Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C:10]3[CH:11]=[C:12]([CH3:22])[CH:13]=[CH:14][C:15]=3[C:16]([CH3:21])([CH3:20])[O:17][C:18]=2[CH:19]=1.Cl.CN(C)CCCN=C=NCC>CO.O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:10]3[CH:11]=[C:12]([CH3:22])[CH2:13][CH2:14][C@H:15]3[C:16]([CH3:21])([CH3:20])[O:17][C:18]=2[CH:19]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)c1ccc(C)cc1-2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21

Procedure:
One hundred mg of a cannabinol derivative having the formula ##STR3## were dissolved in 20 ml of 30% methanol at pH 4.5. To this solution, 84 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added and the pH was adjusted to 4.5. After mixing at room temperature for 30 minutes, 100 mg of methylated bovine serum albumin were added in 20 ml of water with mixing, and the pH was again adjusted to 4.5. The solution was mixed for 1 hour at room temperature and then overnight at 4° C., after which any unconjugated cannabinol derivative was removed by dialysis against 1000-ml volume changes of sodium phosphate buffer at 4° C., to produce a THC-methylated albumin conjugate.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]1[CH:19]([C:20]([O:22]CC)=[O:21])C(O)(C)CC[CH:15]1[C:27]([O:29]CC)=[O:28].[OH-].[Na+].C(O)C>O1CCOCC1.O>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)C1CCC(C)(O)C(C(=O)OCC)C1c1ccc2oc3c(c2c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC(CC(=O)O)c1ccc2oc3c(c2c1)CCCC3

Procedure:
A solution of 44.2 g (0.1 mol) of diethyl 2-(6,7,8,9-tetrahydro-2-dibenzofuranyl)-4-hydroxy-4-methyl-1,3-cyclohexanedicarboxylate in 250 ml of dioxan is added dropwise to a solution of 120 g (3 mols) of sodium hydroxide in 125 ml of water with 250 ml of ethanol at 90° in the course of 30 minutes. The reaction mixture is heated to 90° for 30 minutes and then concentrated to about 1/3rd of its volume by distilling off the solvents. After diluting the mixture with 750 ml of water, 350 ml of concentrated hydrochloric acid are added, with ice-water cooling. The crude acid which has precipitated is filtered off, washed thoroughly with water and dried. 3-(6,7,8,9-Tetrahydro-2-dibenzofuranyl)-glutaric acid is thus obtained as light yellow-brown crystals of melting point 165°-170°. A sample crystallised from ethanol/water melts at 169°-174°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:22])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1CCc2cc(Br)ccc2N1
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (74-3; 15.0 g, 0.066 mol) in toluene (150 mL) was added Lawesson's reagent (13.4 g, 0.033 mol). Reaction mass was refluxed at 100° C. for 3 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+2): 243.9.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([NH:12][C:13]2[CH:22]=[C:21]3[NH:23][N:24]=[C:19]4[C:20]3=[C:15]([CH2:16][CH2:17][NH:18]4)[N:14]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:18]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([NH:12][C:10]([NH:9][C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])=[O:11])[CH:22]=[C:21]3[NH:23][N:24]=[C:19]1[C:20]=23)(=[O:34])[CH3:33]
Reactant: C[C@@H](NC(=O)Nc1cc2[nH]nc3c2c(n1)CCN3)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3[nH]nc1c23
Reaction time: 1 h

Procedure:
(R)-1-(1-phenylethyl)-3-(1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)urea (Example 136; 13 mg, 0.040 mmol) and triethylamine (50 mg, 0.494 mmol) were taken in DCM (0.15 mL) and added acetyl chloride (20 mg, 0.255 mmol) and stirred for 1 hour. The reaction mixture was diluted with DCM, washed with aqueous sodium bicarbonate, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-15% MeOH-DCM) gave (R)-1-(3 acetyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C19H20N6O2 [M+H]+ 365. found 365. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.13-9.05 (m, 1H), 8.05-7.86 (m, 1H), 7.39-7.28 (m, 6H), 7.27-7.18 (m, 1H), 3.06-2.96 (m, 2H), 1.38 (t, J=9.1, 3H), 1.25-1.18 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[N:23][NH2:24])[C@H:19]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:18][CH2:17]1.[F:33][C:34]([F:40])([F:39])[CH2:35][C:36](O)=O.ON1C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:36]([CH2:35][C:34]([F:40])([F:39])[F:33])=[N:24][N:23]=[C:20]2[C@H:19]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=NN
Reactant: O=C(O)CC(F)(F)F
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Reaction time: 18 h
Yield: 89.3 %

Procedure:
Triethylamine (0.259 mL, 1.86 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-hydrazonoazepan-3-ylcarbamate (548 mg, 1.55 mmol), 3,3,3-trifluoropropionic acid (0.205 mL, 2.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimmide hydrochloride (356 mg, 1.86 mmol), and 1-hydroxy-7-azabenzotriazole (253 mg, 1.86 mmol) in dichloromethane (55 mL). After 18 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→96% dichloromethane/methanol) gave the title compound (618 mg). MS 447.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=C[CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[N:36]1C=CN=CC=1C(O)=O>>[C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[N:36][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: O=C(O)c1cnccn1
Reactant: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2C#N)cn1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2cccnc2C#N)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2-cyanopyridin-3-yloxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 218 (step 3) and pyrazine-2-carboxylic acid.
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.Br[CH2:14][CH2:15][O:16]C(=O)C1C=CC=CC=1.N>CN(C=O)C.CO>[OH:16][CH2:15][CH2:14][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=C(OCCBr)c1ccccc1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CCO
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a suspension of 60% NaH in mineral oil (1.70 g, 42.57 mmol) in anhydrous DMF (120 mL) was added adenine (5.23 g, 38.70 mmol) under argon, and the mixture was heated at 60° C. for 1 h. 2-Bromoethylbenzoate (9.2 mL, 58.06 mmol) was added dropwise at 60° C., and the reaction was stirred at this temperature for 16 h. The mixture was then filtered to remove insoluble materiel, the filtrate was evaporated under reduced pressure and co-evaporated three times with toluene. The residue was triturated with EtOAc then filtered to give a white solid, which was immediately resuspended in a saturated ammonia solution in MeOH (400 mL). The reaction mixture was stirred for 14 h at room temperature, and then methanol was removed under reduced pressure. Recrystallization from EtOH afforded compound 2 (5.87 g, 85%): mp 236° C. (Lit. 238-239° C.); 1H NMR (DMSO-d6): 8.13 (s, 1H, H-2), 8.10 (s, 1H, H-8), 7.23 (bs, 2H, NH2), 5.05 (bs, 1H, OH), 4.19 (t, J=5.2 Hz, 2H, CH2O), 3.71 (t, J=5.2 Hz, 2H, CH2N). 13C NMR (DMSO-d6) δ: 155.79, 152.23, 149.44, 141.46, 118.55, 59.17, 45.61. MS (GT, FAB+): 136 (B+1H)+, 180 (M+1H)+, 202 (M+Na)+.
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[S:5][C:6]2[C:11]([NH:12][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:14][OH:15])=[N:10][C:9]([S:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH3:21])=[N:8][C:7]=2[N:29]=1.[CH3:30]O>[Na+].[Cl-]>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C@@H:20]([S:19][C:9]1[N:10]=[C:11]([NH:12][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:14][OH:15])[C:6]2[S:5][C:4]([O:1][CH3:30])=[N:29][C:7]=2[N:8]=1)[CH3:21]
Reactant: [OH-]
Reactant: CCC[C@H](CO)Nc1nc(S[C@@H](C)c2ccccc2F)nc2nc(Cl)sc12
Reactant: CO
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: CCC[C@H](CO)Nc1nc(S[C@@H](C)c2ccccc2F)nc2nc(OC)sc12
Temperature: 50 °C

Procedure:
KOH (0.089 g, 1.58 mmol) was added to (2R)-2-[(2-chloro-5-{[(1S)-1-(2-fluorophenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]pentan-1-ol in MeOH (10 mL) and the mixture was heated to 50° C. After 3 h the mixture was diluted with NaCl (aq) and extracted with CHCl3, the organic phase was dried (MgSO4) and evaporated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[N:7]=[C:8](Cl)[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1)[CH3:2].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C.C(O)C>O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[N:7]=[C:8]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1)[CH3:2]
Reactant: NCc1ccccn1
Reactant: CCOC(=O)Cc1nc(Cl)c2c(-c3ccccc3)csc2n1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A stirred mixture of (4-chloro-5-phenylthieno[2,3-d]pyrimidin-2-yl)acetic acid ethyl ester (0.36 g, 1.08 mmol), 2-aminomethylpyridine (0.12 ml, 1.19 mmol), triethylamine (0.17 ml, 1.19 mmol) and ethanol (8 ml) was heated under reflux for 4 hours. The solution was then cooled to ambient temperature, poured into water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (1:2) gave {5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}acetic acid ethyl ester as a colourless gum (0.41 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[N:20]=[C:19]([CH:21]=[O:22])[C:18]([Cl:23])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:23][C:18]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:20][C:19]=1[CH:21]=[O:22]
Reactant: O=Cc1nc(Br)ccc1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1nc(-c2ccc(C(F)(F)F)nc2)ccc1Cl
Temperature: 75 °C
Yield: 57.5 %

Procedure:
Nitrogen was bubbled through a mixture of 6-(trifluoromethyl)pyridin-3-ylboronic acid (828 mg, 4.34 mmol), 6-bromo-3-chloropicolinaldehyde (956 mg, 4.34 mmol), Na2CO3 (919 mg, 8.67 mmol), DME (20 mL) and water (10 mL) for 35 minutes, followed by the addition of Pd(Ph3P)4 (75 mg, 0.065 mmol). Nitrogen for bubbled through the mixture for 10 minutes. The reaction mixture was heated overnight at 75° C., after which it was cooled to room temperature, followed by the addition of 200 mL EtOAc and washing with 200 mL water and 200 mL brine. The organic phase was separated, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 40 g column, eluted with 0-50% EtOAc in Heptane (25 mL/min) to provide the title compound (715 mg, 2.494 mmol, 57.5% yield) as a yellow solid. MS (ESI+) m/z 319.0 (M+H+MeOH); 1H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.52 (d, J=1.9, 1H), 8.82 (dd, J=8.3, 1.8, 1H), 8.48 (d, J=8.5, 1H), 8.34 (d, J=8.6, 1H), 8.11 (d, J=8.3, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])[CH2:2][CH:3]=[CH2:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C@:52]1([C:61]2[CH:62]=[C:63]([C:67]3[CH:72]=[CH:71][CH:70]=[C:69]([CH:73]=[CH2:74])[CH:68]=3)[CH:64]=[CH:65][CH:66]=2)[CH2:56][NH:55][C@H:54]([C:57]([O:59][CH3:60])=[O:58])[CH2:53]1>C(Cl)Cl>[CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([N:55]1[CH2:56][C@:52]([O:51][CH3:50])([C:61]2[CH:62]=[C:63]([C:67]3[CH:72]=[CH:71][CH:70]=[C:69]([CH:73]=[CH2:74])[CH:68]=3)[CH:64]=[CH:65][CH:66]=2)[CH2:53][C@H:54]1[C:57]([O:59][CH3:60])=[O:58])=[O:12])=[O:7])[CH2:2][CH:3]=[CH2:4]
Reactant: C=Cc1cccc(-c2cccc([C@@]3(OC)CN[C@H](C(=O)OC)C3)c2)c1
Reactant: C=CCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2cccc(-c3cccc(C=C)c3)c2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
(S)-2-((but-3-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (255 mg, 1.111 mmol), DIEA (0.40 mL, 2.223 mmol) and HATU (310 mg, 0.815 mmol) were added to a solution of (2S,4R)-methyl 4-methoxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-2-carboxylate (250 mg 0.741 mmol) in DCM (3 mL). The reaction was stirred at r.t. for 2 hrs. The reaction was evaporated and purified by flash chromatography on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-methyl 1-((S)-2-((but-3-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-2-carboxylate (277 mg, 0.505 mmol, 68% yield) as a white foam. LCMS: rt=2.31 min. [M+H]+=549; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent 13=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min, inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[C-]#N.[K+]>C(O)C.O>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([C:7]([CH:7]([C:6]3[CH:1]=[CH:2][C:3]4[O:11][CH2:10][O:9][C:4]=4[CH:5]=3)[OH:8])=[O:8])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(c1ccc2c(c1)OCO2)C(O)c1ccc2c(c1)OCO2

Procedure:
A solution of piperonal (5 g) in ethanol (6.5 ml) was treated with a solution of potassium cyanide (0.5 g) in water (5 ml), then refluxed for 5 h. The resultant precipitate was filtered off, washed with water then crystallized from ethanol to give DC-0001B (2.24 g, 45%) as an off white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:7][CH:6]=3)[C:9]([CH3:33])=[N:10][C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: COC(=O)C(C)Br
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.0 g) and methyl 2-bromopropanoate (2.50 g) in N,N-dimethylformamide (20 mL) was added cesium carbonate (3.0 g), and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (2.12 g, 89%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:9][N:10]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNc1ccccc1
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccccn1)c1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 50.2 %

Procedure:
A mixture of 2-chloromethylpyridine (50 g), N-methylaniline (42 g), and potassium carbonate (120 g) in N,N-dimethylformamide (200 ml) was stirred for 4 hours at 120° C. The reaction mixture was cooled to room temperature, added to water (1 l), and extracted with ether. The ether extract was washed with water and then treated with activated carbon. After drying over magnesium sulfate, the ether extract was filtered and concentrated. The residue was crystallized from isopropyl alcohol to give N-methyl-N-(2-pyridylmethyl)aniline (39 g).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C:11](=[C:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]4)[CH:10]=[CH:9][C:8]1=[CH:7][C:6](=[O:28])[CH2:5][CH2:4]2.CO.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[OH:28][C@H:6]1[CH2:5][CH2:4][C@@:3]2([CH2:2][OH:1])[C:8]([CH:9]=[CH:10][C:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C:12]=3[CH2:13][CH2:14][C@@H:15]2[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:7]1
Reactant: CC(C)(C)C(=O)O[C@H]1CCC2=C3C=CC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@@]21C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)O[C@H]1CCC2=C3C=CC4=C[C@@H](O)CC[C@]4(CO)[C@H]3CC[C@@]21C

Procedure:
A mixture of 5 g of 19-hydroxy-17β-pivaloxyandrosta-4,6,8(14)-trien-3-one and 50 ml of methanol was cooled below 5° C. by an ice-bath, whereupon 500 mg. of sodium borohydride was added slowly and with stirring. After 85 minutes another 50 mg of sodium borohydride was added. The mixture was stirred with cooling for another 35 minutes, whereupon 10 ml of acetic acid-water 1:10 was added dropwise. After 10 minutes of further stirring without external cooling 2 g of sodium bicarbonate was added. The mixture was then concentrated at reduced pressure to a thick paste and 50 ml of water was added. The precipitate obtained was filtered and digested with benzene to yield 3β,19-dihydroxy-17β-pivaloxyandrosta-4,6,8(14)-triene, uv max 275 (sh), 285 and 300 (sh) mμ.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N+:26]=1[O-:4]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)CCNc1n[n+]([O-])c2c3c(ccc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 29.6 %

Procedure:
H2O2 (70%, 0.33 mL, ca. 6.7 mmol) was added dropwise to a stirred solution of TFAA (0.94 mL, 6.7 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 6 (182 mg, 0.7 mmol) and TFA (0.10 mL, 1.3 mmol) in CHCl3 (15 mL) at 0° C. The solution was stirred at 5° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 7 (60 mg, 31%) as a red solid: mp (MeOH/EtOAc) 153-156° C.; 1H NMR δ 8.12 (d, J=8.7 Hz, 1H, H-5), 7.70 (d, J=8.7 Hz, 1H, H-6), 7.37 (br s, 1H, NH), 3.71 (br t, J=7.4 Hz, 2H, H-9), 3.60-3.64 (m, 2H, CH2N), 3.03 (br t, J=7.8 Hz, 2H, H-7), 2.61 (t, J=6.0 Hz, 2H, CH2N), 2.30 [s, 6H, N(CH3)2], 2.17-2.26 (m, 2H, H-8); 13C NMR δ 149.1, 144.7, 138.6, 138.4, 132.7, 129.1, 115.8, 57.6, 45.2 (2), 38.8, 35.1, 32.9, 24.6; MS m/z 289 (M+, 0.5%), 273 (2), 256 (3), 58 (100); HRMS calcd for C14H19N5O2 (M+) m/z 289.1539, found 289.1536.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:16][C:17]1[N:18]=[C:19]([NH2:28])[S:20][C:21]=1[CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([NH:28][C:19]2[S:20][C:21]([CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26])=[C:17]([CH3:16])[N:18]=2)=[O:14])=[CH:9][CH:10]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Product: Cc1nc(NC(=O)C(C)c2ccc(CC(C)C)cc2)sc1CCO[N+](=O)[O-]
Yield: 63 %

Procedure:
Pet-152 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using 2-(4-isobutyl-phenyl)-propionic acid (Ibuprofen) and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 63%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N+:18]([O-])=O)=[C:14]([CH:17]=2)[NH:15][CH3:16])[CH:6]=[C:5]([CH3:21])[N:4]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:17]=[C:14]([NH:15][CH3:16])[C:13]([NH2:18])=[CH:12][CH:11]=2)[CH:6]=[C:5]([CH3:21])[N:4]=1
Reactant: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1N
Yield: 100.3 %

Procedure:
The reaction and post-treatment were carried out according to Example (1b) using 5-[(2-methoxy-6-methylpyridin-4-yl)oxy]-N-methyl-2-nitroaniline produced in Example (17b) (4.87 g, 16.8 mmol), iron powder (4.70 g, 84.2 mmol), ammonium chloride (0.45 g, 8.42 mmol), ethanol (80 mL) and water (40 mL) to obtain the title compound (4.37 g, 99%) as a brown oil.