Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[O:6]1CC[CH2:9][CH2:8][CH:7]1OCC#C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1.CCOCC>[OH:6][CH2:7][C:8]#[C:9][C:21]([C:20]1[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=1)=[O:22]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C#CCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)C#CCO)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
44.6 ml of n-butyllithium solution (1.6M in hexane) were added to a solution of 10.0 g (71.3 mmol) of 3-[(tetrahydro-2H-pyran-2-yl)oxy]1-propyne in 150 ml of absolute tetrahydrofuran at -78° . The reaction mixture was stirred at -40° for 30 minutes and then treated with 14.0 g (71.3 mmol) of 3,4,5-trimethoxybenzaldehyde in 50 ml of tetrahydrofuran. The reaction mixture was subsequently stirred at 0° for 1 hour and then treated with 100 ml of saturated ammonium chloride solution and 200 ml of ether. The aqueous phase was extracted twice with ether, whereupon the combined organic phases were dried over magnesium sulphate and the solvent was distilled off. The residue was dissolved in 150 ml of methylene chloride and added dropwise at 0° to a suspension of 186 g of manganese dioxide in 300 ml of methylene chloride. The reaction mixture was stirred at room temperature for 30 minutes, filtered over magnesium sulphate and evaporated. The residue was dissolved in 300 ml of tetrahydrofuran/ethanol (1:1) and treated with 2.4 g of pyridinium p-toluenesulphonate. The mixture was stirred at room temperature for 24 hours, 100 ml of water and 200 ml of ether were then added, the aqueous phase was extracted twice with ether, the combined organic phases were dried over magnesium sulphate and the solvent was distilled off. Crystallization from ethyl acetate/hexane yielded 4-hydroxy 1-(3,4,5 -trimethoxyphenyl)-2-butyn- 1-one of melting point 104°-105°.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([N+:20]([O-])=O)=[CH:19][C:12]=3[CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH3:25].C(OCC)(=O)C>[Pd].CO>[NH2:20][C:18]1[CH:17]=[CH:16][C:13]2[CH2:14][CH2:15][N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:23]=[CH:24][C:2]([NH2:1])=[C:3]([CH3:25])[CH:4]=3)[CH2:10][CH2:11][C:12]=2[CH:19]=1
Reactant: Cc1cc(OCCN2CCc3ccc([N+](=O)[O-])cc3CC2)ccc1N
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(OCCN2CCc3ccc(N)cc3CC2)ccc1N

Procedure:
3-[2-(4-Amino-3-methylphenoxy)ethyl]-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.5 g) was stirred at room temperature under a hydrogen atmosphere [344.7 kPa (50 p.s.i.)]in ethyl acetate (20 ml) and methanol (20 ml) containing 5% Pd/C (0.075 g) for 3 hours. The catalyst was then removed by filtration and the filtrate was evaporated in vacuo to give the title compound as an oil, yield 0.385 g, which was used directly without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:32])[CH3:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C[Si](Cl)(C)C>CCCCO>[N:24]1([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:2]3[N:3]=[C:4]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:23][CH:22]=2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1.[N:11]1([C:4]2[C:5]3[CH:10]=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:25][CH2:26][N:27]([C:30](=[O:32])[CH3:31])[CH2:28][CH2:29]4)=[CH:22][CH:23]=3)[N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Clc1nc(N2CCCCC2)c2cc[nH]c2n1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCCC4)c4cc[nH]c4n3)cc2)CC1
Product: c1cc2c(N3CCCCC3)nc(Nc3ccc(N4CCNCC4)cc3)nc2[nH]1

Procedure:
A mixture of 2-chloro-4-(piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (123 mg, 0.520 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (200 mg, 0.913 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in n-BuOH (5 mL) was stirred at 120° C. for 20 h. n-BuOH was removed in vacuo. The residue was purified by HPLC to give N-(4-(piperazin-1-yl)phenyl)-4-(piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (5 mg) (MS 378.5 (M+H)) and 1-(4-(4-(4-(piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (31 mg) (MS 420.5 (M+H); UV 205.8, 275.8 nm).
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[CH3:13][C:14]([CH3:24])([CH2:17][O:18][CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1)[CH:15]=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:13][C:14]([CH3:24])([C:15]#[CH:1])[CH2:17][O:18][CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C=O)COC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC(C)(C)COC1CCOC1
Yield: 69.3 %

Procedure:
(1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (418 mg, 2.17 mmol) was added to a stirred suspension of 2,2-dimethyl-3-(tetrahydro-furan-3-yloxy)-propionaldehyde (250 mg, 1.45 mmol) and K2CO3 (601 mg, 4.35 mmol) in methanol (17.0 mL) at room temperature. After overnight stirring the bulk of the methanol was removed by rotary evaporation and the reaction mixture partitioned between ethyl ether and NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to provide a crude liquid. Purification by flash column chromatography on silica gel using 30% ethyl acetate in hexanes followed by bulb to bulb distillation under reduced pressure provided 3-(2,2-dimethyl-but-3-ynyloxy)-tetrahydro-furan (169 mg, 69%) as a colorless liquid.
Reaction SMILES: [C:1](=O)([OH:3])[O-:2].[Na+:5].[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[Na+].[Na+].S([O-])([O-])(=O)=O.[NH4+:18].[NH4+].C(=O)(O)[O-].[NH4+]>[Cl-].[Na+].O>[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[Na+:5].[Na+:5].[C:1](=[O:3])=[O:2].[NH3:18]
Reactant: [NH4+]
Reactant: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N
Product: O=C=O

Procedure:
" . . . the brine remaining after screening off the solid sodium bicarbonate contains a mixture of unreacted sodium sulfate, ammonium sulfate, ammonium bicarbonate and minor amounts of sodium bicarbonate. This brine is transferred by a pump 36 into a gas recovery boiler 31 where it is heated to a temperature of 95° to 100° C. Under these conditions, the ammonium bicarbonate breaks down and sodium bicarbonate dissolved in the brine reacts with ammonium sulfate to produce sodium sulfate, carbon dioxide and ammonia. Carbon dioxide and ammonia dissolved in the brine boil off, leaving in the solution a mixture composed mostly of sodium and ammonium sulfate. The carbon dioxide and ammonia so regenerated are cooled in a gas cooler 32 and returned to the reactor 21 by a blower 33 after being further cooled in a gas cooler 34. This regeneration step minimizes the amount of carbon dioxide and ammonia used in the process."
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[N:14][N:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=3)=[O:18])[C:12](=[O:27])[CH:11]=2)=[N:6][CH:7]=1.S(Cl)([Cl:30])=O>C(Cl)Cl.C(OC)(C)(C)C>[Cl:30][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][N:13]2[C:12](=[O:27])[CH:11]=[C:10]([O:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[CH:15]=[N:14]2)=[CH:20][CH:21]=1
Reactant: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 400 mg (1.08 mmol) 5-(5-fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 19c) in 10 mL DCM is added 0.12 mL (1.62 mmol) thionylchloride at 0° C. The reaction mixture is stirred 2 h at RT and diluted with tert-butylmethylether. The precipitate is collected and dried.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:15]([C:16]2[CH:20]=[CH:19][O:18][C:17]=2[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:14][CH:13]=[C:12]([NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([NH:5][C:6]1[C:15]([C:16]2[CH:20]=[CH:19][O:18][C:17]=2[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:14][CH:13]=[C:12]([NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.09 mL) was added to a stirred solution of methyl 2-amino-3-[2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl]-6-(2,2-dimethylpropionylamino)-benzoate (Intermediate 35, 0.47 g) in DCM (5 mL) and pyridine (0.16 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM and washed with water and brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 20-50% to give methyl 2-acetylamino-3-[2-(tert-butyldimethylsilanyloxymethyl)-furan-3-yl]-6-(2,2-dimethylpropionylamino)benzoate (0.442 g) as a colourless foam.
Reaction SMILES: [Cl:1][C:2]([CH3:8])([CH3:7])[CH:3]([N:5]=[O:6])[CH3:4].[NH3:9]>CO>[ClH:1].[NH2:9][C:2]([CH3:8])([CH3:7])[C:3](=[N:5][OH:6])[CH3:4]
Reactant: CC(N=O)C(C)(C)Cl
Reactant: N
Solvent: CO
Product: CC(=NO)C(C)(C)N
Product: Cl
Reaction time: 5 h

Procedure:
3-Chloro-3-methyl-2-nitrosobutane (60 g.) was added portionwise to dry methanol (600 ml.) saturated with ammonia at 0°. The solution was left at room temperature for 5 hours then refluxed for 16 hours in the presence of a stream of dry ammonia. The mixture was evaporated to dryness in vacuo at room temperature and the residue extracted with hot dry benzene (900 ml.) followed by boiling secondary butanol (1300 ml.). The secondary butanol extract was evaporated in vacuo at room temperature to a thick slurry. This was cooled, filtered and dried in vacuo (56 g.) m.p. 190° (decomp).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[I:21]I>O1CCCC1>[I:21][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[NH:8][CH:9]=1
Reactant: II
Reactant: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Solvent: C1CCOC1
Product: Cc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.6 %

Procedure:
To a solution of 5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6, 1 g, 2.0 mmol) in 10 mL of tetrahydrofuran, iodine (0.43 g, 1.7 mmol) in 5 mL of tetrahydrofuran is added. The reaction is stirred at room temperature overnight, then quenched with 20 mL of 1M aqueous sodium thiosulfate and extracted with ethyl acetate. The organic layers are combined and washed with water and brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexanes. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a white solid (7, 20 mg). MS (ESI) [M+H+]+=258.70.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][NH2:13].[N:14]1([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:12][N:13]1[C:4](=[O:6])[C:3]2[C:2](=[CH:10][C:9]([CH3:11])=[CH:8][CH:7]=2)[N:1]=[C:28]1[C:27]1[CH:30]=[CH:31][C:24]([O:23][CH2:22][CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(C(=O)O)c(N)c1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: CN
Product: Cc1ccc2c(=O)n(C)c(-c3ccc(OCCCN4CCCCC4)cc3)nc2c1

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-4-methylbenzoic acid, methylamine and 4-(3-piperidin-1-ylpropoxy)benzaldehyde.
Reaction SMILES: C(C1OC1)Br.[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O.[K].[CH3:13][O:14][CH2:15][CH2:16][O:17]C>>[O:14]1[CH:13]2[CH:15]1[C:16](=[O:17])[N:6]([CH2:7][CH2:8][CH3:9])[CH2:10]2
Reactant: O=C1CCCN1
Reactant: COCCOC
Agent: BrCC1CO1
Agent: [K]
Product: CCCN1CC2OC2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 5 liter flask equipped with a stirrer, condenser, thermometer and dropping funnel was charged 604 g. (4.28 moles) epibromohydrin and 2150 ml. of ethyleneglycol dimethylether. To this solution was added, over a half hour period, 263.5 g. (2.14 moles) potassium pyrrolidone. The mixture was stirred 48 hours at 25° C. Potassium bromide was removed by filtration and the product distilled. The fraction boiling at 87° to 100° at 0.07 to 0.1 mm Hg was collected as 201.8 g. of product (67% of Theory) having a purity of 93% analyzed by gas chromatography. The reaction of this example can be described by the equation: ##STR36##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=2)[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1ccc(COc2cccc(C(=O)OC)c2N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)cc1
Yield: 86.9 %

Procedure:
In the same manner as described in Example 38, 0.275 g (0.644 mmol) of the product of Example 37 and 0.295 g (1.288 mmol) of methyl 4-(bromomethyl)benzoate provided 0.322 g (87%) of the desired product as a white solid. Electrospray Mass Spec: 576.2 (M+H)+
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH3:14])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][CH2:18][CH2:19][NH2:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH3:14])=[C:8]([NH:20][CH2:19][CH2:18][CH2:17][OH:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCCO
Reactant: CCCc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCc1c(NCCCO)cnn(C(C)(C)C)c1=O
Reaction time: 12.5 h

Procedure:
A mixture comprising 14.0 g of 2-t-butyl-4-n-propyl-5-chloro-3(2H)pyridazinone, 44 g of 3-hydroxypropylamine and 14.8 g of anhydrous potassium carbonate, was stirred at a temperature of from 145° to 155° C. for 12.5 hours. The reaction solution was returned to room temperature, and about 200 ml of cold water was added. The mixture was stirred. The precipitated white crystals were collected by filtration, and dried to obtain 12.1 g of the above identified compound having a melting point of from 167° to 169° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:13][Mg]Br>C(OCC)C>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]([OH:6])[CH3:13]
Reactant: C[Mg]Br
Reactant: COc1cccc(C=O)c1OC
Solvent: CCOCC
Product: COc1cccc(C(C)O)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 2,3-dimethoxybenzaldehyde (10.0 g, 60.2 mmol) in dry ethyl ether (100 ml) was added at 0° C. with a 3M solution of methylmagnesium bromide in ethyl ether (35 ml) and left under stirring at 0° C. for 0.5 h. Afterwards the reaction mixture was added with a diphasic mixture of ethyl ether and an ammonium chloride saturated solution, extracting the aqueous phase with ethyl ether. The organic extracts were dried and the solvent was evaporated off under reduced pressure, thereby obtaining 10.06 g of the title compound (92% yield).
Reaction SMILES: [CH3:1][C@H: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[N:33]([CH2:34][C@H:35]2[CH2:40][CH2:39][C@H:38]([CH3:41])[CH2:37][CH2:36]2)[C:19]2[C:20]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Cl:32])[CH:31]=3)=[N:21][C:22]([C:24]#[N:25])=[CH:23][C:18]=2[N:17]=1.[F-].[K+].CCN(C(C)C)C(C)C>CCOC(C)=O.CS(C)=O>[Cl:32][C:30]1[CH:31]=[C:26]([C:20]2[C:19]3[N:33]([CH2:34][C@H:35]4[CH2:40][CH2:39][C@H:38]([CH3:41])[CH2:37][CH2:36]4)[C:16]([N:7]4[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@H:2]4[CH3:1])=[N:17][C:18]=3[CH:23]=[C:22]([C:24]#[N:25])[N:21]=2)[CH:27]=[N:28][CH:29]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [F-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 100 °C

Procedure:
To a microwave vial was added (R)-tert-butyl 3-methylpiperazine-1-carboxylate (purchased from Astatech) (180 mg, 0.899 mmol), 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (200 mg, 0.450 mmol, Preparative Example 3.1), potassium fluoride (78 mg, 1.349 mmol), DMSO (1 ml) and DIEA (0.236 ml, 1.349 mmol). The reaction vial was capped and heated to 100° C. overnight. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water and brine, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane to give (R)-tert-butyl 4-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-methylpiperazine-1-carboxylate. MS ESI calc'd. for C30H38ClN7O2 [M+H]+ 564. found 564.
Reaction SMILES: [CH:1]([C:5]1[C:6]([OH:24])=[C:7]([CH:10]=[C:11]([CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:16])[CH:12]=1)C=O)([CH2:3][CH3:4])[CH3:2].[CH:25](C1C(O)=C(C=C(/C=C/C(=O)C2C=CC(C)=CC=2)C=1)C=O)(CC)C.[C:49]([O:57][CH2:58]C)(=[O:56])[CH2:50][C:51]([O:53]CC)=O.N1C=CC=CC=1>O1CCCC1>[CH:1]([C:5]1[CH:12]=[C:11]([CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:16])[CH:10]=[C:7]2[C:6]=1[O:24][C:51](=[O:53])[C:50]([C:49]([O:57][CH3:58])=[O:56])=[CH:25]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc(C=O)c1O
Reactant: CCC(C)c1cc(C=CC(=O)c2ccc(Cl)cc2)cc(C=O)c1O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC(C)c1cc(C=CC(=O)c2ccc(Cl)cc2)cc2cc(C(=O)OC)c(=O)oc12

Procedure:
A solution of 3-sec-butyl-5-(3-(4-chlorophenyl)-3-oxoprop-1-enyl)-2-hydroxybenzaldehyde of formula III (0.5 g, 1.46 mmol), diethyl malonate (0.23 g, 1.46 mmol) in tetrahydrofuran (20 mL) was treated with pyridine (0.4 mL) and refluxed. Most of the excess solvent was evaporated under reduced pressure, and the residue was neutralized with dilute HCl (2 N). To this residue water (30 mL) was added and extracted 3-fold with 25 mL of CHCl3. The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides ethyl 8-sec-butyl-6-(3-(4-chlorophenyl)-3-oxoprop-1-enyl)-2-oxo-2H-chromene-carboxylate (General Formula IV). (0.51 g, 81% yield). White solid, m. p. 119-120° C.; 1H NMR (CDCl3, 300 MHz): δ 8.55 (s, 1H), 7.99 (d, 2H, J=8.6 Hz), 7.84-7.73 (m, 3H), 7.54-7.47 (m, 3H), 4.43 (q, 2H, J=7.1 Hz), 3.45-3.35 (m, 1H), 1.78-1.69 (m, 2H), 1.41 (t, 3H, J=7.1 Hz), 1.32 (d, 3H, J=7.0 Hz), 0.89 (t, 3H, J=7.3 Hz)); 13C NMR (CDCl3, 75 MHz): δ 188.6, 163.9, 156.2, 154.0, 148.5, 143.2, 139.5, 136.8, 136.3, 131.5, 131.4, 130.0, 129.1, 127.3, 122.3, 118.8, 118.2, 62.1, 33.5, 29.7, 20.4, 14.3, 12.0; ESI-MS (m/z): 439 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][C:7]([NH:10][C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])[CH3:8].O=[C:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH2:30]([O:29][C:27]([C:26]1[C:25]([CH3:32])=[N:1][C:2]2[C:3]([C:22]=1[NH2:23])=[C:4]([O:5][CH2:6][C:7]([NH:10][C:11]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:12])([CH3:8])[CH3:9])[CH:19]=[CH:20][CH:21]=2)=[O:28])[CH3:31]
Reactant: CC(C)(COc1cccc(N)c1C#N)NC(=O)C1CCCCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from N-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)cyclohexanecarboxamide (Example 37b) and ethyl 3-oxobutanoate as a bright yellow solid (55%). MS 428 (MH+).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[F:6][C:7]([F:25])([F:24])[C:8]([N:10]([CH2:17][P:18]([O:22]Cl)([O:20]Cl)=[O:19])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9]>CCOCC>[F:6][C:7]([F:25])([F:24])[C:8]([N:10]([CH2:17][P:18]([OH:22])([O:20][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:19])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9]
Reactant: CCCCN
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCOCC
Product: CCCCN(CCCC)OP(=O)(O)CN(CC(=O)OCC)C(=O)C(F)(F)F
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a solution o n-butylamine (3.1 g, 0.0423 mole) in 40 ml. of ether was added dropwise with stirring ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (3.3 g, 0.01 mole) in 50 ml. of ether. The reaction mixture was stirred for 21/2 hours, then filtered and the filtrate was concentrated in vacuo to give a light yellow viscous oil. This oil was dissolved in petroleum ether, washed three times with water, dried over MgSO4, and concentrated in vacuo to give 3.3 g of ethyl N-trifluoroacetyl-N-(dibutylaminophosphonomethyl)glycinate, ND =1.4429.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=O)[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.Cl.Cl.[NH2:28][OH:29].[OH-].[Na+].O>CO>[N:28](=[C:20]1[CH2:22][CH2:23][C@:9]2([OH:24])[C@:10]34[CH2:11][CH2:12][N:13]([CH2:14][CH:15]5[CH2:17][CH2:16]5)[C@@H:8]2[CH2:7][C:6]2[CH:1]=[CH:2][C:3]([OH:25])=[C:4]([O:19][C@@H:18]13)[C:5]4=2)[OH:29]
Reactant: NO
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: ON=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reaction time: 15 h

Procedure:
A mixture of naltrexone hydrochloride (1.34 g, 3 mmol) and hydroxylamine hydrochloride (0.28 g, 4 mmol) was dissolved in 20 mL of MeOH and 2.8 mL of aqueous NaOH added. The mixture was stirred for 15 h. Water was added (100 mL) and the mixture extracted with 150 mL CHCl3 (3×50 mL). The combined extracts were dried (MgSO4) and evaporated. The residue obtained was chromatographed on a column of silica gel (approx. size 40 microns) using ethyl acetate-ethanol-NH4OH (300:1.5:2) as eluent. The combined fractions were evaporated and the residue recrystallized from CH2Cl2 -petroleum ether. Yield: 0.54 g (50.5%) mp 235-236° C. IR (KBr): No C=O absorption at 1720 cm-1. 1H NMR (CDCl3) δ6.7 (2d, 2H, J=10 Hz) 5 (s,C5H); Rf: silica gel 60 in ethylacetate-EtOH-NH4OH (100:1:1) 0.22. Anal. Calcd for C20H24N2O4 : C, 67.40; H, 6.79; N, 7.86. Found: C, 67.12; H, 6.88; N, 7.63.