89%), MS (ISP) m/z=325.5 [(M+H)+], mp 251.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](=O)([O-])O.[K+].CI.O>CN(C=O)C>[CH3:23][O:21][C:20](=[O:22])[CH:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C([O-])O
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101 %

Procedure:
To a solution of N-benzyloxycarbonyl-DL-phenylalanine (155 g, 0.518 mol) in DMF (800 mL) were added mortar-pulverized potassium hydrogencarbonate (104 g, 1.04 mol) and methyl iodide (53 mL, 0.86 mol), and the mixture was stirred at room temperature for 5 hours. This reaction mixture was added to water (1800 mL) and extracted with ethyl acetate-hexane (4:1). The extract was washed successively with 2 portions of water (500 mL each), 5% sodium sulfite aqueous solution (500 ml) and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 164 g (100%) of N-benzyloxycarbonyl-DL-phenylalanine methyl ester as a colorless clear oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[N:35]=[C:34]2[C:30]([N:31]=[CH:32][NH:33]2)=[C:29]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][N:46]([CH:49]4[CH2:52][O:51][CH2:50]4)[CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[N:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[N:35]=[C:34]3[C:30]([N:31]=[CH:32][NH:33]3)=[C:29]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([N:43]4[CH2:44][CH2:45][N:46]([CH:49]5[CH2:50][O:51][CH2:52]5)[CH2:47][CH2:48]4)=[CH:39][CH:38]=3)[N:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3nc[nH]c3n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2cc3c(n2CCN1c1cc(F)cc(-c2nc(Nc4ccc(N5CCN(C6COC6)CC5)cc4)c4nc[nH]c4n2)c1CO)CCCC3
Temperature: 30 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 117h (140 mg, 0.20 mmol) and lithium hydroxide (48 mg, 2.0 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water (5 mL). It was then extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 117 (85 mg, 64%) as a white solid. MS-ESI: [M+H]+ 664.4. 1H NMR (500 MHz, CDCl3) δ 12.45 (s, 1H), 8.26 (s, 1H), 7.86 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.11 (d, J=9.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 2H), 6.88 (s, 1H), 4.74-4.68 (m, 4H), 4.66-4.60 (m, 2H), 4.17-4.09 (m, 3H), 3.91-3.90 (m, 1H), 3.59 (t, J=6.5 Hz, 1H), 3.25-3.23 (m, 4H), 2.59-2.52 (m, 8H), 1.89-1.80 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:49]=[C:50]([C@@H:54]([NH2:56])[CH3:55])[CH:51]=[CH:52][CH:53]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:56][C@H:54]([C:50]4[CH:51]=[CH:52][CH:53]=[C:48]([F:47])[CH:49]=4)[CH3:55])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N)c1cccc(F)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@@H](C)c2cccc(F)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (S)-1-(3-fluorophenyl)ethylamine (Synquest) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: [C:1]1([C:15](O)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].C1(C([O-])=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+:18]([O-])=O.[NH4+].S1(CCCC1)(=O)=O.CN1CCCC1=O>O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:18])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: [NH4+]
Solvent: O=S1(=O)CCCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Replacement of urea with an ammonium salt (or “NH3 reagent”) obtained from ammonia and weak acids (e.g., acetic, carbonic acid, phosphoric acid) produces picramide free of cyanuric acid. Thus, reaction of picric acid or ammonium picrate with an ammonium salt in dipolar aprotic solvents such as sulfolane or N-methylpyrrolidinone (NMP) for several hours at 175–185° C., followed by a water wash, produces picramide that is free of cyanuric acid and ammonium salts. Ammonium hydroxide (28% NH3 in H2O) is unsatisfactory for use as an NH3 reagent as picric acid/ammonium picrate are decomposed to black solids when exposed to the ammonium hydroxide. Example 2 and Table 1 list conversions of 0.18–0.92 g of ammonium picrate in sulfolane to picramide in 8 ml glass pressure tubes.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:33]=[CH:32][C:13]([O:14][C:15]4[N:19](COCC[Si](C)(C)C)[C:18]5[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=5[N:16]=4)=[CH:12][CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:34]=1>C(OCC)(=O)C.Cl>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:33]=[CH:32][C:13]([O:14][C:15]4[NH:19][C:18]5[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=5[N:16]=4)=[CH:12][CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:34]=1
Reactant: Cc1cn2cccc(-c3ccc(Oc4nc5ccccc5n4COCC[Si](C)(C)C)cc3)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cn2cccc(-c3ccc(Oc4nc5ccccc5[nH]4)cc3)c2n1
Yield: 84.9 %

Procedure:
A mixture of 2-[4-(2-methylimidazo[1,2-a]pyridin-8-yl)phenoxy]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.57 g) and 4 M hydrogen chloride-ethyl acetate solution (20 ml) was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (0.35 g).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH3:19][NH:20][C:21](=[O:29])[CH2:22][N:23]1[C:27]([SH:28])=[N:26][N:25]=[N:24]1>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:28][C:27]3[N:23]([CH2:22][C:21](=[O:29])[NH:20][CH3:19])[N:24]=[N:25][N:26]=3)[CH2:15][S:14][C@H:9]12
Reactant: CNC(=O)Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CNC(=O)Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Yield: 44 %

Procedure:
7-ACA and N-methyl-5-mercapto-1H-tetrazol-1-ylacetamide were reacted as in example 23a to give the title compound, 44.0% yield; δ(CF3CO2H), 3.05 (3H,d, J5 Hz, --CONHCH3), 3.92 (2H,s, C2 methylene), 4.63 (2H,bs, --CH2S--), 5.47 (4H,s, --CH2CO-- and β-lactam protons), 7.5-7.8 (1H,m, --CONH--).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:9](=[O:19])[NH:8][C:7]1=[O:20]>C1COCC1>[CH3:18][C:15]1[N:14]=[CH:13][C:12]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:11]=2)=[CH:17][CH:16]=1
Reactant: COC(CCn1cc(-c2ccc(C)nc2)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Product: Cc1ccc(-c2cn(CCC=O)c(=O)[nH]c2=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
1-(3,3-Dimethoxy-propyl)-5-(6-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione (Prep 58, 240 mg, 0.78 mmol) was dissolved in THF (4 mL) and 1N solution of HClaq (1.5 mL) was added. The mixture was stirred at room temperature for 2 hours and then warmed at 45° C. and stirred for an additional hour at this temperature. After neutralization with a 5% solution of NaHCO3 the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give the title compound as foam (90 mg, 45% yield).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 41 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide hydrochloride and n-octyl chloroformate. Yield: 41% of theory, C36H44N6O5 (640.8); Rf value: 0.43 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=641; (M+Na)+=663.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C@H:9]([C:22](O)=[O:23])[C:10]([S:13][C:14](=[S:21])[NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])([CH3:12])[CH3:11])=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH:9]2[C:10]([CH3:12])([CH3:11])[S:13][C:14](=[S:21])[N:15]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:22]2=[O:23])=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)CCNC(=S)SC(C)(C)[C@H](NC(=O)c1ccc(Cl)cc1)C(=O)O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN(C)CCN1C(=O)C(NC(=O)c2ccc(Cl)cc2)C(C)(C)SC1=S

Procedure:
A mixture of 10 g of N-(p-chlorobenzoyl)-S-(2-dimethylaminoethylthiocarbamoyl)-penicillamine, 2 g of glacial acetic acid and 100 ml of chloroform is stirred under reflux for 5 hours. The solvent is then removed under reduced pressure, and the crude product is recrystallized from a mixture of ethyl acetate and isopropyl ether to give 5-(p-chlorobenzamido)-3-(2-dimethylaminoethyl)-6,6-dimethyl-2-thioxo-tetrahydro-2H-1,3-thiazin-4-one as pale yellow crystals, melting at 152°-153° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][C:24]([CH3:32])([CH3:31])[CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[O:22])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][C:24]([CH3:32])([CH3:31])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)CCC(C)(C)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(CCC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-4-methylpentanoate (16 mg, 0.04 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 4 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2 with 0.5% formic acid) to give the title compound in 14 mg. MS: (−) m/z 417.99 (M−1).