Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])=[N:11]1.[CH3:40][OH:41].[OH2:42]>C(#N)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])[N:11]1[C:40]([O:42][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:41]
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Reactant: CO
Reactant: O
Solvent: CC#N
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)n2C(=O)Oc2ccccc2)c1

Procedure:
A solution of 30.7 g (0.05 mole) of 1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-myristoylamino-anilino)-2-pyrazolin-5-one and 15.6 g (0.1 mole) of phenyl chloroformiate in 100 ml of acetonitrile are refluxed for 4 h. The solution is poured out in water and the separated oil is stirred first with water and next with methanol. The precipitate is recrystallized from ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCI
Reactant: O=C1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1ccc2c(c1)CCC2=O
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of 5-hydroxy-1-indanone (1.00 g, 6.74 mmol), 1-iodooctane (1.34 mL, 7.42 mmol) and potassium carbonate (1.40 g, 10.12 mmol) were stirred together in acetonitrile at 80° C. After 3 h, the reaction was cooled, placed onto silica gel and eluted with 15% ethyl acetate/hexane to give 1.14 g of a white solid: 1H NMR (500 MHz, CDCl3): δ 7.67 (d, J=9.2 Hz, 1H), 6.88–6.90 (m, 2H), 4.03 (t, J=6.55 Hz, 2H), 3.08 (t, J=5.9 Hz, 2H), 2.67 (t, J=6.0 Hz, 2H), 1.80 (m, 2H), 1.42–1.50 (m, 2H), 1.24–1.38 (m, 8H), 0.89 (t, J=7.0 Hz, 3H); ESI-MS 261.1 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[CH2:22]([Br:25])[CH:23]=[CH2:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:24]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1)[CH:23]=[CH2:22].[Br:25][CH2:22][C:23]1[CH:6]=[CH:7][C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:24]=1
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCc1ccc2ccccc2c1
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
In an analogous manner to that described in Example 44 (e), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46 (b)] with allyl bromide in the presence of potassium carbonate in acetone there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate, alkylation of which with 2-bromomethylnaphthalene in analogy to Example 1 (g) gave tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless resin; MS: 474 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([O:13][C:12]([NH:11][C@H:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:12]([O:13][CH3:14])=[O:18])[CH:10]=2)[CH2:6][CH2:7]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Yield: 76 %

Procedure:
(R)-tert-Butyl 6-bromo-2,3-dihydro-1H-inden-1-ylcarbamate (15.0 g, 48.07 mmol, 1 eq) was dissolved in a mixture of methanol (200 ml) and DMSO (30 ml) and degassed for 30 min with argon, and palladium acetate (0.53 g, 2.40 mmol, 0.05 eq), 1,3-bis(diphenylphosphine)-propane (0.99 g, 2.40 mmol, 0.05 eq) and triethylamine (20 ml, 144.21 mmol, 3.0 eq) were added. In an autoclave, the reaction was sealed for 16 h at 75° C. at CO pressure (80 psi). Then the reaction mixture was dried under reduced pressure, and the residue was taken up in water (150 ml) and extracted with ethyl acetate (2×300 ml). The combined organic phases were washed with sat. NaCl solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 5% ethyl acetate in hexane) to give the desired product in the form of a white solid. Yield: 76% (10.6 g, 36.43 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[C:32]([N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH2:11][CH2:12]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(C(=O)c2ccccc2)CC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichloro-phenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and benzoyl chloride (0.038 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give N-(1-benzoylpiperidin-4-yl)-2-(2,4-dichlorophenoxy)benzamide (103 mg, 80%) as a white solid, mp 63-66° C. Rf: 0.15 (hexane/AcOEt 4:6) LC/MS (APCI) tr=4.94 min, m/z 471.32 (65), 469.31 (M++H, 100). HPLC tr=2.35 min (98.01%) 1H NMR (270 MHz, CDCl3) δ 1.35 (2H, m, CH2), 1.55 (2H, m, CH2), 1.76 (6H, m, 3CH2), 2.00 (2H, m, CH2), 2.87 (2H, m, CH2), 3.17 (1H, m, ½CH2), 3.87 (1H, br t, ½CH2), 4.19 (1H, m, CH), 4.43 (1H, m, ½CH2) 6.79 (1H, d, J=8.6 Hz, ArH), 7.21 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.25 (1H, m ArH), 7.35 (1H, br d, NH), 7.50 (1H, d, J=2.5 Hz, ArH) and 8.17 (1H, dd, J=7.9, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 23.81, 29.36, 32.26, 33.17 (CH2), 39.60 (CH), 40.78 (CH2), 43.70 (CH), 47.79 (CH2), 118.00, 120.65, 124.43, 124.88, 126.21, 128.57, 130.85, 130.87, 132.74, 133.06, 148.97, 153.09 (ArC), 163.63 and 174.71 (C═O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[O:19][CH3:20].C(=O)([O-])[O-:22].[Cs+].[Cs+].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:11]1[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:22])=[CH:13][C:12]=1[O:19][CH3:20]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C#N)ccc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Cs+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 120 °C

Procedure:
A mixture of 3,4-dichlorophenol (539 mg, 3.31 mmol), 4-fluoro-3-methoxybenzonitrile (500 mg, 3.31 mmol) and cesium carbonate (2.16 g, 6.62 mmol) in DMSO (5 mL) was heated to 120° C. for 18 hours. The reaction was cooled before the addition of 1N NaOH. The reaction was extracted with ethyl acetate and the organic layer separated and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-20% EtOAc in heptane to furnish the title compound as a white solid, 142 mg, 14%.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20]1>CC(O)C>[CH2:1]([N:8]([CH2:20][CH:21]([OH:19])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Oc1ccc(OCCNCc2ccccc2)cc1
Solvent: CC(C)O
Product: Oc1ccc(OCCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1

Procedure:
A mixture of N-benzyl-2-(p-hydroxyphenoxy)ethylamine (2.5 g) and 1,2-epoxy-3-phenoxypropane (1.54 g) in propan-2-ol (50 ml) was heated under reflux for 72 hours. The solvent was removed by evaporation to give N-benzyl-N-(2-p-hydroxyphenoxyethyl)-2-hydroxy-3-phenoxypropylamine as an oil which was essentially pure as indicated by thin layer chromatography (TLC) [using silica plates and 5% methanol in dichloromethane as eluant] and was used without purification.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([O:21]CC)=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)(=O)C.O>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reaction time: 4 h
Yield: 68 %

Procedure:
Ethyl [2-(1-cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetate (2.5 g) was dissolved in acetic acid (35 ml) and to the solution was added 50% sulfulic acid (30 ml). The mixture was relfuxed for 4 hours. The reaction mixture was diluted with water and crystals deposited were filtered off and recrystallized from the mixed solvent of ethyl acetate and methanol to obtain the title compound, yield 68%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.Cl[C:10]1[C:11]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:12][C:13]2[N:14]([C:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])=[N:17][N:18]=2)[N:15]=1.[H-].[Na+]>CN(C=O)C.O>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[C:16]1[N:14]2[N:15]=[C:10]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[CH:4][N:5]=3)[C:11]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:12][C:13]2=[N:18][N:17]=1
Reactant: CC(C)(C)c1cc2nnc(-c3cc(F)ccc3F)n2nc1Cl
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nn2c(-c3cc(F)ccc3F)nnc2cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.1 %

Procedure:
To a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.069 g, 0.4 mmol) and 6-chloro-3-(2,5-difluorophenyl)-7-(1,1-dimethylethyl)-1,2,4-triazolo[4,3-b]pyridazine (0.10 g, 0.31 mmol) in DMF (10 ml) was added sodium hydride (0.015 g of a 60% dispersion in oil, 1.2 mol eq.) and the reaction mixture was stirred at room temperature for 40 minutes. After this time the reaction mixture was diluted with water (80 ml) and the solid that precipitated was collected by filtration and washed several times with water in the sinter funnel. The solid was recrystallised from ethyl acetate/hexane to give pure title compound (0.088 g, 65%). Data for the title compound: 1H NMR (360 MHz, CDCl3) δ1.41 (9H, s), 3.89 (3H, s), 5.54 (2H, s), 7.23-7.26 (2H, m), 7.64 (1H, m), 7.91 (1H, s), 8.00 (1H, s); MS (ES+) m/e 400 [MH]+. Anal. Found C, 57.36; H, 4.61; N, 24.60%. C19H19F2N7O requires C, 57.14; H, 4.79; N, 24.55%.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:24][N:23]=3)[O:19][N:18]=2)[CH:14]=[C:13]([CH3:33])[C:4]=1[O:5][CH2:6][CH2:7]OS(C)(=O)=O)[CH3:2].C[O:35][C:36]([CH:38]1[CH2:41][NH:40][CH2:39]1)=[O:37].C(N(CC)CC)C.Cl>C(O)C.[OH-].[Na+]>[CH2:1]([C:3]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([CH2:29][CH:30]([CH3:31])[CH3:32])=[CH:24][N:23]=3)[O:19][N:18]=2)[CH:14]=[C:13]([CH3:33])[C:4]=1[O:5][CH2:6][CH2:7][N:40]1[CH2:41][CH:38]([C:36]([OH:35])=[O:37])[CH2:39]1)[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCOS(C)(=O)=O
Reactant: COC(=O)C1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19305.2 %

Procedure:
A solution of methanesulfonic acid 2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-ethyl ester (300 mg, 633 μmol), azetidine-3-carboxylic acid methyl ester (218 mg, 1.84 μmol) and triethylamine (129 mg, 1.26 mmol) in ethanol (10 mL) is stirred in a sealed vial at 80° C. for 96 h. The mixture is cooled to rt, diluted with 3 M aq. NaOH and again stirred at rt for 1 h. The mixture is acidified by adding aq. HCl and is then extracted with EA (2×25 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (170 mg) as a colourless oil; LC-MS: tR=0.90 min, [M+H]+=479.10; 1H NMR (CDCl3): δ0.98 (d, J=6.5 Hz, 6H), 1.282 (t, J=7.0 Hz, 3H), 1.93 (hept, J=7.0 Hz, 1H), 2.38 (s, 3H), 2.45 (s, 3H), 2.61 (d, J=7.3 Hz, 2H), 2.73 (q, J=7.3 Hz, 2H), 3.71-3.82 (m, 2H), 3.97-4.08 (m, 1H), 4.19-4.27 (m, 2H), 4.37-4.62 (m, 2H), 4.73-4.97 (m, 2H), 7.87 (s, 1H), 7.89 (s, 1H), 8.07 (s, 1H), 8.53 (s, 1H).
Reaction SMILES: Br[C:2]1[C:12]([CH3:13])=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.ClC1C=CC(C(F)(F)F)=CC=1OC1[CH:19]=[CH:20][C:21]([N+:24]([O-])=O)=[N:22][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOC[CH2:44]1.C(#N)C.O>>[F:9][C:7]1([F:10])[O:8][C:4]2[CH:3]=[C:2]([CH3:44])[C:12]([C:13]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:11][C:5]=2[O:6]1
Reactant: Cc1cc2c(cc1Br)OC(F)(F)O2
Reactant: C1COCCO1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(C(F)(F)F)ccc2Cl)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(cc1-c1ccc(N)nc1)OC(F)(F)O2
Temperature: 90 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
Palladium tetrakis-triphenylphosphine (58 mg, 43 μmol) was added to a degassed solution of bromide 2 (250 mg, 1.0 mmol) and boronate 3 (274 mg, 1.25 mmol) in dioxane:acetonitrile:water (9:9:2, 5 mL) and potassium phosphate (317 mg, 1.5 mmol). The resulting mixture was heated under argon at 90° C. with stirring for 14 hours. The mixture was then cooled, extracted with dichloromethane (3×50 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 4 (236 mg, 90%) as an crystalline solid: LRESIMS m/z 265.2 [M+H]+, calcd. for C13H11F2 N2O2 265.1.
Reaction SMILES: [CH2:1]([N:7]1[C:12]2=[N:13][C:14]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:16]=[C:11]2[CH2:10][CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(=O)([O-])O.[K+].[Br:36][C:37](Br)=[N:38][OH:39]>CCOC(C)=O>[Br:36][C:37]1[CH2:6][CH:5]([CH2:4][CH2:3][CH2:2][CH2:1][N:7]2[C:12]3=[N:13][C:14]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=4)[N:16]=[C:11]3[CH2:10][CH2:9][CH2:8]2)[O:39][N:38]=1
Reactant: ON=C(Br)Br
Reactant: C=CCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCC2CC(Br)=NO2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising 5-(hex-5-enyl)-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate H) (3.98 g, 10 mmol) and potassium hydrogen carbonate (5.01 g, 50.0 mmol) in EtOAc (50 ml) was treated dropwise with dibromoformaldoxime (6.08 g, 30.0 mmol) in EtOAc (50 ml) over 2 hours. The mixture was stirred at room temperature overnight and then filtered. The filtrate was washed with 1H HCl, water, brine and dried by passing through a phase separator. The solvent was removed under reduced pressure to afford the titled compound which was used without further purification.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])(OCC1C=CC=CC=1)OCC1C=CC=CC=1>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Oc1cccc2ccccc12
Agent: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 195 °C
Yield: 85 %

Procedure:
288 parts of α-naphthol, 205 parts of aniline and 10 parts of dibenzyl phosphite are mixed and heated to 195° C. The elimination of water commences at this temperature and has ended when the internal temperature is 235° C. 33 parts of water are removed in the course of 4 hours. After distilling off excess α-naphthol and aniline, 374 parts of phenyl-α-naphthylamine, boiling at 202° - 204° C/5 mm Hg, are obtained; the product has a melting point of 55° - 58° C and corresponds to a yield of 85% of theory.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:16]=[C:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:31][NH2:32].[CH2:33](O)[CH3:34]>>[Cl:23][C:19]1[CH:18]=[C:17]([C:15]2[CH:16]=[C:4]3[N:3]=[C:2]([NH:31][N:32]=[CH:22][C:17]4[CH:15]=[CH:16][CH:4]=[C:33]([CH3:34])[CH:18]=4)[CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]3[N:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: NN
Reactant: Clc1cccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)c1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4cccc(Cl)c4)cc3n2)c1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
There was suspended, in ethanol (2 mL), 5-chloro-2-(3-chloro-phenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (50.5 mg, 0.145 mM) and then potassium carbonate (22.0 mg, 0.160 mM) and hydrazine monohydrate (35.2 μL, 0.725 mM) were added to the suspension. This suspension was stirred at 150° C. for 20 minutes under the irradiation with microwaves. This reaction liquid was diluted with a saturated aqueous common salt solution and then extracted with ethyl acetate. The extracts thus obtained were combined together and dried over anhydrous sodium sulfate and then the solvent was distilled off. The resulting residue was suspended in ethanol (2 mL), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (17.1 μL, 0.145 mM) were added to the suspension and the mixture was stirred at room temperature for one hour. This reaction mixture was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to give the title compound (42.8 mg, overall yield of these two steps: 66%).
Reaction SMILES: [CH3:1][C@@:2]([OH:34])([C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:3]1[C@:8]2([O:28][CH3:29])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.[C:35]([OH:52])(=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>CN1C(=O)CCC1>[CH3:1][C@@:2]([OH:34])([C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:3]1[C@:8]2([O:28][CH3:29])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.[C:35]([O-:52])(=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
10 grams of the lower molecular weight copolymer described in Example 2 was dissolved in 10.1 grams of NMP to give a solution with 50% w/w copolymer and 50% w/w NMP. To this solution was added 0.2085 grams of buprenorphine base. The white powdered base was thoroughly mixed and particles crushed until a clear solution was obtained. Then 0.4170 grams of palmitic acid was added to the polymer/drug/NMP solution to complex with the buprenorphine base to form buprenorphine palmitate. The white flaky palmitic acid was crushed and thoroughly mixed until a clear solution was obtained. The resultant solution was then filtered through a 0.20 μm Teflon filter as described in Example 8 to produce a sterile solution with 1% w/w buprenorphine and 2% w/w palmitic acid. The sterile solution was stored in a glass ampule with a rubber cap until needed.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]#[N:10])[N:3]=1.CS(C)=O.C(N(C(C)C)CC)(C)C.[CH3:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1>C(OCC)(=O)C>[C:9]([C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:25]([CH3:24])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[N:5]=1)#[N:10]
Reactant: N#Cc1nc(N)nc(Cl)n1
Reactant: CNc1cccc(C)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cccc(N(C)c2nc(N)nc(C#N)n2)c1

Procedure:
To 2-amino-4-chloro-6-cyano-[1,3,5]triazine (Prepared in an analogous way to Intermediate 3, 46 mg, 296 μmol) was added 1 mL anhydrous DMSO, diisopropylethylamine (77 μL, 444 μmol) and N-methyl-m-toluidine (40 mg, 326 μmol). The mixture was heated at 90 C for 2 h, allowed to cool and diluted with 10 mL ethyl acetate. The mixture was then extracted with water (10 mL), 0.5 M HCl (3×10 mL), water (10 mL) and saturated brine (10 mL). The organic layer was dried further over anhydrous sodium sulfate and evaporated to give the desired product which was used directly without further purification or characterization (42 mg, 59%).
Reaction SMILES: CN(C)[CH:3]=[O:4].[NH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH2:17])=[C:12]([Cl:18])[CH:11]=1)[OH:9].[C:19]1([CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C.CO.C(N(CC)CC)C>[C:19]1([CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32][NH:6][CH2:7][CH:8]([C:10]2[CH:11]=[C:12]([Cl:18])[C:13]([NH2:17])=[C:14]([Cl:16])[CH:15]=2)[OH:9])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:3]([O-:4])(=[O:9])/[CH:31]=[CH:30]\[C:29]([O-:28])=[O:34]
Reactant: O=C(CCCBr)OCCCc1ccccc1
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc(C(O)CNCCCC(=O)OCCCc2ccccc2)cc1Cl
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
According to method I (dimethylformamide, 2 hours at 90° C.) from 2-amino-1-(4-amino-3,5-dichlorophenyl)ethanol and (3-phenylpropyl)-4-bromobutanoate. Working up by means of chromatography (ethyl acetate/methanol/triethylamine 20:2:1). Recrystallized as the maleate from acetone. Melting point: 70°-71° C.