Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=[C:6]2[CH:5]=1)(=O)[NH2:2].C(Cl)Cl.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][N:7]2[CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=[C:6]2[CH:5]=1)#[N:2]
Reactant: COC(=O)c1cn2ccc(C(N)=O)cc2n1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1cn2ccc(C#N)cc2n1
Temperature: 0 °C
Yield: 29.1 %

Procedure:
To a suspension of methyl 7-carbamoylimidazo[1,2-a]-pyridine-2-carboxylate (1.5 g), methylene chloride (30 ml) and pyridine (2.7 g) was dropwise added trifluoroacetic anhydride (3.6 g) over the period of 5 minutes under cooling with stirring, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was poured into ice water (30 ml) and extracted with 5% solution of methanol in chloroform. The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to a column chromatography on silica gel (50 g) and eluted with 20% solution of methanol in chloroform. The fractions containing the object compound were combined and concentrated to give methyl 7-cyanoimidazo[1,2-a]pyridine-2-carboxylate (0.4 g).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[N:14][N:15]2[CH:19]=[N:18][NH:17][C:16]2=[O:20])[CH:8]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([N:17]1[C:16](=[O:20])[N:15]([N:14]=[CH:13][C:9]2[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=2)[CH:19]=[N:18]1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: O=c1[nH]ncn1N=Cc1cccnc1
Solvent: c1ccncc1
Product: CN(C)C(=O)n1ncn(N=Cc2cccnc2)c1=O
Reaction time: 14 h

Procedure:
3.2 g of dimethylcarbamoyl chloride are added to a suspension of 3.8 g of 4-(pyridin-3-ylmethyleneamino)-1,2,4-triazol-3-one in 50 ml of pyridine. The resulting solution is stirred for 14 hours at 20° and then concentrated by evaporation. Water is added to the residue. The crystals that have precipitated are filtered off with suction and dried under a high vacuum. 3.6 g of crystals of the title compound having a melting point of 181°-182° are obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)=[N:9][C:10]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH:2]([CH3:4])[CH3:3].[O:33]1CCC[CH2:34]1.CN(CCS(O)(=O)=O)C.[OH-].[Na+]>C(Cl)Cl>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([CH:34]=[O:33])[CH2:16][CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)=[CH:27][N:28]=1
Reactant: C1CCOC1
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: CN(C)CCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)Cn1c(N2CCN(C=O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 1.25 h
Yield: 75 %

Procedure:
5-[9-(Isobutyl)-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl]pyrimidin-2-amine (129.8 mg, 0.30 mmol) was added to a tetrahydrofuran solution (7.0 ml) of 1H-benzotriazole-1-carboxyaldehyde (48.4 mg, 0.30 mmol) at room temperature and the resulting mixture was stirred for 75 minutes. Methylene chloride was added to the reaction mixture and the resulting mixture was poured into 2 N aqueous sodium hydroxide solution and extracted with methylene chloride-methanol (10:1). The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=49:1 to 32:1) to give the title compound (103.4 mg, 75%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([F:20])([F:19])[CH2:17]I.O>CS(C)=O>[F:15][C:16]([F:20])([F:19])[CH2:17][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Oc1ccccc1O
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccccc1OCC(F)(F)F
Temperature: 120 °C
Reaction time: 6 h
Yield: 90.5 %

Procedure:
To a solution of catechol (5 g, 0.045 moles) in dimethylsulfoxide (25 ml) were added, potassium carbonate (12.55 g, 0.09 mole) and 2,2,2-trifluoroethyl iodide (4.77 g, 0.023 mole) under stirring. The reaction mixture was stirred vigorously at 120° C. for 6 hours. Water (150 ml) was added to the reaction mixture and the mixture was extracted in Toluene (250 ml). Organic layer was washed with 1 N Sodium hydroxide solution (150 ml), followed by brine wash. The extract was dried over sodium sulphate. The solvent was evaporated under reduced pressure to give 4.0 g of (XI) as oil. Purity (by GC)=96%
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=1.[F:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1N1CCOCC1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1F

Procedure:
A solution of 2,4-difluoronitrobenzene (10.0 mL) and morpholine (17.4 mL) in THF (100 mL) was stirred at RT under N2 for 2 h. The solvent was removed and the residue was partitioned between EtOAc and water. The organic layer was washed brine, dried over MgSO4, and concentrated. The resulting solid was purified by chromatography on silica gel with 20-50% EtOAc in hexane to give 18.1 g of 4-fluoro-2-morpholinonitrobenzene and 1.81 g of 2-fluoro-4-morpholinonitrobenzene. ESI mass spectrum z (rel. intensity) 227.1 (M+H, 100).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5](=[O:8])(=[O:7])[N:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:3]1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:13]([C:12]4[CH:11]=[CH:10][C:9]([N:4]5[CH2:3][CH:2]([CH3:1])[CH2:6][S:5]5(=[O:7])=[O:8])=[CH:17][CH:16]=4)=[O:15])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CC1CN(c2ccc(C(=O)O)cc2)S(=O)(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)CS3(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
4-(4-Methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 15 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (170 mg) described in Preparation Example 83 were dissolved in tetrahydrofuran (10 mL), 1-hydroxybenzotriazole 1 hydrate (139 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (225 mg) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[OH:13][C:14]1[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:23][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([CH3:22])[C:14]=1[O:13][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)[CH:18]=[O:19]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OCc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
0.5M solution of 1-bromomethyl-4-trifluoromethyl-benzene (1.9 g, 8.0 mmol) in DMF was added dropwise to a suspension of 4-hydroxy-3,5-dimethyl-benzaldehyde (930 mg, 7.3 mmol), K2CO3 (1.51 g, 11 mmol) and KI (120 mg, 0.73 mmol) in DMF (100 ml). The reaction mixture was stirred at 90° C. overnight. After cooling, the solid residue was filtered off and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate and the organic layer washed twice with NaOH 1M, dried over Na2SO4 and evaporated to dryness. The residue was purified on silica gel, obtaining 2.24 g of the title compound in a quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[N+](C1C=CC=CC=1)([O-])=O.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCCl>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:26](=[O:28])[CH3:27])=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCCl
Product: CCCc1cc(=O)oc2c(C(C)=O)c(O)cc(O)c12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a mixture of 5,7-dihydroxy-4-propyl-coumarin (2.06 g 9.36 mmol) and anhydrous AICI3 (2.53 g, 18.7 mmol) was added 1,2-dichloroethane (120 mL). The resulting suspension was heated to 75° C. with vigorous stirring. After 30 minutes of stirring, a brown slurry was obtained, then nitrobenzene was introduced into the mixture resulting in an orange colored solution. A solution of anhydrous AICI3 (2.53 g, 18.7 mmol) and acetic anhydride (0.88 mL, 9.36 mmol) in 1,2-dichloroethane (40 mL) was added dropwise over a period of 1-2 hours. After addition, the mixture was allowed to stir at 75° C. for another two hours and subsequently cooled to room temperature. The resulting mixture was poured into ice and 1N HC1. The precipitated product was filtered and then taken into ethyl acetate and the aqueous solution was extracted thoroughly with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting solid was purified by column chromatography (1:1 hexane/ethyl acetate) yielding 5,7-dihydroxy-8-acetyl-4-propyl-coumarin (0.30 g, 12%): mp. 221-224° C.; 1H NMR (DMSO-d6) δ0.94 (t, 3H), 1.58 (sextet, 2H), 2.66 (s, 3H) 2.87 (t, 2H), 6.01 (s, 1H), 6.29 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[C:14]([C:4]1[CH:3]=[C:2]([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: COc1ccc2cccc(F)c2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2cc(C(C)=O)cc(F)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A solution of 1-fluoro-7-methoxynaphthalene (13 g, 0.074 mol) and acetyl chloride (8.01 g, 0.10 mol) in nitrobenzene (120 ml) was treated at 0° C. with powdered anhydrous aluminium chloride (15.59 g, 0.11 mol) over a period of 30 minutes. After stirring at room temperature overnight, the reaction mixture was treated with a mixture of ice (50 g) and concentrated hydrochloric acid (20 ml). The mixture was steam distilled until removal of nitrobenzene was complete. The residue was cooled and the product extracted into ether. The ether layers were washed, dried and concentrated to give a brown solid which was purified by column chromatography on silica gel using petroleum ether/ether mixture as eluant. The product was recrystallised from ether to give a coloured solid 5.33 g. m.p. 96°-7° C.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH:29]([C:35]([O-])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[CH2:1]([O:8][N:9]([C:35](=[O:36])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccnc1NOCc1ccccc1
Reactant: CCOC(=O)C(Cl)C(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N(OCc1ccccc1)c1ncccc1C(=O)OCC
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A solution of the product of Example 157A (1.2 g, 4.4 mmol) and triethylamine (0.49 g, 4.8 mmol) in dichloromethane (25 mL) was treated dropwise with ethyl chloromalonate (0.73 g, 4.8 mmol), stirred for 2 hr and partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3:1) to provide the title compound (1.1 g, 65%). MS (DCI) m/z 387 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5]CC)=O.[Cl-].C[C:14](=[NH2+:16])C>C(#N)C>[C:9]([C:8]1[CH2:14][NH:16][C:3](=[O:5])[C:2]=1[OH:1])(=[O:11])[CH3:10]
Reactant: CC(C)=[NH2+]
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: [Cl-]
Solvent: CC#N
Product: CC(=O)C1=C(O)C(=O)NC1
Temperature: -40 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
A solution of ethyl 2,4-dioxovalerate (1.13 g, 7.11 mmole), dimethylmethylene ammonium chloride (0.67 g, 7.11 mmole) and acetonitrile (3 ml) was stirred at 25° C. over 45 minutes. The resulting yellow homogeneous solution was then cooled to -40° C. and ammonia gas was bubbled through the mixture over 5 minutes, during which time a yellow solid precipitated out of solution. The stirred mixture was allowed to slowly warm to 5° C. over a period of 1 hour before addition of concentrated ammonium hydroxide (4 ml). After stirring for 1 hour, the mixture was concentrated under reduced pressure, diluted with 3N HCl (6 ml) and extracted with ethyl acetate (50 ml×10). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.34 g of the title compound as a yellow amorphous solid. M.P. 178°-180° C. (dec); 1H nmr (250 MHz, DMSO-d6 ) δ 2.42 (s, 3H), 3.78 (s, 2H), 8.87 (s, 1H); Anal. calcd. for C5H7NO3 : C, 51.07; H, 5.00; N, 9.92. Found: C, 51.18; H, 5.23; N, 9.73.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3(O)[CH2:15][O:14][CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:3]=1.C(N(S(F)(F)[F:30])CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([F:30])[CH2:15][O:14][CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)COC1)n2C
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(F)COC1)n2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a stirred solution of (S)-3-(2-chloro-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)oxetan-3-ol (127.6 mg, 0.364 mmol) in anhydrous DCM (8.0 mL) at −78° C. under N2 was added diethylaminosulfur trifluoride (59.5 μL, 0.436 mmol, 1.2 eq.). The reaction mixture was warmed to 0° C. over 3 h, stirred at RT for 2 h, and quenched with 1N sodium hydroxide solution. The reaction mixture was diluted with ethyl acetate. The two phases were separated, and the organic layer was washed with water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in hexane) to give the product as a foam (79.6 mg, 62.0%). 1H NMR (CDCl3, 500 MHz) δ ppm 6.10 to 4.40 (broad s, 2H), 5.30 to 5.19 (m, 2H), 5.10 (dd, J=20.7, 7.8 Hz, 2H), 4.04 to 3.98 (m, 1H), 3.83 to 3.73 (m, 2H), 3.68 (d, J=1.5 Hz, 3H), 3.61 (td, J=11.6, 2.8 Hz, 1H), 3.48 (broad s, 1H), 1.40 (d, J=6.8 Hz, 3H); LC-MS m/z (method A)=342 [M+H]+, RT=2.36 min.
Reaction SMILES: CC1C=C(C)C=C(C)C=1C=[N:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.[CH2:20]([Li])CCC.CI>O1CCCC1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([NH2:5])[CH3:20])=[CH:12][N:11]=1
Reactant: [Li]CCCC
Reactant: Cc1cc(C)c(C=NCc2ccc(Cl)nc2)c(C)c1
Solvent: CI
Solvent: C1CCOC1
Product: CC(N)c1ccc(Cl)nc1
Reaction time: 3 h

Procedure:
To a stirred solution of N-(2,4,6-trimethylbenzylidene)-2-chloro-5-pyridylmethylamine (10.9 g) in dried tetrahydrofuran (150 ml) cooled to -70° C. under N2 atmosphere was added butyl-lithium (10 w/v % in hexane, 26 ml), causing an immediate intense color to occur. After 30 minutes stirring at the temperature, methyl iodide (5.7 g) was added dropwise, and then the mixture was stirred for three hours without cooling. The solvent was removed under reduced pressure. To the residue, ethanol (50 ml) and 2N-hydrochloric acid (50 ml) were added and heated under reflux for one hour. The cooled solution was poured into water (100 ml) and extracted with methylene chloride (50 ml×2). The aqueous fraction was neutralized with 2N-sodium hydroxide and extracted with methylene chloride (50 ml×2). The extract was dried over sodium sulfate and evaporated to obtain 1-(2-chloro-5-pyridyl)ethylamine (4 g). nD20 1.5440
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][CH2:4][CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]1)=[CH:15][C:14]3=[O:26].[O:28]1CCCC1>O>[OH:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16](=[CH:15][C:14](=[O:26])[C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:8]2([CH3:9])[C@H:10]3[CH2:11][CH2:12][C@@H:7]2[O:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:27])[CH3:1])[CH2:17]1
Reactant: C1CCOC1
Reactant: CC(C)CCCO[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4CCCC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Product: CC(C)CCCO[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 3 parts of 3β-{(1,1-dimethylethyl)dimethylsilyl] oxy}-17β-[(4-methylpentyl)oxy]androst-5-en-7-one, 45 parts of tetrahydrofuran, 15 parts of acid, and 10 parts of water is heated at approximately 60° for 48 hours, whereupon 300 parts of water is added and the resultant mixture is extracted with 1,1'-oxybisethane. The extract is washed with aqueous 5% potassium bicarbonate, dried over magnesium sulfate, and strippd of solvent by vacuum distillation. The residue is chromatographed on silica gel, using mixtures of benzene and ethyl actate (initially comprising 10% ethyl acetate and progressively increasing the proportions thereof to 25%) as developing solvent. Eluates are selected via thin layer chromatography which, upon evaporation of solvent and recrystallization of the residues from a mixture of 1,1'-oxybisethane and hexane, afford 3β-hydroxy-17β-[(4-methylpentyl)oxy]androst-5en-7-one melting at approximately 133.5°-134.5°. The product has the formula ##STR8##
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH3:18])=[CH:9][CH:8]=1)#[N:6].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH3:18])=[C:9]([N+:1]([O-:4])=[O:2])[CH:8]=1)#[N:6]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C#N)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1c([N+](=O)[O-])cc(C#N)c2ccccc12
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
A solution of 100% nitric acid (0.91 ml, 22 mmol) in 8 ml of acetic anhydride was added dropwise to a solution of 1-cyano-4-methoxynaphthalene (3.66 g, 20 mmol) in 50 ml of acetic anhydride containing two drops of conc. sulfuric acid while maintaining the temperature at -30° to -40° C. The mixture was stirred for an additional 10 min. and filtered. The solid was washed with water and dried to give 3.5 g (77%) of 4-cyano-1-methoxy-2-nitronaphthalene. The crude product was dissolved in a mixture of 25 ml of tetrahydrofuran and 10 ml of N,N-dimethylformamide. Then 5 ml of cyclohexylamine was added, and the mixture was stirred at room temperature for 2 h. The mixture was evaporated to dryness, and the residue was triturated with light petroleum to give 4,5 g (90%) of 4-cyano-1-cyclohexylamino-2-nitronaphthalene. The crude product, suspended in 200 ml of 96% ethanol was hydrogenated at room temperature and atmospheric pressure in the presence of 5% palladium-on-carbon. When the theoretical amount of hydrogen was taken up, the catalyst was filtered off, and the filtrate was evaporated to dryness. The resulting diaminonaphthalene was immediately suspended in a mixture of 20 ml of dry tetrahydrofuran and dry triethylamine (1.95 ml, 14 mmol). Then a solution of ethyl oxalylchloride (1.56 ml, 14 mmol) in 10 ml of dry tetrahydrofuran was added dropwise with stirring at 0° C. The mixture was stirred at room temperature over night, and then heated at reflux for 1 h. The cooled mixture was filtered, and the solid was washed with tetrahydrofuran and water. Recrystallization from 2-methoxyethanol afforded 1.84 g (41%) of the title compound. M.p. >300° C.; IR (KBr): 2220, 1700 cm-1 ; 1 -NMR (DMSO-d6): 0.93-4.77 (m, 11H, cyclohexyl), 7.97-8.63 (m, 5H, ArH), 11.8 (broad s, 1H, NH); MS (m/z): 319 (M+, 16%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:15]([CH:10]1[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC1CN(Cc2ccccc2)CCC1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCC1CNCCC1O

Procedure:
A mixture of 1-benzyl-3-n-butyl-4-hydroxypiperidine (2.5 g, 10.0 mmole) and 20% palladium hydroxide (0.2 g) in methanol (25 ml) was stirred in hydrogen atmosphere (1 atm.) for 24 hr at 30° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3-n-butyl-4-hydroxypiperidine as oil. Yield 1.4 g (87%), C9H19NO, m/z 158 (M+1) PMR (CDCl3): 0.94 (3H, t, CH3, j=8 Hz), 1.04-1.54 (7H, m, 3×CH2 & H3), 1.74 (1H, m, H5), 1.98 (2H, m, H5, & OH, D2O exchangeable), 2.22 (1H, m, H2), 2.7 (1H, m, H6), 3.12 (1H, m, H2), 3.3 (1H, m, H6), 3.46 (1H, bs, NH, D2O exchangeable), 3.98 (1H, m, H4).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[CH:12][C:13]([F:29])=[C:14]([C@:16]2([CH2:27][F:28])[CH2:21][C@@H:20]([C:22]([F:25])([F:24])[F:23])[O:19][C:18]([NH2:26])=[N:17]2)[CH:15]=1.[C:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1)#[C:31][CH3:32]>O1CCOCC1.O.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:29][C:13]1[CH:12]=[CH:11][C:10]([C:35]2[CH:36]=[N:37][CH:38]=[C:33]([C:30]#[C:31][CH3:32])[CH:34]=2)=[CH:15][C:14]=1[C@:16]1([CH2:27][F:28])[CH2:21][C@@H:20]([C:22]([F:25])([F:24])[F:23])[O:19][C:18]([NH2:26])=[N:17]1
Reactant: CC#Cc1cncc(B(O)O)c1
Reactant: NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC#Cc1cncc(-c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)c1
Yield: 55.5 %

Procedure:
A mixture of potassium phosphate (0.168 g, 0.792 mmol), (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (8a, 0.0985 g, 0.264 mmol), (5-(prop-1-yn-1-yl)pyridin-3-yl)boronic acid (0.106 g, 0.660 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (9.35 mg, 0.013 mmol) in dioxane/water (2.0/0.5 mL) was irradiated at 110° C. for 30 min. The reaction mixture was diluted with water and extracted with DCM three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography: 12 g, 0-100% EtOAc/DCM. The product was obtained as a white solid (0.060 g, 55% yield). MS m/z=410 [M+H]+. Calculated for C20H16F5N3O: 409.4.