Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cccc(Br)n1
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: C1CCOC1
Product: Brc1cccc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 4.4 %

Procedure:
A degassed solution of 2,6-dibromopyridine (4.0 g, 16.5 mmol) and phenylboronic acid (2.1 g, 16.7 mmol) in dry tetrahydrofuran (30 ml) was stirred under an atmosphere of nitrogen then sodium carbonate (3.55 g, 33.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.95 g, 5 mol %) added. This mixture was heated to reflux for 18 h. After cooling to ambient temperature, solvent was removed in vacuo, the residue dissolved in dichloromethane, washed with water and saturated brine, then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with dichloromethane gave 2-bromo-6-phenylpyridine (0.17 g) as a white solid: δH (400 MHz, CDCl3) 7.45 (4H, m), 7.60 (1H, dd, J 8 and 8), 7.70 (1H, d, J 8), 7.99 (2H, d, J 8); m/z (ES+) 233/235 (M++H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][NH:8][C:9]([C:11]12[CH2:18][CH2:17][C:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)=O>C(Cl)Cl>[CH3:7][N:8]=[C:9]([Cl:4])[C:11]12[CH2:18][CH2:17][C:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC12CCC(C(=O)NC)(CC1)CC2
Solvent: ClCCl
Product: CCCCCC12CCC(C(Cl)=NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (846 μL, 9.7 mmol) was added dropwise to a solution of N-methyl-4-pentylbicyclo[2.2.2]octane-1-carboxamide (3-C) (230 mg, 0.97 mmol) in methylene chloride (2.0 mL) and the mixture stirred at room temperature for 4 h. The solvent and excess reagent were removed in vacuo to provide N-methyl-4-pentylbicyclo[2.2.2]octane-1-carboximidoyl chloride (3-D). Toluene (1.5 mL) was added followed by 5-(2-chloro-4-methoxyphenyl)-1H-tetrazole (3-E) (204 mg, 0.97 mmol) and the mixture refluxed for 18 h. The reaction was cooled to room temperature and the precipitate was filtered, washed with cold toluene, hexane, dissolved in methylene chloride, dried (MgSO4) and concentrated in vacuo to provide 3-(2-chloro-4-methoxyphenyl)-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (3-F). Mass spectrum: 402 (M+1); 1H NMR (500 MHz, CDCl3): δ 0.94 (t, 3H); 1.27 (m, 8H); 1.56 (m, 6H); 2.13 (m, 6H); 3.56 (s, 3H); 3.89 (s, 3H); 6.95 (dd, 1H); 7.07 (d, 1H); 7.43 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: Oc1ccc(F)cc1F
Reactant: C1=COCCC1
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc(OC2CCCCO2)c(F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
260.2 g (2.0 mol) of 2,4-difluorophenol and 252.4 g (3.0 mol) of 3,4-dihydro-2H-pyran are introduced into a 750 ml sulfation flask and cooled to 0° C. One drop of polyphosphoric acid is carefully added to the solution, and the mixture is stirred for a further 16 hours at 0° to 5° C. (check using GC and TLC). The mixture is then rendered alkaline using a little powdered sodium hydroxide. The product is distilled at 119°-120° C. in vacuo (22 mbar). 377 g (88% of theory) of a clear, colourless liquid are obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][C@@H:17]([CH3:19])[C@H:16]([CH3:20])[C@@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1.CO>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][C@@H:17]([CH3:19])[C@H:16]([CH3:20])[C@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@H]3O
Solvent: ClCCl
Solvent: CO
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@@H]3O
Temperature: -78 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To a solution of (-)-calanolide A (341 mg, 0.922 mmol) in anhydrous methylene chloride (5 mL) at -78° C. under N2 was added a solution of diethylamidosulfur trifluoride (DAST, 178 mg, 1.11 mmol) in methylene chloride (1 mL) and the resulting yellow solution stirred at -78° C. for 4 hours. The reaction was quenched with 0.5 mL methanol, then allowed to warm to room temperature. The solution was diluted with methylene chloride (20 mL), then washed with water (50 mL) and saturated brine (50 mL). After drying over magnesium sulfate, the solution was filtered and evaporated to provide a light yellow solid. TLC analysis (silica gel, 3% methanol in methylene chloride) showed two components, one fast-moving and one slow. The material was chromatographed through 80 g silica gel, eluting with 1% methanol in CH2Cl2, and the fractions containing the respective components combined and evaporated to afford 198 mg (61% yield) of compound 22 and 75.3 mg (22%) of (-)-calanolide B.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:7])[CH3:4].Cl[CH2:23][C:24]#[N:25].O>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:23][C:24]#[N:25])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2[nH]1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2n1CC#N
Temperature: 75 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of sodium hydride (0.58 g in DMF (12 mL) at 0° C. was slowly added a solution of 5-trifluoromethoxy-1H-indole-2-carboxylic acid ethyl ester (2.64 g) in DMF (12 mL) keeping the temperature below 7.5° C. After gas evolution ceased, chloroacetonitrile was added, and the reaction mixture was stirred for 2 hours at 75° C. After allowing cooling down, water was added, and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with brine then dried with magnesium sulfate, concentrated in vacuo and purified by column chromatography to yield the title compound (2.3 g, 76%). MS (EI): 312.1 (M+).
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][N:28]([CH2:12][CH2:13][CH:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][CH2:15]2)[CH2:27][CH2:26]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: OC1(c2ccccc2)CCN(CCC2COc3ccccc3O2)CC1

Procedure:
The mixture of 6.68 g of 2-(2-tosyloxyethyl)-1,4-benzodioxan, 3.54 g of 4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is refluxed 48 hours. It is filtered, evaporated and the residue recrystallized from isopropanol, to yield the 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan melting at 142°.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:11][C:12]([NH2:14])=[O:13]>C1COCC1.CN(C=O)C>[CH:6]([C:4]1[N:3]=[CH:2][N:1]([CH2:11][C:12]([NH2:14])=[O:13])[CH:5]=1)=[O:7]
Reactant: O=Cc1c[nH]cn1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)Cn1cnc(C=O)c1
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A solution of 1H-imidazole-4-carbaldehyde (1.92 g, 20 mmol) in anhydrous THF (32 mL) and DMF (8 mL) was treated with sodium hydride (60% dispersion in mineral oil, 880 mg, 22 mmol) for 5 mins. 2-Bromoacetamide (3.59 g, 26 mmol) was added and the reaction was stirred continuously overnight. The THF was concentrated, loaded on a silica column, and eluted with 20% methanol in dichloromethane. The solvent was evaporated to yield 2.70 g of the product as a white solid (88.2%). HPLC Method D, r.t.=1.5 min, (96.4% purity at 256 nm). LC/MS calculated mass=153.14, [M−H]−=152, [M+H]+=154.
Reaction SMILES: O[C:2]1[C:11]2[C:10]([C:12](OCC)=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][C:4](=[O:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.[NH2:25][NH2:26]>CO>[C:18]1([CH:3]2[C:2]3=[N:25][NH:26][C:12](=[O:13])[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]=43)[NH:5][C:4]2=[O:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2[nH]c(=O)c(-c3ccccc3)c(O)c12
Solvent: O
Solvent: CO
Product: O=C1Nc2cccc3c(=O)[nH]nc(c23)C1c1ccccc1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 53 %

Procedure:
Ethyl 4-hydroxy-2-oxo-3-phenyl-1,2-dihydroquinoline-5-carboxylate (330 mg, 1.1 mmol) was added to hydrazine monohydrate (1 mL) and methanol (2 mL), the mixture was stirred at 110° C. for 2.5 h by microwave. Then the mixture was cooled to room temperature, the solvent was evaporated in vacuum. The residue was washed with methanol, and then purified by column chromatography (silica gel, dichloromethane/methanol=300:1 to 50:1) to obtain a pale white solid (148 mg, yield 53%). LC-MS (ESI) m/z: 278 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 5.09 (s, 1H), 7.17-7.40 (m, 6H), 7.77-7.81 (m, 2H), 11.10 (s, 1H), 12.57 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH2:22]>>[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[NH:22][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and Nε(tert-butoxycarbonyl)-L-lysine methyl ester (Bachem), the title compound was prepared as an oil. The reaction was monitored by tlc (Rf=0.40 in 50% EtOAc/hexanes) and the product was purified by flash chromatography using 50% EtOAc/hexanes as the eluent.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[I-].[CH3:15][S+](C)(C)=O.O>CS(C)=O>[O:1]1[C:5]2[C:6]([CH:10]3[CH2:15][O:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2ccoc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1cc(C2CO2)c2occc2c1

Procedure:
A solution of benzofuran-7-carboxaldehyde (4.4 g) in dry dimethylsulphoxide was added dropwise to a stirred solution of sodium hydride (60% dispersion in oil, 2.5 g) and trimethylsulphoxonium iodide (7.6 g) in dimethylsulphoxide (50 ml) at room temperature. After 1 hour iced water was added and extracted with diethylether. The extracts were washed with water, dried, filtered and evaporated to a yellow oil. Chromatography on silica eluting with 10:1:90 ether:triethylamine:hexane gave 7-benzofuranyl oxirane as an oil.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([NH:16][C:17]3[C:22]([N+:23]([O-])=O)=[CH:21][N:20]=[C:19]([O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][N:4]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3]1.[Sn](Cl)Cl>CO.CCOC(C)=O>[NH2:23][C:22]1[C:17]([NH:16][C@@H:13]2[CH2:12][CH2:11][C@H:10]([C:8]([N:7]3[CH2:6][CH2:5][N:4]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3][C@H:2]3[CH3:1])=[O:9])[CH2:15][CH2:14]2)=[CH:18][C:19]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:20][CH:21]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2N)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of (R)-tert-butyl 3-methyl-4-(cis-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate (0.2 g, 0.348 mmol) in MeOH (3.48 mL) was added tin(II) chloride (0.264 g, 1.392 mmol). The resulting suspension was stirred at 80° C. for 2 hours. The mixture was cooled to RT, diluted with EtOAc and washed with 1N aqueous NaOH. The organic layer was collected, dried over sodium sulfate and concentrated to afford (R)-tert-butyl 4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate as a tan solid (190 mg, 100%). MS m/z=545.4 [M+H]. Calc'd for C29H48N6O4: 544.4.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)#[CH:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:30]#[C:29][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=3)=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4cccc(C(F)(F)F)c4)cc3F)[nH]c2=O)c1)C1CC1
Yield: 37.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 by using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.050 g, 0.097 mmol), 1-ethynyl-3-(trifluoromethyl)benzene (Intermediate-50, 0.025 g, 0.14 mmol), TBAF (0.061 g, 0.19 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.65-0.70 (m, 4H), 1.60 (m, 1H), 4.31 (d, J=6.0 Hz, 2H), 7.28-7.41 (m, 2H), 7.51-7.61 (m, 4H), 7.67-7.97 (m, 4H), 8.68 (m, 1H), 12.0 (br s, 1H); MS (m/z): 555.05 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8].C(Cl)Cl.[Cl:19][S:20](O)(=[O:22])=[O:21].C([O-])(O)=O.[Na+]>CC(OC)(C)C>[Cl:19][S:20]([C:14]1[C:13]([CH3:15])=[CH:12][C:4]([O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[CH3:1])(=[O:22])=[O:21]
Reactant: CCC(Oc1cc(C)cc(C)c1)C(=O)O
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CCC(Oc1cc(C)c(S(=O)(=O)Cl)c(C)c1)C(=O)O
Temperature: -27 °C
Yield: 54.3 %

Procedure:
A 500 mL 3-neck flask was charged with 3,5-dimethylphenoxybutanoic acid (17) (25 g, 120 mmol) and CH2Cl2 (100 mL). This solution was cooled to −27° C. with mechanical stirring then chlorosulfonic acid (42 g, 360 mmol) was added dropwise over 30 min (temperature reached a max. of −20° C.). The material was stirred for an additional 1 hr at −25° C. then NaHCO3 (20 g, 238 mmol) was added to the reaction mixture. The reaction mixture was then added to 150 g of ice. The reaction mixture was then extracted into EtOAc (750 mL), dried over Na2SO4 (10 g), filtered and then concentrated in vacuo. Two triturations of the crude product with MTBE at 5° C. (50 mL then 25 mL) gave 20.0 g 18 (54% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C.[Pd]>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Reactant: O=C1CCCC1
Agent: [Pd]
Solvent: CCO
Product: CCCCC1OC(=O)c2cc(NC3CCCC3)ccc21

Procedure:
Analogously to the method described in Example 14, 4.1 g (20.0 mmol) of compound obtained in Example 4 in 5 ml of cyclopentanone and 150 ml of 95% ethanol are added to 10% Pd—C catalyst and hydrogenated to give the title compound.
Reaction SMILES: CC(=[N:4][N:5]1[CH:9]=[N:8][NH:7][C:6]1=[O:10])C.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1>C(#N)C>[NH2:4][N:5]1[CH:9]=[N:8][N:7]([C:21]2[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=2)[C:6]1=[O:10]
Reactant: CC(C)=Nn1cn[nH]c1=O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(-n2ncn(N)c2=O)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
A mixture of 7.0 g (0.05 mol) of 4-(1-methyl-ethylideneamino)-2 4-dihydro-3H-1,2,4-triazol-3-one, 21 g (0.15 mol) of potassium carbonate, 11.0 g (0.05 mol) of 4,6-dimethoxy2-methylsulphonyl-pyrimidine and 100 ml of acetonitrile is refluxed for 3 hours. After the mixture has cooled, it is filtered and the filtrate is concentrated, the residue is taken up in 100 ml of ethanol/water (vol. 1:1), and the mixture is stirred for 3 hours at 60° C. after 1 ml of concentrated hydrochloric acid has been added. The mixture is concentrated, the residue is then triturated with ethanol, and the product obtained in the form of crystals is isolated by filtering off with suction. 9.7 g (82% of theory) of 4-amino-2-(4,6-dimethoxy-pyrimidin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one of melting point 238° C. are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].[OH-].C[N+](C)(C)CC1C=CC=CC=1.CO>C(Cl)(Cl)Cl>[CH3:28][O:27][C:23]([CH2:24][CH2:25][N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4]1)=[O:26]
Reactant: C=CC(=O)OC
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Yield: 66.3 %

Procedure:
A mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.43 g), methyl acrylate (1.29 g), 40% methanolic trimethylbenzylammonium hydroxide (0.4 ml) and methanol (2 ml) in chloroform (8 ml) was refluxed for 40 minutes and then evaporated in vacuo. To the residue were added methylene chloride (30 ml) and water (30 ml), and the organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and diethyl ether to give 3-[2-(2-methoxycarbonylethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.37 g).
Reaction SMILES: [CH2:1]1[CH2:4][CH:3]([CH2:5][N:6]2[C@@H:16]3[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]5[O:25][C@H:10]6[C:11]([CH2:13][CH2:14][C@:15]3([OH:26])[C@:9]6([C:19]=45)[CH2:8][CH2:7]2)=[O:12])[CH2:2]1.P(=O)(O)(O)O.[H][H]>CC(O)C.O.[Pt]>[CH:23]1[C:18]2[CH2:17][C@H:16]3[N:6]([CH2:5][CH:3]4[CH2:4][CH2:1][CH2:2]4)[CH2:7][CH2:8][C@:9]45[C@H:10]([C@@H:11]([OH:12])[CH2:13][CH2:14][C@@:15]34[OH:26])[O:25][C:20]([C:19]=25)=[C:21]([OH:24])[CH:22]=1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CCC2)[C@H]1O5
Reactant: [H][H]
Agent: [Pt]
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(C)O
Product: Oc1ccc2c3c1O[C@H]1[C@@H](O)CC[C@@]4(O)[C@@H](C2)N(CC2CCC2)CC[C@]314
Reaction time: 7 h
Yield: 97.5 %

Procedure:
6-ketonalbuphine (40 g, 112.8 mmoles) was dissolved in a mixture of IPA (200 mls) and water (200 mls) containing orthophosphoric acid (1.56 mls). The pH of the reaction mixture was 6.49. The reaction mixture was hydrogenated at 40 psi hydrogen gas and 50° C. in the presence of 10% Platinum on carbon catalyst (2.4 g, 0.56 mmoles Pt). After 7 hours, the pH of the reaction mixture is adjusted with orthophosphoric acid (6.25 mls) and filtered. Ammonia solution (25 mls) was added to bring the pH to 8.5-9.0 and the precipitate filtered, washed with 50% aqueous IPA (60 mls), and dried to provide 39.33 g (97% theory) of Nalbuphine alkaloid of purity 95.6% by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[F:23][C:24]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:25]=1[CH:26]=O.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:26]\[C:25]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:24]=1[F:23])/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1cc(F)ccc1F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C(=C/c1cc(F)ccc1F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A stirred solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (6.1 g) and 2,5-difluorobenzaldehyde (2.0 g) in dry dichloromethane (60 mL), was treated dropwise with a solution of DBU (2.5 mL) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 h, then was concentrated to approximately 20 mL and partitioned between ethyl acetate (150 mL) and 1N hydrochloric acid (50 mL). The organic extract was collected, consecutively washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine, dried (sodium sulfate), filtered and evaporated. The crude product (6.5 g) was purified by flash chromatography (20% ethyl acetate/hexanes) to yield the title compound (4.0 g, 82%). 1H NMR (300 MHz, CDCl3) δ 3.85 (s, 3H), 5.10, (s, 2H), 6.60 (bs, 1H), 6.9-7.1 (m, 2H), 7.21 (m, 1H), 7.2-7.3 (m, 6H). MS APCI, m/z=348 (M+1). LC/MS: 2.53 min.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[S:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].O.[CH:16](O)=[O:17]>>[NH2:8][C:7]1[N:6]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:5](=[S:13])[NH:4][C:3](=[O:14])[C:2]=1[NH:1][CH:16]=[O:17]
Reactant: O=CO
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=S
Solvent: O
Product: CC(C)Cn1c(N)c(NC=O)c(=O)[nH]c1=S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
5,6-Diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (Example 6 (c), 0.25 g, 1.2 mmol) was dissolved in formic acid (1.5 mL) and stirred at ambient temperature for 0.5 h. A pink precipitate started to form after a few minutes. Water was added and the resulting mixture stirred for 10 minutes. The pink solid was collected by filtration, washed with water and dried to yield the title compound (0.25 g, 86%). This material was used without further purification. NMR showed that the product was obtained as a mixture of two tautomers: formamide (major) and imino (minor).