Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[N:9]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([CH:34]3[CH2:36][CH2:35]3)=[CH:26][CH:25]=2)[C:10]([S:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:11][N:12]=1.[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C1COCC1.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>[CH:34]1([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([N:9]3[C:8]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:12][N:11]=[C:10]3[S:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:25][CH:26]=2)[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: OB(O)c1ccccc1
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
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nnc(-c2ccccc2)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 90 °C
Yield: 73.7 %

Procedure:
Aqueous sodium carbonate solution (1M, 614 μL, 0.614 mmol) was added to a solution of tert-butyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate (60 mg, 0.123 mmol), phenylboronic acid (17 mg, 0.135 mmol) and Pd(PPh3)4 (28 mg, 0.024 mmol) in toluene (2 mL) and THF (1 mL). The mixture was bubbled under nitrogen for 5 mins and then heated to 90° C. under nitrogen for 20 hours. After cooling to room temp, water (20 mL) was added and the aqueous layer extracted with dichloromethane (2×20 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (40% EtOAc/hexanes) to give tert-butyl 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-phenyl-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a brown oil (44 mg, 73%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([Sn](CCCC)(CCCC)/[CH:60]=[CH:61]\[O:62][CH2:63][CH3:64])CCC.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH2:63]([O:62]/[CH:61]=[CH:60]\[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[CH3:64]
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(Br)ccn34)c12
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO/C=C\c1ccn2c(C(=O)Nc3cccc4c3c(CC)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 75.9 %

Procedure:
A round bottom flask was charged with 7-Bromo-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (330 mg, 0.674 mmol), trio-tolylphosphine (41 mg, 0.135 mmol), tris(dibenzylideneacetone)dipalladium (62 mg, 0.067 mmol) To the flask were added 10 mL of anhydrous dimethylformamide, followed by (Z)-tributyl(2-ethoxyvinyl)stannane (0.34 ml, 1.01 mmol), and triethylamine (0.11 mL, 0.81 mmol). The reaction mixture was degassed under nitrogen, and stirred at 100° C. for 10 hours. The reaction mixture was cooled, diluted with water, and extracted thoroughly with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to preparative thin-layer chromatography on silica with 5% MeOH-DCM as eluent to afford 246 mg of product as a yellow, foamy solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl.C([O-])(O)=O.[Na+]>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[CH:6]2
Reactant: COc1ccc(-c2cc3cc(OC)ccc3[nH]2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(-c2cc3cc(O)ccc3[nH]2)cc1
Temperature: 0 °C
Yield: 79.1 %

Procedure:
Five g (18.7 mmol) of 5-methoxy 2-(4 methoxyphenyl)indole was dissolved in 30 mL CH2Cl2 under argon, cooled on dry ice/acetone and 70 mL 1 M BBr3 were added with stirring. The solution was warmed to 0° C. for 30 min. It was then stirred at room temperature overnight. The reaction mixture was suspended in sat. NaHCO3 solution and extracted with CH2Cl2 (2×). The organic extract was washed with brine and dried over Na2SO4. Removal of the solvent in vacuo and flash chromatography (5% MeOH in CH2Cl2) gave 3.33 g of 3.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[N+:22]([C:19]1[N:20]=[CH:21][C:16]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)C(=O)C1
Temperature: 120 °C
Yield: 54.6 %

Procedure:
A microwave vial was charged with 332a (1.5 g, 7.5 mmol) in 30 mL of anhydrous 1,4-dioxane, 5-bromo-2-nitropyridine (1.27 g, 6.25 mmol), diacetoxypalladium (71.8 mg, 0.32 mmol), Xantphos (278 mg, 0.48 mmol), and Cs2CO3 (2.04 g, 6.25 mmol). After three cycles of vacuum/argon flash, it was heated at 120° C. under microwave irradiation for 1.5 h. The reaction mixture was filtered and the filtrate was evaporated in vacuum. The residue was purified by silica gel-column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 332b as a yellow solid (1.1 g, 54%). MS: [M+H]+ 323. 1H NMR (500 MHz, CDCl3) δ 8.68 (d, J=2.5 Hz, 1H), 8.31 (d, J=9 Hz, 1H), 8.15 (m, 1H), 4.33 (s, 2H), 3.91 (m, 4H).
Reaction SMILES: C1CCCCC=1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([C:18]1[C:23](Br)=[CH:22][N:21]=[C:20]([O:25][CH3:26])[CH:19]=1)=[O:17])([O-])=O.O.C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[NH2:7][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([O:25][CH3:26])[CH:19]=1)=[O:17]
Reactant: COc1cc(C(=O)c2ccccc2[N+](=O)[O-])c(Br)cn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1=CCCCC1
Solvent: O
Product: COc1cc(C(=O)c2ccccc2N)ccn1
Yield: 99.2 %

Procedure:
Cyclohexene (21 ml) was added to a stirred mixture of (2-nitrophenyl)-(5-bromo-2-methoxypyridin-4-yl)methanone (2.16 g) in ethanol (210 ml). A water slurry of 10% palladium on carbon (216 mg) was added followed by sodium acetate (524 mg). The suspension was heated to reflux for 4.5 hours then the mixture was cooled, filtered and evaporated to dryness. The residue was partitioned between dichloromethane and water. The organic layer was separated and the aqueous re-extracted with dichloromethane (twice). The combined organics were washed with water, brine, dried (sodium sulphate) then evaporated to dryness to give the title compound as a yellow solid (1.45 g). mp 82°-86° C. Rf =0.7 in 5% methanol/dichloromethane on silica plates; 1H NMR (360 MHz, CDCl3) δ 3.99 (3H, s), 6.57 (1H, ddd, J=1 and 7 Hz), 6.72 (1H, d, J=7 Hz), 6.86 (1H, s), 7.00 (1H, dd, J=1 and 5 Hz), 7.31 (1H, ddd, J=1 and 7 Hz), 7.37 (1H, dd, J=1 and 7 Hz), 8.26 (1H, d, J=5 Hz), IR (KBr) 3450, 3350, 1640 and 1620 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH2:16][S:17][CH3:18])[CH:10]([OH:14])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH2:16][S:17][CH3:18])[CH:10]([O:14][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(OC1CCCCO1)C(=O)O
Yield: 28.9 %

Procedure:
A solution of Example 11A (1.62 g, 5.8 mmol), 3,4-dihydro-2H-pyran (0.64 mL, 70 mmol), and pyridinium p-toluenesulfonate (0.15 mL, 0.60 mmol) in dichloromethane (30 mL) was heated to 35° C. for 16 hours and concentrated. The concentrate was diluted with aqueous sodium hydroxide (0.25M, 15 mL) and extracted twice with ethyl acetate. The aqueous layer was adjusted to pH 3 with aqueous H3PO4 (1.0M) and extracted three times with ethyl acetate. These three extracts were combined, washed sequentially with water (20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated to provide the desired product (0.61 g). MS (APCI(+)) m/e 364 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].BrN1C(=O)CCC1=O.[O:23]([C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:43])[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+].FC(F)(OC1C=C(CBr)C=CC=1)C(F)F>C(Cl)(Cl)(Cl)Cl.COCCOC.N(C(C)(C)C#N)=NC(C)(C)C#N.O>[O:43]=[C:36]([C:33]1[CH:34]=[CH:35][C:30]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:31][CH:32]=1)[CH:37]([CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:2]([F:14])([F:1])[CH:3]([F:4])[F:5])[CH:8]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: CCOC(=O)CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (7.8 g, 37.5 mmol) in carbon tetrachloride (80 ml) were added N-bromosuccinimide (7.33 g, 41.2 mmol) and 2,2′-azobis(isobutyronitrile) (300 mg, 1.87 mmol), and the mixture was heated under reflux for 6 hrs. After cooling, the reaction solution was filtered, and the filtrate was concentrated to prepare ethyl 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(4-phenoxyphenyl)-3-oxopropionate (10.7 g, 37.5 mmol) in 1,2-dimethoxyethane (120 ml) was added sodium hydride (60% in oil, 1.50 g, 37.5 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (10 ml), and the reaction solution was stirred at room temperature for 1 hr. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-oxo-3-(4-phenyloxyphenyl)-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate (9.92 g, 54%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.N[C:25]1C2=CC=C(C3CCN(C(OC(C)(C)C)=O)CC=3)N2N=CN=1>>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[N:6]2[N:5]=[C:4]([CH3:25])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(N)ncnn23)CC1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CC1
Product: Cc1nc(N)c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)n2n1

Procedure:
The title compound was prepared in the same manner described for the preparation of tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate and substituting tert-butyl 4-(4-amino-2-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate for tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate. 1H-NMR (CD2 Cl2): δ 6.59 (d, 1 H), 6.41 (d, 1 H), 5.53 (br s, 2 H), 4.18 (m, 2 H), 3.33 (m, 1 H), 2.89 (m, 2 H), 2.36 (s, 3 H), 2.03 (m, 2 H), 1.58 (m, 2 H), 1.45 (s, 9 H). MS: LC/MS (+esi), m/z=332 [M+H]. RT=2.39 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH:8]=[CH:7]2.C1(CCCC2C=C[N+]([O-:27])=CC=2)C=CC=CC=1.Cl[O-].[Na+]>C(Cl)Cl.CC(C1C=C(C=N[C@@H]2[C@@H](N=CC3C([O-])=C(C(C)(C)C)C=C(C(C)(C)C)C=3)CCCC2)C([O-])=C(C(C)(C)C)C=1)(C)C.[Cl-].[Mn+3]>[Br:1][C:2]1[C:10]2[CH2:9][C@H:8]3[O:27][C@H:7]3[C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1
Reactant: Fc1cc(Br)c2c(c1)C=CC2
Reactant: [O-][n+]1ccc(CCCc2ccccc2)cc1
Agent: [Mn+3]
Agent: CC(C)(C)c1cc(C=N[C@H]2CCCC[C@@H]2N=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2[O-])c([O-])c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: ClCCl
Product: Fc1cc(Br)c2c(c1)[C@@H]1O[C@@H]1C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 164.4 %

Procedure:
To a solution of 9 g (42.3 mmol) of 7-Bromo-5-fluoro-1H-indene (5a) in CH2Cl2 at 0° C. was added (S,S)-(+)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III)-chloride (Jacobsen catalyst; 1.2 g, 1.7 mmol) and 4-(3-phenylpropyl)pyridine N-oxide (1.8 g, 8.5 mmol). After stirring for 15 min at 0° C., the 0° C. cold buffered sodium hypochlorite solution was added and the mixture was stirred at 0° C. for 3 h. The resulting liquid layers were separated and the aqueous layer was extracted 3 times with CH2Cl2. The combined organic layers were washed with brine and dried over MgSO4. Solvents were evaporated and the crude product was purified by silica gel chromatography (eluting with 5 to 50% ethyl acetate in heptane). The product was recrystallized from heptane to give 3.2 g of (1aS,6aR)-5-Bromo-3-fluoro-6,6a-dihydro-1aH-1-oxa-cyclopropa[a]indene (6a) as white needles.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.OO.CC(C)=[O:28].Cl>C(O)=O.CO>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@:17]2([OH:28])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: CC(C)=O
Agent: Cl
Agent: OO
Solvent: CO
Solvent: O=CO
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 20 h
Yield: 80 %

Procedure:
Thebaine (67 g, 0.215 mol) was dissolved in formic acid (98-100%, 120 g) and hydrogen peroxide (30% in water, 24.5 g, 0.216 mol) added at 0° C. The mixture was pumped continuously at 2 ml/min through a 30 ml continuous flow reactor at 80° C. (15 min residence time). An analytical control after the continuous reactor showed less than 1% Thebaine remaining. The continuous stream was added directly to acetone, containing 32% HCl, whereupon the 14-Hydroxycodeinone HCl was precipitated and isolated in 80% yield. The 14-Hydroxycodeinone HCl was then dissolved in MeOH and HCOOH (4:1 w/w) and hydrogenated at 80° C. under 15 bar H2 pressure. The hydrogenation was stirred for 20 h. After the hydrogenation, the catalyst was filtered off and the crude mixture was either basified with NaOH to obtain the low impurity Oxycodone base, or treated with HCl in 2-Propanol to give the Oxycodone HCl. The 14-Hydroxycodeinone content of the base was 48 ppm.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC1C[O:46][CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH:14]3[CH2:45][O:46][CH2:15]3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: BrC1COC1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(C3COC3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromooxetane and isolated as light-brown solid (2.8 mg, 20%). MS (m/e): 339.3 (MH+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C.C(Cl)Cl.CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:14]3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2ccc(NC3CCCNC3)cc2)cn1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1cn(-c2ccc(NC3CCCN(Cc4ccc5c(c4)OCO5)C3)cc2)cn1
Temperature: 50 °C

Procedure:
3-[(4-(Imidazol-1-yl)phenyl)amino]piperidine (330 mg, 1.36 mmol) was dissolved in DMF and then treated with 5-chloromethyl-1,3-benzodioxole (1.0 eq.), K2CO3 (2.5 eq.) and Nal (0.1 eq.). The resulting mixture was heated at 50° C. for 1 hour. Filtration of the mixture and evaporation of the solvent in vacuo gave a crude product (411 mg). Flash column chromatography on silical gel with 1-2.5% methanol in methylene chloride afforded 3-[(4-(imidazol-1-yl)phenyl)amino]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine (110 mg), 1H NMR(CDCl3) 7.70 (s, 1), 7.10 (m, 4), 6.80 (s, 1), 6.70 (m, 2), 6.60 (d, 2), 5.90 (s, 2), 4.30 (m, 1), 3.60 (m, 1), 3.40 (AB q, 2), 2.70 (m, 1), 2.40 (m, 3), 1.50-1.80 (m, 4) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[CH:38]=2)=[O:36])[CH:30]=[CH:31][C:32]=1[CH3:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18]([NH:26][C:27]2[CH:28]=[C:29]([NH:34][C:35]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[CH:38]=3)=[O:36])[CH:30]=[CH:31][C:32]=2[CH3:33])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Reactant: COc1ccc(C(=O)O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 26, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-methoxybenzoic acid was reacted with N-(3-amino4-methylphenyl)-2-morpholinopyridine-4-carboxamide to give N-{3-[3-(1-tert-butoxycarbonylpiperidin-4-yloxy)4-methoxybenzamido]-4-methylphenyl}-2-morpholinopyridine-4-carboxamide; NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 1.72 (m, 2H), 1.85 (m, 2H), 2.21 (s, 3H), 3.15 (m, 2H), 3.5 (t, 4H), 3.76 (m, 6H), 3.83 (s, 1H), 4.41 (m, 1H), 6.84 (d, 1H), 6.87 (d, 1H), 7.01 (s, 1H), 7.16 (d, 1H), 7.37 (m, 1H), 7.44 (d, 1H), 7.57 (m, 2H), 8.03 (d, 1H), 8.21 (d, 1H), 9.8 (s, 1H), 10.22 (s, 1H); Mass Spectrum: M+H+ 646.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([N:20]=[C:21]([N:24]([CH3:33])[N:25]=CC1C=CC=CC=1)SC)#[N:19].[OH-].[Na+]>Cl>[CH3:33][N:24]1[C:21]([NH:17][CH2:16][CH2:15][CH2:14][O:13][N:11]2[CH:12]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=[N:10]2)=[N:20][C:18]([NH2:19])=[N:25]1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Reactant: NCCCOn1cc(CN2CCCCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(N)nc1NCCCOn1cc(CN2CCCCC2)cn1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
5 g of 3-(4-piperidinomethylpyrazol-1-yloxy)-propylamine and 4.9 g of methyl N-cyano-1-methyl-2-(phenylmethylene)-hydrazinecarboximidothioate are combined, and heated at 70° C. for 1 hour. Thereafter, the reaction mixture is taken up with 40 ml of 1N hydrochloric acid, stirred for 1 hour at room temperature, rendered alkaline with sodium hydroxide solution and extracted with methylene chloride. The residue which remains after the solvent has been expelled is chromatographed over neutral Al2O3 (activity level III), using methylene chloride/3% strength methanol as the mobile phase. The oily title compound is reacted with tartaric acid in isopropanol to give an amorphous solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:22]([NH:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)Nc1ccccc1
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
To a stirred suspension of glycine methyl ester hydrochloride (4.52 g, 36 mmol) in methylene chloride (200 mL) was added triethylamine (5.0 mL, 36 mmol) at room temperature and stirred for 15 minutes. To the reaction mixture was added dropwise phenyl isocyanate (3.57 g, 30 mmol). The reaction mixture was stirred at room temperature for 2 hours and washed with 1N HCl (2×80 mL) and brine (80 mL). The organic layer was dried (Na2SO4) and concentrated to give the ester compound (6.2 g, ˜100%). 1H NMR (400 MHz, DMSO-d6) δ: 8.80 (s, 1H), 7.39 (d, 2H), 7.22 (t, 2H), 6.89 (m, 1H), 6.45 (t, 1H), 3.88 (d, 2H), 3.66 (s, 3H).