Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.I[C:14]1[CH:22]=[CH:21][C:17]2[N:18]=[CH:19][S:20][C:16]=2[CH:15]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:20]1[C:16]2[CH:15]=[C:14]([N:9]3[CH2:10][CH2:11][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:8]3=[O:12])[CH:22]=[CH:21][C:17]=2[N:18]=[CH:19]1
Reactant: O=C1NCCN1c1cccnc1
Reactant: Ic1ccc2ncsc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cccnc2)CCN1c1ccc2ncsc2c1
Yield: 45.8 %

Procedure:
Using the same reaction conditions as in Example 1, 1-pyridin-3-yl-imidazolidin-2-one (I-1b: 62 mg, 0.3831 mmol) was reacted with 6-iodo-benzothiazole (100 mg, 0.3831 mmol), 1,4-dioxane (10 mL), copper iodide (7 mg, 0.03831 mmol), trans-1,2-diamino cyclohexane (6 mg, 0.5747 mmol) and potassium carbonate (105 mg, 0.7662 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform), afforded 52 mg of the product (46.01% yield).
Reaction SMILES: [O:1]=[C:2]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:1][CH:2]1[C:12]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: O=C1c2ccccc2Sc2ccccc2C12CCNCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OC1c2ccccc2Sc2ccccc2C12CCNCC2
Reaction time: 16 h

Procedure:
A solution of 2.4 g of 10,11-dihydro-11-oxospiro[dibenz(b,f)thiepin-10,4'-piperidine], free base of Example 3, in 20 ml of tetrahydrofuran is added dropwise to a refluxing slurry of 1.5 g of lithium aluminum hydride in 20 ml of tetrahydrofuran. After total addition, stirring is continued at reflux for an addition 4 hours and then at ambient temperature for 16 hours. Thereafter, the reaction mixture is decomposed by adding sequentially 1.7 ml of water with 1.7 ml of 15% sodium hydroxide and 5.2 ml of water. The diluted mixture is filtered and the filtrate is concentrated under vacuum, providing 10,11-dihydro-11-hydroxyspiro[dibenz(b,f)thiepin-10,4'-piperidine].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>CCOCC>[CH2:7]([C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[CH2:16][OH:17])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(Cl)cc1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1ccc(Cl)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 28.4 g (0.75 mole) of lithium aluminum hydride in 800 ml of ether, which was cooled to 0°, was added dropwise 85.1 g (0.345 mmole) of 2-benzyl-4-chlorobenzoic acid in 250 ml of ether. The mixture was allowed to warm to room temperature, and was stirred for 2 hr. The excess lithium aluminum hydride was discharged by the addition of 28.5 ml of water, 28.5 ml of 10% aqueous sodium hydroxide, and 85.5 ml of water. The precipitate was removed by filtration and the filtrate was dried with sodium sulfate. Removal of the ether at reduced pressure gave a colorless oil which crystallized upon standing, mp 46.5°-49°.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(N(C)C)=O.[CH2:20]([N:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>O>[CH2:20]([N:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCN(Cc1ccccc1)C(=O)Cl
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCN(Cc1ccccc1)C(=O)N(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 3.89 g. of diphenylamine in 25 ml. of dimethylacetamide is added during one hour to a stirred mixture of 5.19 g. of N-benzyl-N-(n-butyl)carbamyl chloride, 0.685 g. of sodium hydride, and 65 ml. of dimethylacetamide under a nitrogen atmosphere at 45°-50° C. The mixture is stirred for 2 hours at 50° C. and then poured into water. The mixture is extracted with methylene chloride and the extract is evaporated. The residue is purified by chromatography using silica gel as the adsorbant and acetone-hexane as the eluent. After evaporation of the eluent, the residue is evaporatively distilled at 165° C. under reduced pressure (150 microns) to yield 1-benzyl-1-(n-butyl)-3,3-diphenylurea as a viscous, clear, clorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=[O:19])[CH2:13][C:12]=3[CH:21]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(-c2ccc3c(c2)CC(C(=O)O)CCO3)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
Into a suspension of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (280 mg) in methanol (20 ml)/ethyl acetate (10 ml) was added 10% palladium on charcoal (50% water content, 70 mg). Hydrogen gas was introduced, and the resulting mixture was stirred at room temperature for 17 hours and at 50° C. for 3 hours, and was then filtered to remove the catalyst. The filtrate was concentrated, and the residue was recrystallized from ethyl acetate/hexane to obtain 7-(4-methylphenyl)-2,3,4,5-tetrahydro-1-benzooxepine-4-carboxylic acid (187 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14](=[O:16])[NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[CH2:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]1[C:14](=[O:16])[NH2:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(C(N)=O)C1
Reaction time: 18 h
Yield: 93.1 %

Procedure:
A solution of (RS)-1-(tert-butyloxycarbonyl)-3-carbamoylpiperazine (ref Bruce et al. Syn. Comm. 1995, 2673-84) (25 g, 0.109 mol) and benzaldehyde (11.1 ml, 0.109 mol) in 1,2-dichloroethane (550 ml) was stirred at room temperature for 1.5 h. Sodium triacetoxyborohydride (34.7 g, 0.163 mol) was added in one portion and the resultant stirred for a further 18 h. Dichloromethane (400 ml) was added and the mixture washed with saturated sodium hydrogen carbonate (600 ml). The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 10-70% ethyl acetate in hexane to afford the title compound as a colourless solid (32.4 g, 93%).
Reaction SMILES: [Cl-].[Cl-].[Na+].Cl.[Na].[C:6]([O-:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([O-:16])=[O:15])([C:10]([O-:12])=[O:11])[OH:9].[Na+].[Na+].[Na+]>>[C:6]([OH:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([OH:16])=[O:15])([C:10]([OH:12])=[O:11])[OH:9]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
After adjusting the stationary state, the chloride content of the discharged solution was 890 m.equ. of which 870 m.equ. were sodium chloride and 20 m.equ hydrochloric acid. 8 m.equ of chloride ions were contained in the control solution. When the bed was charged with sodium ions of the sodium citrate, 865 m.equ. of citric acid were produced.
Reaction SMILES: [C:1]([Li])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C#CCCCC.C([Li])CCC.[C:19]1([B:25](OC(C)C)[O:26][CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.[B].C=C(C)C>C(OCC)C>[C:6]1([B:25]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:26][CH:27]([CH3:28])[CH3:29])[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: [Li]C#CCCCC
Reactant: CC(C)OB(OC(C)C)c1ccccc1
Agent: C#CCCCC
Agent: C=C(C)C
Agent: Cl
Solvent: CCOCC
Product: CCCCC#CB(OC(C)C)c1ccccc1

Procedure:
The title compound was prepared following the method of Example 14, using 1-hexynyllithium (64 mmol) prepared from 1-hexyne and n-butyl lithium in ethyl ether (64 mL) and phenyldiisopropoxyborane (11.96 g, 58 mmol) dissolved in ethyl ether (60 mL) and quenched with hydrogen chloride in ethyl ether (18.7 mL, 64 mmol). Yield. 11.2 g (86%), bp 102°-105° C. (0.4 mm Hg); n20D 1.5008; proton NMR (CDCl3) δ7.90 (m, 2H), 7.31 (m, 3H), 4.87 (septet, J=18 Hz, 1H), 2.33 (triplet, J=18 Hz, 2H), 1.23 (d, J=18 Hz, 6H), 0.90 (triplet, 3H); boron NMR (CDCl3) δ+36.5 ppm(s); mass spectrum (chemical ionization, isobutene) m/e 229 (M+H, 10%); IR (thin film) 2195, 1324 cm-1.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[N:32]2[CH2:37][CH2:36][CH2:35][C@H:34]([NH:38]C(=O)OCC3C=CC=CC=3)[CH2:33]2)=[O:24])=[N:14]C2C([CH:21]=1)=CC=C(Br)C=2)=O)C1C=CC=CC=1.CC1(C)C(C)(C)OB(C2CCN(C(O[CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=O)CC=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+].[Pd]>[NH2:11][C:12]1[C:13]([C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[N:32]2[CH2:37][CH2:36][CH2:35][C@H:34]([NH2:38])[CH2:33]2)=[O:24])=[N:14][C:71]2[C:70]([CH:21]=1)=[CH:69][CH:68]=[C:67]([CH:66]1[CH2:31][CH2:26][NH:25][CH2:23][CH2:13]1)[CH:72]=2
Reactant: CC1(C)OB(C2=CCN(C(=O)OCc3ccccc3)CC2)OC1(C)C
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1)OCc1ccccc1
Agent: Cl[Pd+]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Product: Nc1cc2ccc(C3CCNCC3)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a screw-cap vial equipped with a magnetic stir bar was added benzyl [(3S)-1-(3-{[(3-{[(benzyloxy)carbonyl]amino}-7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)piperidin-3-yl]carbamate (56.4 mg, 0.0795 mmol), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Ark Pharm, 48.2 mg, 0.140 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Aldrich, 3.2 mg, 0.0041 mmol) and K3PO4 (53.4 mg, 0.252 mmol). The vial was sealed with a Teflon®-lined septum, and was then evacuated and backfilled with nitrogen three times. 1,4-Dioxane (1.00 mL) was added via a syringe, followed by deoxygenated water (0.50 mL). The mixture was heated at 60° C. for 1 h. After cooling to room temperature, the reaction mixture was filtered through a silica gel plug (eluted with MeCN), and concentrated under reduced pressure. The resulting residue was dissolved in MeOH (4.0 mL) and 10 wt % Pd on carbon (43.4 mg, 0.0408 mmol) was added. The mixture was stirred at room temperature under hydrogen (1 atm.) for 15 h. The reaction mixture was then filtered through a pad of diatomaceous earth (eluted with MeOH) and concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.05% TFA, at a flow rate of 30 mL/min.) to afford the title compound tetrakistrifluoroacetate salt as a yellow solid (13.1 mg, 18%). LCMS calc. for C25H32N7O (M+H)+: m/z=446.3. found 446.2. 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.98 (s, 1H), 8.97-8.90 (m, 1H), 8.84-8.69 (m, 1H), 8.43 (d, J=6.6 Hz, 1H), 8.31 (s, 2H), 7.74-7.65 (m, 2H), 7.56 (s, 1H), 7.45-7.38 (m, 2H), 3.88-3.76 (m, 1H), 3.59-3.46 (m, 2H), 3.43 (d, J=11.5 Hz, 2H), 3.36-3.25 (m, 2H), 3.13-3.03 (m, 2H), 3.03-2.95 (m, 1H), 2.12-2.03 (m, 3H), 2.03-1.95 (m, 1H), 1.94-1.81 (m, 2H), 1.81-1.65 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.O[C@H]1C[NH:22][C@H](C(O)=O)C1.C([O-])([O-])=O.[K+].[K+].N>CS(C)=O.O.[Cu]I>[CH3:17][C:13]1[C:14]([NH2:16])=[N:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([NH2:22])[CH:3]=3)[O:8][CH2:9][CH2:10]2)[N:12]=1
Reactant: CC1=NC2(CCOc3ccc(Br)cc32)N=C1N
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Cu]I
Agent: N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
A mixture of 6-bromo-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine (Intermediate 4, 115 mg, 0.39 mmol), trans-4-hydroxy-L-proline (51 mg, 0.39 mmol), CuI (37 mg, 0.20 mmol), and K2CO3 (162 mg, 1.17 mmol) in DMSO (0.9 mL) was stirred at r.t. for 15 min. Ammonia, (30-33% in H2O, 0.37 mL, 5.86 mmol) was added and the mixture was subjected to microwave irradiation at 110° C. for 3 h. The mixture was diluted with DMSO and water and filtered through a pad of diatomaceous earth. NaCl (s) was added and the aqueous mixture was extracted with EtOAc (5×35 mL). The combined organic phases were dried (Na2SO4) and evaporated to give a crude product which was purified by flash chromatography (4 g silica, eluent: CHCl3/(MeOH/NH3) gradient) affording the title compound (59 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.76-1.92 (m, 2 H), 2.19 (s, 3 H), 4.18-4.34 (m, 2 H), 4.45 (br. s., 2 H), 5.69 (d, 1 H), 6.35 (dd, 1 H), 6.45 (br. s., 2 H), 6.50 (d, 1 H); MS (ES+) m/z 231 [M+H]+.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24](Br)[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[Li]C(C)(C)C.[C:37](=[O:39])=[O:38]>C1COCC1.Cl>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[CH:28]=[CH:27][C:26]3[CH:25]=[C:24]([C:37]([OH:39])=[O:38])[CH:23]=[CH:22][C:21]=3[CH:20]=2)=[CH:12][C:11]=1[C:1]12[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1ccc(-c2ccc3cc(Br)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C=O
Agent: Cl
Agent: [H-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-bromonaphthalene (50 mg, 0.11 mmol) in THF (1 ml) was introduced into a Schlenk tube and was heated until its complete dissolution. Next, NaH (4.5 mg, 60% dispersion in mineral oil, 0.11 mmol) was added under argon atmosphere and at room temperature, and the mixture was stirred for 10 minutes. The obtained mixture was cooled to −60° C. and t-BuLi (1.7 M in penthane, 0.22 mmol) was added, dropwise, during a period of 30 minutes. Next, and at the same temperature, a continuous mild flow of CO2 (anhydrous gas) was introduced in the reaction for 1 h. After bringing the reaction to room temperature during 30 minutes with continuous flow of CO2, the mixture was diluted with aq HCl (5 ml, 2 M) and was vigorously stirred for 10 minutes. The resulting mixture was extracted with CHCl3 (3×5 ml) and the joined organic phases were evaporated to dryness once dried with Na2SO4, giving the crude of Adapalene.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH:8]1[C:20]2[C:19]3[CH2:18][CH2:17][NH2+:16][CH2:15][C:14]=3[CH:13]=[N:12][C:11]=2[NH:10][N:9]=1.CCN(C(C)C)C(C)C.[N:30]([C:33]1[CH:34]=[C:35]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40])=[C:31]=[O:32].ClCCl>ClC(Cl)C.C(OCC)C>[CH3:40][O:39][C:38]1[CH:37]=[CH:36][C:35]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][C:33]=1[NH:30][C:31]([N:16]1[CH2:15][C:14]2[CH:13]=[N:12][C:11]3[NH:10][N:9]=[CH:8][C:20]=3[C:19]=2[CH2:18][CH2:17]1)=[O:32]
Reactant: COc1ccc(-c2ccccc2)cc1N=C=O
Reactant: c1nc2[nH]ncc2c2c1C[NH2+]CC2
Agent: O=C([O-])C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COc1ccc(-c2ccccc2)cc1NC(=O)N1CCc2c(cnc3[nH]ncc23)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate (0.06 g, 0.15 mmol) and Hunig's Base (0.2 mL) in dichloroethane (2 mL) was added 3-isocyanato-4-methoxybiphenyl (0.034 g, 0.15 mmol). The mixture was stirred at room temperature for 24 hours before being poured into dichloromethane (50 mL) and washed with water (100 mL). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give an off white solid. Trituration with diethylether (20 mL) gave N-(4-methoxybiphenyl-3-yl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide as an off white powder (0.030 g, 40%). M.p.=148-151° C. 1H NMR (DMSO-d6) 400 MHz δ 8.37 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.58-7.30 (m, 6H), 7.10 (d, J=8.4 Hz, 1H), 4.80 (s, 2H), 3.87-3.83 (m, 5H), 3.17 (s, 2H). LCMS [M+H]: 400.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[CH:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.Cl.[C:38]1([CH2:44][O:45][NH2:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:11])[NH:46][O:45][CH2:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:12]([N:14]2[C@H:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NOCc1ccccc1
Reactant: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)O)CC2CCCC2)n1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCc1cccc(NC(=O)[C@@H]2CC=NN2C(=O)[C@@H](CC(=O)NOCc2ccccc2)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (314 mg, 0.79 mmol) in dichloromethane (DCM) (10 mL) was added N-methylmorpholine (0.22 mL, 2.04 mmol), O-(phenylmethyl)hydroxylamine hydrochloride (188 mg, 1.18 mmol), EDC (181 mg, 0.94 mmol) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (107 mg, 0.79 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was then washed with water (5 mL) and NaHCO3 solution (5 mL×3), and concentrated to provide the crude product as a mixture of diastereomers. This mixture was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(6-ethyl-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (157 mg, 39% yield). MS: 506 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:17][CH2:18][CH3:19])[C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][CH2:7]2.[N+:20](C)([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:17][CH2:18][CH3:19])[C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][CH2:7]2
Reactant: C[N+](=O)[O-]
Reactant: CCCN(C(=O)CC)C1CCc2cccc(Cl)c2C1
Product: CCCN(C(=O)CC)C1CCc2c([N+](=O)[O-])ccc(Cl)c2C1
Temperature: 0 °C
Yield: 31 %

Procedure:
To an ice-cold solution of compound 6 (12.5 g, 44.5 mmol) in nitromethane (100 ml) was added (dropwise) "nitrating acid" (32.6 ml) (see synthesis of compound 3) until all starting material was consumed (monitored with gas chromatography after basification of analytical samples and extraction with Et2O). Ice-water/Et2O was added, shaken and extracted one additional time (Et2O). The combined organic extracts were dried (Na2SO4), filtered and the solvent was evaporated (12.5 g, 87%). The resulting residue was chromatographed using flash chromatography on a silica column, using petroleum ether/E2O (1:2) as eluant, yielding 4.5 g (31%) of 8-chloro-5-nitro-2-(N-n-propyl-N-propionylamino)tetralin (7a) and 3.5 g (24% of 8-chloro-7-nitro-2-(N-n-propyl-N-propionylamino)tetralin (7b). Unseparated material could be recycled in second chromatography.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:24][CH2:25][C@@H:26]2[O:31][C:30]3[C:32]([CH:39]=O)=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:29]=3[O:28][CH2:27]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[N:4]#[C:3][CH:5]=[CH:39][C:32]1[C:30]2[O:31][CH:26]([CH2:25][O:24][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=3)(=[O:22])=[O:23])[CH2:27][O:28][C:29]=2[CH:35]=[CH:34][C:33]=1[N+:36]([O-:38])=[O:37]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(C=CC#N)c3O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.44 g (11 mmole) of 60% sodium hydride/mineral oil dispersion in 100 mL of DMF was add 1.8 g (10 mmole) of diethyl cyanomethyl-phosphonate. The mixture was stirred for 30 minutes at room temperature under nitrogen and then 3.0 g (7.6 mmole) of [(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate added and stirring at room temperature continued overnight. The solvent was then removed in vacuum and replaced with 400 mL of dichloromethane. The solution was washed with 300 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum to a yellow oil. This was column chromatographed on silica gel with methylene chloride as eluant to give 2.5 g of the (R)-enantiomer of the title compound as a yellow solid (m.p. 117-118° C.).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]([C:18]1[CH:23]=[C:22]([SH:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])[CH3:16].C(N(CC)CC)C.Cl>C(#N)C>[CH3:28][C:25]([C:20]1[CH:21]=[C:22]([S:24][CH2:2][C:3]([NH:5][C:6]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:13])=[O:4])[CH:23]=[C:18]([C:15]([CH3:17])([CH3:16])[CH3:14])[C:19]=1[OH:29])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by dissolving 2-chloro-N-(2,6-dimethylphenyl)acetamide (1.8 g, 0.0091 mole) and 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.17 g, 0.0091 mole) in acetonitrile (20 ml) under argon. Triethylamine (1.25 ml) was added and the solution stirred at room temperature under argon for 12 hours. The solution was acidified with 10% hydrochloric acid with stirring, extracted with ethyl acetate (3X), the extracts combined, washed with water and dried over sodium sulfate. The solvent was removed on a rotary evaporator and the product purified by chromatography over silica and recrystallized from ethyl acetate/benzene, m.p. ca. 137.7° C.