Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([O:8][CH2:9][C:10]([CH3:12])=[CH2:11])=[CH:6][CH:5]=[CH:4][C:3]=1[O:13][CH3:14].CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC.O>C1(C)C=CC=CC=1>[CH3:11][C:10]1([CH3:12])[C:2]2[C:3]([O:13][CH3:14])=[CH:4][CH:5]=[CH:6][C:7]=2[O:8][CH2:9]1
Reactant: C=C(C)COc1cccc(OC)c1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1C(C)(C)CO2
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a solution of 2-iodo-1-(methyloxy)-3-[(2-methyl-2-propen-1-yl)oxy]benzene (Intermediate 4, 6.08 g) in toluene (50 ml, SCRC) were added AIBN (3.61 g, 21.99 mmol, SCRC) and tributylstannane (11.60 g, 40.0 mmol, Aldrich). The reaction mixture was heated at reflux for 3 hours and then cooled to room temperature. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3 times 200 ml, SCRC). The combined organic layers were dried, evaporated and purified by silica gel chromatography with as eluents EtOAc/PE (1/50) to afford the title compound as a yellow liquid (2.7 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[N:16]1([C:21]2[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[NH2:24])[CH:20]=[CH:19][N:18]=[CH:17]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N:16]1([C:21]2[CH:22]=[C:23]([NH:24][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=3)[CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:27]=2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: Nc1cc(-n2ccnc2)cc(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 21 h
Yield: 84.3 %

Procedure:
To 3-Iodo-4-methylbenzoic acid (3.07 g, 0.0117 mol) was added thionyl chloride (10 mL) and refluxed for 2 h. The excess thionyl chloride was carefully removed and the resulting acid chloride was dried in vacuo for 2 h. The residue was then dissolved in DCM (anhydrous, 25 mL) and cooled on ice. To the cooled solution was added 3-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline 5 (3.46 g, 0.0152 mol) in DCM followed by the dropwise addition of diisopropylethylamine (8.2 mL, 0.047 mol). This was stirred at ambient temperature for 21 h. The white solid that separated was filtered and washed with water and dried to provide 4.65 g of product. Additional product could be obtained from the filtrate following concentration and purification by silica gel flash chromatography in EtOAc/hexanes.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C@H:8]1[O:13][C@@H:12]([CH3:14])[CH2:11][N:10]([C:15]2[C:28]([C:29](O)=[O:30])=[CH:27][C:18]3[C:19]([C:22]4[S:23][CH:24]=[CH:25][N:26]=4)=[N:20][O:21][C:17]=3[C:16]=2[CH3:32])[CH2:9]1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>CN(C=O)C.ClCCl>[CH3:7][C@H:8]1[O:13][C@@H:12]([CH3:14])[CH2:11][N:10]([C:15]2[C:28]([CH:29]=[O:30])=[CH:27][C:18]3[C:19]([C:22]4[S:23][CH:24]=[CH:25][N:26]=4)=[N:20][O:21][C:17]=3[C:16]=2[CH3:32])[CH2:9]1
Reactant: Cc1c(N2C[C@@H](C)O[C@@H](C)C2)c(C(=O)O)cc2c(-c3nccs3)noc12
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(N2C[C@@H](C)O[C@@H](C)C2)c(C=O)cc2c(-c3nccs3)noc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.31 g, 2.4 mmol) was added to a stirred solution of 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-methyl-3-(1,3-thiazol-2-yl)-1,2-benzoxazole-5-carboxylic acid (Intermediate 326, 0.18 g, 0.4 mmol) and two drops DMF in dichloromethane (5 mL) at 0° C. and the mixture was stirred at room temperature for 2 hours. Solvent was removed under reduced pressure and the residue was dissolved in THF (10 mL) and the solution was cooled to −78° C. and 1M solution of lithium tri(t-butoxy)aluminium hydride (0.28 g, 1.1 mmol) was added slowly and it was stirred for 30 mins at the same temperature. The reaction was quenched with 1.5N hydrochloric acid and extracted with ethyl acetate, the combined organic layers were dried over sodium sulfate and the solvent was removed. The brown viscous oil thus obtained was purified by silica gel column chromatography (20% ethyl acetate in hexane) affording the product as yellow solid. Yield: 0.06 g (35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([CH:7]([C:15](=[O:17])[CH3:16])C(OC(C)(C)C)=O)=[O:6]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH2:7][C:15](=[O:17])[CH3:16])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CC(=O)c1cccc(Cl)c1
Yield: 91.2 %

Procedure:
A solution of tert-butyl 2-(3-chlorobenzoyl)-3-oxobutanoate (8.82 g) in trifluoroacetic acid (40 mL) was stirred for 1 hour under an ice-bath. The volatile was removed in vacuo, and the residue was partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give 1-(3-chlorophenyl)-1,3-butanedione as a pale orange crystal (5.33 g).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[N:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[C:20]([C:29]([OH:31])=O)[CH:19]=2)[CH:14]=[C:15]([F:17])[CH:16]=1.[O:32]=[C:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[N:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[C:20]([C:29]([N:37]3[CH2:36][CH2:35][NH:34][C:33](=[O:32])[CH2:38]3)=[O:31])[CH:19]=2)[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: O=C1CNCCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.07 ml (0.43 mmol) of N,N-diisopropylethylamine is added to a solution of 75 mg (0.21 mmol, 90% purity) of the compound of Example 22A, 23 mg (0.23 mmol) of 2-oxopiperazine, and 113 mg (0.30 mmol) of HATU in 2 ml of THF, and the mixture that is obtained is stirred for 3 hours at room temperature. The reaction mixture is separated by means of preparative HPLC (mobile solvent: acetonitrile/water gradient), and the title compound is obtained in a quantitative yield (87 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]=[CH2:10])[C:3]=1[CH3:11].[Cu][C:13]#[N:14].C(N)CN.O>CN1CCCC1=O>[C:13]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]=[CH2:10])[C:3]=1[CH3:11])#[N:14]
Reactant: N#C[Cu]
Reactant: C=CCc1cccc(Cl)c1C
Solvent: CN1CCCC1=O
Solvent: NCCN
Solvent: O
Product: C=CCc1cccc(C#N)c1C
Temperature: 190 °C
Reaction time: 14 h
Yield: 50.9 %

Procedure:
30 g of 1-chloro-2-methyl-3-prop-2-enylbenzene are dissolved in 150 ml of N-methylpyrrolidone, and 25 g of copper(I) cyanide are added. The reaction mixture is heated at 190° C. for 30 hours while stirring. After the mixture has been cooled to 20° C., 125 ml of ethylenediamine and 300 ml of water are added. Stirring is then carried out for 1 hour at 50° C. and for 14 hours at 20° C. Working up is effected by extracting with diethyl ether, washing the organic phase and drying over sodium sulfate, removing the drying agent and distilling off the organic solvent. 24.5 g of crude product are obtained. After chromatography (silica gel/toluene), 14.4 g of pure 1-cyano-2-mehtyl-3-prop-2-enylbenzene are isolated.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>C(OCC)(=O)C>[C:14]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:16])[CH3:15]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(=O)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(aminomethyl)benzoic acid (20.46 g) in ethyl acetate (100 ml) was added an aqueous solution (100 ml) of sodium hydroxide (12 g) and acetic anhydride (14 ml) was further added at 5-7° C. The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was made acidic with 10% hydrochloric acid and extracted with ethyl acetate:ethanol (10:1). The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-yellow solid (27.2 g). The obtained solid was crystallized from ethyl acetate:ethanol (1:1, 500 ml) to give the title compound (16.7 g) as white crystals, m.p.=200-202° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)[CH:13]=[N:12]2)=[C:5]([CH3:28])[CH:4]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:14]2[CH:13]=[N:12][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:4][C:5]=3[CH3:28])=[O:27])[C:16](=[O:17])[CH:15]=2)=[N:21][CH:22]=1
Reactant: C1CCNC1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccc(F)cn2)cc1=O
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCCC2)ccc1C(=O)Cn1ncc(OCc2ccc(F)cn2)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-fluoro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 6b, 112 mg, 0.25 mmol) in DMF (2 mL) is added pyrrolidine (63 μL, 0.75 mmol). The reaction mixture is stirred for 60 min at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [C:1]([NH:4][CH:5]([O:16][CH2:17][CH3:18])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(Br)(Br)Br.O([C:25]1[CH:30]=CC=[CH:27][CH:26]=1)[Na]>>[C:1]([NH:4][CH:5]([O:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:30][CH:18]=1)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Reactant: [Na]Oc1ccccc1
Agent: BrB(Br)Br
Product: CC(=O)NC(Oc1ccccc1)C(=O)NCc1ccccc1

Procedure:
Using 2-acetamido-N-benzyl-2-ethoxyacetamide (3.00 g, 12.0 mmol), BBr3 (1M in CH2Cl2, 15.0 mL, 15.0 mmol), and NaOPh (4.18 g, 30 mmol) gave a brown oily residue which was purified by flash column chromatography on SiO2 gel using first CHCl3 and then 2% MeOH/CHCl3 as the eluents to give the desired product. The compound was recrystallized from chloroform/hexane.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].Cl[C:15]([CH3:19])([CH3:18])[C:16]#[CH:17]>CCOCC.O.[Cu]>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CC(C)(C)Cl
Agent: [Cu]
Solvent: O
Solvent: CCOCC
Product: C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a mixture of 1-(1,1-dimethylethoxycarbonyl)piperazine (3.29 g), copper powder (20 mg), cuprous chloride (20 mg), ether (4 ml), and water (1 ml) under nitrogen at 0° is added a solution of 3-chloro-3-methyl-1-butyne in ether (1 ml) in 4 portions over 15 min. The mixture is stirred at 20°-25° for 2 hr, diluted with ether (25 ml) and water (10 ml), and the layers are separated. The aqueous layer is extracted with ether (3×25 ml), and the combined organic layer is washed with saline (25 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid which is then chromatographed on silica gel (70-230, 100 g), eluting with ethyl acetate/hexane (25/75). Pooling of fractions giving an Rf =0.48 by TLC (ethyl acetate/hexane, 50/50) and removal of solvent under reduced pressure gives the title compound, mp 105.5°-107°.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:31]1[C:35]([CH:36]2[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]2)=[N:34][N:33]=[N:32]1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH:34]1[C:35]([CH:36]2[CH2:37][CH2:38][CH:39]([C:42]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]5[N:17]=[C:18]([C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[O:19][C:20]=5[C:21]([F:22])([F:24])[F:23])=[O:15])=[CH:9][CH:8]=4)[CH2:2][CH2:3]3)=[O:43])[CH2:40][CH2:41]2)=[N:31][N:32]=[N:33]1
Reactant: O=C(O)C1CCC(c2nnn[nH]2)CC1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCN(C(=O)C3CCC(c4nnn[nH]4)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 60 h
Yield: 48.8 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (130 mg, 0.31 mmol), 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic acid (61 mg, 0.31 mmol), DMAP (2 mg, 0.016 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.37 mmol) in anhydrous DMF (2 mL) was stirred at room temperature for 2.5 days. The reaction was diluted in water (100 mL) and extracted with dichloromethane (2×100 mL) and ethyl acetate (1×100 mL), the organic layers combined, dried over sodium sulfate and purified by flash chromatograph with increasing concentrations of methanol in dichloromethane (0 to 10% over 20 min) to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{4-[4-(1H-tetrazol-5-yl)-cyclohexanecarbonyl]-piperazin-1-yl}-phenyl)-amide (90 mg, 49%) as a light yellow solid. LCMS calcd for C29H29F3N8O3 (m/e) 594, obsd 595 (M+H).
Reaction SMILES: NC1C(=O)NC=C(C)C=1SC1C=C(C)C=C(C)C=1.[CH2:19]([C:21]1[C:22]([S:31][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=2)=[C:23]([N+:28]([O-])=O)[C:24](=[O:27])[NH:25][CH:26]=1)[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:28][C:23]1[C:24](=[O:27])[NH:25][CH:26]=[C:21]([CH2:19][CH3:20])[C:22]=1[S:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1
Reactant: CCc1c[nH]c(=O)c([N+](=O)[O-])c1Sc1cc(C)cc(C)c1
Agent: Cc1cc(C)cc(Sc2c(C)c[nH]c(=O)c2N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1c[nH]c(=O)c(N)c1Sc1cc(C)cc(C)c1
Temperature: 70 °C
Yield: 64.2 %

Procedure:
As described for compound 8a in example 17, stannous chloride dihydrate (6.67 g, 29.6 mmoles) was added to a suspension of compound 7b (1.80 g, 5.9 mmoles) in ethyl acetate (100 ml). The mixture was heated at 70° C. under an argon atmosphere for 1 hour. After cooling to 0° C., the solution was neutralised with a saturated solution of sodium carbonate (90 ml). The precipitate was removed by filtration. The filtered phases were separated and the aqueous phase was extracted with dichloromethane. The collected organic phases were washed with a saturated aqueous sodium chloride solution (3×120 ml), dried over magnesium sulphate and evaporated. The residue was purified by column chromatography with a mixture of dichloromethane and ethanol (9:1) as eluant to give the product 8b (1.04 g, 64%) in the form of a pale beige solid: melting point 208-209° C.; NMR-1H (DMSO-d6) δ 11.51 (1H, s, NH-1), 6.81 (1H, s, H-4'), 6.68 (2H, s, H-2' and 6'), 6.56 (1H, s, H-6), 5.43 (2H, s, NH2 -3), 2.40 (2H, q, J=7.5 Hz, CH2CH3), 2.21 (6H, s, CH3 -3' and 5'), 1.04 (3H, t, J=7 Hz, CH2CH3). Anal. C15H18N2OS 0.25H2O (C, H, N, S).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11](C#CCCCC([O-])=O)=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1/[CH:5]=[CH:4]/[CH2:3][CH2:2][OH:1]
Reactant: O=C([O-])CCCC#Cc1ccc(OC2CCCCO2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC/C=C/c1ccccc1OC1CCCCO1
Yield: 192.9 %

Procedure:
To an anhydrous tetrahydrofuran solution containing 2.4 g of 4-[4-(2-tetrahydropyranyloxy)phenyl]-3-butynylacetate was added 1 g of lithium aluminium hydride and the mixture was refluxed for 12 hours. After the reaction was finished, a saturated sodium sulfate aqueous solution was slowly added to the reaction mixture, and the precipitates formed were removed by filtration, then the filtrate was dried with anhydrous sodium sulfate, and concentrated to dryness. The residue thus obtained was purified by means of a silica gel column chromatography to yield 2 g of 4-[(2-tetrahydropyranyloxy)phenyl]-3(E)-butenylalcohol as in the form of colorless oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([I:9])[CH:4]=1.[CH3:10][CH:11]([C:13]1[NH:17][C:16]2[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:15]=2[N:14]=1)[CH3:12]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[OH-].[Na+].ClCCl>[I:9][C:5]1[CH:4]=[C:3]([CH2:2][N:14]2[C:15]3[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:16]=3[N:17]=[C:13]2[CH:11]([CH3:12])[CH3:10])[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)c1nc2c([nH]1)CCCC2=O
Reactant: BrCc1cccc(I)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(n1Cc1cccc(I)c1)C(=O)CCC2
Reaction time: 2.75 h
Yield: 53.7 %

Procedure:
1-(bromomethyl)-3-iodobenzene (9.76 g) was added to a stirred solution of tetrabutylammonium bromide (4.41 g), Intermediate 56 (2nd alternative preparation) (4.88 g) and 1-(bromomethyl)-3-iodobenzene (9.76 g) in Toluene (100 mL) and NaOH (5M, Aq) (46.5 mL). The reaction mixture was allowed to stir vigorously, so as to ensure mixture of the 2 phases, at room temperature for 2.75 hr. The reaction mixture was partitioned between DCM (80 mL) and water (80 mL) and aqueous layer was washed with further DCM (2×80 mL). The organic layers were combined, filtered through a hydrophobic frit and concentrated in vacuo to give 16.84 g of crude product as a brown oil. The sample was loaded in dichloromethane and purified by column chromatography (silica) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the required products 5.8 g as a yellow oil which solidified. LC/MS MH+ 394, Rt 2.85 min (5 min run).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17]([C@@H:19]2[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]2[C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=2)=[O:18])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C>O>[C:7]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17]([C@@H:19]2[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:26]=2)=[O:18])[CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccnc(Cl)n2)no1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccnc(N3CCOCC3)n2)no1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Morpholine (0.01 mL, 0.115 mmol) is added to a solution of (2S,4R)-1-(2-chloro-pyrimidin-4-yl)-4-hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (42 mg, 0.115 mmol) and diisopropylethylamine (0.02 mL, 0.115 mol). The reaction is stirred at 60° C. overnight. More morpholine (0.01 mL, 0.115 mmol) is added and the reaction is stirred at 80° C. for 3.5 hours. The reaction is diluted with water and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with methanol/dichloromethane provides the title compound. ESI m/z 417 [M+H+].
Reaction SMILES: Cl.[CH3:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]=1[CH2:13][C:14]1[NH:15][CH2:16][CH2:17][N:18]=1>[Pd].O>[CH3:2][C@@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C@@H:4]1[CH2:13][C:14]1[NH:18][CH2:17][CH2:16][N:15]=1
Reactant: CC1=C(CC2=NCCN2)CCc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: O
Product: C[C@@H]1c2ccccc2CC[C@@H]1CC1=NCCN1
Yield: 97.8 %

Procedure:
A mixture of 2.0 g of 2-[(3,4-dihydro-1-methyl-2-naphthalenyl)methyl]-4,5-dihydro-1H-imidazole hydrochloride (Example 1b) and 200 mg of palladium-on-carbon catalyst in 100 ml of distilled water was hydrogenated until the mass spectrum showed no evidence of starting material. The product was isolated and recrystallized from ethanol to give 1.7 g of cis-4,5-dihydro-2-[(1,2,3,4-tetrahydro-1-methyl-2-naphthalenyl)methyl]-1H-imidazole in the form of its monohydrochloride salt, m.p. 214.5°-216° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:16]([NH:26][CH2:27][C:28](O)=[O:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)C(C)C)(C)C>[CH2:19]([O:18][C:16]([NH:26][CH2:27][C:28]([N:5]([CH2:4][CH:3]([O:14][CH3:15])[O:2][CH3:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:29])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(CNCc1ccc(F)cc1)OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(CN(Cc1ccc(F)cc1)C(=O)CNC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2,2-dimethoxyethyl)-N-(4-fluorobenzyl)amine (50.6 g, 237.3 mmol), N-CBZ-glycine (54.6 g, 260.8 mmol), EDC (50.0 g, 260.8 mmol), and HOBt (4.2 g, 27 mmol) in anhydrous DMF (500 mL), N,N-diisopropylethylamine (˜10 mL) was added until the solution is about pH 7. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between dichloromethane (1 L) and water (250 mL). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound. ES MS (M−OCH3)=374.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[C:13]2[NH:12][C:11]3=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[N:16][N:10]3[C:9](=[O:20])[C:8]=2[CH:7]=[CH:6][CH:5]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:2][O:3][C:4]1[C:13]2[N:12]([CH3:21])[C:11]3=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[N:16][N:10]3[C:9](=[O:20])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc2c(=O)n3nc(C(=O)O)cc3[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cccc2c(=O)n3nc(C(=O)O)cc3n(C)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4,9-dihydro-5-methoxy-9-oxo-pyrazolo-[5,1-b]quinazoline-2-carboxylic acid, hydrate (1:0.25) (2.64 g; 0.01 mole), anhydrous potassium carbonate (5.52 g; 0.04 mole) and methyl iodide (15 ml) in dimethyl formamide (75 ml) is stirred at room temperature for 2 days. Water is added and the grey solid is filtered off and taken up in 2(N) sodium hydroxide solution (50 ml) and methanol (50 ml). The mixture is heated under reflux for 2 hrs and the methanol is distilled off in vacuo. The aqueous solution is acidified with conc. HCl and the yellow precipitate is collected and recrystallized from methanol (275 ml), water (5 ml). Yield 0.33 g; mp 255° (d).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:4].[N:16]#[C:17]Br>>[CH3:8][C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:15])[CH2:6][CH2:5][C@H:2]1[CH2:3][O:4][C:17]([NH2:16])=[N:1]1
Reactant: N#CBr
Reactant: CC(C)(CC[C@H](N)CO)c1ccccc1
Product: CC(C)(CC[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1d (S)-2-amino-5-methyl-5-phenyl-hexan-1-ol was reacted with cyanogen bromide to give (S)-4-(3-methyl-3-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 233.1 ([M+H]+))