Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:22][C:6]2=[C:7]([CH3:21])[N:8]=[CH:9][C:10]([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[C:5]2[CH2:4][O:3]1.C(O)=O>C1COCC1.O>[OH:22][C:6]1[C:5]([CH2:4][OH:3])=[C:10]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH:9]=[N:8][C:7]=1[CH3:21]
Reactant: Cc1ncc(COc2ccc(C#N)cc2)c2c1OC(C)(C)OC2
Solvent: C1CCOC1
Solvent: O
Solvent: O=CO
Product: Cc1ncc(COc2ccc(C#N)cc2)c(CO)c1O
Yield: 91.8 %

Procedure:
A solution of 4-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethoxy)-benzonitrile (12) (3.10 g, 10 mmol) in THF (30 mL) was heated in a solution of 10% formic acid in water for 2 hours at 80° C. Upon evaporating the solvent, the crude product was washed with a mixture of ethyl acetate and hexane (1:2, 200 mL) to give 4-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethoxy)-benzonitrile (13) (2.48 g, 92% yield).
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[SH:13][C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)(=O)C>[S:13]([C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])([OH:3])(=[O:2])=[O:1]
Reactant: CCOC(=O)C1=C(S)CCCC1
Reactant: O
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCCC1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 166.1 %

Procedure:
Sodium peroxyborate tetrahydrate (22.3 g) was admixed with acetic acid (120 ml) and heated to 50 to 55° C. and then a solution of ethyl 2-mercapto-1-cyclohexene-1-carboxylate (9.0 g) in acetic acid (15 ml) was added dropwise over 2 hours. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (200 ml) and stirred at room temperature for 3 hours and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (50 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in acetonitrile (150 ml) and stirred at room temperature for 2 hours. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (300 ml) and the powder which precipitated was isolated by filtration to obtain ethyl 2-sulfo-1-cyclohexene-1-carboxylate as a white powder (18.8 g) containing inorganic substances.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@H:6]1[O:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].[OH-].[K+].C(Cl)(Cl)Cl.CO.O.C(OC(=O)C)(=O)C.N1C=CC=CC=1>CO.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@H:6]1[O:7][CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCBr)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CCO[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
2-Bromoethyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (1) (98 mg; 0.22 mmol) was dissolved in methanol (5 ml) and aqueous potassium hydroxide (0.3M, 5 ml) and hydrogenated (Pd/C 10%; 47 mg) at atmospheric pressure for 3 h. The reaction mixture (pH 6) was filtered and evaporated to give a residue that was pure by TLC (SiO2, chloroform/methanol/water 65:35:10, lower phase). The residue was acetylated (acetic anhydride/pyridine 1:1; 60°; 1.5 h) and the reaction mixture was cooled, filtered and evaporated with toluene and ethanol several times and finally dried (0.1 torr). Crystallization from ether/isooctane gave the title compound (32). Yield: 55 mg (68%). Mp 92°-93°; [α]D22 -31.0° (c 1.2; benzene); [α]D24 -14.4° (c 1.2; CDCl3) (Lit/56 mp 88°; [α]D20 -29.8° (c 10; benzene)]; 1 H-NMR (CDCl3, TMS) δ 5.40 (dd, 1H, J4,5 =1.0 Hz, J4,3 =3.5 Hz, H4), 5.22 (dd, 1H, J2,3 =10.5 Hz, J1,2 =8.0 Hz, H2), 5.02 (dd, 1H, H3), 4.48 (d, 1H, H1), 4.16 (m, 2H, H6), 3.93 (oct, 1H, Jgem =10.0 Hz, Jvic =7.0 Hz, OCH2CH3), 3.89 (dd, 1H, J5,6 ~4 Hz, H5) 3.60 (oct, 1H, OCH2CH3), 2.17, 2.07, 2.06, 1.99 (s, 3H each, CH3CO), 1.22 (t, 3H, OCH2CH3). 13C-NMR (CDCl3, TMS) δ 170.4, 170.3, 170.2, 169.4 (CO), 101.1 (Cl), 71.0, 70.6, 68.9, 67.1 (C2-C5), 65.7 (CH2CH3), 61.3 (C6), 20.8, 20.7, 20.7, 20.6 (CH3CO), 15.1 (CH2CH3).
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[Cl:41][C:42]1[C:43]([F:52])=[CH:44][C:45]([F:51])=[C:46]([CH:50]=1)[C:47](O)=[O:48]>>[N:6]1([S:10]([NH:13][C:47](=[O:48])[C:46]2[CH:50]=[C:42]([Cl:41])[C:43]([F:52])=[CH:44][C:45]=2[F:51])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-2,4-difluorobenzoic acid, the title compound was obtained as a colorless powder (7.0 g, 70%): 1H NMR (300 MHz, DMSO-d6) δ 12.07 (br s, 1H), 7.99 (t, J=7.6 Hz, 1H), 7.71 (t, J=9.8 Hz, 1H), 4.03 (t, J=7.7 Hz, 4H), 2.20-2.10 (m, 2H); MS (ES−) m/z 309.1, 311.1 (M−1).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.[NH2:18][NH2:19]>C(O)C>[C:10]1([C:9]2[NH:19][N:18]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]n1
Yield: 67 %

Procedure:
To a solution of ethyl 2,4-dioxo-4-phenylbutanoate (16.0 g) in ethanol (150 mL) was added hydrazine monohydrate (4.0 mL), and the mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether to give the title compound as a pale-brown solid (yield 12.0 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]2=[O:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)CCCC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCC(=O)N1c1cc(Cl)cc(Cl)c1
Reaction time: 1 h

Procedure:
A mixture comprising 27.6 g. of N-(3,5-dichlorophenyl) glutaric acid monoamide, 50 g. of acetic anhydride and 1 g. of anhydrous sodium acetate was fed to a 100 ml. four-necked flask and was heated with stirring at 80° - 90° C. for 1 hour. Thereafter, the acetic acid and acetic anhydride were removed by distillation under reduced pressure, and the residue was washed with water and then dried to obtain 24.8 g. of the above-mentioned compound in the form of white crystals, m.p. 172.5° - 174.5° C.
Reaction SMILES: C[O:2][CH:3]([O:15]C)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1Br.C([Li])CCC.[CH3:22][O:23][C:24]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[CH:28][C:25]=1[CH:26]=[O:27].O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:13][O:12][C:7]1[C:8]([O:10][CH3:11])=[C:9]([C:26](=[O:27])[C:25]2[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([O:32][CH3:33])[C:24]=2[O:23][CH3:22])[C:4]([C:3]([OH:2])=[O:15])=[CH:5][CH:6]=1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: COc1cc(Br)c(C(OC)OC)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2c(C(=O)O)ccc(OC)c2OC)c(OC)c1OC
Reaction time: 1 h
Yield: 40.4 %

Procedure:
A solution of 2-bromo-4,5-dimethoxybenzaldehyde dimethyl acetal (14.8 g) in tetrahydrofuran (50 ml) is cooled to −70° C., and thereto is added dropwise a 1.6 M solution of n-butyl lithium in hexane (33.4 ml) under nitrogen atmosphere over a period of 20 minutes. The mixture is reacted at −60T for 30 minutes, and thereto is added dropwise a solution of 2,3,4-trimethoxybenz aldehyde (10.0 g) in tetrahydrofuran (30 ml) over a period of 10 minutes. After reaction for one hour, to the mixture are added water and ethyl acetate (200 ml). The ethyl acetate layer is separated, washed, dried, and thereto is added an acidic ion-exchange resin (IRA-120) (7.0 g). The mixture is allowed to stand at room temperature for one hour. The mixture is filtered, and the filtrate is concentrated under reduced pressure. To the resultant are added pyridine (150 ml), 1.8M aqueous potassium hydroxide solution (150 ml), and the mixture is warmed to 80T. To the mixture is added solid potassium permanganate (24.1 g) in portions, and the mixture is reacted at the same temperature for one hour. The insoluble materials are removed by filtration, and to the filtrate are added conc. hydrochloric acid (200 ml) and ethyl acetate (300 ml) under ice-cooling. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 4,5-dimethoxy-6-(2,3,4-trimethoxybenzoyl)benzoic acid (7.72 g) as listed in Table 52.
Reaction SMILES: [O:1]=O.O=[O+][O-].[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=C)([O-:8])=[O:7].CSC>C(Cl)Cl>[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:1])([O-:8])=[O:7]
Reactant: O=O
Reactant: C=Cc1ccccc1[N+](=O)[O-]
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: O=Cc1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 91.5 %

Procedure:
Oxygen enriched with 10 m-moles of ozone are introduced at -20° C. in the course of 15 minutes into a solution of 1.50 g of o-nitrostyrene in 160 ml of methylene chloride. The faintly blue solution is scavenged with nitrogen until the colour has disappeared, treated with 10 ml of dimethyl sulphide and left to stand overnight at room temperature. The clear solution is concentrated in vacuo and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed with water and sodium chloride solution, dried over sodium sulphate and concentrated. The crude product (1.75 g) is taken up in benzene and the solution is chromatographed through a column of silica gel (15 g). The first 100 ml of eluate are concentrated in vacuo, affording 1.39 g of pure o-nitrobenzaldehyde. Yield: 91.5% of theory.
Reaction SMILES: [CH:1]([N:4]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:18]C)[O:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])([CH3:3])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:18][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH2:17][C@@H:8]([N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6][CH3:7])[CH2:9][O:10]2
Reactant: CCCN(C(C)C)[C@H]1COc2cccc(OC)c2C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(C(C)C)[C@H]1COc2cccc(O)c2C1
Temperature: -60 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
The HCl-salt of (R)-3-(N-isopropyl-N-n-propylamino)-5-methoxychroman (15.5 g, 52 mmol) was mixed with CH2Cl2 (100 mL) under nitrogen atmosphere and cooled to -60° C. BBr3 (27.2 g, 110 mmol) dissolved in CH2Cl2 (50 mL), was added slowly. The temperature was then raised to 0° C. and the reaction mixture was stirred at 0° C. for 12 h. The reaction mixture was then slowly added to a stirred saturated NaHCO3 solution. The layers were separated and the water layer was extracted once with CH2Cl2. The combined organic layers were dried (MgSO4). Removal of the solvent in vacuo gave the phenolic title compound. Yield: 98%. [α]D22 (Base)=-83° (C=0.1;MeOH).Mp(HCl-salt): 215°-222° C. (decomposes).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([OH:35])=O)[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:37]([C:40]1([O:43][S:44](=[O:47])(=[O:46])[NH2:45])[CH2:42][CH2:41]1)[CH2:38][CH3:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([NH:45][S:44]([O:43][C:40]2([CH2:37][CH2:38][CH3:39])[CH2:42][CH2:41]2)(=[O:47])=[O:46])=[O:35])[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)O
Reactant: CCCC1(OS(N)(=O)=O)CC1
Product: CCCC1(OS(=O)(=O)NC(=O)C2(NC(=O)C3CC(Oc4nccc5cc(OC)ccc45)CN3C(=O)OC(C)(C)C)CC2CC)CC1

Procedure:
2-[2-Ethyl-1-(1-propyl-cyclopropoxysulfonylaminocarbonyl)-cyclopropylcarbamoyl]-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared according to the method presented in Example 27. Treatment of 2-(1-carboxy-2-ethyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 mmol) occurred under the same conditions, adjusted for scale with the exception of utilizing sulfamic acid 1-propyl-cyclopropyl ester to afford acylsulfamate (200 mg, 61%): LCMS found 660.9 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[AlH4-].[Li+].O.[OH-].[Na+]>CCOCC.C1COCC1>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1
Reactant: O=C1CCC(CCO)CC1
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCC1CCC(O)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-(2-Hydroxyethyl)cyclohexanone (2.00 g, 0.0141 mol) was dissolved in ether (30.00 mL) and was cooled at 0° C. To the reaction was added 1.0 M lithium tetrahydroaluminate in ether (14.1 mL) and the resulting mixture was stirred at 0° C. for 2 hours and at 25° C. for 16 hours. To the reaction was added THF (20.00 mL) and this mixture was cooled at 0° C. and then water (0.40 mL, 0.022 mol) was added, followed by 1.00 M sodium hydroxide (0.40 mL). To the reaction was then added ether (100.00 mL) and the resulting mixture was stirred for 10 minutes, then was filtered and the filtrate was concentrated using a rotary evaporator to provide the crude product. The crude product was used in the next reaction without further purification.
Reaction SMILES: CC1(C)O[O:3]1.[CH3:6][C@H:7]1[C@H:28]2[O:29][C@@H:30]3[C@@:65]([CH3:68])([CH2:66][CH2:67][C@@H:27]2[O:26][C@@H:10]2[CH2:11][C@:12]4([CH3:25])[O:18][C@@H:17]5[C:19]([CH3:24])=[CH:20][C:21]([O:23][C@H:16]5[CH2:15][C@H:13]4[O:14][C@H:9]2[CH2:8]1)=[O:22])[O:64][C@@:33]1([CH3:69])[CH2:34][C@H:35]2[O:43][C@H:42]4[CH2:44][C@H:45]5[O:51][C@@:50]6([CH3:62])[C@@H:52]([OH:61])[CH2:53][C@@H:54]([CH2:56][C:57]([CH:59]=[O:60])=[CH2:58])[O:55][C@@H:49]6[CH2:48][C@@H:46]5[O:47][C@@H:41]4[CH:40]=[CH:39][CH2:38][C@:36]2([CH3:63])[O:37][C@@H:32]1[CH2:31]3>CC(C)=O>[CH3:6][C@H:7]1[CH:28]2[O:29][CH:30]3[C@@:65]([CH3:68])([CH2:66][CH2:67][CH:27]2[O:26][CH:10]2[CH2:11][C@:12]4([CH3:25])[O:18][CH:17]5[C:19]([CH3:24])=[CH:20][C:21]([O:23][CH:16]5[CH2:15][CH:13]4[O:14][CH:9]2[CH2:8]1)=[O:22])[O:64][C@@:33]1([CH3:69])[CH2:34][CH:35]2[O:43][CH:42]4[CH2:44][CH:45]5[O:51][C@@:50]6([CH3:62])[CH:52]([OH:61])[CH2:53][CH:54]([CH2:56][C:57]([CH:59]=[O:60])=[CH2:58])[O:55][CH:49]6[CH2:48][CH:46]5[O:47][CH:41]4[CH:40]4[O:3][CH:39]4[CH2:38][C@@:36]2([CH3:63])[O:37][CH:32]1[CH2:31]3
Reactant: C=C(C=O)C[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]3C[C@@H]4O[C@@H]5C[C@]6(C)O[C@]7(C)CC[C@@H]8O[C@@H]9C[C@]%10(C)O[C@@H]%11C(C)=CC(=O)O[C@H]%11C[C@H]%10O[C@H]9C[C@@H](C)[C@H]8O[C@H]7C[C@H]6O[C@@]5(C)CC=C[C@H]4O[C@H]3C[C@H]2O1
Reactant: CC1(C)OO1
Agent: C=C(C=O)C[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]3C[C@@H]4O[C@@H]5C[C@]6(C)O[C@]7(C)CC[C@@H]8O[C@@H]9C[C@]%10(C)O[C@@H]%11C(C)=CC(=O)O[C@H]%11C[C@H]%10O[C@H]9C[C@@H](C)[C@H]8O[C@H]7C[C@H]6O[C@@]5(C)C/C=C\[C@H]4O[C@H]3C[C@H]2O1
Solvent: CC(C)=O
Product: C=C(C=O)CC1CC(O)[C@]2(C)OC3CC4OC5C[C@]6(C)O[C@]7(C)CCC8OC9C[C@]%10(C)OC%11C(C)=CC(=O)OC%11CC%10OC9C[C@@H](C)C8OC7CC6O[C@]5(C)CC5OC5C4OC3CC2O1
Yield: 95 %

Procedure:
Epoxidation of the C-27, C-28 Double Bond of PbTx-2 To Provide PbTx-6. Dimethyldioxirane was generated in a distillation apparatus, connected to a dry ice condenser, according to the procedure described by Adam17 for a small-scale preparation. The receiving flask was charged with PbTx-2 (2.33 mg) in 5.0 mL of acetone and was cooled in an ice/salt bath. The reaction was monitored by HPLC. When all of the PbTx-2 was consumed, the acetone was evaporated in vacuo, and the residue taken up in 1.0 mL of methanol and purified by HPLC to provide 2.25 mg (95%) of PbTx-6. DCI MS (NH3): 911 (M+1), 928 (M+NH4), 893 (M−H2O). 1H and 13C NMR were identical to that reported by Shimizu.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[C:29]1[O:33][CH:32]=[N:31][CH:30]=1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.20 min; Mass spectrum (ESI+): m/z=440 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[C:21]([CH3:28])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:6]=1>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[NH2:25][C:23]1[CH:22]=[C:21]([CH3:28])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:6]=2)=[C:2]([Cl:1])[CH:24]=1
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1Oc1ccc(O)c(COc2ccc(F)cc2)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(Cl)c1Oc1ccc(O)c(COc2ccc(F)cc2)c1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a warm (100° C.) solution of 4-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(4-fluorophenoxymethyl)-phenol (100 mg) in glacial acetic acid (2.5 mL) was added zinc dust (243 mg) and heating was continued for 30 min. The reaction mixture was cooled, diluted with ethyl acetate and filtered through Celite®. The filtrate was washed with 1M aqueous sodium bicarbonate, dried over sodium sulfate, concentrated in vacuo and flashed chromatographed (30% ethyl acetate/hexanes) to afford 4-(4-amino-2-chloro-6-methyl-phenoxy)-2-(4-fluoro-phenoxymethyl)-phenol (90 mg) as a tan solid.
Reaction SMILES: [CH3:1][CH:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.CN(C(ON1N=[N:34][C:29]2[CH:30]=[CH:31][CH:32]=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.NC1C=NC=CC=1>CN(C=O)C>[N:33]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:34][C:15]([C:10]2[CH:11]=[CH:12][C:13]3[CH:14]=[C:6]4[C:5](=[O:18])[NH:4][CH2:3][CH:2]([CH3:1])[N:7]4[C:8]=3[CH:9]=2)=[O:17])[CH:28]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CNC(=O)c2cc3ccc(C(=O)Nc4cccnc4)cc3n21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a solution of 4-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid (step f) (20 mg, 0.08 mmol) in 1 mL of DMF was added HATU (34.3 mg, 0.082 mmol), HOAt (6, 0.04 mmol) and diisopropylethylamine (29 uL, 0.164 mmol). After 15 min, 3-amino-pyridine in 1 mL of DMF was added. The mixture was stirred at room temperature for 48 h. The reaction was extracted with EtOAc several times, washed with water and brine. The combined organics were dried over MgSO4, filtered, and concentrated in vacuum. Purification by silica gel chromatography gave 23 mg of 4-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid pyridin-3-ylamide 87% as a white solid. ESI-MS m/z 321.34 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13](=[O:14])[NH:22][CH3:21])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (125 mg, 0.41 mmol), HATU (235 mg, 0.6 mmol), methylamine (0.25 mL, 2M in THF) and DIPEA (0.29 mL, 1.6 mmol) in DMF (2 mL). MS (LC-MS): 633.0 [2M]+; tR (HPLC conditions c): 4.55 min.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2]C(C)=O.[N+:10]([O-])([OH:12])=[O:11]>C(OC(=O)C)(=O)C>[N+:10]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C[N+](=O)[O-]

Procedure:
Another route was disclosed by early researchers Bouveault and Wahl, Bull. Soc. Chim. France, 31, 847-54 (1904), whereby ethyl acetoacetate was reacted with absolute nitric acid in acetic anhydride at 30°-35° C., but low yields of ethyl nitroacetate were reported. This work was later confirmed by Arndt and Rose in J. Chem. Soc. 1935, 1-10. The major product produced using the conditions of Bouveault and Wahl was found to be diethyl2-oxofurazan dicarboxylate.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4([C:28](O)=[O:29])[CH2:27][CH2:26]4)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[NH3:39]>>[OH:1][C:2]([CH3:37])([CH3:38])[CH2:3][C@@:4]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4([C:28]([NH2:39])=[O:29])[CH2:26][CH2:27]4)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(-c2ccnc(C3(C(=O)O)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N
Product: C[C@@H](c1ccc(-c2ccnc(C3(C(N)=O)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 68 %

Procedure:
The title compound was prepared from 1-[4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridin-2-yl]-cyclopropanecarboxylic acid and ammonia (32% in water) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 68% of theory; LC (method 1): tR=2.45 min; Mass spectrum (ESI+): m/z=514 [M+H]+.